Breast cancer, ER-positive

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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: these are regimens typically studied for hormone receptor-positive, HER2-negative tumors, without additional targetable mutations. Please see the main breast cancer page for other regimens, including chemotherapy regimens that might have been evaluated in hormone receptor-positive populations.
*Regimens for ER/HER2 co-expressing ("double positive") breast cancer are here.
*Regimens for BRCA-mutated breast cancer are here.
*Regimens for PIK3CA-mutated breast cancer are here.
Last updated on 2024-12-02:82 regimens on this page
118 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ASCO==
*2024: Burstein et al. Endocrine and Targeted Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer—Capivasertib-Fulvestrant: ASCO Rapid Recommendation Update EuroPMC
**2016: Rugo et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline EuroPMC
*2023: Burstein et al. Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update EuroPMC
*2022: Andre et al. Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update EuroPMC
**2016: Harris et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline link to PMC article EuroPMC
*2022: Giordano et al. Abemaciclib With Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update EuroPMC
**2018: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: ASCO Clinical Practice Guideline focused update EuroPMC
**2016: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline update on ovarian suppression EuroPMC
**2014: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline focused update link to PMC article EuroPMC
*2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline link to PMC article EuroPMC
*2015: Van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical Practice Guideline link to PMC article EuroPMC
==ASCO/CAP==
*2020: Allison et al. Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update EuroPMC
**2010: Hammond et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Breast Cancer.
== St Gallen Breast Guidelines ==
*2019: Burstein et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 EuroPMC
*2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017 link to PMC article EuroPMC
*2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 EuroPMC
=Neoadjuvant endocrine therapy, premenopausal=
==Anastrozole & Goserelin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Masuda et al. 2012 (STAGE)	2007-2009 	Phase 3 (E-switch-ic)	Goserelin & Tamoxifen	Higher RR (primary endpoint)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
*Goserelin (Zoladex) 3.6 mg IM depot once on day 1
28-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===References===
# STAGE: Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, Nishimura R, Iwase H, Kamigaki S, Takei H, Noguchi S. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012 Apr;13(4):345-52. Epub 2012 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00605267
==Anastrozole, Goserelin, Palbociclib==
===Regimen===
Study 	Dates of enrollment	Evidence
Ma et al. 2017 (NeoPalAna)	2013-2015 	Phase 2
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg IM once on day 1
====Targeted therapy====
*Palbociclib (Ibrance) as follows:
**Cycles 2 to 5: 125 mg PO once per day on days 1 to 21
28-day cycle for 5 cycles
====Subsequent treatment====
*Surgery
===References===
# NeoPalAna: Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A, Hoog J, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras H, Guo Z, Lee MV, Spies NC, Skidmore ZL, Griffith OL, Griffith M, Thomas S, Bumb C, Vij K, Bartlett CH, Koehler M, Al-Kateb H, Sanati S, Ellis MJ. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017 Aug 1;23(15):4055-4065. Epub 2017 Mar 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01723774
==Goserelin & Tamoxifen==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Masuda et al. 2012 (STAGE)	2007-2009 	Phase 3 (C) 	Anastrozole & Goserelin	Lower RR
Kim et al. 2020 (NEST) 	2012-2014 	Phase 3 (E-switch-ooc)	AC-D 	Inconclusive whether non-inferior clinical response (primary endpoint)
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg IM depot once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day
28-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===References===
#ZIPP: Baum M, Hackshaw A, Houghton J, Rutqvist, Fornander T, Nordenskjold B, Nicolucci A, Sainsbury R; ZIPP International Collaborators Group. Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Eur J Cancer. 2006 May;42(7):895-904. Epub 2006 Mar 20. link to original article EuroPMC
##Update: Hackshaw A, Baum M, Fornander T, Nordenskjold B, Nicolucci A, Monson K, Forsyth S, Reczko K, Johansson U, Fohlin H, Valentini M, Sainsbury R. Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):341-9. Epub 2009 Feb 24. link to original article link to PMC article EuroPMC
# STAGE: Masuda N, Sagara Y, Kinoshita T, Iwata H, Nakamura S, Yanagita Y, Nishimura R, Iwase H, Kamigaki S, Takei H, Noguchi S. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial. Lancet Oncol. 2012 Apr;13(4):345-52. Epub 2012 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00605267
# NEST: Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W, Nam SJ, Gong GY, Kim HJ, Ahn SH. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res. 2020 May 27;22(1):54. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01622361
# STO-5: Johansson A, Dar H, van 't Veer LJ, Tobin NP, Perez-Tenorio G, Nordenskjöld A, Johansson U, Hartman J, Skoog L, Yau C, Benz CC, Esserman LJ, Stål O, Nordenskjöld B, Fornander T, Lindström LS. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial. J Clin Oncol. 2022 Dec 10;40(35):4071-4082. Epub 2022 Jul 21. link to original article link to PMC article EuroPMC
=Neoadjuvant therapy, postmenopausal=
==Anastrozole monotherapy==
===Regimen variant #1, 3-month course===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Smith et al. 2005 (IMPACT) 	1997-2002 	Phase 3 (E-switch-ic) 	1. Anastrozole & Tamoxifen2. Tamoxifen	Did not meet primary endpoint of ORR
Cataliotti et al. 2006 (PROACT)	2000-2002 	Phase 3 (E-switch-ic) 	Tamoxifen 	Did not meet primary endpoint of ORR
Semiglazov et al. 2007 	Not reported 	Randomized Phase 2 (E-switch-ooc)	Doxorubicin & Paclitaxel (AT) 	Did not meet primary endpoint of ORR
Note: while Semiglazov et al. 2007 was a technically negative study, it is one of very few that directly compare endocrine therapy to chemotherapy.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
12-week course
====Subsequent treatment====
*Surgery
===Regimen variant #2, 4-month course===
Study 	Dates of enrollment	Evidence 	Efficacy
Ellis et al. 2011 (ACOSOG Z1031)	2006-2009 	Screening Phase 2	cRR: 69% (95% CI, 60-77)
Note: ACOSOG Z1031 was randomized but with the intent to select candidates for phase 3 trials; efficacy comparisons were not made. 
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
16- to 18-week course
====Subsequent treatment====
*Surgery
===Regimen variant #3, 6-month course===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ma et al. 2024 (Alliance A011106)	2014-02 to 2018-11 	Phase 3 (C)	1. Anastrozole & Fulvestrant2. Fulvestrant	Did not meet primary endpoint of ESDR
====Eligibility criteria====
*Palpable clinical stage II or III (T2 to T4c, any N, M0)
====Biomarker eligibility criteria====
*ER-rich (Allred score 6 to 8 or greater than 66%)
*HER2-negative
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
28-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===References===
# IMPACT: Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G; IMPACT Trialists Group. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005 Aug 1;23(22):5108-16. Epub 2005 Jul 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# PROACT: Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, Dube P, de Oliveira CT. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer. 2006 May 15;106(10):2095-103. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00232661
#Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ACOSOG Z1031: Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00265759
# Meta-analysis: Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, Moy B, Bardia A. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2016 Nov 1;2(11):1477-1486. link to original article link to PMC article EuroPMC
#POETIC: Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Morden J, Sidhu K, Dodson A, Bliss JM, Dowsett M. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443-1454. link to original article link to PMC article EuroPMC NCT02338310
#Alliance A011106: Ma CX, Suman VJ, Sanati S, Vij K, Anurag M, Leitch AM, Unzeitig GW, Hoog J, Fernandez-Martinez A, Fan C, Gibbs RA, Watson MA, Dockter TJ, Hahn O, Guenther JM, Caudle A, Crouch E, Tiersten A, Mita M, Razaq W, Hieken TJ, Wang Y, Rimawi MF, Weiss A, Winer EP, Hunt KK, Perou CM, Ellis MJ, Partridge AH, Carey LA. Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2024 Mar 1;10(3):362-371. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01953588
==Anastrozole & Palbociclib==
===Regimen===
Study 	Dates of enrollment	Evidence
Ma et al. 2017 (NeoPalAna)	2013-2015 	Phase 2
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) as follows:
**Cycles 2 to 5: 125 mg PO once per day on days 1 to 21
28-day cycle for 5 cycles
====Subsequent treatment====
*Surgery
===References===
# NeoPalAna: Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A, Hoog J, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras H, Guo Z, Lee MV, Spies NC, Skidmore ZL, Griffith OL, Griffith M, Thomas S, Bumb C, Vij K, Bartlett CH, Koehler M, Al-Kateb H, Sanati S, Ellis MJ. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017 Aug 1;23(15):4055-4065. Epub 2017 Mar 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01723774
==Doxorubicin & Paclitaxel (AT)==
AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Semiglazov et al. 2007	Not reported 	Randomized Phase 2 (C)	1a. Anastrozole1b. Exemestane	Did not meet primary endpoint of ORR
Note: while this is a technically negative study, it is one of very few that directly compare endocrine therapy to chemotherapy.
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===References===
#Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Exemestane monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Semiglazov et al. 2007	Not reported 	Randomized Phase 2 (E-switch-ooc)	Doxorubicin & Paclitaxel (AT)	Did not meet primary endpoint of ORR
Note: while this is a technically negative study, it is one of very few that directly compare endocrine therapy to chemotherapy.
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
3-month course
====Subsequent treatment====
*Surgery
===References===
#Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Meta-analysis: Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, Moy B, Bardia A. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2016 Nov 1;2(11):1477-1486. link to original article link to PMC article EuroPMC
==Letrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Eiermann et al. 2001 (P024) 	1998-03 to 1999-08 	Phase 2b/3 (E-switch-ic)	Tamoxifen 	Higher ORR (primary endpoint)
Ellis et al. 2011 (ACOSOG Z1031)	2006-2009 	Screening Phase 2 	 	cRR: 75% (95% CI, 66-82)
Note: ACOSOG Z1031 gave a total treatment duration of 16 to 18 weeks, which is approximately 4 months. Also, this trial was randomized but with the intent to select candidates for phase III trials; efficacy comparisons were not made. 
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
4-month course
====Subsequent treatment====
*Surgery
===References===
# P024: Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M, Semiglazov V; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001 Nov;12(11):1527-32. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Biomarker analysis: Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15;19(18):3808-16. link to original article EuroPMC
# ACOSOG Z1031: Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00265759
# Meta-analysis: Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ, Moy B, Bardia A. Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. JAMA Oncol. 2016 Nov 1;2(11):1477-1486. link to original article link to PMC article EuroPMC
#POETIC: Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Morden J, Sidhu K, Dodson A, Bliss JM, Dowsett M. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443-1454. link to original article link to PMC article EuroPMC NCT02338310
==Tamoxifen monotherapy==
===Regimen variant #1, 12 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Smith et al. 2005 (IMPACT) 	1997-2002 	Phase 3 (C)	1. Anastrozole & Tamoxifen2. Anastrozole	Did not meet primary endpoint of ORR
Cataliotti et al. 2006 (PROACT)	2000-2002 	Phase 3 (C)	Anastrozole 	Did not meet primary endpoint of ORR
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
12-week course
====Subsequent treatment====
*Surgery
===Regimen variant #2, 4 months===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Eiermann et al. 2001 (P024)	1998-03 to 1999-08 	Phase 2b/3 (C)	Letrozole 	Lower ORR
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
4-month course
====Subsequent treatment====
*Surgery
===References===
# P024: Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M, Semiglazov V; Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001 Nov;12(11):1527-32. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# IMPACT: Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G; IMPACT Trialists Group. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005 Aug 1;23(22):5108-16. Epub 2005 Jul 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# PROACT: Cataliotti L, Buzdar AU, Noguchi S, Bines J, Takatsuka Y, Petrakova K, Dube P, de Oliveira CT. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial. Cancer. 2006 May 15;106(10):2095-103. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00232661
=Neoadjuvant response criteria=
==Clinical response rate (cRR)==
Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.
</div>
===References===
# Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. link to original article EuroPMC
</div>
==Miller-Payne scoring system==
*Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
*Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high 
*Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
*Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells) 
*Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma in situ may be present) 
</div>
===References===
# Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. link to original article EuroPMC
</div>
==Residual cancer burden (RCB)==
*The RCB is calculated as follows: RCB = 1.4 (finv*dprim)0.17 + [4(1 - 0.75LN)dmet]0.17
**where dprim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, finv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and dmet is the diameter of the largest metastasis in an axillary lymph node.
**The cut-off points are 1.36 and 3.28.
</div>
===References===
# Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. link to original article EuroPMC
</div>
==Residual disease in breast and nodes (RDBN)==
*Level 1: pCR in breast and nodes with or without in situ carcinoma
*Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.
</div>
===References===
# Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. link to original article EuroPMC
</div>
==Sataloff's classification==
*Breast: 
**T-A: Total or nearly total therapeutic effect 
**T-B: Greater than 50% therapeutic effect
**T-C: Less than 50% therapeutic effect 
**T-D: No therapeutic effect
*Lymph node:
**N-A: Therapeutic effect but no metastasis
**N-B: No metastasis, no therapeutic effect
**N-C: Therapeutic effect but metastasis
**N-D: Metastasis, no therapeutic effect
</div>
===References===
# Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. EuroPMC
</div>
==Tumor response ratio==
Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.
*TRR = 0: pathologic complete response (pCR)
*TRR greater than 0 up to 0.4: strong partial response
*TRR greater than 0.4 up to 1.0: weak partial response (WPR)
*TRR greater than 1.0: tumor growth
</div>
===References===
# Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. link to original article EuroPMC
</div>
==ypTNM staging==
This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.
=Adjuvant therapy, premenopausal women and men=
==Anastrozole & Goserelin==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (C)	1a. Anastrozole, Goserelin, Ribociclib1b. Goserelin, Letrozole, Ribociclib	Shorter iDFS1 (primary endpoint)iDFS36: 87.6% vs 90.7%(HR 1.33, 95% CI 1.12-1.59)
1Reported efficacy is based on the 2024 update.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg SC once on day 1
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Anastrozole, Goserelin, Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (E-RT-esc)	1a. Anastrozole & Goserelin1b. Letrozole & Goserelin	Longer iDFS1 (primary endpoint)iDFS36: 90.7% vs 87.6%(HR 0.75, 95% CI 0.63-0.89)
1Reported efficacy is based on the 2024 update.
====Eligibility criteria====
*Anatomic stage II or III; premenopausal women or men
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg SC once on day 1
====Targeted therapy====
*Ribociclib (Kisqali) as follows:
**Cycles 1 to 39: 400 mg PO once per day on days 1 to 21
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Exemestane & OFS==
Exemestane & OFS: Exemestane & Ovarian Function Suppression
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pagani et al. 2014 (TEXT)	2003-2011 	Phase 3 (E-switch-ic)	1. Tamoxifen 	Longer DFS (primary endpoint)
Pagani et al. 2014 (TEXT)	2003-2011 	Phase 3 (E-switch-ic)	2. Tamoxifen & OFS	Longer DFS (primary endpoint)DFS60: 91.1% vs 87.3%(HR 0.72, 95% CI 0.60-0.85)
Pagani et al. 2014 (SOFT)	2003-2011 	Phase 3 (E-switch-ic)	1. Tamoxifen 	Longer DFS (primary endpoint)
Pagani et al. 2014 (SOFT)	2003-2011 	Phase 3 (E-switch-ic)	2. Tamoxifen & OFS	Longer DFS (primary endpoint)DFS60: 91.1% vs 87.3%(HR 0.72, 95% CI 0.60-0.85)
Note: Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
*Ovarian function suppression by the following study-specific criteria:
**TEXT: Triptorelin (Trelstar LA) 3.75 mg IM once on day 1
***"Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
**SOFT: Choice of mechanism left to investigators
28-day cycle for 65 cycles (5 years)
===References===
# TEXT: Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066703
## HRQoL analysis: Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 2015 Jul;16(7):848-58. Epub 2015 Jun 16. link to original article link to PMC article EuroPMC
## Pooled update: Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Láng I, Gómez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM; SOFT and TEXT Investigators and International Breast Cancer Study Group. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. J Clin Oncol. 2020 Apr 20;38(12):1293-1303. Epub 2019 Oct 16. link to original article link to PMC article EuroPMC
##Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article EuroPMC
# SOFT: Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066690
## Update: Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436-46. Epub 2014 Dec 11. link to original article link to PMC article EuroPMC
## HRQoL analysis: Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 2015 Jul;16(7):848-58. Epub 2015 Jun 16. link to original article link to PMC article EuroPMC
## Pooled update: Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Láng I, Gómez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM; SOFT and TEXT Investigators and International Breast Cancer Study Group. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. J Clin Oncol. 2020 Apr 20;38(12):1293-1303. Epub 2019 Oct 16. link to original article link to PMC article EuroPMC
##Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article link to PMC article EuroPMC
##Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article EuroPMC
#POSITIVE: Partridge AH, Niman SM, Ruggeri M, Peccatori FA, Azim HA Jr, Colleoni M, Saura C, Shimizu C, Sætersdal AB, Kroep JR, Mailliez A, Warner E, Borges VF, Amant F, Gombos A, Kataoka A, Rousset-Jablonski C, Borstnar S, Takei J, Lee JE, Walshe JM, Ruíz-Borrego M, Moore HCF, Saunders C, Bjelic-Radisic V, Susnjar S, Cardoso F, Smith KL, Ferreiro T, Ribi K, Ruddy K, Kammler R, El-Abed S, Viale G, Piccart M, Korde LA, Goldhirsch A, Gelber RD, Pagani O; International Breast Cancer Study Group; POSITIVE Trial Collaborators. Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. N Engl J Med. 2023 May 4;388(18):1645-1656. link to original article link to PMC article EuroPMC
==Goserelin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Davidson et al. 2005 (ECOG E5188)	1989-1994 	Phase 3 (C) 	Goserelin & Tamoxifen x 5 y	Shorter DFS (co-primary endpoint)DFS108: 60% vs 68%(HR 1.35, 95% CI 1.10-1.67)
Jonat et al. 2002 (ZEBRA) 	1990-1996 	Phase 3 (E-switch-ooc)	CMF 	Equivalent DFS1 (co-primary endpoint)(HR 1.01, 95% CI 0.84-1.20)
1Reported results for ZEBRA are for the ER-positive patients only.
====Preceding treatment====
*ECOG E5188 & ZEBRA: Surgery
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg IM depot once on day 1
28-day cycle for 26 cycles (2 years)
===References===
# ZEBRA: Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association study. J Clin Oncol. 2002 Dec 15;20(24):4628-35. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E5188: Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005 Sep 1;23(25):5973-82. Epub 2005 Aug 8. link to original article EuroPMC
==Goserelin & Letrozole==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (C)	1a. Anastrozole, Goserelin, Ribociclib1b. Goserelin, Letrozole, Ribociclib	Shorter iDFS1 (primary endpoint)iDFS36: 87.6% vs 90.7%(HR 1.33, 95% CI 1.12-1.59)
1Reported efficacy is based on the 2024 update.
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Goserelin, Letrozole, Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (E-RT-esc)	1a. Anastrozole & Goserelin1b. Letrozole & Goserelin	Longer iDFS1 (primary endpoint)iDFS36: 90.7% vs 87.6%(HR 0.75, 95% CI 0.63-0.89)
1Reported efficacy is based on the 2024 update.
====Eligibility criteria====
*Anatomic stage II or III; premenopausal women or men
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg SC once on day 1
====Targeted therapy====
*Ribociclib (Kisqali) as follows:
**Cycles 1 to 39: 400 mg PO once per day on days 1 to 21
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Goserelin & Tamoxifen==
===Regimen variant #1, 3+5===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jakesz et al. 2002 (ABCSG 5)	1990-1999 	Phase 3 (E-switch-ooc)	CMF 	Seems to have longer RFS (co-primary endpoint)RFS60: 81% vs 76%(aHR 0.71, 95% CI 0.53-0.94)
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Goserelin (Zoladex) as follows:
**Cycles 1 to 39: 3.6 mg IM depot once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
28-day cycle for 65 cycles (5 years)
===Regimen variant #2, 5+5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Davidson et al. 2005 (ECOG E5188)	1989-1994 	Phase 3 (E-esc)	Goserelin x 5 y	Longer DFS (co-primary endpoint)DFS108: 68% vs 60%(HR 0.74, 95% CI 0.60-0.91)
====Preceding treatment====
*Surgery, then adjuvant CAF x 6
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg IM depot once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
28-day cycle for 65 cycles (5 years)
===References===
# ABCSG 5: Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, Seifert M, Haider K, Mlineritsch B, Steindorfer P, Kwasny W, Fridrik M, Steger G, Wette V, Samonigg H; ABCSG. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol. 2002 Dec 15;20(24):4621-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00309478
# ECOG E5188: Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005 Sep 1;23(25):5973-82. Epub 2005 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Leuprolide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Schmid et al. 2007 (TABLE)	1995-1998 	Phase 3 (E-switch-ooc)	CMF 	Did not meet primary endpoint of RFSRFS60: 63.9% vs 63.4%(HR 1.03, 0.79-1.35)Longer OS (secondary endpoint)
====Endocrine therapy====
*Leuprolide (Lupron) 11.25 mg SC once on day 1
3-month cycle for 8 cycles (2 years)
===References===
# TABLE: Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Tamoxifen monotherapy==
===Regimen variant #1, 2 years of 20 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rydén et al. 2005 (SBII:2pre)	1986-1991 	Phase 3 (E-esc)	Observation	Longer RFS (primary endpoint)(RR 0.65, 95% CI 0.48-0.89)
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
28-day cycle for 26 cycles (2 years)
===Regimen variant #2, 5 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-OAS)	1992-2000 	Phase 3 (C) 	Tamoxifen & OFS 	Did not meet co-primary endpoints of RFS/OS 	
Colleoni et al. 2006 (IBCSG 13-93) 	1993-1999 	Phase 3 (E-esc)	Observation 	Longer DFS1 (primary endpoint)DFS60: 75% vs 62%(HR 0.59, 95% CI 0.46-0.75) 	
Bramwell et al. 2009 (NCIC-CTG MA.12) 	1993-2000 	Phase 3 (E-esc)	Placebo 	Did not meet primary endpoint of OSOS60: 87% vs 82%(HR 0.78, 95% CI 0.57-1.06) 	
Tevaarwerk et al. 2014 (ECOG E-3193) 	1994-1997 	Phase 3 (C) 	Tamoxifen & OFS 	Did not meet co-primary endpoint of DFSDFS60: 87.9% vs 89.7%(aHR 1.18, 95% CI 0.64-2.13)Did not meet co-primary endpoint of OSOS60: 95.2% vs 97.6%(aHR 1.19, 95% CI 0.52-2.70)	Fewer menopausal symptoms
Pagani et al. 2014 (SOFT) 	2003-2011 	Phase 3 (C) 	1. Exemestane & OFS	Shorter DFS 	
Pagani et al. 2014 (SOFT) 	2003-2011 	Phase 3 (C) 	2. Tamoxifen & OFS 	Seems to have shorter DFS2 	
Kim et al. 2019 (ASTRRA) 	2009-2014 	Phase 3 (C) 	Tamoxifen & OFS 	Shorter DFS3 (primary endpoint)DFS96: 80.2% vs 85.4%(HR 1.49, 95% CI 1.15-1.96)Did not meet secondary endpoint of OS3 	
1Reported efficacy is for the ER+ cohort.
2Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen-only arm; reported efficacy for this arm is based on the 2022 update.
3Reported efficacy for ASTRRA is based on the 2023 update.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day or 10 mg PO twice per day (the latter dosing is typical in older trials only)
28-day cycle for 65 cycles (5 years)
===References===
# SBII:2pre: Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two years of adjuvant tamoxifen provides a survival benefit compared with no systemic treatment in premenopausal patients with primary breast cancer: Long-term follow-up (> 25 years) of the phase III SBII:2pre trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. link to original article EuroPMC
## Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L; South Swedish and South-East Swedish Breast Cancer Groups. Effects of adjuvant tamoxifen over three decades on breast cancer-free and distant recurrence-free interval among premenopausal women with oestrogen receptor-positive breast cancer randomised in the Swedish SBII:2pre trial. Eur J Cancer. 2019 Mar;110:53-61. Epub 2019 Feb 12. link to original article EuroPMC
# IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article EuroPMC
# NCRI ABC-OAS: Adjuvant Breast Cancer Trials Collaborative Group. Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst. 2007 Apr 4;99(7):516-25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002582
# NCIC-CTG MA.12: Bramwell VHC, Pritchard KI, Tu D, Tonkin K, Vachhrajani H, Vandenberg TA, Robert J, Arnold A, O'Reilly SE, Graham B, Shepherd L. A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada--Clinical Trials Group Trial, MA.12). Ann Oncol. 2010 Feb;21(2):283-290. Epub 2009 Jul 23. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002542
# SOFT: Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066690
## Update: Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436-46. Epub 2014 Dec 11. link to original article link to PMC article EuroPMC
## HRQoL analysis: Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 2015 Jul;16(7):848-58. Epub 2015 Jun 16. link to original article link to PMC article EuroPMC
## Pooled update: Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Láng I, Gómez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM; SOFT and TEXT Investigators and International Breast Cancer Study Group. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. J Clin Oncol. 2020 Apr 20;38(12):1293-1303. Epub 2019 Oct 16. link to original article link to PMC article EuroPMC
##Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article link to PMC article EuroPMC
##Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article EuroPMC
# ECOG E-3193: Tevaarwerk AJ, Wang M, Zhao F, Fetting JH, Cella D, Wagner LI, Martino S, Ingle JN, Sparano JA, Solin LJ, Wood WC, Robert NJ. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2014 Dec 10;32(35):3948-58. Epub 2014 Oct 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# ASTRRA: Kim HA, Lee JW, Nam SJ, Park BW, Im SA, Lee ES, Jung YS, Yoon JH, Kang SS, Lee SJ, Park KH, Jeong J, Cho SH, Kim SY, Kim LS, Moon BI, Lee MH, Kim TH, Park C, Jung SH, Gwak G, Kim J, Kang SH, Jin YW, Kim HJ, Han SH, Han W, Hur MH, Noh WC; Korean Breast Cancer Study Group. Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial. J Clin Oncol. 2020 Feb 10;38(5):434-443. Epub 2019 Sep 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00912548
##Update: Baek SY, Noh WC, Ahn SH, Kim HA, Ryu JM, Kim SI, Lee EG, Im SA, Jung Y, Park MH, Park KH, Kang SH, Jeong J, Park E, Kim SY, Lee MH, Kim LS, Lim W, Kim S, Kim HJ. Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial. J Clin Oncol. 2023 Nov 1;41(31):4864-4871. Epub 2023 Aug 22. link to original article EuroPMC
==Tamoxifen & OFS==
Tamoxifen & OFS: Tamoxifen & OFS: Ovarian Function Suppression
===Regimen variant #1, 3 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gnant et al. 2009 (ABCSG-12)	1999-2006 	Phase 3 (C)	1. Anastrozole, Goserelin, Zoledronic acid2. Tamoxifen, Goserelin, Zoledronic acid	Shorter DFS (primary endpoint)DFS48: 92.8% vs 94%(HR 1.56, 95% CI 1.10-2.17)
Gnant et al. 2009 (ABCSG-12)	1999-2006 	Phase 3 (C)	3. Anastrozole & Goserelin 	Did not meet primary endpoint of DFSDFS48: 92.8% vs 92%(HR 0.91, 95% CI 0.65-1.28)
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
*Goserelin (Zoladex) 3.6 mg SC once on day 1
28-day cycle for 39 cycles (3 years)
===Regimen variant #2, 5 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Tevaarwerk et al. 2014 (ECOG E-3193)	1994-1997 	Phase 3 (E-esc)	Tamoxifen 	Did not meet co-primary endpoint of DFSDFS60: 89.7% vs 87.9%(aHR 0.85, 95% CI 0.47-1.56)Did not meet co-primary endpoint of OSOS60: 97.6% vs 95.2%(aHR 0.84, 95% CI 0.37-1.92) 	More menopausal symptoms
Pagani et al. 2014 (TEXT) 	2003-2011 	Phase 3 (E-esc)	1. Exemestane & OFS	Shorter DFS (primary endpoint) 	
Pagani et al. 2014 (TEXT) 	2003-2011 	Phase 3 (E-esc)	2. Tamoxifen 	Might have longer DFS1 (primary endpoint) 	
Pagani et al. 2014 (SOFT) 	2003-2011 	Phase 3 (E-esc)	1. Exemestane & OFS	Shorter DFS (primary endpoint) 	
Pagani et al. 2014 (SOFT) 	2003-2011 	Phase 3 (E-esc)	2. Tamoxifen 	Seems to have longer DFS1 (primary endpoint)DFS144: 76.1% vs 71.9%(HR 0.82, 95% CI 0.69-0.98)Might have longer OS1 (secondary endpoint)OS144: 89% vs 86.8%(HR 0.78, 95% CI 0.60-1.01)	
Perrone et al. 2019 (HOBOE) 	2004-2015 	Phase 3 (C) 	1. Letrozole & OFS 	Might have shorter DFS 	
Perrone et al. 2019 (HOBOE) 	2004-2015 	Phase 3 (C) 	2. ZL & OFS 	Shorter DFS 	Better tolerated
Kim et al. 2019 (ASTRRA) 	2009-2014 	Phase 3 (E-esc)	Tamoxifen 	Longer DFS2 (primary endpoint)DFS96: 85.4% vs 80.2%(HR 0.67, 95% CI 0.51-0.87)Did not meet secondary endpoint of OS2 	
1Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen-only arm; reported efficacy for this arm is based on the 2022 update.
2Reported efficacy for ASTRRA is based on the 2023 update.
Note: These regimens are intended for premenopausal patients. Patients in HOBOE stopped triptorelin if they reached 55 years of age.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
*Ovarian function suppression by the following study-specific criteria:
**TEXT: Triptorelin (Trelstar LA) 3.75 mg IM once on day 1
***"Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
**SOFT: Choice of mechanism left to investigators
**HOBOE: Triptorelin (Trelstar LA) 3.75 mg IM once on day 1
**ASTRRA: Goserelin (Zoladex) as follows:
***Cycles 1 to 26: 3.6 mg SC once on day 1
28-day cycle for 65 cycles (5 years)
===References===
# ABCSG-12: Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rücklinger E, Marth C, Greil R; ABCSG. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009 Feb 12;360(7):679-91. Erratum in: N Engl J Med. 2009 May 28;360(22):2379. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00295646
## Update: Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; ABCSG. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011 Jul;12(7):631-41. Epub 2011 Jun 5. linkt o original article EuroPMC
# SOFT: Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066690
## Update: Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015 Jan 29;372(5):436-46. Epub 2014 Dec 11. link to original article link to PMC article EuroPMC
## HRQoL analysis: Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 2015 Jul;16(7):848-58. Epub 2015 Jun 16. link to original article link to PMC article EuroPMC
## Pooled update: Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Láng I, Gómez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM; SOFT and TEXT Investigators and International Breast Cancer Study Group. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. J Clin Oncol. 2020 Apr 20;38(12):1293-1303. Epub 2019 Oct 16. link to original article link to PMC article EuroPMC
##Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article link to PMC article EuroPMC
##Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article EuroPMC
# TEXT: Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066703
## HRQoL analysis: Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA. Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol. 2015 Jul;16(7):848-58. Epub 2015 Jun 16. link to original article link to PMC article EuroPMC
## Pooled update: Pagani O, Francis PA, Fleming GF, Walley BA, Viale G, Colleoni M, Láng I, Gómez HL, Tondini C, Pinotti G, Di Leo A, Coates AS, Goldhirsch A, Gelber RD, Regan MM; SOFT and TEXT Investigators and International Breast Cancer Study Group. Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT. J Clin Oncol. 2020 Apr 20;38(12):1293-1303. Epub 2019 Oct 16. link to original article link to PMC article EuroPMC
##Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article EuroPMC
# ECOG E-3193: Tevaarwerk AJ, Wang M, Zhao F, Fetting JH, Cella D, Wagner LI, Martino S, Ingle JN, Sparano JA, Solin LJ, Wood WC, Robert NJ. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2014 Dec 10;32(35):3948-58. Epub 2014 Oct 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# HOBOE: Perrone F, De Laurentiis M, De Placido S, Orditura M, Cinieri S, Riccardi F, Ribecco AS, Putzu C, Del Mastro L, Rossi E, Tinessa V, Mosconi AM, Nuzzo F, Di Rella F, Gravina A, Iodice G, Landi G, Pacilio C, Forestieri V, Lauria R, Fabbri A, Ibrahim T, De Maio E, Barni S, Gori S, Simeon V, Arenare L, Daniele G, Piccirillo MC, Normanno N, de Matteis A, Gallo C. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019 Sep;118:178-186. Epub 2019 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00412022
##Update: Gravina A, Gargiulo P, De Laurentiis M, Arenare L, De Placido S, Orditura M, Cinieri S, Riccardi F, Ribecco AS, Putzu C, Del Mastro L, Rossi E, Ciardiello F, Di Rella F, Nuzzo F, Pacilio C, Caputo R, Cianniello D, Forestieri V, Giuliano M, Arpino G, Orlando L, Mocerino C, Schettino C, Piccirillo MC, Gallo C, Perrone F. Ten-year update of HOBOE phase III trial comparing triptorelin plus either tamoxifen or letrozole or zoledronic acid + letrozole in premenopausal hormone receptor-positive early breast cancer patients. ESMO Open. 2025 Jan;10(1):104085. Epub 2025 Jan 3. link to original article link to PMC article EuroPMC
# ASTRRA: Kim HA, Lee JW, Nam SJ, Park BW, Im SA, Lee ES, Jung YS, Yoon JH, Kang SS, Lee SJ, Park KH, Jeong J, Cho SH, Kim SY, Kim LS, Moon BI, Lee MH, Kim TH, Park C, Jung SH, Gwak G, Kim J, Kang SH, Jin YW, Kim HJ, Han SH, Han W, Hur MH, Noh WC; Korean Breast Cancer Study Group. Adding Ovarian Suppression to Tamoxifen for Premenopausal Breast Cancer: A Randomized Phase III Trial. J Clin Oncol. 2020 Feb 10;38(5):434-443. Epub 2019 Sep 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00912548
##Update: Baek SY, Noh WC, Ahn SH, Kim HA, Ryu JM, Kim SI, Lee EG, Im SA, Jung Y, Park MH, Park KH, Kang SH, Jeong J, Park E, Kim SY, Lee MH, Kim LS, Lim W, Kim S, Kim HJ. Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial. J Clin Oncol. 2023 Nov 1;41(31):4864-4871. Epub 2023 Aug 22. link to original article EuroPMC
=Adjuvant therapy=
==Abemaciclib & ET==
Abemaciclib & ET: Abemaciclib & Endocrine Therapy
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (monarchE)	2017-2019 	Phase 3 (E-RT-esc)	Endocrine therapy	Longer IDFS1 (primary endpoint)IDFS60: 83.6% vs 76%(HR 0.68, 95% CI 0.60-0.77)
1Reported efficacy is based on the 2024 update.
Note: the type and dosage of endocrine therapy was not specified in the protocol and was left to clinician discretion.
====Targeted therapy====
*Abemaciclib (Verzenio) as follows:
**Cycles 1 to 26: 150 mg PO twice per day on days 1 to 28
====Endocrine therapy====
*Endocrine therapy (clinician choice)
28-day cycle for 65 to 130 cycles (5 to 10 years)
===References===
#monarchE: Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, Zhang QY, Martinez Rodriguez JL, Campone M, Hamilton E, Sohn J, Guarneri V, Okada M, Boyle F, Neven P, Cortés J, Huober J, Wardley A, Tolaney SM, Cicin I, Smith IC, Frenzel M, Headley D, Wei R, San Antonio B, Hulstijn M, Cox J, O'Shaughnessy J, Rastogi P; monarchE Committee Members and Investigators. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020 Dec 1;38(34):3987-3998. Epub 2020 Sep 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03155997
##Update: Harbeck N, Rastogi P, Martin M, Tolaney SM, Shao ZM, Fasching PA, Huang CS, Jaliffe GG, Tryakin A, Goetz MP, Rugo HS, Senkus E, Testa L, Andersson M, Tamura K, Del Mastro L, Steger GG, Kreipe H, Hegg R, Sohn J, Guarneri V, Cortés J, Hamilton E, André V, Wei R, Barriga S, Sherwood S, Forrester T, Munoz M, Shahir A, San Antonio B, Nabinger SC, Toi M, Johnston SRD, O'Shaughnessy J; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021 Dec;32(12):1571-1581. Epub 2021 Oct 14. link to original article EuroPMC
##PRO analysis: Rugo HS, O'Shaughnessy J, Boyle F, Toi M, Broom R, Blancas I, Gumus M, Yamashita T, Im YH, Rastogi P, Zagouri F, Song C, Campone M, San Antonio B, Shahir A, Hulstijn M, Brown J, Zimmermann A, Wei R, Johnston SRD, Reinisch M, Tolaney SM; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022 Jun;33(6):616-627. Epub 2022 Mar 23. PMID: 35337972. link to original article EuroPMC
##Update: Johnston SRD, Toi M, O'Shaughnessy J, Rastogi P, Campone M, Neven P, Huang CS, Huober J, Jaliffe GG, Cicin I, Tolaney SM, Goetz MP, Rugo HS, Senkus E, Testa L, Del Mastro L, Shimizu C, Wei R, Shahir A, Munoz M, San Antonio B, André V, Harbeck N, Martin M; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023 Jan;24(1):77-90. Epub 2022 Dec 6. link to original article EuroPMC
##Update: Rastogi P, O'Shaughnessy J, Martin M, Boyle F, Cortes J, Rugo HS, Goetz MP, Hamilton EP, Huang CS, Senkus E, Tryakin A, Cicin I, Testa L, Neven P, Huober J, Shao Z, Wei R, André V, Munoz M, San Antonio B, Shahir A, Harbeck N, Johnston S. Adjuvant Abemaciclib Plus Endocrine Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, High-Risk Early Breast Cancer: Results From a Preplanned monarchE Overall Survival Interim Analysis, Including 5-Year Efficacy Outcomes. J Clin Oncol. 2024 Mar 20;42(9):987-993. Epub 2024 Jan 9. Erratum in: J Clin Oncol. 2024 Apr 30. link to original article link to PMC article EuroPMC
==Anastrozole monotherapy==
===Regimen variant #1, 3 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Jakesz et al. 2007 (ABCSG-6a) 	Not reported 	Phase 3 (E-esc)	No further treatment	Seems to have longer RFS (primary endpoint)RR120: 7.1% vs 11.8%(HR 0.62, 95% CI 0.40-0.96)	
Tjan-Heijnen et al. 2017 (DATA)	2006-2009 	Phase 3 (C) 	Anastrozole x 6 y 	Might have shorter aDFS1 (primary endpoint)DFS120: 66% vs 69.2%(HR 1.16, 95% CI 0.99-1.39)	Less toxic
1Reported efficacy for DATA is based on the 2023 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*ABCSG-6a: Adjuvant Tamoxifen x 5 y versus Aminoglutethemide & Tamoxifen x 5 y
*DATA: Adjuvant tamoxifen x 2-3 y
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for 39 cycles (3 years, for a total of 5 to 8 years of hormonal therapy)
===Regimen variant #2, 5 years===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Baum et al. 2002 (ATAC) 	1996-2000 	Phase 3 (E-RT-switch-ic) 	1. Anastrozole & Tamoxifen 	Not reported
Baum et al. 2002 (ATAC) 	1996-2000 	Phase 3 (E-RT-switch-ic) 	2. Tamoxifen 	Longer DFS1 (co-primary endpoint)RFS120: 80.3% vs 76%(HR 0.86, 95% CI 0.78-0.95)
Goss et al. 2013 (NCIC-CTG MA.27) 	2003-2008 	Phase 3 (C) 	Exemestane 	Did not meet primary endpoint of EFSEFS48: 91.2% vs 91%(sHR 0.98, 95% CI 0.85-1.15)
Smith et al. 2017 (FACE) 	2005-2008 	Phase 3 (E-switch-ic) 	Letrozole 	Did not meet primary endpoint of DFS60DFS60: 82.9% vs 84.9%(HR 1.08, 95% CI 0.93-1.25)
De Placido et al. 2018 (FATA-GIM3) 	2007-2012 	Phase 3 (E-switch-ic) 	1. Exemestane2. Letrozole3. Tamoxifen-Anastrozole; 2y + 3y4. Tamoxifen-Exemestane; 2y + 3y5. Tamoxifen-Letrozole; 2y + 3y 	Did not meet primary endpoint of DFS
Iwase et al. 2023 (AERAS) 	2007-11 to 2012-11 	Non-randomized part of phase 3 RCT	 	
Ruíz-Borrego et al. 2019 (GEICAM/2006-10)	2008-2010 	Phase 3 (C) 	Anastrozole & Fulvestrant 	Did not meet primary endpoint of DFSDFS84: 83.3% vs 86.9%(HR 1.19, 95% CI 0.82-1.72)
Bachelot et al. 2022 (UNIRAD) 	2013-2020 	Phase 3 (C) 	1a. Anastrozole & Everolimus1b. Letrozole & Everolimus1a. Tamoxifen & Everolimus 	Did not meet primary endpoint of DFSDFS36: 89% vs 88%(HR 1.05, 95% CI 0.76-1.45)
Mayer et al. 2021 (PALLAS) 	2015-2018 	Phase 3 (C) 	Patient's choice of:1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib1d. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFSIDFS36: 88.5% vs 88.2%(HR 1.08, 95% CI 0.87-1.32)
Slamon et al. 2024 (NATALEE) 	2019-01-10 to 2021-04-20	Phase 3 (C) 	1a. Anastrozole & Ribociclib1b. Letrozole & Ribociclib 	Shorter iDFS2 (primary endpoint)iDFS36: 87.6% vs 90.7%(HR 1.33, 95% CI 1.12-1.59)
1Reported efficacy for this arm of ATAC is based on the 2010 update for hormone-receptor positive patients.
2Reported efficacy for NATALEE is based on the 2024 update.
Note: In UNIRAD, the type and total duration of ET were not specified; 19% of patients received anastrozole. 
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for 65 cycles (5 years)
====Subsequent treatment====
*AERAS: Anastrozole continuation x 5 years versus Observation
===Regimen variant #3, 6 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Tjan-Heijnen et al. 2017 (DATA)	2006-2009 	Phase 3 (E-esc)	Anastrozole x 3 y	Might have longer aDFS1 (primary endpoint)DFS120: 69.2% vs 66%(HR 0.86, 95% CI 0.72-1.01)	More toxic
1Reported efficacy is based on the 2023 update.
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Adjuvant Tamoxifen x 2-3 y
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for 78 cycles (6 years)
===Regimen variant #4, 7 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Gnant et al. 2021 (SALSA)	2004-2010 	Phase 3 (C)	Anastrozole x 10 y	Did not meet primary endpoint of DFSDFS120: 73.6% vs 73.9%(HR 0.99, 95% CI 0.85-1.15)	Less toxic
Note: there does not appear to be a true comparator arm in this study design; this arm had a shorter duration and was less toxic.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for 91 cycles (7 years)
===Regimen variant #5, 5 additional years (10 years total)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Iwase et al. 2023 (AERAS)	2007-11 to 2012-11 	Phase 3 (E-esc)	Observation	Longer DFS (primary endpoint)DFS60: 91% vs 86%(HR 0.61, 95% CI 0.46-0.82)
====Preceding treatment====
*Adjuvant Anastrozole x 5 y or Tamoxifen-Anastrole; 2-3 y + 2-3 y (5 y total)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for 65 cycles (10 years total)
===References===
# ATAC: Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun 22;359(9324):2131-9. Erratum in: Lancet 2002 Nov 9;360(9344):1520. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00849030
## Update: Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article EuroPMC
## Update: Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M; Arimidex Tamoxifen Alone or in Combination (ATAC) Trialists' Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article EuroPMC
## Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. Epub 2010 Nov 17. link to original article EuroPMC
# ABCSG-6a: Jakesz R, Greil R, Gnant M, Schmid M, Kwasny W, Kubista E, Mlineritsch B, Tausch C, Stierer M, Hofbauer F, Renner K, Dadak C, Rücklinger E, Samonigg H; ABCSG. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst. 2007 Dec 19;99(24):1845-53. Epub 2007 Dec 11. Erratum in: J Natl Cancer Inst. 2008 Feb 6;100(3):226. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00300508
# NCIC-CTG MA.27: Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC-CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066573
# FACE: Smith I, Yardley D, Burris H, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Comarella L, Salomon H, Wamil B, O'Shaughnessy J. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol. 2017 Apr 1;35(10):1041-1048. Epub 2017 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00248170
# DATA: Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, Swinkels ACP, Smorenburg CH, van der Sangen MJC, Kroep JR, De Graaf H, Honkoop AH, Erdkamp FLG, van den Berkmortel FWPJ, de Boer M, de Roos WK, Linn SC, Imholz ALT, Seynaeve CM; BOOG. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1502-1511. Epub 2017 Oct 12. Erratum in: Lancet Oncol. 2017 Nov;18(11):e642. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00301457
##Update: Tjan-Heijnen VCG, Lammers SWM, Geurts SME, Vriens IJH, Swinkels ACP, Smorenburg CH, van der Sangen MJC, Kroep JR, de Graaf H, Honkoop AH, Erdkamp FLG, de Roos WK, Linn SC, Imholz ALT; Dutch Breast Cancer Research Group (BOOG) for the DATA Investigators. Extended adjuvant aromatase inhibition after sequential endocrine therapy in postmenopausal women with breast cancer: follow-up analysis of the randomised phase 3 DATA trial. EClinicalMedicine. 2023 Mar 20;58:101901. link to original article link to PMC article EuroPMC
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
# GEICAM/2006-10: Ruíz-Borrego M, Guerrero-Zotano A, Bermejo B, Ramos M, Cruz J, Baena-Cañada JM, Cirauqui B, Rodríguez-Lescure Á, Alba E, Martínez-Jáñez N, Muñoz M, Antolín S, Álvarez I, Del Barco S, Sevillano E, Chacón JI, Antón A, Escudero MJ, Ruiz V, Carrasco E, Martín M; GEICAM. Phase III evaluating the addition of fulvestrant (F) to anastrozole (A) as adjuvant therapy in postmenopausal women with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (EBC): results from the GEICAM/2006-10 study. Breast Cancer Res Treat. 2019 Aug;177(1):115-125. Epub 2019 May 31. link to original article contain protocol EuroPMC NCT00543127
# PALLAS: Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Theall KP, Lu DR, Bartlett CH, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Feb;22(2):212-222. Epub 2021 Jan 15. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT02513394
##Update: Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, Fox P, Wolff AC, Chan A, Winer EP, Pfeiler G, Miller KD, Colleoni M, Suga JM, Rubovsky G, Bliss JM, Mayer IA, Singer CF, Nowecki Z, Hahn O, Thomson J, Wolmark N, Amillano K, Rugo HS, Steger GG, Hernando Fernández de Aránguiz B, Haddad TC, Perelló A, Bellet M, Fohler H, Metzger Filho O, Jallitsch-Halper A, Solomon K, Schurmans C, Theall KP, Lu DR, Tenner K, Fesl C, DeMichele A, Mayer EL; PALLAS groups and investigators. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022 Jan 20;40(3):282-293. Epub 2021 Dec 7. link to original article link to PMC article EuroPMC
# SALSA: Gnant M, Fitzal F, Rinnerthaler G, Steger GG, Greil-Ressler S, Balic M, Heck D, Jakesz R, Thaler J, Egle D, Manfreda D, Bjelic-Radisic V, Wieder U, Singer CF, Melbinger-Zeinitzer E, Haslbauer F, Sevelda P, Trapl H, Wette V, Wimmer K, Gampenrieder SP, Bartsch R, Kacerovsky-Strobl S, Suppan C, Brunner C, Deutschmann C, Soelkner L, Fesl C, Greil R; Austrian Breast and Colorectal Cancer Study Group. Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. N Engl J Med. 2021 Jul 29;385(5):395-405. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00295620
# RxPONDER: Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, Lin NU, Perez EA, Goldstein LJ, Chia SKL, Dhesy-Thind S, Rastogi P, Alba E, Delaloge S, Martin M, Kelly CM, Ruiz-Borrego M, Gil-Gil M, Arce-Salinas CH, Brain EGC, Lee ES, Pierga JY, Bermejo B, Ramos-Vazquez M, Jung KH, Ferrero JM, Schott AF, Shak S, Sharma P, Lew DL, Miao J, Tripathy D, Pusztai L, Hortobagyi GN. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021 Dec 16;385(25):2336-2347. Epub 2021 Dec 1. link to original article link to PMC article EuroPMC NCT01272037
#UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article does not contain dosing details in manuscript EuroPMC NCT01805271
# AERAS: Iwase T, Saji S, Iijima K, Higaki K, Ohtani S, Sato Y, Hozumi Y, Hasegawa Y, Yanagita Y, Takei H, Tanaka M, Masuoka H, Tanabe M, Egawa C, Komoike Y, Nakamura T, Ohtsu H, Mukai H. Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial. J Clin Oncol. 2023 Jun 20;41(18):3329-3338. Epub 2023 Apr 20. link to original article EuroPMC UMIN000000818
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Anastrozole & Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (E-RT-esc)	1a. Anastrozole1b. Letrozole	Longer iDFS1 (primary endpoint)iDFS36: 90.7% vs 87.6%(HR 0.75, 95% CI 0.63-0.89)
1Reported efficacy is based on the 2024 update.
====Eligibility criteria====
*Anatomic stage II or III; postmenopausal women
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) as follows:
**Cycles 1 to 39: 400 mg PO once per day on days 1 to 21
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Aromatase inhibitor monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Gnant et al. 2015 (ABCSG-18)	2006-12-18 to 2013-07-22	Phase 3 (C)	AI & Denosumab	Seems to have shorter DFS1 (secondary endpoint)DFS96: 77.5% vs 80.6%(HR 1.22, 95% CI 1.02-1.45)	Shorter time to first clinical fracture (primary endpoint)
1Reported efficacy is based on the 2019 update.
Note: This section contains trials that do not specify the type of aromatase inhibitor to be used. Presumably, these trials are referring to third-generation AIs (anastrozole, exemestane, and/or letrozole).
====Preceding treatment====
*Surgery; additional treatment not specified
====Endocrine therapy====
*Aromatase inhibitor
===References===
#ABCSG-18: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43. Epub 2015 May 31. link to original article does not contain dosing details EuroPMC NCT00556374
##Update: Gnant M, Pfeiler G, Steger GG, Egle D, Greil R, Fitzal F, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Jakesz R, Marth C, Sevelda P, Mlineritsch B, Exner R, Fesl C, Frantal S, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):339-351. Epub 2019 Feb 19. link to original article EuroPMC
==Exemestane monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mamounas et al. 2008 (NSABP B-33) 	2001-2003 	Phase 3 (E-esc) 	Placebo 	Might have longer DFS (primary endpoint)DFS48: 91% vs 89%(HR not reported, p=0.07)
Goss et al. 2013 (NCIC-CTG MA.27) 	2003-2008 	Phase 3 (E-switch-ic)	Anastrozole 	Did not meet primary endpoint of EFSEFS48: 91% vs 91.2%(sHR 1.02, 95% CI 0.87-1.18)
De Placido et al. 2018 (FATA-GIM3)	2007-2012 	Phase 3 (E-switch-ic)	1. Anastrozole2. Letrozole3. Tamoxifen-Anastrozole; 2y + 3y4. Tamoxifen-Exemestane; 2y + 3y5. Tamoxifen-Letrozole; 2y + 3y 	Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS) 	2015-2018 	Phase 3 (C) 	Patient's choice of:1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib1d. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFSIDFS36: 88.5% vs 88.2%(HR 1.08, 95% CI 0.87-1.32)
====Preceding treatment====
*NSABP B-33: Adjuvant Tamoxifen x 5 y
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# NSABP B-33: Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00016432
# NCIC-CTG MA.27: Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC-CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00066573
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
# PALLAS: Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Theall KP, Lu DR, Bartlett CH, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Feb;22(2):212-222. Epub 2021 Jan 15. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT02513394
##Update: Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, Fox P, Wolff AC, Chan A, Winer EP, Pfeiler G, Miller KD, Colleoni M, Suga JM, Rubovsky G, Bliss JM, Mayer IA, Singer CF, Nowecki Z, Hahn O, Thomson J, Wolmark N, Amillano K, Rugo HS, Steger GG, Hernando Fernández de Aránguiz B, Haddad TC, Perelló A, Bellet M, Fohler H, Metzger Filho O, Jallitsch-Halper A, Solomon K, Schurmans C, Theall KP, Lu DR, Tenner K, Fesl C, DeMichele A, Mayer EL; PALLAS groups and investigators. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022 Jan 20;40(3):282-293. Epub 2021 Dec 7. link to original article link to PMC article EuroPMC
==Letrozole monotherapy==
===Regimen variant #1, 2 additional years of therapy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Del Mastro et al. 2021 (GIM4)	2005-2010 	Phase 3 (C)	Letrozole x 5 y	Shorter iDFSiDFS144: 62% vs 67%(HR 1.28, 95% CI 1.08-1.54)
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. This is the lower bound of duration of therapy for GIM4.
====Preceding treatment====
*GIM4: Adjuvant Tamoxifen x 2-3 y
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
2 additional years of endocrine therapy
===Regimen variant #2, 2.5 additional years of therapy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Blok et al. 2017 (IDEAL)	2007-2011 	Phase 3 (C)	Letrozole x 10 y	Did not meet primary endpoint of DFS(HR 0.92, 95% CI 0.74-1.16)
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. Continuation of treatment was started within 2 years of the completion of the first 5 years of treatment.
====Preceding treatment====
*Any adjuvant endocrine therapy for 5 years
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
2.5 additional years of endocrine therapy
===Regimen variant #3, 3 additional years of therapy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Del Mastro et al. 2021 (GIM4)	2005-2010 	Phase 3 (C)	Letrozole x 5 y	Shorter iDFSiDFS144: 62% vs 67%(HR 1.28, 95% CI 1.08-1.54)
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. This is the upper bound of duration of therapy for GIM4.
====Preceding treatment====
*GIM4: Adjuvant Tamoxifen x 2-3 y
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
3 additional years of endocrine therapy
===Regimen variant #4, 5 years of therapy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	1. Letrozole, then Tamoxifen; 2y + 3y 	Did not meet primary endpoint of DFS1 	
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	2. Tamoxifen x 5y 	Might have longer OS1 (secondary endpoint) 	
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	3. Tamoxifen, then Letrozole; 2y + 3y 	Did not meet primary endpoint of DFS1 	
Goss et al. 2016 (NCIC-CTG MA.17R)	Not reported to 2009 	Phase 3 (C) 	Letrozole x 10 y 	Shorter DFSDFS60: 91% vs 95%(HR 1.52, 95% CI 1.10-2.08) 	No clinical difference in QoL
Smith et al. 2017 (FACE) 	2005-2008 	Phase 3 (E-switch-ic) 	Anastrozole 	Did not meet primary endpoint of DFS60DFS60: 84.9% vs 82.9%(HR 0.93, 95% CI 0.80-1.07)	
De Placido et al. 2018 (FATA-GIM3)	2007-2012 	Phase 3 (E-switch-ic) 	1. Anastrozole2. Exemestane3. Tamoxifen-Anastrozole; 2y + 3y4. Tamoxifen-Exemestane; 2y + 3y5. Tamoxifen-Letrozole; 2y + 3y 	Did not meet primary endpoint of DFS 	
Bachelot et al. 2022 (UNIRAD) 	2013-2020 	Phase 3 (C) 	1a. Anastrozole & Everolimus1b. Letrozole & Everolimus1a. Tamoxifen & Everolimus 	Did not meet primary endpoint of DFSDFS36: 89% vs 88%(HR 1.05, 95% CI 0.76-1.45) 	
Loibl et al. 2021 (PENELOPE-B) 	2014-2017 	Phase 3 (C) 	1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib1d. Palbociclib & Tamoxifen 	Did not meet primary endpoint of IDFSDFS36: 77.7% vs 81.2%(sHR 1.08, 95% CI 0.85-1.35)	
Mayer et al. 2021 (PALLAS) 	2015-2018 	Phase 3 (C) 	Patient's choice of:1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib1d. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFSIDFS36: 88.5% vs 88.2%(HR 1.08, 95% CI 0.87-1.32)	
Slamon et al. 2024 (NATALEE) 	2019-01-10 to 2021-04-20	Phase 3 (C) 	1a. Anastrozole & Ribociclib1b. Letrozole & Ribociclib 	Shorter iDFS2 (primary endpoint)iDFS36: 87.6% vs 90.7%(HR 1.33, 95% CI 1.12-1.59) 	
1Reported efficacy for BIG 1-98 is based on the 2011 and 2018 updates.
2Reported efficacy for NATALEE is based on the 2024 update.
Note: PENELOPE-B did not specify the type of ET, leaving it to local discretion. In UNIRAD, the type and total duration of ET were not specified; 32% of patients received letrozole.
====Preceding treatment====
*PENELOPE-B: Neoadjuvant chemotherapy, then surgery, then adjuvant RT per local guidelines 
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #5, 5 additional years of therapy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Goss et al. 2003 (NCIC-CTG MA.17) 	1998-2002 	Phase 3 (E-RT-esc)	Placebo 	Longer DFS (primary endpoint)DFS48: 93% vs 87%(HR 0.57, 95% CI 0.43-0.75) 	No clinical difference in QoL
Del Mastro et al. 2021 (GIM4) 	2005-2010 	Phase 3 (E-esc) 	Letrozole x 2-3 y 	Longer iDFS (primary endpoint)iDFS144: 67% vs 62%(HR 0.78, 95% CI 0.65-0.93) 	
Mamounas et al. 2018 (NSABP B-42) 	2006-2010 	Phase 3 (E-esc) 	Placebo 	Seems to have longer DFS (primary endpoint)DFS84: 85% vs 81%(HR 0.85, 95% CI 0.73-0.999)	
Zdenkowski et al. 2016 (ANZ0501 LATER)	2007-2012 	Phase 3 (E-esc) 	Observation 	Longer iDFS (primary endpoint)Might have longer DFS (secondary endpoint) 	
Goss et al. 2016 (NCIC-CTG MA.17R) 	Not reported to 2009	Phase 3 (E-esc) 	Letrozole x 5 y 	Longer DFS (primary endpoint)DFS60: 95% vs 91%(HR 0.66, 95% CI 0.48-0.91) 	No clinical difference in QoL
Blok et al. 2017 (IDEAL) 	2007-2011 	Phase 3 (E-esc) 	Letrozole x 7.5 y 	Did not meet primary endpoint of DFS(HR 0.92, 95% CI 0.74-1.16) 	
Colleoni et al. 2017 (SOLE) 	2007-2012 	Phase 3 (C) 	Letrozole; intermittent	Did not meet primary endpoint of DFSDFS60: 87.5% vs 85.8%(HR 0.93, 95% CI 0.79-1.08) 	
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Continuation of treatment was started within 2 years of the completion of the first 5 years of treatment or immediately; see individual trials for details.
====Preceding treatment====
*NCIC-CTG MA.17: Most patients received 5 years of adjuvant tamoxifen therapy prior to starting letrozole
*GIM4: Adjuvant Tamoxifen x 2-3 y
*NSABP B-42: Adjuvant AI x 5 y or AI and tamoxifen for a total of 5 y
*ANZ0501 LATER: At least 4 years of any adjuvant endocrine therapy
*NCIC-CTG MA.17R: Adjuvant Letrozole for 5 years
*IDEAL: Any adjuvant endocrine therapy for 5 years
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
5 additional years of endocrine therapy
===References===
# NCIC-CTG MA.17: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. link to original article EuroPMC NCT00003140
## Update: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC-CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. link to original article EuroPMC
## HRQoL analysis: Whelan TJ, Goss PE, Ingle JN, Pater JL, Tu D, Pritchard K, Liu S, Shepherd LE, Palmer M, Robert NJ, Martino S, Muss HB. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol. 2005 Oct 1;23(28):6931-40. Epub 2005 Sep 12. link to original article EuroPMC
## Update: Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC-CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. link to original article EuroPMC
## Subgroup analysis: Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. link to original article EuroPMC
## Update: Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC-CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. link to original article link to PMC article EuroPMC
# BIG 1-98: Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; BIG. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004205
## Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article EuroPMC
## Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG; International Breast Cancer Study Group. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article EuroPMC
## Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article EuroPMC
## Update: Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS; BIG. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76. link to original article link to PMC article EuroPMC
## Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG; International Breast Cancer Study Group. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. Epub 2011 Oct 20. link to original article link to PMC article EuroPMC
## Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; BIG; International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019 Jan 10;37(2):105-114. Epub 2018 Nov 26. link to original article link to PMC article EuroPMC
# ANZ0501 LATER: Zdenkowski N, Forbes JF, Boyle FM, Kannourakis G, Gill PG, Bayliss E, Saunders C, Della-Fiorentina S, Kling N, Campbell I, Mann GB, Coates AS, Gebski V, Davies L, Thornton R, Reaby L, Cuzick J, Green M; Australia and New Zealand Breast Cancer Trials Group. Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial. Ann Oncol. 2016 May;27(5):806-12. Epub 2016 Feb 9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC ACTRN12607000137493
# NCIC-CTG MA.17R: Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending aromatase-inhibitor adjuvant therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. Epub 2016 Jun 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00754845
## HRQoL analysis: Lemieux J, Brundage MD, Parulekar WR, Goss PE, Ingle JN, Pritchard KI, Celano P, Muss H, Gralow J, Strasser-Weippl K, Whelan K, Tu D, Whelan TJ. Quality of life from Canadian Cancer Trials Group MA.17R: a randomized trial of extending adjuvant letrozole to 10 years. J Clin Oncol. 2018 Feb 20;36(6):563-571. Epub 2018 Jan 12. link to original article link to PMC article EuroPMC
# FACE: Smith I, Yardley D, Burris H, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Comarella L, Salomon H, Wamil B, O'Shaughnessy J. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol. 2017 Apr 1;35(10):1041-1048. Epub 2017 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00248170
# IDEAL: Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, Duijm-de Carpentier M, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers GJ, Nortier JWR, Rutgers EJT, van de Velde CJH; IDEAL Study Group. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006-05). J Natl Cancer Inst. 2018 Jan 1;110(1). Epub 2017 Aug 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NTR3077
# SOLE: Colleoni M, Luo W, Karlsson P, Chirgwin J, Aebi S, Jerusalem G, Neven P, Hitre E, Graas MP, Simoncini E, Kamby C, Thompson A, Loibl S, Gavilá J, Kuroi K, Marth C, Müller B, O'Reilly S, Di Lauro V, Gombos A, Ruhstaller T, Burstein H, Ribi K, Bernhard J, Viale G, Maibach R, Rabaglio-Poretti M, Gelber RD, Coates AS, Di Leo A, Regan MM, Goldhirsch A; SOLE Investigators. Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):127-138. Epub 2017 Nov 17. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00553410
## HRQoL analysis: Ribi K, Luo W, Colleoni M, Karlsson P, Chirgwin J, Aebi S, Jerusalem G, Neven P, Di Lauro V, Gomez HL, Ruhstaller T, Abdi E, Biganzoli L, Müller B, Barbeaux A, Graas MP, Rabaglio M, Francis PA, Foukakis T, Pagani O, Graiff C, Vorobiof D, Maibach R, Di Leo A, Gelber RD, Goldhirsch A, Coates AS, Regan MM, Bernhard J; SOLE Investigators. Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial. Br J Cancer. 2019 May;120(10):959-967. Epub 2019 Apr 10. Erratum in: Br J Cancer. 2020 Jan 16 link to original article link to PMC article EuroPMC
## Update: Jerusalem G, Farah S, Courtois A, Chirgwin J, Aebi S, Karlsson P, Neven P, Hitre E, Graas MP, Simoncini E, Abdi E, Kamby C, Thompson A, Loibl S, Gavilá J, Kuroi K, Marth C, Müller B, O'Reilly S, Gombos A, Ruhstaller T, Burstein HJ, Rabaglio M, Ruepp B, Ribi K, Viale G, Gelber RD, Coates AS, Loi S, Goldhirsch A, Regan MM, Colleoni M; SOLE Investigators. Continuous versus intermittent extended adjuvant letrozole for breast cancer: final results of randomized phase III SOLE (Study of Letrozole Extension) and SOLE Estrogen Substudy. Ann Oncol. 2021 Oct;32(10):1256-1266. Epub 2021 Aug 10. link to original article EuroPMC
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
# NSABP B-42: Mamounas EP, Bandos H, Lembersky BC, Jeong JH, Geyer CE Jr, Rastogi P, Fehrenbacher L, Graham ML, Chia SK, Brufsky AM, Walshe JM, Soori GS, Dakhil SR, Seay TE, Wade JL 3rd, McCarron EC, Paik S, Swain SM, Wickerham DL, Wolmark N. Use of letrozole after aromatase inhibitor-based therapy (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2019 Jan;20(1):88-99. Epub 2018 Nov 30. Erratum in: Lancet Oncol. 2019 Jan;20(1):e10. link to original article link to PMC article EuroPMC NCT00382070
# PALLAS: Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Theall KP, Lu DR, Bartlett CH, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Feb;22(2):212-222. Epub 2021 Jan 15. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT02513394
##Update: Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, Fox P, Wolff AC, Chan A, Winer EP, Pfeiler G, Miller KD, Colleoni M, Suga JM, Rubovsky G, Bliss JM, Mayer IA, Singer CF, Nowecki Z, Hahn O, Thomson J, Wolmark N, Amillano K, Rugo HS, Steger GG, Hernando Fernández de Aránguiz B, Haddad TC, Perelló A, Bellet M, Fohler H, Metzger Filho O, Jallitsch-Halper A, Solomon K, Schurmans C, Theall KP, Lu DR, Tenner K, Fesl C, DeMichele A, Mayer EL; PALLAS groups and investigators. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022 Jan 20;40(3):282-293. Epub 2021 Dec 7. link to original article link to PMC article EuroPMC
# PENELOPE-B: Loibl S, Marmé F, Martin M, Untch M, Bonnefoi H, Kim SB, Bear H, McCarthy N, Melé Olivé M, Gelmon K, García-Sáenz J, Kelly CM, Reimer T, Toi M, Rugo HS, Denkert C, Gnant M, Makris A, Koehler M, Huang-Bartelett C, Lechuga Frean MJ, Colleoni M, Werutsky G, Seiler S, Burchardi N, Nekljudova V, von Minckwitz G. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021 May 10;39(14):1518-1530. Epub 2021 Apr 1. link to original article does not contain dosing details EuroPMC NCT01864746
# GIM4: Del Mastro L, Mansutti M, Bisagni G, Ponzone R, Durando A, Amaducci L, Campadelli E, Cognetti F, Frassoldati A, Michelotti A, Mura S, Urracci Y, Sanna G, Gori S, De Placido S, Garrone O, Fabi A, Barone C, Tamberi S, Bighin C, Puglisi F, Moretti G, Arpino G, Ballestrero A, Poggio F, Lambertini M, Montemurro F, Bruzzi P; Gruppo Italiano Mammella investigators. Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Oct;22(10):1458-1467. Epub 2021 Sep 17. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01064635
#UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article does not contain dosing details in manuscript EuroPMC NCT01805271
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Letrozole & Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2024 (NATALEE)	2019-01-10 to 2021-04-20	Phase 3 (E-RT-esc)	1a. Anastrozole1b. Letrozole	Longer iDFS1 (primary endpoint)iDFS36: 90.7% vs 87.6%(HR 0.75, 95% CI 0.63-0.89)
1Reported efficacy is based on the 2024 update.
====Eligibility criteria====
*Anatomic stage II or III; postmenopausal women
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) as follows:
**Cycles 1 to 39: 400 mg PO once per day on days 1 to 21
28-day cycle for 65 cycles (5 years)
===References===
#NATALEE: Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03701334
##Update: Hortobagyi GN, Lacko A, Sohn J, Cruz F, Ruiz Borrego M, Manikhas A, Hee Park Y, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Martin M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Parnizari F, Zarate JP, Li Z, Waters S, Chakravartty A, Slamon D. A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial. Ann Oncol. 2025 Jan 28;36(2):149-157. Epub 2024 Oct 21. link to original article EuroPMC
==Letrozole-Tamoxifen==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98)	1998-2003 	Phase 3 (E-RT-switch-ic)	1. Letrozole x 5y 	Did not meet primary endpoint of DFS1
Thürlimann et al. 2005 (BIG 1-98)	1998-2003 	Phase 3 (E-RT-switch-ic)	2. Tamoxifen x 5y 	Not reported
Thürlimann et al. 2005 (BIG 1-98)	1998-2003 	Phase 3 (E-RT-switch-ic)	3. Tamoxifen, then Letrozole; 2y + 3y	Did not meet primary endpoint of DFS1
====Endocrine therapy====
*Letrozole (Femara) as follows:
**Cycles 1 to 26: 2.5 mg PO once per day
*Tamoxifen (Nolvadex) as follows:
**Cycles 27 to 65: 20 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# BIG 1-98: Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; BIG. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004205
## Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article EuroPMC
## Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG; International Breast Cancer Study Group. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article EuroPMC
## Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article EuroPMC
## Update: Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS; BIG. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76. link to original article link to PMC article EuroPMC
## Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG; International Breast Cancer Study Group. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. Epub 2011 Oct 20. link to original article link to PMC article EuroPMC
## Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; BIG; International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019 Jan 10;37(2):105-114. Epub 2018 Nov 26. link to original article link to PMC article EuroPMC
==Tamoxifen monotherapy==
===Regimen variant #1, 1 year===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rydén et al. 1992 (SSBCG II:I) 	Not reported 	Phase 3 (C) 	1. RT2. Tamoxifen & RT 	Did not meet endpoint of OS
Knoop et al. 2001 (DBCG 77C) 	1977-1982 	Phase 3 (E-esc)	Observation 	Did not meet primary endpoint of DFS
Rivkin et al. 1994 (SWOG S7827) 	1979-1989 	Phase 3 (C) 	1. CMFVP2. CMFVPT 	Did not meet primary endpoint of DFS
Overgaard et al. 1999 (DBCG 82C)	1982-1990 	Phase 3 (C) 	1. CMFT 	Shorter DFS1
Overgaard et al. 1999 (DBCG 82C)	1982-1990 	Phase 3 (C) 	2. Tamoxifen & RT 	Seems to have shorter OS
Andersen et al. 2008 (DBCG 89C) 	1990-1994 	Phase 3 (C) 	1. Tamoxifen x 2 y2. TAM/MA	Did not meet primary endpoint of DFS
1Reported efficacy for this arm of DBCG 82C versus CMFT is based on the 2013 update.
Note: Knoop et al. 2001 is a retrospective biomarker analysis; we are not aware of another primary publication for DBCG 77C.
====Preceding treatment====
*Mastectomy
====Endocrine therapy====
*Tamoxifen (Nolvadex) 30 mg PO once per day
28-day cycle for 13 cycles (1 year)
===Regimen variant #2, 2 years of 20 mg/day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Baum et al. 1983 (NATO) 	1977-1981 	Phase 3 (E-RT-esc)	Observation 	Longer OS
Cummings et al. 1985 (ECOG 1178) 	1978-1982 	Phase 3 (E-RT-esc)	Placebo 	Longer DFS
Bianco et al. 1988 (GUN) 	1978-1983 	Phase 3 (E-esc) 	Observation 	Seems to have longer DFS
Rutqvist et al. 1996 	1983-1991 	Phase 3 (C) 	Tamoxifen x 5 y	Seems to have shorter OS
Baum & Odling-Smee 1996 (CRUK Over 50s)	Not reported to 1994	Phase 3 (C) 	Tamoxifen x 5 y	Shorter EFS
Jakesz et al. 1999 	1984-1990 	Phase 3 (C) 	AV-CMF-TAM 	Did not meet primary endpoint of OS
Sacco et al. 2003 (SITAM 01) 	1989-1996 	Phase 3 (C) 	Tamoxifen x 5 y	Did not meet primary endpoint of DFS
Shien et al. 2014 (JCOG9401) 	1994-1999 	Phase 3 (C) 	ACT 	Did not meet primary endpoint of OSOS60: 76.9% vs 85%(HR 1.72, 95% CI 0.72-4.17)
Kimura et al. 2012 	1998-2001 	Phase 3 (C) 	Toremifene 	Non-inferior OS60 (primary endpoint)OS60: 96.9% vs 97%
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
28-day cycle for 26 cycles (2 years)
===Regimen variant #3, 2 years of 30 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jensen et al. 2017 (CBC 02) 	1975-1978 	Phase 3 (E-esc) 	Observation	Seems to have longer OS
Pritchard et al. 1996 (NCIC-CTG MA.4)	1984-1990 	Phase 3 (E-RT-de-esc)	CMFT 	Did not meet endpoint of OS
====Endocrine therapy====
*Tamoxifen (Nolvadex) 30 mg PO once per day
**In CBC 02, the dose was 10 mg PO three times per day
28-day cycle for 26 cycles (2 years)
===Regimen variant #4, 2 years of 40 mg/d, then 3 years of 20 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Schmid et al. 2003 (ABCSG-6)	1990-1995 	Phase 3 (C)	Aminoglutethemide & Tamoxifen	Did not meet primary endpoint of OS
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 26: 40 mg PO once per day
**Cycles 27 to 65: 20 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #5, 3 years of 20 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Morales et al. 2006	1991-1999 	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS60
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Morales et al. 2006: Adjuvant chemotherapy
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
28-day cycle for 39 cycles (3 years)
===Regimen variant #6, 3 years of 30 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Namer et al. 2006 (FASG 02) 	1986-1990 	Phase 3 (C)	FEC50-Tam 	Shorter DFS
Namer et al. 2006 (FASG 07) 	1991-1998 	Phase 3 (C)	FEC50-Tam 	Shorter DFS
Fargeot et al. 2004 (FASG 08)	1991-2001 	Phase 3 (C)	Epirubicin & Tamoxifen	Did not meet primary endpoint of DFS60
====Endocrine therapy====
*Tamoxifen (Nolvadex) 30 mg PO once per day
28-day cycle for 39 cycles (3 years)
===Regimen variant #7, 20 mg/day x 5 years===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Stewart et al. 1987 (Scottish Tamoxifen Trial)	1978-1984 	Phase 3 (E-esc) 	Observation 	Longer OS1 	
Fisher et al. 1989 (NSABP B-14) 	1982-1987 	Phase 3 (E-RT-esc) 	Placebo 	Longer OS2 	
Tormey et al. 1996 (ECOG E4181) 	1982 to not reported	Phase 3 (C) 	Tamoxifen; indefinitely 	Did not meet endpoint of OS 	
Tormey et al. 1996 (ECOG E5181) 	1982-02 to 1987-06 	Phase 3 (C) 	Tamoxifen; indefinitely 	Did not meet endpoint of OS 	
Rutqvist et al. 1996 	1983-1991 	Phase 3 (E-esc) 	Tamoxifen x 2 y 	Seems to have longer OS 	
Fisher et al. 1990 (NSABP B-16) 	1985-1988 	Phase 3 (C) 	1. ACT 	Seems to have shorter OS 	
Fisher et al. 1990 (NSABP B-16) 	1985-1988 	Phase 3 (C) 	2. PFT 	Seems to have shorter DDFS 	
Mustacchi et al. 1994 (GRETA) 	1987-1992 	Phase 3 (C) 	Tamoxifen alone (no surgery) 	Did not meet endpoint of OS 	
Baum & Odling-Smee 1996 (CRUK Over 50s) 	Not reported to 1994	Phase 3 (E-esc) 	Tamoxifen x 2 y 	Longer EFS3 	
Fisher et al. 1997 (NSABP B-20) 	1988-1993 	Phase 3 (C) 	1. CMFT 	Might have shorter OS2 	
Fisher et al. 1997 (NSABP B-20) 	1988-1993 	Phase 3 (C) 	2. MFT 	Not reported2 	
Sacco et al. 2003 (SITAM 01) 	1989-1996 	Phase 3 (E-esc) 	Tamoxifen x 2 y 	Did not meet primary endpoint of DFS 	
Fisher et al. 2001 (NSABP B-23) 	1991-1998 	Phase 3 (E-esc) 	Placebo 	Did not meet primary endpoint of OS 	
Baum et al. 2002 (ATAC) 	1996-2000 	Phase 3 (C) 	1. Anastrozole & Tamoxifen 	Did not meet co-primary endpoint of DFS 	
Baum et al. 2002 (ATAC) 	1996-2000 	Phase 3 (C) 	2. Anastrozole 	Shorter DFS4 	
Assikis et al. 2003 	1986-1994 	Phase 3 (E-switch-ooc) 	FAC-MV 	Did not meet primary endpoint of OS 	
Hutchins et al. 2005 (INT-0102) 	1989-1993 	Phase 3 (E-esc) 	Observation 	Did not meet primary endpoint of DFS 	
Albain et al. 2009 (SWOG-8814) 	1989-1995 	Phase 3 	See link 	See link 	
Fisher et al. 2002 (NSABP B-21) 	1989-1998 	Phase 3 (E-de-esc) 	1. RT2. Tamoxifen & RT 	Shorter DFS (secondary endpoint) 	
Fyles et al. 2004 	1992-2000 	Non-randomized part of RCT 	 	 	
Pagani et al. 2004 (IBCSG 12-93) 	1993-1999 	Phase 3 (C) 	Toremifene 	Non-inferior DFS 	
Pagani et al. 2004 (IBCSG 14-93) 	1993-1999 	Phase 3 (C) 	Toremifene 	Non-inferior DFS 	
Hughes et al. 2004 (CALGB 9343) 	1994-1999 	Non-randomized part of RCT 	 	 	
Rao et al. 2010 (ECOG EB193) 	1995-1999 	Phase 3 (C) 	Fenretinide & Tamoxifen 	Did not meet primary endpoint of DFS 	
Pritchard et al. 2011 (NCIC-CTG MA.14) 	1996-2000 	Phase 3 (C) 	Tamoxifen & Octreotide LAR 	Did not meet primary endpoint of EFS 	
Jakesz et al. 2005 (ARNO 95) 	1996-2003 	Phase 3 (C) 	Tamoxifen, then Anastrozole; 2y + 3y 	Seems to have shorter OS5 (secondary endpoint)OS60: 88% vs 96%(HR 1.89, 95% CI 1.01-3.57)Shorter EFS (primary endpoint) 	
Jakesz et al. 2005 (ABCSG-8) 	1996-2003 	Phase 3 (C) 	Tamoxifen, then Anastrozole; 2y + 3y 	Shorter EFSEFS36: 92.70% vs 95.80%(HR 1.67, 95% CI 1.23-2.27) 	
Davies et al. 2013 (ATLAS) 	1996-2005 	Phase 3 (C) 	Tamoxifen x 10y 	Shorter OS 	
Coombes et al. 2004 (IES) 	1998-2003 	Phase 3 (C) 	Tamoxifen-Exemestane; 5 years total 	Shorter DFS (primary endpoint)DFS36: 86.8% vs 91.5%(HR 1.47, 95% CI 1.22-1.79)Seems to have shorter OS6 (secondary endpoint)	
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (C) 	1. Letrozole x 5y 	Might have shorter OS7 	
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (C) 	2. Letrozole, then Tamoxifen; 2y + 3y 	Not reported 	
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (C) 	3. Tamoxifen, then Letrozole; 2y + 3y 	Not reported 	
Mamounas et al. 2008 (NSABP B-33) 	2001-2003 	Non-randomized part of phase 3 RCT	 	 	
van de Velde et al. 2011 (TEAM) 	2001-2006 	Phase 3 (C) 	Tamoxifen-Exemestane; 5 years total 	Did not meet primary endpoint of DFS60 	
Aihara et al. 2010 (N-SAS BC03) 	2002-2005 	Phase 3 (C) 	Tamoxifen x 1-4y, then Anastrozole x 1-4y (5y total) 	Did not meet primary endpoint of DFS 	Similar toxicity
Sparano et al. 2018 (TAILORx) 	2006-2010 	Non-randomized part of phase 3 RCT	 	 	
Kalinsky et al. 2021 (RxPONDER) 	2011-2017 	Non-randomized part of phase 3 RCT	 	 	
Bachelot et al. 2022 (UNIRAD) 	2013-2020 	Phase 3 (C) 	1a. Anastrozole & Everolimus1b. Letrozole & Everolimus1a. Tamoxifen & Everolimus 	Did not meet primary endpoint of DFSDFS36: 89% vs 88%(HR 1.05, 95% CI 0.76-1.45) 	
Mayer et al. 2021 (PALLAS) 	2015-2018 	Phase 3 (C) 	Patient's choice of:1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib1d. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFSIDFS36: 88.5% vs 88.2%(HR 1.08, 95% CI 0.87-1.32) 	
1Reported efficacy for the Scottish Tamoxifen Trial is based on the 2001 update.
2Reported efficacy for NSABP B-14 & NSABP B-20 is based on the 2004 update.
3Reported efficacy for CRUK Over 50s is based on the 2011 update.
4Reported efficacy for this arm of ATAC is based on the 2010 update for hormone-receptor positive patients.
5Reported efficacy for ARNO 95 is based on the 2007 update.
6Reported efficacy for IES is based on the 2011 update.
7Reported efficacy for BIG 1-98 is based on the 2011 & 2018 updates.
Note: in Fyles et al. 2004 and CALGB 9343, the randomization was to radiation therapy or no radiation therapy; all patients received 5 years of tamoxifen. In UNIRAD, the type and total duration of ET were not specified; 44% of patients received tamoxifen. Tormey et al. 1996 is an update of ECOG E5181 but appears to be the first publication of ECOG E4181.
====Preceding treatment====
*NSABP B-23: Surgery, then adjuvant CMF x 6 versus AC x 4
*INT-0102: Surgery, then adjuvant CAF x 6 versus CMF x 6
*SWOG-8814: Surgery versus surgery followed by adjuvant CAF x 6
*TAILORx: Surgery, then adjuvant AC x 4 or ddAC x 4 or AC-T or ddAC-T or CMF x 6 to 8 or FEC x 6 or TAC x 4 to 6 or TC x 4 versus no chemotherapy
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
**Some older trials report using 10 mg PO twice per day
28-day cycle for 65 cycles (5 years)
====Subsequent treatment====
*NSABP B-33: Adjuvant Exemestane versus Placebo
*TAILORx, post-menopausal at year 6: Adjuvant AI x 5 years
===Regimen variant #8, 30 mg/day x 5 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jakesz et al. 2005 (ARNO 95)	1996-2003 	Phase 3 (C)	Tamoxifen, then Anastrozole; 2y + 3y	Seems to have shorter OS1 (secondary endpoint)OS60: 88% vs 96%(HR 1.89, 95% CI 1.01-3.57)Shorter EFS (primary endpoint)
1Reported efficacy for ARNO 95 is based on the 2007 update.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 30 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #9, 10 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Davies et al. 2013 (ATLAS)	1996-2005 	Phase 3 (E-esc)	Tamoxifen x 5y	Longer OS (primary endpoint)
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
28-day cycle for 130 cycles (10 years)
===References===
# NATO: Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet. 1983 Feb 5;1(8319):257-61. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Update: Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Richards D, Ellis SH. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: analysis at six years by Nolvadex Adjuvant Trial Organisation. Lancet. 1985 Apr 13;1(8433):836-40. link to original article EuroPMC
# ECOG 1178: Cummings FJ, Gray R, Davis TE, Tormey DC, Harris JE, Falkson G, Arseneau J. Adjuvant tamoxifen treatment of elderly women with stage II breast cancer: a double-blind comparison with placebo. Ann Intern Med. 1985 Sep;103(3):324-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Scottish Tamoxifen Trial: Stewart HJ, Taylor W, Forrest P. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial: report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet. 1987 Jul 25;2(8552):171-5. link to original article EuroPMC
## Update: Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, Prescott RJ, George WD; Scottish Cancer Trials Breast Group. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. Br J Cancer. 1996 Jul;74(2):297-9. link to original article link to PMC article EuroPMC
## Update: Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001 Mar 21;93(6):456-62. link to original article EuroPMC
# GUN: Bianco AR, De Placido S, Gallo C, Pagliarulo C, Marinelli A, Petrella G, D'Istria M, Delrio G. Adjuvant therapy with tamoxifen in operable breast cancer: 10 year results of the Naples (GUN) study. Lancet. 1988 Nov 12;2(8620):1095-9. link to original article EuroPMC
# NSABP B-14: Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, Margolese R, Robidoux A, Shibata H, Terz J, Peterson AHG, Feldman MI, Farrar W, Evans J, Lickley HL, Ketner M. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschênes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AH, Feldman MI, Farrar W, Evans J, Lickley HL. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42. link to original article EuroPMC
## Update: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001 May 2;93(9):684-90. link to original article EuroPMC
## Pooled update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article EuroPMC
## Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article EuroPMC
# NSABP B-16: Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. link to original article EuroPMC
## Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article EuroPMC
# SSBCG II:I: Rydén S, Fernö M, Möller T, Aspegren K, Bergljung L, Killander D, Landberg T. Long-term effects of adjuvant tamoxifen and/or radiotherapy: the South Sweden Breast Cancer Trial. Acta Oncol. 1992;31(2):271-4. link to original article EuroPMC
## Update: Killander F, Anderson H, Rydén S, Möller T, Aspegren K, Ceberg J, Danewid C, Malmström P. Radiotherapy and tamoxifen after mastectomy in postmenopausal women -- 20 year follow-up of the South Sweden Breast Cancer Group randomised trial SSBCG II:I. Eur J Cancer. 2007 Sep;43(14):2100-8. Epub 2007 Jul 17. link to original article EuroPMC
# GRETA: Mustacchi G, Milani S, Pluchinotta A, De Matteis A, Rubagotti A, Perrota A; Group for Research on Endocrine Therapy in the Elderly. Tamoxifen or surgery plus tamoxifen as primary treatment for elderly patients with operable breast cancer: the GRETA trial. Anticancer Res. 1994 Sep-Oct;14(5B):2197-200. EuroPMC
## Update: Mustacchi G, Ceccherini R, Milani S, Pluchinotta A, De Matteis A, Maiorino L, Farris A, Scanni A, Sasso F; Italian Cooperative Group GRETA. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol. 2003 Mar;14(3):414-20. link to original article EuroPMC
## Update: Mustacchi G, Scanni A, Capasso I, Farris A, Pluchinotta A, Isola G. Update of the phase III trial 'GRETA' of surgery and tamoxifen versus tamoxifen alone for early breast cancer in elderly women. Future Oncol. 2015;11(6):933-41. Epub 2014 Nov 10. link to original article EuroPMC
# SWOG S7827: Rivkin SE, Green S, Metch B, Cruz AB, Abeloff MD, Jewell WR, Costanzi JJ, Farrar WB, Minton JP, Osborne CK. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1994 Oct;12(10):2078-85. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# NCIC-CTG MA.4: Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J; National Cancer Institute of Canada Clinical Trials Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996 Oct;14(10):2731-7. link to original article EuroPMC
## Update: Pritchard KI, Paterson AH, Fine S, Paul NA, Zee B, Shepherd LE, Abu-Zahra H, Ragaz J, Knowling M, Levine MN, Verma S, Perrault D, Walde PL, Bramwell VH, Poljicak M, Boyd N, Warr D, Norris BD, Bowman D, Armitage GR, Weizel H, Buckman RA; NCIC-CTG. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1997 Jun;15(6):2302-11. link to original article EuroPMC
# Rutqvist LE, Hatschek T, Rydén S, Bergh J, Bengtsson NO, Carstenssen J, Nordenskjöld B, Wallgren A; Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst. 1996 Nov 6;88(21):1543-9. link to original article EuroPMC
# ECOG E4181: Tormey DC, Gray R, Falkson HC; ECOG. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst. 1996 Dec 18;88(24):1828-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E5181: Tormey DC, Gray R, Abeloff MD, Roseman DL, Gilchrist KW, Barylak EJ, Stott P, Falkson G. Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 1992 Dec;10(12):1848-56. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Tormey DC, Gray R, Falkson HC; ECOG. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst. 1996 Dec 18;88(24):1828-33. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# CRUK Over 50s: Baum M, Odling-Smee W; Current Trials working Party of the Cancer Research Campaign Breast Cancer Trials Group. Preliminary results from the cancer research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. J Natl Cancer Inst. 1996 Dec 18;88(24):1834-9. Erratum in: J Natl Cancer Inst 1997 Apr 16;89(8):590. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Hackshaw A, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol. 2011 May 1;29(13):1657-63. Epub 2011 Mar 21. link to original article EuroPMC
# NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article EuroPMC
## Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article EuroPMC
# DBCG 82C: Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Jakesz R, Hausmaninger H, Haider K, Kubista E, Samonigg H, Gnant M, Manfreda D, Tschurtschenthaler G, Kolb R, Stierer M, Fridrik M, Mlineritsch B, Steindorfer P, Mittlböck M, Steger G; ABCSG. Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol. 1999 Jun;17(6):1701-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article EuroPMC
## Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article EuroPMC
# DBCG 77C: Knoop AS, Bentzen SM, Nielsen MM, Rasmussen BB, Rose C. Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients. J Clin Oncol. 2001 Jul 15;19(14):3376-84. link to original article EuroPMC
# ATAC: Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun 22;359(9324):2131-9. Erratum in: Lancet 2002 Nov 9;360(9344):1520. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00849030
## Update: Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article EuroPMC
## Update: Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M; Arimidex Tamoxifen Alone or in Combination (ATAC) Trialists' Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article EuroPMC
## Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. Epub 2010 Nov 17. link to original article EuroPMC
# NSABP B-21: Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, Margolese RG, Nesbitt L, Paik S, Pisansky TM, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002 Oct 15;20(20):4141-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ABCSG-6: Schmid M, Jakesz R, Samonigg H, Kubista E, Gnant M, Menzel C, Seifert M, Haider K, Taucher S, Mlineritsch B, Steindorfer P, Kwasny W, Stierer M, Tausch C, Fridrik M, Wette V, Steger G, Hausmaninger H; ABCSG. Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6. J Clin Oncol. 2003 Mar 15;21(6):984-90. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00309491
# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# SITAM 01: Sacco M, Valentini M, Belfiglio M, Pellegrini F, De Berardis G, Franciosi M, Nicolucci A; Italian Interdisciplinary Group for Cancer Care Evaluation. Randomized trial of 2 versus 5 years of adjuvant tamoxifen for women aged 50 years or older with early breast cancer: Italian Interdisciplinary Group Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01. J Clin Oncol. 2003 Jun 15;21(12):2276-81. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Belfiglio M, Valentini M, Pellegrini F, De Berardis G, Franciosi M, Rossi MC, Sacco M, Nicolucci A; Interdisciplinary Group for Cancer Care Evaluated (GIVIO) Group. Twelve-year mortality results of a randomized trial of 2 versus 5 years of adjuvant tamoxifen for postmenopausal early-stage breast carcinoma patients (SITAM 01). Cancer. 2005 Dec 1;104(11):2334-9. link to original article EuroPMC
# IES: Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00038467
## Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article EuroPMC
## Update: Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, van de Velde CJ, Lønning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. J Clin Oncol. 2012 Mar 1;30(7):709-17. Epub 2011 Oct 31. link to original article EuroPMC 
# Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, Weir LM, Olivotto IA. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):963-70. link to original article EuroPMC
# CALGB 9343: Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, Wheeler J, Champion LA, Smith TJ, Smith BL, Shapiro C, Muss HB, Winer E, Hudis C, Wood W, Sugarbaker D, Henderson IC, Norton L; CALGB; Radiation Therapy Oncology Group; ECOG. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):971-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, Muss HB, Smith BL, Hudis CA, Winer EP, Wood WC. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013 Jul 1;31(19):2382-7. Epub 2013 May 20. link to original article link to PMC article EuroPMC
# IBCSG 12-93: Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002529
# IBCSG 14-93: Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# FASG 08: Fargeot P, Bonneterre J, Roché H, Lortholary A, Campone M, Van Praagh I, Monnier A, Namer M, Schraub S, Barats JC, Guastalla JP, Goudier MJ, Chapelle-Marcillac I. Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French Adjuvant Study Group 08 trial. J Clin Oncol. 2004 Dec 1;22(23):4622-30. Epub 2004 Oct 25. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Review: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. link to original article EuroPMC
# ABCSG-8: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG; GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00291759
## Update: Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. link to original article EuroPMC
# ARNO 95: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG; GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article EuroPMC
# INT-0102: Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article EuroPMC
# BIG 1-98: Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; BIG. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004205
## Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article EuroPMC
## Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG' International Breast Cancer Study Group. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article EuroPMC
## Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article EuroPMC
## Update: Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS; BIG. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76. link to original article link to PMC article EuroPMC
## Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG; International Breast Cancer Study Group. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. Epub 2011 Oct 20. link to original article link to PMC article EuroPMC
## Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; BIG; International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019 Jan 10;37(2):105-114. Epub 2018 Nov 26. link to original article link to PMC article EuroPMC
# FASG 02: Namer M, Fargeot P, Roché H, Campone M, Kerbrat P, Romestaing P, Monnier A, Luporsi E, Montcuquet P, Bonneterre J; French Adjuvant Study Group. Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol. 2006 Jan;17(1):65-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# FASG 07: Namer M, Fargeot P, Roché H, Campone M, Kerbrat P, Romestaing P, Monnier A, Luporsi E, Montcuquet P, Bonneterre J; French Adjuvant Study Group. Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol. 2006 Jan;17(1):65-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Morales L, Canney P, Dyczka J, Rutgers E, Coleman R, Cufer T, Welnicka-Jaskiewicz M, Nortier J, Bogaerts J, Therasse P, Paridaens R; EORTC Breast Group; Scottish Breast Cancer Trials Group. Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer: a randomised phase III trial of the European Organisation for Research and Treatment of Cancer Breast Group. Eur J Cancer. 2007 Jan;43(2):331-40. Epub 2006 Nov 28. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# DBCG 89C: Andersen J, Kamby C, Ejlertsen B, Cold S, Ewertz M, Jacobsen EH, Philip P, Møller KA, Jensen D, Møller S. Tamoxifen for one year versus two years versus 6 months of Tamoxifen and 6 months of megestrol acetate: a randomized comparison in postmenopausal patients with high-risk breast cancer (DBCG 89C). Acta Oncol. 2008;47(4):718-24. link to original article EuroPMC
# NSABP B-33: Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article does not contain dosing details in manuscript EuroPMC NCT00016432
# SWOG-8814: Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00929591
# N-SAS BC03: Aihara T, Takatsuka Y, Ohsumi S, Aogi K, Hozumi Y, Imoto S, Mukai H, Iwata H, Watanabe T, Shimizu C, Nakagami K, Tamura M, Ito T, Masuda N, Ogino N, Hisamatsu K, Mitsuyama S, Abe H, Tanaka S, Yamaguchi T, Ohashi Y. Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study. Breast Cancer Res Treat. 2010 Jun;121(2):379-87. link to original article dosing details in abstract have been reviewed by our editors EuroPMC UMIN C000000056
# ECOG EB193: Rao RD, Cobleigh MA, Gray R, Graham ML 2nd, Norton L, Martino S, Budd GT, Ingle JN, Wood WC. Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group. Med Oncol. 2011 Dec;28 Suppl 1:S39-47. Epub 2010 Sep 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002646
# TEAM: van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00279448; NCT00032136; NCT00036270
## Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article EuroPMC
# NCIC-CTG MA.14: Pritchard KI, Shepherd LE, Chapman JA, Norris BD, Cantin J, Goss PE, Dent SF, Walde D, Vandenberg TA, Findlay B, O'Reilly SE, Wilson CF, Han L, Piura E, Whelan TJ, Pollak MN. Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC-CTG MA.14. J Clin Oncol. 2011 Oct 10;29(29):3869-76. Epub 2011 Sep 12. link to original article EuroPMC NCT00002864
## Update: Chapman JA, Costantino JP, Dong B, Margolese RG, Pritchard KI, Shepherd LE, Gelmon KA, Wolmark N, Pollak MN. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC-CTG MA.14 and NSABP B-29. Breast Cancer Res Treat. 2015 Sep;153(2):353-60. Epub 2015 Aug 15. link to original article link to PMC article EuroPMC
# Kimura M, Tominaga T, Kimijima I, Takatsuka Y, Takashima S, Nomura Y, Kasumi F, Yamaguchi A, Masuda N, Noguchi S, Eshima N. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer. Breast Cancer. 2014 May;21(3):275-83. Epub 2012 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ATLAS: Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805-16. Erratum in: Lancet. 2013 Mar 9;381(9869):804. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00003016
# JCOG9401: Shien T, Iwata H, Aogi K, Fukutomi T, Inoue K, Kinoshita T, Takahashi M, Matsui A, Shibata T, Fukuda H. Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: results of a Japan Clinical Oncology Group Study (JCOG9401). Int J Clin Oncol. 2014 Dec;19(6):982-8. Epub 2014 Jan 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# CBC 02: Jensen MB, Krarup JF, Palshof T, Mouridsen HT, Ejlertsen B. Two years of tamoxifen or no adjuvant systemic therapy for patients with high-risk breast cancer: long-term follow-up of the Copenhagen Breast Cancer Trial. Acta Oncol. 2018 Jan;57(1):26-30. Epub 2017 Nov 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT00310180
# PALLAS: Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, Miller KD, Zdenkowski N, Winer EP, Pfeiler G, Goetz M, Ruiz-Borrego M, Anderson D, Nowecki Z, Loibl S, Moulder S, Ring A, Fitzal F, Traina T, Chan A, Rugo HS, Lemieux J, Henao F, Lyss A, Antolin Novoa S, Wolff AC, Vetter M, Egle D, Morris PG, Mamounas EP, Gil-Gil MJ, Prat A, Fohler H, Metzger Filho O, Schwarz M, DuFrane C, Fumagalli D, Theall KP, Lu DR, Bartlett CH, Koehler M, Fesl C, DeMichele A, Gnant M. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Feb;22(2):212-222. Epub 2021 Jan 15. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT02513394
##Update: Gnant M, Dueck AC, Frantal S, Martin M, Burstein HJ, Greil R, Fox P, Wolff AC, Chan A, Winer EP, Pfeiler G, Miller KD, Colleoni M, Suga JM, Rubovsky G, Bliss JM, Mayer IA, Singer CF, Nowecki Z, Hahn O, Thomson J, Wolmark N, Amillano K, Rugo HS, Steger GG, Hernando Fernández de Aránguiz B, Haddad TC, Perelló A, Bellet M, Fohler H, Metzger Filho O, Jallitsch-Halper A, Solomon K, Schurmans C, Theall KP, Lu DR, Tenner K, Fesl C, DeMichele A, Mayer EL; PALLAS groups and investigators. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022 Jan 20;40(3):282-293. Epub 2021 Dec 7. link to original article link to PMC article EuroPMC
# RxPONDER: Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, Lin NU, Perez EA, Goldstein LJ, Chia SKL, Dhesy-Thind S, Rastogi P, Alba E, Delaloge S, Martin M, Kelly CM, Ruiz-Borrego M, Gil-Gil M, Arce-Salinas CH, Brain EGC, Lee ES, Pierga JY, Bermejo B, Ramos-Vazquez M, Jung KH, Ferrero JM, Schott AF, Shak S, Sharma P, Lew DL, Miao J, Tripathy D, Pusztai L, Hortobagyi GN. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021 Dec 16;385(25):2336-2347. Epub 2021 Dec 1. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01272037
#UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article does not contain dosing details in manuscript EuroPMC NCT01805271
# SWOG S1207: Chavez-MacGregor M, Miao J, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Razaq W, O'Dea A, Kaklamani V, Silber ALM, Flaum LE, Andreopoulou E, Wendt AG, Carney JF, Sharma P, Gralow JR, Lew DL, Barlow WE, Hortobagyi GN. Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer. J Clin Oncol. 2024 Sep 1;42(25):3012-3021. Epub 2024 Jun 4. link to original article does not contain dosing details in manuscript EuroPMC NCT01674140
==Tamoxifen-Anastrozole==
===Regimen variant #1, 20 mg/d tamoxifen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jakesz et al. 2005 (ABCSG-8) 	1996-2003 	Phase 3 (E-switch-ic)	Tamoxifen 	Longer EFS (primary endpoint)EFS36: 95.8% vs 92.7%(HR 0.60, 95% CI 0.44-0.81)
Jakesz et al. 2005 (ARNO 95) 	1996-2003 	Phase 3 (E-switch-ic)	Tamoxifen 	Seems to have longer OS1 (secondary endpoint)OS60: 96% vs 88%(HR 0.53, 95% CI 0.28-0.99)Longer EFS (primary endpoint)
De Placido et al. 2018 (FATA-GIM3)	2007-2012 	Phase 3 (C) 	1. Anastrozole2. Exemestane3. Letrozole4. Tamoxifen-Exemestane; 2y + 3y5. Tamoxifen-Letrozole; 2y + 3y	Did not meet primary endpoint of DFS
1Reported efficacy for ARNO 95 is based on the 2007 update; OS60 is estimated from the KM curve in Figure 2B.
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 26: 20 mg PO once per day
*Anastrozole (Arimidex) as follows:
**Cycles 27 to 65: 1 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #2, 30 mg/d tamoxifen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jakesz et al. 2005 (ARNO 95)	1996-2003 	Phase 3 (E-switch-ic)	Tamoxifen 	Seems to have longer OS1 (secondary endpoint)OS60: 96% vs 88%(HR 0.53, 95% CI 0.28-0.99)Longer EFS (primary endpoint)
1Reported efficacy for ARNO 95 is based on the 2007 update; OS60 is estimated from the KM curve in Figure 2B.
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 26: 30 mg PO once per day
*Anastrozole (Arimidex) as follows:
**Cycles 27 to 65: 1 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# ABCSG-8: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG; GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00291759
## Update: Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. link to original article EuroPMC
# ARNO 95: Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG; GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article EuroPMC
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
==Tamoxifen-Exemestane==
===Regimen variant #1, 2y + 3y===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Coombes et al. 2004 (IES) 	1998-2003 	Phase 3 (E-switch-ic)	Tamoxifen x 5 y 	Longer DFS (primary endpoint)DFS36: 91.5% vs 86.8%(HR 0.68, 95% CI 0.56-0.82)Seems to have longer OS1 (secondary endpoint)(HR 0.86, 95% CI 0.75-0.99)
De Placido et al. 2018 (FATA-GIM3)	2007-2012 	Phase 3 (C) 	1. Anastrozole2. Exemestane3. Letrozole4. Tamoxifen-Anastrozole; 2y + 3y5. Tamoxifen-Letrozole; 2y + 3y	Did not meet primary endpoint of DFS
1Reported efficacy for IES is based on the 2011 update.
Note: this is the lower bound of tamoxifen treatment duration for IES.
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 26: 20 mg PO once per day
*Exemestane (Aromasin) as follows:
**Cycles 27 to 65: 25 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #2, 2.5y + 2.5y===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
van de Velde et al. 2011 (TEAM)	2001-2006 	Phase 3 (E-switch-ic)	Tamoxifen x 5y	Did not meet primary endpoint of DFS60
Note: this is the lower bound of tamoxifen treatment duration for TEAM.
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 32: 20 mg PO once per day
*Exemestane (Aromasin) as follows:
**Cycles 33 to 65: 25 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #3, 3y + 2y===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Coombes et al. 2004 (IES) 	1998-2003 	Phase 3 (E-switch-ic)	Tamoxifen x 5 y	Longer DFS (primary endpoint)DFS36: 91.5% vs 86.8%(HR 0.68, 95% CI 0.56-0.82)Seems to have longer OS1 (secondary endpoint)(HR 0.86, 95% CI 0.75-0.99)
van de Velde et al. 2011 (TEAM)	2001-2006 	Phase 3 (E-switch-ic)	Tamoxifen x 5y 	Did not meet primary endpoint of DFS60
1Reported efficacy for IES is based on the 2011 update.
Note: this is the upper bound of tamoxifen treatment duration for IES & TEAM.
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 39: 20 mg PO once per day
*Exemestane (Aromasin) as follows:
**Cycles 40 to 65: 25 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# IES: Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00038467
## Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article EuroPMC
## Update: Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, van de Velde CJ, Lønning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. J Clin Oncol. 2012 Mar 1;30(7):709-17. Epub 2011 Oct 31. link to original article EuroPMC
# TEAM: van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00279448; NCT00032136; NCT00036270
## Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article EuroPMC
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
==Tamoxifen-Letrozole==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	1. Letrozole, then Tamoxifen; 2y + 3y 	Did not meet primary endpoint of DFS1
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	2. Tamoxifen x 5y 	Not reported
Thürlimann et al. 2005 (BIG 1-98) 	1998-2003 	Phase 3 (E-RT-switch-ic)	3. Letrozole x 5y 	Did not meet primary endpoint of DFS1
De Placido et al. 2018 (FATA-GIM3)	2007-2012 	Phase 3 (C) 	1. Anastrozole2. Exemestane3. Letrozole4. Tamoxifen-Anastrozole; 2y + 3y5. Tamoxifen-Exemestane; 2y + 3y	Did not meet primary endpoint of DFS
====Endocrine therapy====
*Tamoxifen (Nolvadex) as follows:
**Cycles 1 to 26: 20 mg PO once per day
*Letrozole (Femara) as follows:
**Cycles 27 to 65: 2.5 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# BIG 1-98: Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; BIG. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004205
## Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article EuroPMC
## Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG; International Breast Cancer Study Group. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article EuroPMC
## Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article EuroPMC
## Update: Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS; BIG. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76. link to original article link to PMC article EuroPMC
## Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG; International Breast Cancer Study Group. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. Epub 2011 Oct 20. link to original article link to PMC article EuroPMC
## Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; BIG; International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019 Jan 10;37(2):105-114. Epub 2018 Nov 26. link to original article link to PMC article EuroPMC
# FATA-GIM3: De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00541086
==Toremifene monotherapy==
===Regimen variant #1, 40 mg/day x 2y===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kimura et al. 2012	1998-2001 	Phase 3 (E-switch-ic)	Tamoxifen 	Non-inferior OS60 (primary endpoint)OS60: 97% vs 96.9%
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Toremifene (Fareston) 40 mg PO once per day
28-day cycle for 26 cycles (2 years)
===Regimen variant #2, 40 mg/day x 5y===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Toi et al. 2021	2012-2016 	Phase 3 (C)	S-1 & Toremifene	Shorter IDFS (primary endpoint)IDFS60: 82% vs 87%(HR 1.59, 95% CI 1.23-2.04)
Note: this is the lower bound of a range specified by Toi et al. 2021.
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Toremifene (Fareston) 40 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #3, 60 mg/day x 5y===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Pagani et al. 2004 (IBCSG 12-93)	1993-1999 	Phase 3 (E-switch-ic)	Tamoxifen 	Non-inferior DFS1DFS60: 72% vs 69%(RR 0.95, 95% CI 0.76-1.18)
Pagani et al. 2004 (IBCSG 14-93)	1993-1999 	Phase 3 (E-switch-ic)	Tamoxifen 	Non-inferior DFS1DFS60: 72% vs 69%(RR 0.95, 95% CI 0.76-1.18)
1It is not clear from the manuscript whether these trials had a non-inferiority design, but it appears to be the case. The results are from pooled analysis.
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Toremifene (Fareston) 40 mg PO once per day
28-day cycle for 65 cycles (5 years)
===Regimen variant #4, 120 mg/day x 5y===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Toi et al. 2021	2012-2016 	Phase 3 (C)	S-1 & Toremifene	Shorter IDFS (primary endpoint)IDFS60: 82% vs 87%(HR 1.59, 95% CI 1.23-2.04)
Note: this is the upper bound of a range specified by Toi et al. 2021.
====Preceding treatment====
*Surgery
====Endocrine therapy====
*Toremifene (Fareston) 120 mg PO once per day
28-day cycle for 65 cycles (5 years)
===References===
# IBCSG 12-93: Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002529
# IBCSG 14-93: Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Kimura M, Tominaga T, Kimijima I, Takatsuka Y, Takashima S, Nomura Y, Kasumi F, Yamaguchi A, Masuda N, Noguchi S, Eshima N. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer. Breast Cancer. 2014 May;21(3):275-83. Epub 2012 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Toi M, Imoto S, Ishida T, Ito Y, Iwata H, Masuda N, Mukai H, Saji S, Shimizu A, Ikeda T, Haga H, Saeki T, Aogi K, Sugie T, Ueno T, Kinoshita T, Kai Y, Kitada M, Sato Y, Jimbo K, Sato N, Ishiguro H, Takada M, Ohashi Y, Ohno S. Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):74-84. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000003969
=Metastatic disease, first-line therapy, premenopausal=
==Anastrozole & Goserelin==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (C)	1a. Anastrozole, Goserelin, Ribociclib1b. Goserelin, Letrozole, Ribociclib1c. Goserelin, Ribociclib, Tamoxifen	Shorter PFSMedian PFS: 13 vs 23.8 mo(HR 1.82, 95% CI 1.45-2.27)Seems to have shorter OS1Median OS: 48 vs 58.7 mo(HR 1.32, 95% CI 1.04-1.64)
1Reported efficacy is based on the 2022 update.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg SC once on day 1
28-day cycles
===References===
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Anastrozole, Goserelin, Ribociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (E-RT-esc)	1a. Anastrozole & Goserelin1b. Goserelin & Letrozole1c. Goserelin & Tamoxifen	Longer PFS (primary endpoint)Median PFS: 23.8 vs 13 mo(HR 0.55, 95% CI 0.44-0.69)Seems to have longer OS1 (secondary endpoint)Median OS: 58.7 vs 48 mo(HR 0.76, 95% CI 0.61-0.96)
1Reported efficacy for OS is based on the 2022 update.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Goserelin (Zoladex) 3.6 mg SC once on day 1
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
===References===
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Goserelin & Letrozole==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (C)	1a. Anastrozole, Goserelin, Ribociclib1b. Goserelin, Letrozole, Ribociclib1c. Goserelin, Ribociclib, Tamoxifen	Shorter PFSMedian PFS: 13 vs 23.8 mo(HR 1.82, 95% CI 1.45-2.27)Seems to have shorter OS1Median OS: 48 vs 58.7 mo(HR 1.32, 95% CI 1.04-1.64)
1Reported efficacy is based on the 2022 update.
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
===References===
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Goserelin, Letrozole, Ribociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (E-RT-esc)	1a. Anastrozole & Goserelin1b. Goserelin & Letrozole1c. Goserelin & Tamoxifen	Longer PFS (primary endpoint)Median PFS: 23.8 vs 13 mo(HR 0.55, 95% CI 0.44-0.69)Seems to have longer OS1 (secondary endpoint)Median OS: 58.7 vs 48 mo(HR 0.76, 95% CI 0.61-0.96)
1Reported efficacy for OS is based on the 2022 update.
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
===References===
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Goserelin, Ribociclib, Tamoxifen==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (E-RT-esc)	1a. Anastrozole & Goserelin1b. Goserelin & Letrozole1c. Goserelin & Tamoxifen	Longer PFS (primary endpoint)Median PFS: 23.8 vs 13 mo(HR 0.55, 95% CI 0.44-0.69)Seems to have longer OS1 (secondary endpoint)Median OS: 58.7 vs 48 mo(HR 0.76, 95% CI 0.61-0.96)
1Reported efficacy for OS is based on the 2022 update.
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
===References===
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Goserelin & Tamoxifen==
===Regimen variant #1, monthly goserelin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Noguchi et al. 2015 	Not reported 	Phase 3 (C)	Goserelin & Tamoxifen; q3mo 	Non-inferior PFS24wk (primary endpoint)PFS24wk: 60.2% vs 61.5%
Tripathy et al. 2018 (MONALEESA-7)	2014-2016 	Phase 3 (C)	1a. Anastrozole, Goserelin, Ribociclib1b. Goserelin, Letrozole, Ribociclib1c. Goserelin, Ribociclib, Tamoxifen	Shorter PFSMedian PFS: 13 vs 23.8 mo(HR 1.82, 95% CI 1.45-2.27)Seems to have shorter OS1Median OS: 48 vs 58.7 mo(HR 1.32, 95% CI 1.04-1.64)
1Reported efficacy for MONALEESA-7 is based on the 2022 update.
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
28-day cycles
===Regimen variant #2, q3mo goserelin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Noguchi et al. 2015	Not reported 	Phase 3 (E-switch-ic)	Goserelin & Tamoxifen; monthly	Non-inferior PFS24wk (primary endpoint)PFS24wk: 61.5% vs 60.2%
====Endocrine therapy====
*Goserelin (Zoladex) 10.8 mg SC once on day 1
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 84
12-week cycles
===References===
#Noguchi S, Kim HJ, Jesena A, Parmar V, Sato N, Wang HC, Lokejaroenlarb S, Isidro J, Kim KS, Itoh Y, Shin E. Phase 3, open-label, randomized study comparing 3-monthly with monthly goserelin in pre-menopausal women with estrogen receptor-positive advanced breast cancer. Breast Cancer. 2016 Sep;23(5):771-9. Epub 2015 Sep 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01073865
# MONALEESA-7: Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. Epub 2018 May 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02278120
##Update: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article EuroPMC
##HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article EuroPMC
##Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article EuroPMC
==Tamoxifen monotherapy==
===Regimen variant #1, 20 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ingle et al. 1986a	1978-1984 	Phase 3 (E-RT-switch-ic)	Bilateral oophorectomy	Did not meet endpoints
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
**Some earlier trials used 10 mg PO twice per day instead
Continued indefinitely
===Regimen variant #2, 40 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Buchanan et al. 1986	1979-1983 	Phase 3 (E-RT-switch-ic) 	Bilateral oophorectomy	Might have longer PFS
Crump et al. 1997 	Not reported 	Randomized (E-RT-switch-ic)	Bilateral oophorectomy	Did not meet pooled endpoint of ORR
Note: while Crump et al. 1997 is a meta-analysis, it is also the primary report for a randomized trial used to support registration of this drug.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 40 mg PO once per day
**Some earlier trials used 20 mg PO twice per day instead
Continued indefinitely
===References===
# Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK, Ahmann DL, Chang MN, Bisel HF, Windschitl HE, Twito DI, Pfeifle DM. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 1986 Feb;4(2):178-85. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Buchanan RB, Blamey RW, Durrant KR, Howell A, Paterson AG, Preece PE, Smith DC, Williams CJ, Wilson RG. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol. 1986 Sep;4(9):1326-30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, Meakin JW, Shelley W, Pritchard KI. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997 Jul;44(3):201-10. link to original article EuroPMC
=Metastatic disease, first-line therapy=
==Abemaciclib & Anastrozole==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Goetz et al. 2017 (MONARCH 3)	2014-11-18 to 2015-11-11	Phase 3 (E-RT-esc)	1a. Anastrozole1b. Letrozole	Longer PFS1 (primary endpoint)Median PFS: 28.2 vs 14.8 mo(HR 0.54, 95% CI 0.42-0.70)Might have longer OS2 (secondary endpoint)Median OS: 66.8 vs 53.7 mo(HR 0.80, 95% CI 0.64-1.015)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
1Reported efficacy is based on the 2019 update.
2Reported efficacy is based on the 2024 update.
====Targeted therapy====
*Abemaciclib (Verzenio) 150 mg PO twice per day on days 1 to 28
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
# MONARCH 3: Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02246621
##Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article EuroPMC
##HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article EuroPMC
##Update: Goetz MP, Toi M, Huober J, Sohn J, Trédan O, Park IH, Campone M, Chen SC, Manso LM, Paluch-Shimon S, Freedman OC, O'Shaughnessy J, Pivot X, Tolaney SM, Hurvitz SA, Llombart-Cussac A, André V, Saha A, van Hal G, Shahir A, Iwata H, Johnston SRD. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024 Aug;35(8):718-727. Epub 2024 May 8. link to original article EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Abemaciclib & Letrozole==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Goetz et al. 2017 (MONARCH 3)	2014-11-18 to 2015-11-11	Phase 3 (E-RT-esc)	1a. Anastrozole1b. Letrozole	Longer PFS1 (primary endpoint)Median PFS: 28.2 vs 14.8 mo(HR 0.54, 95% CI 0.42-0.70)Might have longer OS2 (secondary endpoint)Median OS: 66.8 vs 53.7 mo(HR 0.80, 95% CI 0.64-1.015)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
1Reported efficacy is based on the 2019 update.
2Reported efficacy is based on the 2024 update.
====Targeted therapy====
*Abemaciclib (Verzenio) 150 mg PO twice per day on days 1 to 28
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
# MONARCH 3: Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02246621
##Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article EuroPMC
##HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article EuroPMC
##Update: Goetz MP, Toi M, Huober J, Sohn J, Trédan O, Park IH, Campone M, Chen SC, Manso LM, Paluch-Shimon S, Freedman OC, O'Shaughnessy J, Pivot X, Tolaney SM, Hurvitz SA, Llombart-Cussac A, André V, Saha A, van Hal G, Shahir A, Iwata H, Johnston SRD. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024 Aug;35(8):718-727. Epub 2024 May 8. link to original article EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Anastrozole monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bonneterre et al. 2000 (TARGETBreast) 	1995-1998 	Phase 3 (E-RT-switch-ic)	Tamoxifen 	Equivalent TTP (co-primary endpoint)Median TTP: 8.2 vs 8.3 mo(HR 0.99, 95% CI 0.86)
Nabholtz et al. 2000 (Arimidex Study Group 2000)	1996-1998 	Phase 3 (E-RT-switch-ic)	Tamoxifen 	Equivalent TTP (co-primary endpoint)Median TTP: 11.1 vs 5.6 mo(HR 0.69, 95% CI 0.86)
Milla-Santos et al. 2003 	1997-1999 	Phase 3 (E-switch-ic) 	Tamoxifen 	Longer OS (co-primary endpoint)Median OS: 17.4 vs 16 mo(HR 0.64, 95% CI 0.47-0.86)
Bergh et al. 2012 (FACT) 	2004-2008 	Phase 3 (C) 	Anastrozole & Fulvestrant 	Did not meet primary endpoint of TTPMedian TTP: 10.2 vs 10.8 mo(HR 1.01, 95% CI 0.83-1.23)
Mehta et al. 2012 (SWOG S0226) 	2004-2009 	Phase 3 (C) 	Anastrozole & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS: 13.5 vs 15 mo(HR 1.25, 95% CI 1.06-1.47)Seems to have shorter OS (secondary endpoint)Median OS: 41.3 vs 47.7 mo(HR 1.23, 95% CI 1.00-1.54)
Iwata et al. 2013 (A5991048) 	2005-2010 	Phase 3 (E-switch-ic) 	Exemestane 	Inconclusive whether non-inferior TTP
Robertson et al. 2016 (FALCON) 	2012-10-17 to 2014-07-11	Phase 3 (C) 	Fulvestrant 	Seems to have shorter PFSMedian PFS: 13.8 vs 16.6 mo(HR 1.25, 95% CI 1.00-1.56)
Goetz et al. 2017 (MONARCH 3) 	2014-11-18 to 2015-11-11	Phase 3 (C) 	1a. Abemaciclib & Anastrozole1b. Abemaciclib & Letrozole 	Shorter PFS1Median PFS: 14.8 vs 28.2 mo(HR 1.85, 95% CI 1.43-2.38)Might have shorter OS2Median OS: 53.7 vs 66.8 mo(HR 1.25, 95% CI 0.99-1.56)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Abemaciclib & Anastrozole1b. Abemaciclib & Letrozole1c. Anastrozole & Palbociclib1d. Anastrozole & Ribociclib1e. Letrozole & Palbociclib1f. Letrozole & Ribociclib	Might have shorter PFS-2 (primary endpoint)Median PFS-2: 26.8 vs 31 mo(sHR 1.15, 95% CI 0.97-1.35)
Zhang et al. 2023 (DAWNA-2) 	2019-07-19 to 2020-12-25	Phase 3 (C) 	1a. Anastrozole & Dalpiciclib1b. Dalpiciclib & Letrozole 	Shorter PFS (primary endpoint)Median PFS: 18.2 vs 30.6 mo(sHR 1.96, 95% CI 1.45-2.78)
1Reported PFS efficacy for MONARCH 3 is based on the 2019 update.
2Reported OS efficacy for MONARCH 3 is based on the 2024 update.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Abemaciclib & Fulvestrant or Fulvestrant & Palbociclib or Fulvestrant & Ribociclib
===References===
# TARGETBreast: Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000 Nov 15;18(22):3748-57. Erratum in: J Clin Oncol. 2012 Jan 20;30(3):343. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Arimidex Study Group 2000: Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M; Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol. 2000 Nov 15;18(22):3758-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, Casanovas J, Puig-Gali M. Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer: a prospective, randomized, phase III study. Am J Clin Oncol. 2003 Jun;26(3):317-22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# FACT: Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-25. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00256698
# SWOG S0226: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00075764
## Update: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234. Erratum in: N Engl J Med. 2019 Jun 6;380(23):2282. link to original article link to PMC article EuroPMC
# A5991048: Iwata H, Masuda N, Ohno S, Rai Y, Sato Y, Ohsumi S, Hashigaki S, Nishizawa Y, Hiraoka M, Morimoto T, Sasano H, Saeki T, Noguchi S. A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer. Breast Cancer Res Treat. 2013 Jun;139(2):441-51. Epub 2013 May 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00143390
# FALCON: Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005. Epub 2016 Nov 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01602380
##HRQoL analysis: Robertson JFR, Cheung KL, Noguchi S, Shao Z, Degboe A, Lichfield J, Thirlwell J, Fazal M, Ellis MJ. Health-related quality of life from the FALCON phase III randomised trial of fulvestrant 500 mg versus anastrozole for hormone receptor-positive advanced breast cancer. Eur J Cancer. 2018 May;94:206-215. link to original article link to EuroPMC
# MONARCH-3: Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02246621
#DAWNA-2: Zhang P, Zhang Q, Tong Z, Sun T, Li W, Ouyang Q, Hu X, Cheng Y, Yan M, Pan Y, Teng Y, Yan X, Wang Y, Xie W, Zeng X, Wang X, Hu C, Geng C, Zhang H, Li W, Wu X, Zhong J, Xu J, Shi Y, Wei W, Bayaxi N, Zhu X, Xu B. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Jun;24(6):646-657. Epub 2023 May 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03966898
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Anastrozole & Fulvestrant==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bergh et al. 2012 (FACT) 	2004-2008 	Phase 3 (E-esc)	Anastrozole	Did not meet primary endpoint of TTPMedian TTP: 10.8 vs 10.2 mo(HR 0.99, 95% CI 0.81-1.20)
Mehta et al. 2012 (SWOG S0226)	2004-2009 	Phase 3 (E-esc)	Anastrozole	Longer PFS (primary endpoint)Median PFS: 15 vs 13.5 mo(HR 0.80, 95% CI 0.68-0.94)Seems to have longer OS (secondary endpoint)Median OS: 47.7 vs 41.3 mo(HR 0.81, 95% CI 0.65-1.00)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once on day 1, then 250 mg IM once on day 15
**Cycle 2 onwards: 250 mg IM once on day 1
28-day cycles
====Dose and schedule modifications====
*Patients in SWOG S0226 who progressed while on therapy were allowed to receive a higher dose of fulvestrant, 500 mg IM once on day 1
===References===
# FACT: Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-25. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00256698
# SWOG S0226: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00075764
## Update: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234. Erratum in: N Engl J Med. 2019 Jun 6;380(23):2282. link to original article link to PMC article EuroPMC
==Anastrozole & Palbociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sonke et al. 2024 (SONIA)	2017-11-23 to 2021-09-01	Phase 3 (C)	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Anastrozole & Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sonke et al. 2024 (SONIA)	2017-11-23 to 2021-09-01	Phase 3 (C)	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Exemestane monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Paridaens et al. 2008 (EORTC 10951)	1996-2002 	Phase 3 (E-switch-ic)	Tamoxifen 	Did not meet primary endpoint of PFS
Falandry et al. 2008 (CELAROM) 	2003-09 to 2004-12 	Phase 3 (C) 	Celecoxib & Exemestane	Did not meet primary endpoint of PFSMedian PFS: 9.8 vs 9.8 mo
Iwata et al. 2013 (A5991048) 	2005-2010 	Phase 3 (E-switch-ic)	Anastrozole 	Inconclusive whether non-inferior TTP
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
Continued indefinitely
===References===
# EORTC 10951: Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P; European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008 Oct 20;26(30):4883-90. Epub 2008 Sep 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002777
# CELAROM: Falandry C, Debled M, Bachelot T, Delozier T, Crétin J, Romestaing P, Mille D, You B, Mauriac L, Pujade-Lauraine E, Freyer G. Celecoxib and exemestane versus placebo and exemestane in postmenopausal metastatic breast cancer patients: a double-blind phase III GINECO study. Breast Cancer Res Treat. 2009 Aug;116(3):501-8. Epub 2008 Nov 20. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00525096
# A5991048: Iwata H, Masuda N, Ohno S, Rai Y, Sato Y, Ohsumi S, Hashigaki S, Nishizawa Y, Hiraoka M, Morimoto T, Sasano H, Saeki T, Noguchi S. A randomized, double-blind, controlled study of exemestane versus anastrozole for the first-line treatment of postmenopausal Japanese women with hormone-receptor-positive advanced breast cancer. Breast Cancer Res Treat. 2013 Jun;139(2):441-51. Epub 2013 May 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00143390
==Fulvestrant monotherapy==
===Regimen variant #1, 250 mg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Howell et al. 2004 	1998-2000 	Phase 3 (E-switch-ic)	Tamoxifen 	Might have shorter TTP (primary endpoint)Median TTP: 6.8 vs 8.3 mo(HR 1.18, 95% CI 0.98-1.44)
Martín et al. 2015 (LEA)	2007-2011 	Phase 3 (C) 	1a. Fulvestrant & Bevacizumab1b. Letrozole & Bevacizumab	Did not meet primary endpoint of PFSMedian PFS: 14.4 vs 19.3 mo(HR 1.20, 95% CI 0.94-1.54)
====Endocrine therapy====
*Fulvestrant (Faslodex) 250 mg IM once on day 1
28-day cycles
===Regimen variant #2, 500 mg===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Robertson et al. 2016 (FALCON) 	2012-10-17 to 2014-07-11	Phase 3 (E-RT-switch-ic)	Anastrozole 	Seems to have longer PFS (primary endpoint)Median PFS: 16.6 vs 13.8 mo(HR 0.80, 95% CI 0.64-0.999)
Slamon et al. 2018 (MONALEESA-3)	2015-06 to 2016-06 	Phase 3 (C) 	Fulvestrant & Ribociclib	Shorter PFS (primary endpoint)Median PFS: 12.8 vs 20.5 mo(HR 1.69, 95% CI 1.37-2.08)Shorter OS1 (secondary endpoint)Median OS: 41.5 vs 53.7 mo(HR 1.37, 95% CI 1.11-1.69)
1Reported efficacy for MONALEESA-3 is based on the 2021 update.
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
28-day cycles
===References===
# Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# LEA: Martín M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Muñoz M, Garcia-Saenz JÁ, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, de la Haba-Rodríguez J. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. 2015 Mar 20;33(9):1045-52. Epub 2015 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00545077
# FALCON: Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005. Epub 2016 Nov 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01602380
##HRQoL analysis: Robertson JFR, Cheung KL, Noguchi S, Shao Z, Degboe A, Lichfield J, Thirlwell J, Fazal M, Ellis MJ. Health-related quality of life from the FALCON phase III randomised trial of fulvestrant 500 mg versus anastrozole for hormone receptor-positive advanced breast cancer. Eur J Cancer. 2018 May;94:206-215. link to original article link to EuroPMC
# MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02422615
## Update: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. Epub 2019 Dec 11. link to original article EuroPMC
##HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article EuroPMC
## Update: Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, Petrakova K, Valeria Bianchi G, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Ji Y, Wang C, Deore U, Chakravartty A, Zarate JP, Taran T, Fasching PA. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021 Aug;32(8):1015-1024. Epub 2021 Jun 5. Erratum in: Ann Oncol. 2021 Oct;32(10):1307. link to original article EuroPMC
==Fulvestrant & Ribociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3)	2015-06 to 2016-06 	Phase 3 (E-RT-esc)	Fulvestrant	Longer PFS (primary endpoint)Median PFS: 20.5 vs 12.8 mo(HR 0.59, 95% CI 0.48-0.73)Longer OS1 (secondary endpoint)Median OS: 53.7 vs 41.5 mo(HR 0.73, 95% CI 0.59-0.90)
1Reported efficacy is based on the 2021 update.
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
===References===
# MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02422615
## Update: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. Epub 2019 Dec 11. link to original article EuroPMC
##HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article EuroPMC
## Update: Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, Petrakova K, Valeria Bianchi G, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Ji Y, Wang C, Deore U, Chakravartty A, Zarate JP, Taran T, Fasching PA. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021 Aug;32(8):1015-1024. Epub 2021 Jun 5. Erratum in: Ann Oncol. 2021 Oct;32(10):1307. link to original article EuroPMC
==Goserelin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jonat et al. 1995	1988-1991 	Phase 3 (C)	Goserelin & Tamoxifen	Seems to have shorter TTP
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
28-day cycles
===References===
# Jonat W, Kaufmann M, Blamey RW, Howell A, Collins JP, Coates A, Eiermann W, Jänicke F, Njordenskold B, Forbes JF, Kolvenbag GJCM. A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer. 1995;31A(2):137-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Goserelin & Tamoxifen==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jonat et al. 1995	1988-1991 	Phase 3 (E-esc)	Goserelin 	Seems to have longer TTP
====Endocrine therapy====
*Goserelin (Zoladex) 3.6 mg SC once on day 1
*Tamoxifen (Nolvadex) 20 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# Jonat W, Kaufmann M, Blamey RW, Howell A, Collins JP, Coates A, Eiermann W, Jänicke F, Njordenskold B, Forbes JF, Kolvenbag GJCM. A randomised study to compare the effect of the luteinising hormone releasing hormone (LHRH) analogue goserelin with or without tamoxifen in pre- and perimenopausal patients with advanced breast cancer. Eur J Cancer. 1995;31A(2):137-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Letrozole monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Mouridsen et al. 2001 (ILBCG) 	1996-1999 	Phase 3 (E-RT-switch-ic)	Tamoxifen 	Longer TTP (primary endpoint)Median TTP: 41 vs 26 weeks(HR 0.70, 95% CI 0.60-0.82)
Goss et al. 2007 (Biomed 777-CLP-29)	2002-2005 	Phase 3 (C) 	Atamestane & Toremifene 	Did not meet primary endpoint of TTP
Wolff et al. 2012 (HORIZONBRCA) 	2004-2006 	Phase 3 (C) 	Letrozole & Temsirolimus 	Did not meet primary endpoint of PFSMedian PFS: 8.9 vs 9 mo(HR 1.11, 95% CI 0.93-1.32)
Martín et al. 2015 (LEA) 	2007-2011 	Phase 3 (C) 	1a. Fulvestrant & Bevacizumab1b. Letrozole & Bevacizumab 	Did not meet primary endpoint of PFSMedian PFS: 14.4 vs 19.3 mo(HR 1.20, 95% CI 0.94-1.54)
Dickler et al. 2016 (CALGB 40503) 	2008-2011 	Phase 3 (C) 	Letrozole & Bevacizumab 	Seems to have shorter PFSMedian PFS: 15.6 vs 20.2 mo(HR 1.33, 95% CI 1.04-1.69)
Finn et al. 2014 (PALOMA-1/TRIO-18) 	2009-2012 	Randomized Phase 2 (C) 	Letrozole & Palbociclib 	Shorter PFSMedian PFS: 10.2 vs 20.2 mo(HR 2.04, 95% CI 1.33-3.12)
Finn et al. 2016 (PALOMA-2) 	2013-02 to 2014-07 	Phase 3 (C) 	Letrozole & Palbociclib 	Shorter PFS (primary endpoint)Median PFS: 14.5 vs 24.8 mo(HR 1.72, 95% CI 1.39-2.17)Did not meet secondary endpoint of OS1Median OS: 51.2 vs 53.9 mo(HR 1.04, 95% CI 0.85-1.28)
Hortobagyi et al. 2016 (MONALEESA-2)	2014-01-24 to 2015-03-24	Phase 3 (C) 	Letrozole & Ribociclib 	Shorter PFS1 (primary endpoint)Median PFS: 16 vs 25.3 mo(HR 1.75, 95% CI 1.43-2.17)Shorter OS2 (secondary endpoint)Median OS: 51.4 vs 63.9 mo(HR 1.32, 95% CI 1.08-1.59)
Goetz et al. 2017 (MONARCH 3) 	2014-11-18 to 2015-11-11	Phase 3 (C) 	1a. Abemaciclib & Anastrozole1b. Abemaciclib & Letrozole 	Shorter PFS3Median PFS: 14.8 vs 28.2 mo(HR 1.85, 95% CI 1.43-2.38)Might have shorter OS4Median OS: 53.7 vs 66.8 mo(HR 1.25, 95% CI 0.99-1.56)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Abemaciclib & Anastrozole1b. Abemaciclib & Letrozole1c. Anastrozole & Palbociclib1d. Anastrozole & Ribociclib1e. Letrozole & Palbociclib1f. Letrozole & Ribociclib	Might have shorter PFS-2 (primary endpoint)Median PFS-2: 26.8 vs 31 mo(sHR 1.15, 95% CI 0.97-1.35)
Zhang et al. 2023 (DAWNA-2) 	2019-07-19 to 2020-12-25	Phase 3 (C) 	1a. Anastrozole & Dalpiciclib1b. Dalpiciclib & Letrozole 	Shorter PFS (primary endpoint)Median PFS: 18.2 vs 30.6 mo(sHR 1.96, 95% CI 1.45-2.78)
1Reported efficacy for MONALEESA-2 is based on the 2018 update.
2Reported efficacy for MONALEESA-2 is based on the 2022 update.
3Reported PFS efficacy for MONARCH 3 is based on the 2019 update.
4Reported OS efficacy for MONARCH 3 is based on the 2024 update.
Note: HORIZON is labeled HORIZONBRCA to distinguish from the study of the same name in multiple myeloma.
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Abemaciclib & Fulvestrant or Fulvestrant & Palbociclib or Fulvestrant & Ribociclib
===References===
# ILBCG: Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jänicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001 May 15;19(10):2596-606. Erratum in: J Clin Oncol 2001 Jul 1;19(13):3302. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003 Jun 1;21(11):2101-9. link to original article EuroPMC
# Biomed 777-CLP-29: Goss P, Bondarenko IN, Manikhas GN, Pendergrass KB, Miller WH Jr, Langecker P, Blanchett D. Phase III, double-blind, controlled trial of atamestane plus toremifene compared with letrozole in postmenopausal women with advanced receptor-positive breast cancer. J Clin Oncol. 2007 Nov 1;25(31):4961-6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00044291
# HORIZONBRCA: Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P, Chan A, Hachemi S, Strahs A, Cincotta M, Berkenblit A, Krygowski M, Kang LL, Moore L, Hayes DF. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013 Jan 10;31(2):195-202. Epub 2012 Dec 10. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC NCT00083993
# PALOMA-1/TRIO-18: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. Epub 2014 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00721409
# LEA: Martín M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Muñoz M, Garcia-Saenz JÁ, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, de la Haba-Rodríguez J. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. 2015 Mar 20;33(9):1045-52. Epub 2015 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00545077
# CALGB 40503: Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016 Aug 1;34(22):2602-9. Epub 2016 May 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00601900
# MONALEESA-2: Hortobagyi GN, Stemmer SM, Burris HA 3rd, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. Epub 2016 Oct 7.link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01958021
## Subgroup analysis: Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, Villanueva C, Jakobsen E, Alba E, Wist E, Favret AM, Bachelot T, Hegg R, Wheatley-Price P, Souami F, Sutradhar S, Miller M, Germa C, Burris HA. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018 Feb;167(3):659-669. Epub 2017 Oct 22. link to original article link to PMC article EuroPMC
## HRQoL analysis: Verma S, O'Shaughnessy J, Burris HA, Campone M, Alba E, Chandiwana D, Dalal AA, Sutradhar S, Monaco M, Janni W. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib plus letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article EuroPMC
## Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. link to original article EuroPMC
##Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, Campone M, Petrakova K, Winer EP, Janni W, Conte P, Cameron DA, André F, Arteaga CL, Zarate JP, Chakravartty A, Taran T, Le Gac F, Serra P, O'Shaughnessy J. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022 Mar 10;386(10):942-950. link to original article EuroPMC
# PALOMA-2: Finn RS, Martín M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01740427
##PRO analysis: Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, Neven P, Shparyk Y, Mori A, Lu DR, Bhattacharyya H, Bartlett C, Iyer S, Johnston S, Ettl J, Harbeck N. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018 Apr 1;29(4):888-894. link to original article link to PMC article EuroPMC
## Update: Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, Harbeck N, Castrellon A, Iyer S, Lu DR, Mori A, Gauthier ER, Bartlett CH, Gelmon KA, Slamon DJ. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr;174(3):719-729. Epub 2019 Jan 10. link to original article link to PMC article EuroPMC
## Subgroup analysis: Im SA, Mukai H, Park IH, Masuda N, Shimizu C, Kim SB, Im YH, Ohtani S, Huang Bartlett C, Lu DR, Iyer S, Mori Y, Mori A, Gauthier E, Finn RS, Toi M. Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study. JCO Glob Oncol. 2019 May;5:1-19. link to original article link to PMC article EuroPMC
##Update: Slamon DJ, Diéras V, Rugo HS, Harbeck N, Im SA, Gelmon KA, Lipatov ON, Walshe JM, Martin M, Chavez-MacGregor M, Bananis E, Gauthier E, Lu DR, Kim S, Finn RS. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol. 2024 Mar 20;42(9):994-1000. Epub 2024 Jan 22. link to original article link to PMC article EuroPMC
# MONARCH 3: Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Trédan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. Epub 2017 Oct 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02246621
##Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article EuroPMC
##HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article EuroPMC
##Update: Goetz MP, Toi M, Huober J, Sohn J, Trédan O, Park IH, Campone M, Chen SC, Manso LM, Paluch-Shimon S, Freedman OC, O'Shaughnessy J, Pivot X, Tolaney SM, Hurvitz SA, Llombart-Cussac A, André V, Saha A, van Hal G, Shahir A, Iwata H, Johnston SRD. Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: final overall survival results of MONARCH 3. Ann Oncol. 2024 Aug;35(8):718-727. Epub 2024 May 8. link to original article EuroPMC
#DAWNA-2: Zhang P, Zhang Q, Tong Z, Sun T, Li W, Ouyang Q, Hu X, Cheng Y, Yan M, Pan Y, Teng Y, Yan X, Wang Y, Xie W, Zeng X, Wang X, Hu C, Geng C, Zhang H, Li W, Wu X, Zhong J, Xu J, Shi Y, Wei W, Bayaxi N, Zhu X, Xu B. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Jun;24(6):646-657. Epub 2023 May 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03966898
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Letrozole & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Martín et al. 2015 (LEA) 	2007-2011 	Phase 3 (E-esc)	1a. Fulvestrant1b. Letrozole	Did not meet primary endpoint of PFSMedian PFS: 19.3 vs 14.4 mo(HR 0.83, 95% CI 0.65-1.06)
Dickler et al. 2016 (CALGB 40503)	2008-2011 	Phase 3 (E-esc)	Letrozole 	Seems to have longer PFS (primary endpoint)Median PFS: 20.2 vs 15.6 mo(HR 0.75, 95% CI 0.59-0.96)
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 21
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# LEA: Martín M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Muñoz M, Garcia-Saenz JÁ, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, de la Haba-Rodríguez J. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. 2015 Mar 20;33(9):1045-52. Epub 2015 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00545077
# CALGB 40503: Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016 Aug 1;34(22):2602-9. Epub 2016 May 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00601900
==Letrozole & Palbociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Finn et al. 2014 (PALOMA-1/TRIO-18)	2009-2012 	Randomized Phase 2 (E-esc)	Letrozole 	Longer PFS (primary endpoint)Median PFS: 20.2 vs 10.2 mo(HR 0.49, 95% CI 0.32-0.75)
Finn et al. 2016 (PALOMA-2) 	2013-02 to 2014-07 	Phase 3 (E-RT-esc) 	Letrozole 	Longer PFS (primary endpoint)Median PFS: 24.8 vs 14.5 mo(HR 0.58, 95% CI 0.46-0.72)Did not meet secondary endpoint of OS1Median OS: 53.9 vs 51.2 mo(HR 0.96, 95% CI 0.78-1.18)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
Cortés et al. 2024 (AMEERA-5) 	2020-10-14 to 2021-12-02	Phase 3 (C) 	Amcenestrant & Palbociclib 	Did not meet primary endpoint of PFSPFS6: 86.9% vs 82.7%(sHR 0.83, 95% CI 0.64-1.06)
1Reported OS efficacy for PALOMA-2 is based on the 2024 update.
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
# PALOMA-1/TRIO-18: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. Epub 2014 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00721409
# PALOMA-2: Finn RS, Martín M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01740427
##PRO analysis: Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, Neven P, Shparyk Y, Mori A, Lu DR, Bhattacharyya H, Bartlett C, Iyer S, Johnston S, Ettl J, Harbeck N. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018 Apr 1;29(4):888-894. link to original article link to PMC article EuroPMC
## Update: Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, Harbeck N, Castrellon A, Iyer S, Lu DR, Mori A, Gauthier ER, Bartlett CH, Gelmon KA, Slamon DJ. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr;174(3):719-729. Epub 2019 Jan 10. link to original article link to PMC article EuroPMC
## Subgroup analysis: Im SA, Mukai H, Park IH, Masuda N, Shimizu C, Kim SB, Im YH, Ohtani S, Huang Bartlett C, Lu DR, Iyer S, Mori Y, Mori A, Gauthier E, Finn RS, Toi M. Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study. JCO Glob Oncol. 2019 May;5:1-19. link to original article link to PMC article EuroPMC
##Update: Slamon DJ, Diéras V, Rugo HS, Harbeck N, Im SA, Gelmon KA, Lipatov ON, Walshe JM, Martin M, Chavez-MacGregor M, Bananis E, Gauthier E, Lu DR, Kim S, Finn RS. Overall Survival With Palbociclib Plus Letrozole in Advanced Breast Cancer. J Clin Oncol. 2024 Mar 20;42(9):994-1000. Epub 2024 Jan 22. link to original article link to PMC article EuroPMC
#AMEERA-5: Cortés J, Hurvitz SA, O'Shaughnessy J, Delaloge S, Iwata H, Rugo HS, Neven P, Kanagavel D, Cohen P, Paux G, Cartot-Cotton S, Stefanova-Urena M, Deyme L, Aouni J, Sebastien B, Bardia A. Randomized Phase III Study of Amcenestrant Plus Palbociclib Versus Letrozole Plus Palbociclib in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Primary Results From AMEERA-5. J Clin Oncol. 2024 Aug 1;42(22):2680-2690. Epub 2024 Jun 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04478266
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Letrozole & Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hortobagyi et al. 2016 (MONALEESA-2)	2014-01-24 to 2015-03-24	Phase 3 (E-RT-esc)	Letrozole 	Longer PFS1 (primary endpoint)Median PFS: 25.3 vs 16 mo(HR 0.57, 95% CI 0.46-0.70)Longer OS2 (secondary endpoint)Median OS: 63.9 vs 51.4 mo(HR 0.76, 95% CI 0.63-0.93)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	1a. Anastrozole1b. Letrozole	Might have longer PFS-2 (primary endpoint)Median PFS-2: 31 vs 26.8 mo(sHR 0.87, 95% CI 0.74-1.03)
1Reported efficacy for MONALEESA-2 is based on the 2018 update.
2Reported efficacy for MONALEESA-2 is based on the 2022 update.
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
====Subsequent treatment====
*SONIA, at time of progression: Second-line Fulvestrant
===References===
# MONALEESA-2: Hortobagyi GN, Stemmer SM, Burris HA 3rd, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, André F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. Epub 2016 Oct 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01958021
## Subgroup analysis: Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, Villanueva C, Jakobsen E, Alba E, Wist E, Favret AM, Bachelot T, Hegg R, Wheatley-Price P, Souami F, Sutradhar S, Miller M, Germa C, Burris HA. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018 Feb;167(3):659-669. Epub 2017 Oct 22. link to original article link to PMC article EuroPMC
## HRQoL analysis: Verma S, O'Shaughnessy J, Burris HA, Campone M, Alba E, Chandiwana D, Dalal AA, Sutradhar S, Monaco M, Janni W. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib plus letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article EuroPMC
## Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. link to original article EuroPMC
##Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Hart L, Campone M, Petrakova K, Winer EP, Janni W, Conte P, Cameron DA, André F, Arteaga CL, Zarate JP, Chakravartty A, Taran T, Le Gac F, Serra P, O'Shaughnessy J. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022 Mar 10;386(10):942-950. link to original article EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Palbociclib & Tamoxifen==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Noguchi et al. 2024 (PATHWAY)	2018-02-15 to 2019-07-30	Phase 3 (E-esc)	Tamoxifen 	Longer PFS (primary endpoint)Median PFS: 24.4 vs 11.1 mo(HR 0.60, 95% CI 0.43-0.85)
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
28-day cycles
===References===
#PATHWAY: Noguchi E, Yamanaka T, Mukai H, Yamamoto N, Chung CF, Lu YS, Chang DY, Sohn J, Kim GM, Lee KH, Lee SC, Iwasa T, Iwata H, Watanabe K, Jung KH, Tanabe Y, Kang SY, Yasojima H, Aogi K, Tokunaga E, Sim SH, Yap YS, Matsumoto K, Tseng LM, Umeyama Y, Sudo K, Kojima Y, Hata T, Kuchiba A, Shibata T, Nakamura K, Fujiwara Y, Tamura K, Yonemori K. A phase 3 study (PATHWAY) of palbociclib plus tamoxifen in patients with HR-positive/HER2-negative advanced breast cancer. NPJ Breast Cancer. 2024 Aug 22;10(1):76. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03423199
==Tamoxifen monotherapy==
===Regimen variant #1, 20 mg/day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Ingle et al. 1981 	1977-1980 	Phase 3 (E-switch-ic) 	DES 	Did not meet primary endpoint of ORR
Gale et al. 1994 	1977 to not reported 	Phase 3 (E-switch-ic) 	1. Aminoglutethimide2. Bilateral adrenalectomy	Did not meet co-primary endpoints of DOR/TTF/OS
Powles et al. 1984 	1979-1983 	Phase 3 (C) 	TAD 	Seems to have lower ORR
Bratherton et al. 1984 	Not reported 	Phase 3 (C) 	Tamoxifen; 40 mg/day 	Did not meet co-primary endpoints of ORR/PFS
Ingle et al. 1986 	Not reported 	Phase 3 (C) 	Aminoglutethemide, Hydrocortisone, Tamoxifen 	Did not meet co-primary endpoints of ORR/TTP/OS
Muss et al. 1988 	1981-1984 	Phase 3 (C) 	Megestrol 	Did not meet primary endpoint of ORR
Ingle et al. 1988 	1981-1985 	Phase 3 (C) 	Fluoxymesterone & Tamoxifen 	Seems to have shorter TTP1
Rubens et al. 1988 	1981-1986 	Phase 3 (C) 	Tamoxifen & Prednisolone 	Seems to have shorter OS
Castiglione-Gertsch et al. 1993 	1982-1985 	Phase 3 (C) 	MPA 	Might have shorter TTP
Gazet et al. 1988 	1982-1987 	Phase 3 (E-switch-ooc)	Surgery 	Did not meet endpoint of DFS
Borner et al. 1994 (SAKK 23/82) 	1982-1991 	Phase 3 (E-esc) 	Observation 	Might have longer DFS2
Stuart et al. 1996 	1985-1988 	Phase 3 (C) 	Megestrol 	Did not meet endpoint of ORR
Ingle et al. 1991 	1985-1989 	Phase 3 (C) 	Tamoxifen & Prednisolone 	Did not meet co-primary endpoints of ORR/TTP/OS
Muss et al. 1994 	1985-1990 	Phase 3 (C) 	MPA 	Might have shorter OS
Hayes et al. 1995 	1988-1991 	Phase 3 (C) 	1. Toremifene; 60 mg/day 	Did not meet primary endpoint of ORR
Hayes et al. 1995 	1988-1991 	Phase 3 (C) 	2. Toremifene; 200 mg/day 	Did not meet primary endpoint of ORR
Thürlimann et al. 1996 (SAKK 20/88) 	1988-1994 	Phase 3 (C) 	Fadrozole 	Might have longer TTTF
Buzdar et al. 2002 	1995-1997 	Phase 3 (C) 	Droloxifene 	Longer TTP (primary endpoint)Median TTP: 228 vs 183 days(HR 0.78, 95% CI 0.67-0.90)
Bonneterre et al. 2000 (TARGETBreast) 	1995-1998 	Phase 3 (C) 	Anastrozole 	Equivalent TTP
Nabholtz et al. 2000 (Arimidex Study Group 2000)	1996-1998 	Phase 3 (C) 	Anastrozole 	Equivalent TTP (co-primary endpoint)Median TTP: 5.6 vs 11.1 mo(HR 1.44, 95% CI 1.16)
Bajetta et al. 2002 	1996-1998 	Phase 3 (C) 	Octreotide LAR & Tamoxifen 	Did not meet primary endpoint of PFSMedian PFS: 26.9 vs 25 weeks(HR 0.91)
Mouridsen et al. 2001 (ILBCG) 	1996-1999 	Phase 3 (C) 	Letrozole 	Shorter TTPMedian TTP: 26 vs 41 weeks(HR 1.43, 95% CI 1.22-1.67)
Paridaens et al. 2008 (EORTC 10951) 	1996-2002 	Phase 3 (C) 	Exemestane 	Did not meet primary endpoint of PFS
Howell et al. 2004 	1998-2000 	Phase 3 (C) 	Fulvestrant 	Might have longer TTPMedian TTP: 8.3 vs 6.8 mo(HR 0.85, 95% CI 0.69-1.02)
Deshmane et al. 2007 	Not reported 	Phase 3 (C) 	Arzoxifene 	Longer PFS (primary endpoint)Median PFS: 7.5 vs 4 mo(HR 0.68, 95% CI 0.52-0.91)
Noguchi et al. 2024 (PATHWAY) 	2018-02-15 to 2019-07-30	Phase 3 (E-esc) 	Tamoxifen 	Shorter PFS (primary endpoint)Median PFS: 11.1 vs 24.4 mo(HR 1.67, 95% CI 1.18-2.33)
1Reported efficacy for Ingle et al. 1988 is based on the 1991 update.
2Reported efficacy for SAKK 23/82 is based on the 2003 update.
Note: patients in Gazet et al. 1988 had resectable disease but did not undergo surgery in this arm. Patients in SAKK 23/82 had isolated locoregional recurrence.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
**Some earlier trials used 10 mg PO twice per day instead
28-day cycles
===Regimen variant #2, 30 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gundersen et al. 1990a	Not reported 	Phase 3 (C)	Tamoxifen/MPA	Seems to have lower ORR
====Endocrine therapy====
*Tamoxifen (Nolvadex) 30 mg PO once per day
Continued indefinitely
===Regimen variant #3, 40 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Morgan et al. 1976 	Not reported 	Non-randomized 	 	
Kiang et al. 1977 	1975-1976 	Non-randomized 	 	
Bratherton et al. 1984 	Not reported 	Phase 3 (E-esc)	Tamoxifen; 20 mg/day 	Did not meet co-primary endpoints of ORR/PFS
Forbes 1986 	1978-1981 	Randomized (C) 	1. AC2. ACT 	Did not meet primary endpoint of OS
Kellokumpu-Lehtinen et al. 1987	1979-1983 	Randomized (C) 	Nandrolone 	Did not meet primary endpoint of ORR
van Veelen et al. 1986 	1980-1984 	Phase 3 (C) 	MPA 	Did not meet primary endpoint of ORR
Gill et al. 1993 	1984-1989 	Phase 3 (C) 	1. Megestrol2. Megestrol & Tamoxifen 	Did not meet endpoint of ORR
Pyrhönen et al. 1997 	1986-1992 	Phase 3 (C) 	Toremifene; 60 mg/day 	Seems to have longer TTP
Gershanovich et al. 1997 	1987-1992 	Phase 3 (C) 	1. Toremifene; 60 mg/day 	Did not meet co-primary endpoints of ORR/TTP
Gershanovich et al. 1997 	1987-1992 	Phase 3 (C) 	2. Toremifene; 240 mg/day 	Did not meet co-primary endpoints of ORR/TTP
Beex et al. 2006 (EORTC 10863) 	1987-1997 	Phase 3 (C) 	1. Tamoxifen; intermittent2. Tamoxifen/MPA; intermittent	Did not meet primary endpoint of PFS
Milla-Santos et al. 2001 	1996-1999 	Phase 3 (C) 	Toremifene; 60 mg/day 	Did not meet co-primary endpoints of ORR/TTP/OS
Milla-Santos et al. 2003 	1997-1999 	Phase 3 (C) 	Anastrozole 	Shorter OS (co-primary endpoint)Median OS: 16 vs 17.4 mo(HR 1.56, 95% CI 1.16-2.13)
====Endocrine therapy====
*Tamoxifen (Nolvadex) 40 mg PO once per day
**Some earlier trials used 20 mg PO twice per day instead
Continued indefinitely
===References===
# Morgan LR Jr, Schein PS, Woolley PV, Hoth D, Macdonald J, Lippman M, Posey LE, Beazley RW. Therapeutic use of tamoxifen in advanced breast cancer: correlation with biochemical parameters. Cancer Treat Rep. 1976 Oct;60(10):1437-43. EuroPMC
# Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977 Dec;87(6):687-90. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981 Jan 1;304(1):16-21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Powles TJ, Ashley S, Ford HT, Gazet JC, Nash AG, Neville AM, Coombes RC. Treatment of disseminated breast cancer with tamoxifen, aminoglutethimide, hydrocortisone, and danazol, used in combination or sequentially. Lancet. 1984 Jun 23;1(8391):1369-73. link to original article EuroPMC
# Bratherton DG, Brown CH, Buchanan R, Hall V, Kingsley Pillers EM, Wheeler TK, Williams CJ. A comparison of two doses of tamoxifen (Nolvadex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer. 1984 Aug;50(2):199-205. link to original article link to PMC article EuroPMC
# Forbes JF; Australian and New Zealand Breast Cancer Trials Group. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986 Feb;4(2):186-93. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Ingle JN, Green SJ, Ahmann DL, Long HJ, Edmonson JH, Rubin J, Chang MN, Creagan ET. Randomized trial of tamoxifen alone or combined with aminoglutethimide and hydrocortisone in women with metastatic breast cancer. J Clin Oncol. 1986 Jun;4(6):958-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# van Veelen H, Willemse PH, Tjabbes T, Schweitzer MJ, Sleijfer DT. Oral high-dose medroxyprogesterone acetate versus tamoxifen: a randomized crossover trial in postmenopausal patients with advanced breast cancer. Cancer. 1986 Jul 1;58(1):7-13. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Kellokumpu-Lehtinen P, Huovinen R, Johansson R. Hormonal treatment of advanced breast cancer: a randomized trial of tamoxifen versus nandrolone decanoate. Cancer. 1987 Nov 15;60(10):2376-81. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Gazet JC, Markopoulos C, Ford HT, Coombes RC, Bland JM, Dixon RC. Prospective randomised trial of tamoxifen versus surgery in elderly patients with breast cancer. Lancet. 1988 Mar 26;1(8587):679-81. link to original article EuroPMC
# Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, Marschke RF, Long HJ, Gerstner JG, Windschitl HE, Everson LK, Pfeifle DM. Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer. J Clin Oncol. 1988 May;6(5):825-31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Update: Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, Tschetter LK, Long HJ, Gerstner JG, Windschitl HE, Levitt R, Pfeifle DM. Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer: an updated analysis. Cancer. 1991 Feb 15;67(4):886-91. link to original article EuroPMC
# Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR, Capizzi RL, Christian R, Cruz JM, Jackson DV, Powell BL, Richards F, White DR, Zekan PJ, Spurr CL, Pope E, Case D, Morgan TM. Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1988 Jul;6(7):1098-106. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Rubens RD, Tinson CL, Coleman RE, Knight RK, Tong D, Winter PJ, North WR. Prednisolone improves the response to primary endocrine treatment for advanced breast cancer. Br J Cancer. 1988 Nov;58(5):626-30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
# Gundersen S, Kvinnsland S, Lundgren S, Klepp O, Lund E, Børmer O, Høst H. Cyclical use of tamoxifen and high-dose medroxyprogesterone acetate in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat. 1990 Nov;17(1):45-50. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gesme DH Jr, Windschitl HE, Pfeifle DM, Etzell PS, Gerstner JG, Long HJ, Foley JF, Loprinzi CL, Dalton RJ; NCCTG. A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer: a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Cancer. 1991 Jul 1;68(1):34-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Castiglione-Gertsch M, Pampallona S, Varini M, Cavalli F, Brunner K, Senn HJ, Goldhirsch A, Metzger U. Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?. Ann Oncol. 1993 Nov;4(9):735-40. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Gill PG, Gebski V, Snyder R, Burns I, Levi J, Byrne M, Coates A. Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. Ann Oncol. 1993 Nov;4(9):741-4. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Gale KE, Andersen JW, Tormey DC, Mansour EG, Davis TE, Horton J, Wolter JM, Smith TJ, Cummings FJ; Eastern Cooperative Oncology Group. Hormonal treatment for metastatic breast cancer: an Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer. 1994 Jan 15;73(2):354-61. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Muss HB, Case LD, Atkins JN, Bearden JD 3rd, Cooper MR, Cruz JM, Jackson DV Jr, O'Rourke MA, Pavy MD, Powell BL, Richards F, Spurr CL, Eagle K, White DR. Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol. 1994 Aug;12(8):1630-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# SAKK 23/82: Borner M, Bacchi M, Goldhirsch A, Greiner R, Harder F, Castiglione M, Jungi WF, Thürlimann B, Cavalli F, Obrecht JP, Leyvraz S, Alberto P, Adam H, Varini M, Loehnert T, Senn HJ, Metzger U, Brunner K; Swiss Group for Clinical Cancer Research. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. J Clin Oncol. 1994 Oct;12(10):2071-7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Update: Waeber M, Castiglione-Gertsch M, Dietrich D, Thürlimann B, Goldhirsch A, Brunner KW, Borner MM; Swiss Group for Clinical Cancer Research. Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol. 2003 Aug;14(8):1215-21. link to original article EuroPMC
# Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I, Schoenfelder J. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SAKK 20/88: Thürlimann B, Beretta K, Bacchi M, Castiglione-Gertsch M, Goldhirsch A, Jungi WF, Cavalli F, Senn HJ, Fey M, Löhnert T. First-line fadrozole HCI (CGS 16949A) versus tamoxifen in postmenopausal women with advanced breast cancer: prospective randomised trial of the Swiss Group for Clinical Cancer Research SAKK 20/88. Ann Oncol. 1996 Jul;7(5):471-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC 
# Stuart NS, Warwick J, Blackledge GR, Spooner D, Keen C, Taylor AR, Tyrell C, Webster DJ, Earl H. A randomised phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer. Eur J Cancer. 1996 Oct;32A(11):1888-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J; Eastern European Study Group. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'Nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
# TARGETBreast: Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000 Nov 15;18(22):3748-57. Erratum in: J Clin Oncol. 2012 Jan 20;30(3):343. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Arimidex Study Group 2000: Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M; Arimidex Study Group. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol. 2000 Nov 15;18(22):3758-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Milla-Santos A, Milla L, Rallo L, Solano V. Phase III randomized trial of toremifene vs tamoxifen in hormonodependant advanced breast cancer. Breast Cancer Res Treat. 2001 Jan;65(2):119-24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ILBCG: Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jänicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001 May 15;19(10):2596-606. Erratum in: J Clin Oncol 2001 Jul 1;19(13):3302. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003 Jun 1;21(11):2101-9. link to original article EuroPMC
# Bajetta E, Procopio G, Ferrari L, Martinetti A, Zilembo N, Catena L, Alú M, Della TS, Alberti D, Buzzoni R. A randomized, multicenter prospective trial assessing long-acting release octreotide pamoate plus tamoxifen as a first line therapy for advanced breast carcinoma. Cancer. 2002 Jan 15;94(2):299-304. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Buzdar A, Hayes D, El-Khoudary A, Yan S, Lønning P, Lichinitser M, Gopal R, Falkson G, Pritchard K, Lipton A, Wolter K, Lee A, Fly K, Chew R, Alderdice M, Burke K, Eisenber P; Droloxifene 301 Study Group. Phase III randomized trial of droloxifene and tamoxifen as first-line endocrine treatment of ER/PgR-positive advanced breast cancer. Breast Cancer Res Treat. 2002 May;73(2):161-75. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, Casanovas J, Puig-Gali M. Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer: a prospective, randomized, phase III study. Am J Clin Oncol. 2003 Jun;26(3):317-22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# EORTC 10863: Beex L, Rose C, Mouridsen H, Jassem J, Nooij M, Estape J, Paridaens R, Piccart M, Gorlia T, Lardenoije S, Baila L. Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863). Eur J Cancer. 2006 Dec;42(18):3178-85. Epub 2006 Oct 12. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Deshmane V, Krishnamurthy S, Melemed AS, Peterson P, Buzdar AU. Phase III double-blind trial of arzoxifene compared with tamoxifen for locally advanced or metastatic breast cancer. J Clin Oncol. 2007 Nov 1;25(31):4967-73. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# EORTC 10951: Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P; European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008 Oct 20;26(30):4883-90. Epub 2008 Sep 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002777
#PATHWAY: Noguchi E, Yamanaka T, Mukai H, Yamamoto N, Chung CF, Lu YS, Chang DY, Sohn J, Kim GM, Lee KH, Lee SC, Iwasa T, Iwata H, Watanabe K, Jung KH, Tanabe Y, Kang SY, Yasojima H, Aogi K, Tokunaga E, Sim SH, Yap YS, Matsumoto K, Tseng LM, Umeyama Y, Sudo K, Kojima Y, Hata T, Kuchiba A, Shibata T, Nakamura K, Fujiwara Y, Tamura K, Yonemori K. A phase 3 study (PATHWAY) of palbociclib plus tamoxifen in patients with HR-positive/HER2-negative advanced breast cancer. NPJ Breast Cancer. 2024 Aug 22;10(1):76. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03423199
==Tamoxifen & Prednisolone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rubens et al. 1988	1981-1986 	Phase 3 (E-esc)	Tamoxifen 	Seems to have longer OS
Ingle et al. 1991 	1985-1989 	Phase 3 (E-esc)	Tamoxifen 	Did not meet co-primary endpoints of ORR/TTP/OS
====Endocrine therapy====
*Tamoxifen (Nolvadex) 10 mg PO twice per day
*Prednisolone (Millipred) 5 mg PO twice per day
Continued indefinitely
===References===
# Rubens RD, Tinson CL, Coleman RE, Knight RK, Tong D, Winter PJ, North WR. Prednisolone improves the response to primary endocrine treatment for advanced breast cancer. Br J Cancer. 1988 Nov;58(5):626-30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
# Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gesme DH Jr, Windschitl HE, Pfeifle DM, Etzell PS, Gerstner JG, Long HJ, Foley JF, Loprinzi CL, Dalton RJ; NCCTG. A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer: a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Cancer. 1991 Jul 1;68(1):34-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Toremifene monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pyrhönen et al. 1997 	1986-1992 	Phase 3 (E-RT-switch-ic)	Tamoxifen; 40 mg/day 	Seems to have shorter TTP
Gershanovich et al. 1997	1987-1992 	Phase 3 (E-RT-switch-ic)	1. Tamoxifen; 40 mg/day 	Did not meet co-primary endpoints of ORR/TTP
Gershanovich et al. 1997	1987-1992 	Phase 3 (E-RT-switch-ic)	2. Toremifene; 240 mg/day	Did not meet co-primary endpoints of ORR/TTP
Hayes et al. 1995 	1988-1991 	Phase 3 (E-RT-switch-ic)	1. Tamoxifen 	Did not meet primary endpoint of ORR
Hayes et al. 1995 	1988-1991 	Phase 3 (E-RT-switch-ic)	2. Toremifene; 200 mg/day	Did not meet primary endpoint of ORR
Milla-Santos et al. 2001	1996-1999 	Phase 3 (E-switch-ic) 	Tamoxifen; 40 mg/day 	Did not meet co-primary endpoints of ORR/TTP/OS
====Endocrine therapy====
*Toremifene (Fareston) 60 mg PO once per day
Continued indefinitely
===References===
# Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I, Schoenfelder J. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J; Eastern European Study Group. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'Nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
# Milla-Santos A, Milla L, Rallo L, Solano V. Phase III randomized trial of toremifene vs tamoxifen in hormonodependant advanced breast cancer. Breast Cancer Res Treat. 2001 Jan;65(2):119-24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Metastatic disease, maintenance after first-line therapy=
==Anastrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019 	Phase 3 (C)	1a. Anastrozole & Everolimus1b. Everolimus & Exemestane1c. Everolimus & Letrozole	Did not meet primary endpoint of PFSMedian PFS: 7.2 vs 11 mo(HR 1.41, 95% CI 0.94-2.13)
Note: this trial accrued less than 50% of the planned patients.
====Preceding treatment====
*At least 6 cycles of "standard" first-line chemotherapy
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
Continued indefinitely
===References===
#MAIN-A: Guarneri V, Giorgi CA, Cinieri S, Bengala C, Mariani G, Bisagni G, Frassoldati A, Zamagni C, De Rossi C, Amoroso V, Andreetta C, Ferro A, Zambelli A, Gori S, Garrone O, Dieci MV, Orlando L, Pastina I, Beninato T, Moretti G, Genovesi E, Cinefra M, Vicini R, Magni G, De Salvo GL, Conte P. Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial. Eur J Cancer. 2021 Sep;154:21-29. Epub 2021 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2013-004153-24
==Exemestane monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019 	Phase 3 (C)	1a. Anastrozole & Everolimus1b. Everolimus & Exemestane1c. Everolimus & Letrozole	Did not meet primary endpoint of PFSMedian PFS: 7.2 vs 11 mo(HR 1.41, 95% CI 0.94-2.13)
Note: this trial accrued less than 50% of the planned patients.
====Preceding treatment====
*At least 6 cycles of "standard" first-line chemotherapy
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
Continued indefinitely
===References===
#MAIN-A: Guarneri V, Giorgi CA, Cinieri S, Bengala C, Mariani G, Bisagni G, Frassoldati A, Zamagni C, De Rossi C, Amoroso V, Andreetta C, Ferro A, Zambelli A, Gori S, Garrone O, Dieci MV, Orlando L, Pastina I, Beninato T, Moretti G, Genovesi E, Cinefra M, Vicini R, Magni G, De Salvo GL, Conte P. Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial. Eur J Cancer. 2021 Sep;154:21-29. Epub 2021 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2013-004153-24
==Letrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019 	Phase 3 (C)	1a. Anastrozole & Everolimus1b. Everolimus & Exemestane1c. Everolimus & Letrozole	Did not meet primary endpoint of PFSMedian PFS: 7.2 vs 11 mo(HR 1.41, 95% CI 0.94-2.13)
Note: this trial accrued less than 50% of the planned patients.
====Preceding treatment====
*At least 6 cycles of "standard" first-line chemotherapy
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
===References===
#MAIN-A: Guarneri V, Giorgi CA, Cinieri S, Bengala C, Mariani G, Bisagni G, Frassoldati A, Zamagni C, De Rossi C, Amoroso V, Andreetta C, Ferro A, Zambelli A, Gori S, Garrone O, Dieci MV, Orlando L, Pastina I, Beninato T, Moretti G, Genovesi E, Cinefra M, Vicini R, Magni G, De Salvo GL, Conte P. Everolimus plus aromatase inhibitors as maintenance therapy after first-line chemotherapy: Final results of the phase III randomised MAIN-A (MAINtenance Afinitor) trial. Eur J Cancer. 2021 Sep;154:21-29. Epub 2021 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2013-004153-24
=Metastatic disease, subsequent lines of therapy=
==Abemaciclib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Dickler et al. 2017 (MONARCH 1)	2014-2015 	Phase 2 (RT)
====Targeted therapy====
*Abemaciclib (Verzenio) 200 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#MONARCH 1: Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Clin Cancer Res. 2017 Sep 1;23(17):5218-5224. Epub 2017 May 22. Erratum in: Clin Cancer Res. 2018 Nov 1;24(21):5485. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02102490
==Abemaciclib & Fulvestrant==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sledge et al. 2017 (MONARCH 2)	2014-08 to 2015-12 	Phase 3 (E-RT-esc)	Fulvestrant	Longer PFS (primary endpoint)Median PFS: 16.4 vs 9.3 mo(HR 0.55, 95% CI 0.45-0.68)Longer OS1 (secondary endpoint)Median OS: 46.7 vs 37.3 mo(HR 0.76, 95% CI 0.61-0.95)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	Fulvestrant	Might have shorter PFS-2 (primary endpoint)Median PFS-2: 26.8 vs 31 mo(sHR 1.15, 95% CI 0.97-1.35)
1Reported efficacy for MONARCH 2 is based on the 2019 update.
====Preceding treatment====
*SONIA: First-line Anastrozole or Letrozole, with progression
====Targeted therapy====
*Abemaciclib (Verzenio) 150 mg PO twice per day on days 1 to 28
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
28-day cycles
===References===
# MONARCH 2: Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. Epub 2017 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02107703
## Update: Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Conte P, Lu Y, Barriga S, Hurt K, Frenzel M, Johnston S, Llombart-Cussac A. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019 Sep 29;6(1):116-124. Epub 2019 Sep 29. link to original article link to PMC article EuroPMC
##HRQoL analysis: Kaufman PA, Toi M, Neven P, Sohn J, Grischke EM, Andre V, Stoffregen C, Shekarriz S, Price GL, Carter GC, Sledge GW Jr. Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist. 2020 Feb;25(2):e243-e251. Epub 2019 Oct 24. link to original article link to PMC article EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Anastrozole monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jonat et al. 1996 	1993-03 to 1994-09 	Phase 3 (E-RT-switch-ic)	1. Anastrozole; 10 mg/day	Not reported
Jonat et al. 1996 	1993-03 to 1994-09 	Phase 3 (E-RT-switch-ic)	2. Megestrol 	Seems to have longer OS1
Buzdar et al. 1996 	Not reported 	Phase 3 (E-RT-switch-ic)	1. Anastrozole; 10 mg/day	Not reported
Buzdar et al. 1996 	Not reported 	Phase 3 (E-RT-switch-ic)	2. Megestrol 	Seems to have longer OS1 (secondary endpoint)
Osborne et al. 2002 (Trial 0021)	1997 to not reported	Phase 3 (C) 	Fulvestrant 250 mg 	Did not meet primary endpoint of TTP
Howell et al. 2002 (Trial 0020) 	Not reported 	Phase 3 (C) 	Fulvestrant 250 mg 	Seems to have non-inferior TTP
Rose et al. 2003 	1997-12 to 1999-11 	Phase 3 (E-swith-ic) 	Letrozole 	Did not meet primary endpoint of TTP
Xu et al. 2010 	2005-2007 	Phase 3 (C) 	Fulvestrant 250 mg 	Did not meet primary endpoint of TTP
Bidard et al. 2022 (EMERALD) 	2019-02 to 2020-10 	Phase 3 (C) 	Elacestrant 	Shorter PFSPFS12: 9.4% vs 22.3%(HR 1.43, 95% CI 1.14-1.82)
1Reported efficacy for Jonat et al. 1996 and Buzdar et al. 1996 is based on the 1998 pooled update.
Note: Buzdar et al. 1996 is an update to Jonat et al. 1996 as well as a primary publication.
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
Continued indefinitely
===References===
# Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L, Roche H, Lundgren S, Hellmund R, Azab M. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer. 1996 Mar;32A(3):404-12. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Pooled update: Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. link to original article EuroPMC
## Pooled update: Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. link to original article EuroPMC
# Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. link to original article EuroPMC
## Update: Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A; Arimidex Study Group. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Cancer. 1997 Feb 15;79(4):730-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Pooled update: Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. link to original article EuroPMC
# Trial 0021: Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002 Aug 15;20(16):3386-95. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00635713
## Pooled update: Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003 Jul 15;98(2):229-38. link to original article EuroPMC
## Pooled update: Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005 Jul 15;104(2):236-9. link to original article EuroPMC
# Trial 0020: Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003 Jul 15;98(2):229-38. link to original article EuroPMC
## Pooled update: Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005 Jul 15;104(2):236-9. link to original article EuroPMC
# Rose C, Vtoraya O, Pluzanska A, Davidson N, Gershanovich M, Thomas R, Johnson S, Caicedo JJ, Gervasio H, Manikhas G, Ben Ayed F, Burdette-Radoux S, Chaudri-Ross HA, Lang R. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003 Nov;39(16):2318-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Xu B, Jiang Z, Shao Z, Wang J, Feng J, Song S, Chen Z, Gu K, Yu S, Zhang Y, Wang C, Zhang F, Yang J. Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomised phase III trial. Cancer Chemother Pharmacol. 2011 Jan;67(1):223-30. Epub 2010 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EMERALD: Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. Epub 2022 May 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03778931
==Anastrozole & Fulvestrant==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2013 (SoFEA)	2004-2010 	Phase 3 (E-esc)	1. Exemestane 	Did not meet primary endpoint of PFSMedian PFS: 4.4 vs 3.4 mo
Johnston et al. 2013 (SoFEA)	2004-2010 	Phase 3 (E-esc)	2. Fulvestrant	Did not meet primary endpoint of PFSMedian PFS: 4.4 vs 4.8 mo(HR 1.00, 95% CI 0.83-1.21)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once on day 1, then 250 mg IM once on day 15
**Cycle 2 onwards: 250 mg IM once on day 1
28-day cycles
===References===
# SoFEA: Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, Im YH, Braybrooke JP, Brunt AM, Cheung KL, Jyothirmayi R, Robinson A, Wardley AM, Wheatley D, Howell A, Coombes G, Sergenson N, Sin HJ, Folkerd E, Dowsett M, Bliss JM; SoFEA investigators. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013 Sep;14(10):989-98. Epub 2013 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00253422; NCT00944918
==Anastrozole & Palbociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bidard et al. 2022 (PADA-1)	2017-2019 	Phase 3 (C)	Fulvestrant & Palbociclib	Shorter PFSMedian PFS: 5.7 vs 11.9 mo(HR 1.64, 95% CI 1.16-2.33)
====Biomarker eligibility criteria====
*PADA-1: ESR1 mutation, detected in blood
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
===References===
#PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03079011
==Capecitabine monotherapy==
===Regimen variant #1, 1000 mg/m2 PO twice per day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Martin et al. 2020 (PEARL cohort 1) 	2014-2018 	Phase 3 (C)	Exemestane & Palbociclib 	Did not meet primary endpoint of PFSMedian PFS: 10.6 vs 8 mo(HR 0.90, 95% CI 0.71-1.15)
Martin et al. 2020 (PEARL cohort 2) 	2016-2018 	Phase 3 (C)	Fulvestrant & Palbociclib	Did not meet primary endpoint of PFSMedian PFS: 10 vs 7.5 mo(HR 0.88, 95% CI 0.67-1.18)
Rugo et al. 2022 (TROPiCS-02) 	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan 	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (C)	Dato-DXd 	Shorter PFS (co-primary endpoint)Median PFS: 4.9 vs 6.9 mo(HR 1.59, 95% CI 1.32-1.92)
Note: this variant was used in patients older than 70 years of age in PEARL, and is the lower bound of dosing in TROPiCS-02.
====Biomarker eligibility criteria====
*PEARL cohort 2: ESR1 mutations
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===Regimen variant #2, 1250 mg/m2 PO twice per day===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Martin et al. 2020 (PEARL cohort 1) 	2014-2018 	Phase 3 (C)	Exemestane & Palbociclib 	Did not meet primary endpoint of PFSMedian PFS: 10.6 vs 8 mo(HR 0.90, 95% CI 0.71-1.15)
Martin et al. 2020 (PEARL cohort 2) 	2016-2018 	Phase 3 (C)	Fulvestrant & Palbociclib	Did not meet primary endpoint of PFSMedian PFS: 10 vs 7.5 mo(HR 0.88, 95% CI 0.67-1.18)
Rugo et al. 2022 (TROPiCS-02) 	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan 	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (C)	Dato-DXd 	Shorter PFS (co-primary endpoint)Median PFS: 4.9 vs 6.9 mo(HR 1.59, 95% CI 1.32-1.92)
Note: this variant was used in patients 70 years of age and younger in PEARL, and is the upper bound of dosing in TROPiCS-02.
====Biomarker eligibility criteria====
*PEARL cohort 2: ESR1 mutations
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
# PEARL: Martin M, Zielinski C, Ruiz-Borrego M, Carrasco E, Turner N, Ciruelos EM, Muñoz M, Bermejo B, Margeli M, Anton A, Kahan Z, Csöszi T, Casas MI, Murillo L, Morales S, Alba E, Gal-Yam E, Guerrero-Zotano A, Calvo L, de la Haba-Rodriguez J, Ramos M, Alvarez I, Garcia-Palomo A, Huang Bartlett C, Koehler M, Caballero R, Corsaro M, Huang X, Garcia-Sáenz JA, Chacón JI, Swift C, Thallinger C, Gil-Gil M. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL. Ann Oncol. 2021 Apr;32(4):488-499. Epub 2020 Dec 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02028507
#TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03901339
##Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article EuroPMC
##HRQoL analysis: Rugo HS, Schmid P, Tolaney SM, Dalenc F, Marmé F, Shi L, Verret W, Shah A, Gharaibeh M, Bardia A, Cortes J. Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial. Oncologist. 2024 Sep 6;29(9):768-779. link to original article link to PMC article EuroPMC
#TROPION-Breast01: Bardia A, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Zhang Q, Tsurutani J, Kalinsky K, Rubini Liedke PE, Xu L, Fairhurst RM, Khan S, Denduluri N, Rugo HS, Xu B, Pistilli B; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025 Jan 20;43(3):285-296. Epub 2024 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05104866
#EVER-132-002: Xu B, Wang S, Yan M, Sohn J, Li W, Tang J, Wang X, Wang Y, Im SA, Jiang D, Valdez T, Dasgupta A, Zhang Y, Yan Y, Komatsubara KM, Chung WP, Ma F, Dai MS. Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024 Dec;30(12):3709-3716. Epub 2024 Oct 1. link to original article link to PMC article EuroPMC NCT04639986
==Capecitabine & Fulvestrant==
===Regimen===
Study 	Dates of enrollment 	Evidence
Schwartzberg et al. 2013 (ALSSMBC0606)	2007 to not reported	Phase 2
====Chemotherapy====
*Capecitabine (Xeloda) by the following weight-based criteria:
**Less than 80 kg: 1000 mg PO once every morning and 500 mg PO once every evening
**80 kg or more: 1000 mg PO twice per day
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once on day 1, then 250 mg IM once on day 15
**Cycle 2 onwards: 250 mg IM once on day 1
28-day cycles
===References===
# ALSSMBC0606: Schwartzberg LS, Wang G, Somer BG, Blakely LJ, Wheeler BM, Walker MS, Stepanski EJ, Houts AC. Phase II trial of fulvestrant with metronomic capecitabine for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Breast Cancer. 2014 Feb;14(1):13-9. Epub 2013 Sep 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00534417
==Capivasertib & Fulvestrant==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Turner et al. 2023 (CAPItello-291)	2020-06-02 to 2021-10-13	Phase 3 (E-RT-esc)	Fulvestrant	Longer PFS1 (co-primary endpoint)Median PFS: 7.3 vs 3.1 mo(HR 0.50, 95% CI 0.38-0.65)
1Reported efficacy is based on the AKT pathway-altered population, which was the subject of FDA approval.
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
====Targeted therapy====
*Capivasertib (Truqap) 400 mg PO twice per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
28-day cycles
===References===
#CAPItello-291: Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04305496
##PRO analysis: Oliveira M, Rugo HS, Howell SJ, Dalenc F, Cortes J, Gomez HL, Hu X, Toi M, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Nowecki Z, Park YH, Sohn JH, Tokunaga E, Yousef S, Zhukova L, Fulford M, Andrews H, Wadsworth I, D'Cruz C, Turner NC; CAPItello-291 study group. Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2024 Sep;25(9):1231-1244. link to original article EuroPMC
==Datopotamab deruxtecan monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Capecitabine1b. Eribulin1c. Gemcitabine1d. Vinorelbine	Longer PFS (co-primary endpoint)Median PFS: 6.9 vs 4.9 mo(HR 0.63, 95% CI 0.52-0.76)
====Antibody-drug conjugate therapy====
*Datopotamab deruxtecan (Datroway) 6 mg/kg IV once on day 1
21-day cycles
===References===
#TROPION-Breast01: Bardia A, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Zhang Q, Tsurutani J, Kalinsky K, Rubini Liedke PE, Xu L, Fairhurst RM, Khan S, Denduluri N, Rugo HS, Xu B, Pistilli B; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025 Jan 20;43(3):285-296. Epub 2024 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05104866
==Elacestrant monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bidard et al. 2022 (EMERALD)	2019-02 to 2020-10 	Phase 3 (E-RT-switch-ic)	1a. Anastrozole1b. Exemestane1c. Fulvestrant1d. Letrozole	Longer PFS1 (primary endpoint)PFS12: 22.3% vs 9.4%(HR 0.70, 95% CI 0.55-0.88)
1Reported efficacy is for all patients; the FDA approval is only for patients with ESR1 mutations.
====Endocrine therapy====
*Elacestrant (Orserdu) 400 mg PO once per day
Continued indefinitely
===References===
#EMERALD: Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. Epub 2022 May 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03778931
==Eribulin monotherapy==
===Regimen variant #1, 1.23 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02)	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
Note: This is the European dosing in TROPiCS-02.
====Chemotherapy====
*Eribulin (Halaven) 1.23 mg/m2 IV once per day on days 1 & 8
21-day cycles
===Regimen variant #2, 1.4 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (C)	Dato-DXd 	Shorter PFS (co-primary endpoint)Median PFS: 4.9 vs 6.9 mo(HR 1.59, 95% CI 1.32-1.92)
Note: This is the North American dosing in TROPiCS-02.
====Chemotherapy====
*Eribulin (Halaven) 1.4 mg/m2 IV once per day on days 1 & 8
21-day cycles
===References===
#TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03901339
##Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article EuroPMC
##HRQoL analysis: Rugo HS, Schmid P, Tolaney SM, Dalenc F, Marmé F, Shi L, Verret W, Shah A, Gharaibeh M, Bardia A, Cortes J. Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial. Oncologist. 2024 Sep 6;29(9):768-779. link to original article link to PMC article EuroPMC
#TROPION-Breast01: Bardia A, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Zhang Q, Tsurutani J, Kalinsky K, Rubini Liedke PE, Xu L, Fairhurst RM, Khan S, Denduluri N, Rugo HS, Xu B, Pistilli B; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025 Jan 20;43(3):285-296. Epub 2024 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05104866
#EVER-132-002: Xu B, Wang S, Yan M, Sohn J, Li W, Tang J, Wang X, Wang Y, Im SA, Jiang D, Valdez T, Dasgupta A, Zhang Y, Yan Y, Komatsubara KM, Chung WP, Ma F, Dai MS. Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024 Dec;30(12):3709-3716. Epub 2024 Oct 1. link to original article link to PMC article EuroPMC NCT04639986
==Everolimus & Exemestane==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Baselga et al. 2011 (BOLERO-2)	2009-2011 	Phase 3 (E-RT-esc)	Exemestane	Longer PFS1 (primary endpoint)Median PFS: 7.8 vs 3.2 mo(HR 0.45, 95% CI 0.38-0.54)Did not meet secondary endpoint of OS2 (secondary endpoint)Median OS: 31 vs 26.6 mo(HR 0.89, 95% CI 0.73-1.10)
1Reported efficacy for PFS is based on the 2013 update.
2Reported efficacy for OS is based on the 2014 update.
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
Continued indefinitely
===References===
# BOLERO-2: Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00863655
##HRQoL analysis: Burris HA 3rd, Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, Baselga J, Petrakova K, Hortobagyi GN, Komorowski A, Chouinard E, Young R, Gnant M, Pritchard KI, Bennett L, Ricci JF, Bauly H, Taran T, Sahmoud T, Noguchi S. Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer. 2013 May 15;119(10):1908-15. Erratum in: Cancer. 2019 Apr 15;125(8):1387-1388. link to original article EuroPMC
## Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Epub 2013 Oct 25. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to original article link to PMC article EuroPMC
## Update: Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA 3rd, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014 Dec;25(12):2357-62. Epub 2014 Sep 17. link to original article link to PMC article EuroPMC
==Everolimus & Tamoxifen==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bachelot et al. 2012 (TAMRAD)	2008-2009 	Randomized Phase 2 (E-esc)	Tamoxifen 	Longer OS (secondary endpoint)Median OS: NYR vs 32.9 mo(HR 0.45, 95% CI 0.24-0.81)
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
Continued indefinitely
===References===
# TAMRAD: Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01298713
==Exemestane monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kaufmann et al. 2000 	1995-1998 	Phase 3 (E-RT-switch-ic)	Megestrol 	Inconclusive whether equivalent ORR (primary endpoint)ORR: 15% vs 12.4%Seems to have longer OS (secondary endpoint)Median OS: NYR vs 123.4 weeks
Chia et al. 2008 (EFECT) 	2003-2005 	Phase 3 (E-switch-ic) 	Fulvestrant 	Did not meet primary endpoint of TTP
Johnston et al. 2013 (SoFEA) 	2004-2010 	Phase 3 (C) 	1. Anastrozole & Fulvestrant2. Fulvestrant	Did not meet primary endpoint of PFS
Baselga et al. 2011 (BOLERO-2) 	2009-2011 	Phase 3 (C) 	Everolimus & Exemestane 	Shorter PFS1 (primary endpoint)Median PFS: 3.2 vs 7.8 mo(HR 2.22, 95% CI 1.85-2.63)
Connolly et al. 2021 (ECOG-ACRIN E2112)	2014-2018 	Phase 3 (C) 	Entinostat & Exemestane 	Did not meet primary endpoint of PFSMedian PFS: 3.1 vs 3.3 mo(HR 1.15, 95% CI 0.88-1.49)
Jiang et al. 2019 (ACEbrca) 	2015-2017 	Phase 3 (C) 	Exemestane & Tucidinostat 	Seems to have shorter PFSMedian PFS: 3.8 vs 7.4 mo(HR 1.33, 95% CI 1.02-1.72)
Bidard et al. 2022 (EMERALD) 	2019-02 to 2020-10 	Phase 3 (C) 	Elacestrant 	Shorter PFSPFS12: 9.4% vs 22.3%(HR 1.43, 95% CI 1.14-1.82)
Xu et al. 2023 (EOC103A3101) 	2019-04-16 to 2020-05-13	Phase 3 (C) 	Entinostat & Exemestane 	Seems to have shorter PFS (primary endpoint)Median PFS: 3.72 vs 6.32 mo(HR 1.32, 95% CI 1.02-1.72)
1Reported efficacy for BOLERO-2 is based on the 2013 update.
Note: there is a regimen called ACE; the study is labeled as ACEbrca to reduce confusion.
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day
Continued indefinitely
===References===
# Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G; Exemestane Study Group. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol. 2000 Apr;18(7):1399-411. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G. Exemestane improves survival in metastatic breast cancer: results of a phase III randomized study. Clin Breast Cancer. 2000 Sep;1 Suppl 1:S15-8. link to original article EuroPMC
# EFECT: Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00065325
# BOLERO-2: Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00863655
##HRQoL analysis: Burris HA 3rd, Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, Baselga J, Petrakova K, Hortobagyi GN, Komorowski A, Chouinard E, Young R, Gnant M, Pritchard KI, Bennett L, Ricci JF, Bauly H, Taran T, Sahmoud T, Noguchi S. Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer. 2013 May 15;119(10):1908-15. Erratum in: Cancer. 2019 Apr 15;125(8):1387-1388. link to original article EuroPMC
## Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Epub 2013 Oct 25. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to original article link to PMC article EuroPMC
## Update: Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, Noguchi S, Perez A, Rugo HS, Deleu I, Burris HA 3rd, Provencher L, Neven P, Gnant M, Shtivelband M, Wu C, Fan J, Feng W, Taran T, Baselga J. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014 Dec;25(12):2357-62. Epub 2014 Sep 17. link to original article link to PMC article EuroPMC
# SoFEA: Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, Im YH, Braybrooke JP, Brunt AM, Cheung KL, Jyothirmayi R, Robinson A, Wardley AM, Wheatley D, Howell A, Coombes G, Sergenson N, Sin HJ, Folkerd E, Dowsett M, Bliss JM; SoFEA investigators. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013 Sep;14(10):989-98. Epub 2013 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00253422; NCT00944918
# ACEbrca: Jiang Z, Li W, Hu X, Zhang Q, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Pan Y, Sun Y, Wang H, Ouyang T, Gu K, Feng J, Wang X, Wang S, Liu T, Gao J, Cristofanilli M, Ning Z, Lu X. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):806-815. Epub 2019 Apr 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02482753
##Update: Zhang Q, Li W, Hu X, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Ning Z, Jiang Z. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer: a long-term safety and overall survival update from the randomised, double-blind, placebo-controlled, phase 3 trial. Transl Breast Cancer Res. 2023 Jul 30;4:18. link to original article link to PMC article EuroPMC
# ECOG-ACRIN E2112: Connolly RM, Zhao F, Miller KD, Lee MJ, Piekarz RL, Smith KL, Brown-Glaberman UA, Winn JS, Faller BA, Onitilo AA, Burkard ME, Budd GT, Levine EG, Royce ME, Kaufman PA, Thomas A, Trepel JB, Wolff AC, Sparano JA. E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer; A Trial of the ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2021 Oct 1;39(28):3171-3181. Epub 2021 Aug 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02115282
#EMERALD: Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. Epub 2022 May 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03778931
#EOC103A3101: Xu B, Zhang Q, Hu X, Li Q, Sun T, Li W, Ouyang Q, Wang J, Tong Z, Yan M, Li H, Zeng X, Shan C, Wang X, Yan X, Zhang J, Zhang Y, Wang J, Zhang L, Lin Y, Feng J, Chen Q, Huang J, Zhang L, Yang L, Tian Y, Shang H. Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Acta Pharm Sin B. 2023 May;13(5):2250-2258. Epub 2023 Feb 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03538171
==Exemestane & Palbociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bidard et al. 2022 (PADA-1)	2017-2019 	Phase 3 (C)	Fulvestrant & Palbociclib	Shorter PFSMedian PFS: 5.7 vs 11.9 mo(HR 1.64, 95% CI 1.16-2.33)
====Biomarker eligibility criteria====
*PADA-1: ESR1 mutation, detected in blood
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
===References===
#PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03079011
==Exemestane & Tucidinostat==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jiang et al. 2019 (ACEbrca)	2015-2017 	Phase 3 (E-esc)	Exemestane	Seems to have longer PFS (primary endpoint)Median PFS: 7.4 vs 3.8 mo(HR 0.75, 95% CI 0.58-0.98)
Note: there is a regimen called ACE; the study is labeled as ACEbrca to reduce confusion.
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day on days 1 to 28
====Targeted therapy====
*Chidamide (Epidaza) 30 mg PO once per day on days 1, 4, 8, 11, 15, 18, 22, 25
28-day cycles
===References===
# ACEbrca: Jiang Z, Li W, Hu X, Zhang Q, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Pan Y, Sun Y, Wang H, Ouyang T, Gu K, Feng J, Wang X, Wang S, Liu T, Gao J, Cristofanilli M, Ning Z, Lu X. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):806-815. Epub 2019 Apr 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02482753
##Update: Zhang Q, Li W, Hu X, Sun T, Cui S, Wang S, Ouyang Q, Yin Y, Geng C, Tong Z, Cheng Y, Ning Z, Jiang Z. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer: a long-term safety and overall survival update from the randomised, double-blind, placebo-controlled, phase 3 trial. Transl Breast Cancer Res. 2023 Jul 30;4:18. link to original article link to PMC article EuroPMC
==Fulvestrant monotherapy==
===Regimen variant #1, 500 mg===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Di Leo et al. 2010 (CONFIRM) 	2005-2007 	Phase 3 (E-RT-esc)	Fulvestrant; 250 mg 	Longer PFS (primary endpoint)Median PFS: 6.5 vs 5.5 mo(HR 0.80, 95% CI 0.68-0.94)Seems to have longer OS1 (secondary endpoint)Median OS: 26.4 vs 22.3 mo(HR 0.81, 95% CI 0.69-0.96)
Baselga et al. 2017 (BELLE-2) 	2012-2014 	Phase 3 (C) 	Buparlisib & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS: 5 vs 6.9 mo(HR 1.28, 95% CI 1.12-1.49)Might have shorter OS2 (secondary endpoint)Median OS: 30.4 vs 33.2 mo(HR 1.15, 95% CI 0.98-1.35)
Turner et al. 2015 (PALOMA-3) 	2013-10-07 to 2014-08-26	Phase 3 (C) 	Fulvestrant & Palbociclib 	Shorter PFS (primary endpoint)Median PFS: 3.8 vs 9.2 mo(HR 2.38, 95% CI 1.79-3.12)Seems to have shorter OS3 (secondary endpoint)Median OS: 28 vs 34.8 mo(HR 1.23, 95% CI 1.01-1.54)
Di Leo et al. 2017 (BELLE-3) 	2013-2016 	Phase 3 (C) 	Buparlisib & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS: 1.8 vs 3.9 mo(HR 1.49, 95% CI 1.19-1.89)
Sledge et al. 2017 (MONARCH 2) 	2014-08 to 2015-12 	Phase 3 (C) 	Abemaciclib & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS: 9.3 vs 16.4 mo(HR 1.82, 95% CI 1.47-2.22)Shorter OS4 (secondary endpoint)Median OS: 37.3 vs 46.7 mo(HR 1.32, 95% CI 1.05-1.64)
Slamon et al. 2018 (MONALEESA-3) 	2015-06 to 2016-06 	Phase 3 (C) 	Fulvestrant & Ribociclib 	Shorter PFS (primary endpoint)Median PFS: 12.8 vs 20.5 mo(HR 1.69, 95% CI 1.37-2.08)Shorter OS5 (secondary endpoint)Median OS: 41.5 vs 53.7 mo(HR 1.37, 95% CI 1.11-1.69)
Bidard et al. 2022 (EMERALD) 	2019-02 to 2020-10 	Phase 3 (C) 	Elacestrant 	Shorter PFSPFS12: 9.4% vs 22.3%(HR 1.43, 95% CI 1.14-1.82)
Xu et al. 2021 (DAWNA-1) 	2019-06-25 to 2020-09-02	Phase 3 (C) 	Dalpiciclib & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS: 7.2 vs 15.7 mo(HR 2.38, 95% CI 1.72-3.23)
Turner et al. 2023 (CAPItello-291)	2020-06-02 to 2021-10-13	Phase 3 (C) 	Capivasertib & Fulvestrant	Shorter PFSMedian PFS: 3.1 vs 7.3 mo(HR 2.00, 95% CI 1.54-2.63)
Xu et al. 2025 (LEONARDA-1) 	2021-09-10 to 2022-07-28	Phase 3 (C) 	Lerociclib & Fulvestrant 	Shorter PFS (primary endpoint)Median PFS 5.49 vs 11.07 mo(HR 2.22, 95% CI 1.52-3.22)
1Reported efficacy for CONFIRM is based on the 2013 update.
2Reported efficacy for BELLE-2 is based on the 2018 update.
3Reported efficacy for PALOMA-3 is based on the 2022 update.
4Reported efficacy for MONARCH 2 is based on the 2019 update.
5Reported efficacy for MONALEESA-3 is based on the 2021 update.
Note: while this regimen was inferior in BELLE-2 and BELLE-3, the authors note that "no further studies [of this combination] are being pursued because of the toxicity associated with [the experimental arm]."
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
28-day cycles
===Regimen variant #2, 250 mg===
Historic variant
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Howell et al. 1995 	Not reported 	Phase 1/2, fewer than 20 pts	 	
Osborne et al. 2002 (Trial 0021)	1997 to not reported	Phase 3 (E-RT-switch-ic) 	Anastrozole 	Did not meet primary endpoint of TTPMedian TTP: 5.4 vs 3.4 mo(HR 0.92, 95.14% CI 0.74-1.14)
Howell et al. 2002 (Trial 0020) 	Not reported 	Phase 3 (E-RT-switch-ic) 	Anastrozole 	Seems to have non-inferior TTP (primary endpoint)Median TTP: 5.5 vs 5.1 mo(HR 0.98, 95.14% CI 0.80-1.21)
Perey et al. 2006 (SAKK 21/00) 	Not reported 	Phase 2 	 	
Di Leo et al. 2010 (CONFIRM) 	2005-2007 	Phase 3 (C) 	Fulvestrant; 500 mg	Shorter PFS (primary endpoint)Median PFS: 5.5 vs 6.5 mo(HR 1.25, 95% CI 1.06-1.47)Seems to have shorter OS1 (secondary endpoint)Median OS: 22.3 vs 26.4 mo(HR 1.23, 95% CI 1.04-1.45)
Xu et al. 2010 	2005-2007 	Phase 3 (E-switch-ic) 	Anastrozole 	Might have shorter TTP (primary endpoint)Median TTP: 110 vs 159 days(HR 1.31, 95% CI 0.95-1.82)
1Reported efficacy for CONFIRM is based on the 2013 update.
====Endocrine therapy====
*Fulvestrant (Faslodex) 250 mg IM once on day 1
28-day cycles
===Regimen variant #3, 250 mg, with loading dose===
Historic variant
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Chia et al. 2008 (EFECT) 	2003-2005 	Phase 3 (E-switch-ic)	Exemestane 	Did not meet primary endpoint of TTP
Johnston et al. 2013 (SoFEA) 	2004-2010 	Phase 3 (E-switch-ic)	1. Exemestane 	Did not meet primary endpoint of PFSMedian PFS: 4.8 vs 3.4 mo(HR 0.95, 95% CI 0.79-1.14)
Johnston et al. 2013 (SoFEA) 	2004-2010 	Phase 3 (E-switch-ic)	2. Anastrozole & Fulvestrant	Did not meet primary endpoint of PFSMedian PFS: 4.8 vs 4.4 mo
Burstein et al. 2014 (CALGB 40302)	2006-2010 	Phase 3 (C) 	Fulvestrant & Lapatinib 	Did not meet primary endpoint of PFSMedian PFS: 3.8 vs 4.7 mo(HR 1.04, 95% CI 0.82-1.33)
Note: EFECT states that the 2nd dose of cycle 1 is to be given on day 14, but also notes in the abstract that the first day of the cycle is day 0. Based on other published fulvestrant schedules, we note the second dose as on day 15.
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once on day 1, then 250 mg IM once on day 15
**Cycle 2 onwards: 250 mg IM once on day 1
28-day cycles
===References===
# Howell A, DeFriend D, Robertson J, Blamey R, Walton P. Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet. 1995 Jan 7;345(8941):29-30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Trial 0021: Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R, Buzdar A. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002 Aug 15;20(16):3386-95. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00635713
## Pooled update: Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003 Jul 15;98(2):229-38. link to original article EuroPMC
## Pooled update: Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005 Jul 15;104(2):236-9. link to original article EuroPMC
# Trial 0020: Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials. Cancer. 2003 Jul 15;98(2):229-38. link to original article EuroPMC
## Pooled update: Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones SE, Come SE, Osborne CK, Robertson JF. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer. 2005 Jul 15;104(2):236-9. link to original article EuroPMC
# SAKK 21/00: Perey L, Paridaens R, Hawle H, Zaman K, Nolé F, Wildiers H, Fiche M, Dietrich D, Clément P, Köberle D, Goldhirsch A, Thürlimann B. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol. 2007 Jan;18(1):64-9. Epub 2006 Oct 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# EFECT: Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00065325
# CONFIRM: Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martín M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010 Oct 20;28(30):4594-600. Epub 2010 Sep 20. Erratum in: J Clin Oncol. 2011 Jun 1;29(16):2293. link to original article EuroPMC NCT00099437
## Update: Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, Martin M. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014 Jan;106(1):djt337. Epub 2013 Dec 7. link to original article link to PMC article EuroPMC
# Xu B, Jiang Z, Shao Z, Wang J, Feng J, Song S, Chen Z, Gu K, Yu S, Zhang Y, Wang C, Zhang F, Yang J. Fulvestrant 250 mg versus anastrozole for Chinese patients with advanced breast cancer: results of a multicentre, double-blind, randomised phase III trial. Cancer Chemother Pharmacol. 2011 Jan;67(1):223-30. Epub 2010 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SoFEA: Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L, Im YH, Braybrooke JP, Brunt AM, Cheung KL, Jyothirmayi R, Robinson A, Wardley AM, Wheatley D, Howell A, Coombes G, Sergenson N, Sin HJ, Folkerd E, Dowsett M, Bliss JM; SoFEA investigators. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial. Lancet Oncol. 2013 Sep;14(10):989-98. Epub 2013 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00253422; NCT00944918
# CALGB 40302: Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, Lake DE, Ma C, Blackwell KL, Winer EP, Hudis CA. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014 Dec 10;32(35):3959-66. Epub 2014 Oct 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00390455
# PALOMA-3: Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. Epub 2015 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01942135
## Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original article EuroPMC
## PRO analysis: Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, André F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun;27(6):1047-1054. Epub 2016 Mar 30. link to original article link to PMC article EuroPMC
## Subgroup analysis: Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im SA, Masuda N, Loi S, André F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017 Sep;22(9):1028-1038. Epub 2017 Jun 26. link to original article link to PMC article EuroPMC
## Update: Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. Epub 2018 Oct 20. link to original article EuroPMC
## Update: Cristofanilli M, Rugo HS, Im SA, Slamon DJ, Harbeck N, Bondarenko I, Masuda N, Colleoni M, DeMichele A, Loi S, Iwata H, O'Leary B, André F, Loibl S, Bananis E, Liu Y, Huang X, Kim S, Lechuga Frean MJ, Turner NC. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study. Clin Cancer Res. 2022 Aug 15;28(16):3433-3442. link to original article link to PMC article EuroPMC
# BELLE-2: Baselga J, Im SA, Iwata H, Cortés J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):904-916. Epub 2017 May 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01610284
## Update: Campone M, Im SA, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Le Mouhaër S, Sankaran B, Bourdeau L, El-Hashimy M, Sellami D, Baselga J. Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: overall survival results from BELLE-2. Eur J Cancer. 2018 Nov;103:147-154. Epub 2018 Sep 18. link to original article EuroPMC
# MONARCH 2: Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. Epub 2017 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02107703
## Update: Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Conte P, Lu Y, Barriga S, Hurt K, Frenzel M, Johnston S, Llombart-Cussac A. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019 Sep 29;6(1):116-124. Epub 2019 Sep 29. link to original article link to PMC article EuroPMC
##HRQoL analysis: Kaufman PA, Toi M, Neven P, Sohn J, Grischke EM, Andre V, Stoffregen C, Shekarriz S, Price GL, Carter GC, Sledge GW Jr. Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist. 2020 Feb;25(2):e243-e251. Epub 2019 Oct 24. link to original article link to PMC article EuroPMC
# BELLE-3: Di Leo A, Johnston S, Lee KS, Ciruelos E, Lønning PE, Janni W, O'Regan R, Mouret-Reynier MA, Kalev D, Egle D, Csőszi T, Bordonaro R, Decker T, Tjan-Heijnen VCG, Blau S, Schirone A, Weber D, El-Hashimy M, Dharan B, Sellami D, Bachelot T. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jan;19(1):87-100. Epub 2017 Dec 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01633060
# MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02422615
## Update: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. Epub 2019 Dec 11. link to original article EuroPMC
##HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article EuroPMC
## Update: Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, Petrakova K, Valeria Bianchi G, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Ji Y, Wang C, Deore U, Chakravartty A, Zarate JP, Taran T, Fasching PA. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021 Aug;32(8):1015-1024. Epub 2021 Jun 5. Erratum in: Ann Oncol. 2021 Oct;32(10):1307. link to original article EuroPMC
#DAWNA-1: Xu B, Zhang Q, Zhang P, Hu X, Li W, Tong Z, Sun T, Teng Y, Wu X, Ouyang Q, Yan X, Cheng J, Liu Q, Feng J, Wang X, Yin Y, Shi Y, Pan Y, Wang Y, Xie W, Yan M, Liu Y, Yan P, Wu F, Zhu X, Zou J; DAWNA-1 Study Consortium. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021 Nov;27(11):1904-1909. Epub 2021 Nov 4. link to original article EuroPMC NCT03927456
#EMERALD: Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. Epub 2022 May 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03778931
#CAPItello-291: Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04305496
##PRO analysis: Oliveira M, Rugo HS, Howell SJ, Dalenc F, Cortes J, Gomez HL, Hu X, Toi M, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Nowecki Z, Park YH, Sohn JH, Tokunaga E, Yousef S, Zhukova L, Fulford M, Andrews H, Wadsworth I, D'Cruz C, Turner NC; CAPItello-291 study group. Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2024 Sep;25(9):1231-1244. link to original article EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
#LEONARDA-1: Xu B, Zhang Q, Luo Y, Tong Z, Sun T, Shan C, Liu X, Yao Y, Zhao B, Wang S, Zeng X, Hu C, Yan X, Wang X, Jia H, Chen Z, Qiu F, Wu X, Zhang D, Li T. Lerociclib plus fulvestrant in patients with HR+/HER2- locally advanced or metastatic breast cancer who have progressed on prior endocrine therapy: LEONARDA-1 a phase III randomized trial. Nat Commun. 2025 Jan 16;16(1):716. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05054751
==Fulvestrant & Palbociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Turner et al. 2015 (PALOMA-3)	2013-10-07 to 2014-08-26	Phase 3 (E-RT-esc) 	Fulvestrant 	Longer PFS (primary endpoint)Median PFS: 9.2 vs 3.8 mo(HR 0.42, 95% CI 0.32-0.56)Seems to have longer OS1 (secondary endpoint)Median OS: 34.8 vs 28 mo(HR 0.81, 95% CI 0.65-0.99)
Bidard et al. 2022 (PADA-1) 	2017-2019 	Phase 3 (E-switch-ic)	1a. Anastrozole & Palbociclib1b. Exemestane & Palbociclib1c. Letrozole & Palbociclib	Longer PFS (co-primary endpoint)Median PFS: 11.9 vs 5.7 mo(HR 0.61, 95% CI 0.43-0.86)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	Fulvestrant 	Might have shorter PFS-2 (primary endpoint)Median PFS-2: 26.8 vs 31 mo(sHR 1.15, 95% CI 0.97-1.35)
Ahmed Shaaban et al. 2024 	2022-07 to 2023-12 	Phase 3 (E-switch-ic)	Fulvestrant & Ribociclib 	See note
1Reported efficacy for PALOMA-3 is based on the 2022 update.
Note: Details including fulvestrant dosing and primary endpoint declaration are scanty in Ahmed Shaaban et al. 2024; the trial is included here as it is likely one of the very few that compares two different CDK4/6 inhibitors.
====Biomarker eligibility criteria====
*PADA-1: ESR1 mutation, detected in blood
====Preceding treatment====
*SONIA: First-line Anastrozole or Letrozole, with progression
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
===References===
# PALOMA-3: Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. Epub 2015 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01942135
## Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original article EuroPMC
## PRO analysis: Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, André F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun;27(6):1047-1054. Epub 2016 Mar 30. link to original article link to PMC article EuroPMC
## Subgroup analysis: Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im SA, Masuda N, Loi S, André F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017 Sep;22(9):1028-1038. Epub 2017 Jun 26. link to original article link to PMC article EuroPMC
## Update: Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. Epub 2018 Oct 20. link to original article EuroPMC
## Update: Cristofanilli M, Rugo HS, Im SA, Slamon DJ, Harbeck N, Bondarenko I, Masuda N, Colleoni M, DeMichele A, Loi S, Iwata H, O'Leary B, André F, Loibl S, Bananis E, Liu Y, Huang X, Kim S, Lechuga Frean MJ, Turner NC. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study. Clin Cancer Res. 2022 Aug 15;28(16):3433-3442. link to original article link to PMC article EuroPMC
#PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03079011
#Ahmed Shaaban MH, Elbaiomy MA, Eltantawy A, El-Gilany Abdel-Fattah AH, Shamaa SSA. Comparing Ribociclib versus Palbociclib as a Second Line Treatment in Combination with Fulvestrant in Metastatic Breast Cancer: A Randomised Clinical Trial. Asian Pac J Cancer Prev. 2024 Sep 1;25(9):3039-3049. link to original article contains partial dosing details in abstract EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Fulvestrant & Ribociclib==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3)	2015-06 to 2016-06 	Phase 3 (E-RT-esc) 	Fulvestrant 	Longer PFS (primary endpoint)Median PFS: 20.5 vs 12.8 mo(HR 0.59, 95% CI 0.48-0.73)Longer OS1 (secondary endpoint)Median OS: 53.7 vs 41.5 mo(HR 0.73, 95% CI 0.59-0.90)
Sonke et al. 2024 (SONIA) 	2017-11-23 to 2021-09-01	Phase 3 (C) 	Fulvestrant 	Might have shorter PFS-2 (primary endpoint)Median PFS-2: 26.8 vs 31 mo(sHR 1.15, 95% CI 0.97-1.35)
Ahmed Shaaban et al. 2024 	2022-07 to 2023-12 	Phase 3 (E-switch-ic)	Fulvestrant & Palbociclib	See note
1Reported efficacy for MONALEESA-3 is based on the 2021 update.
Note: Details including fulvestrant dosing and primary endpoint declaration are scanty in Ahmed Shaaban et al. 2024; the trial is included here as it is likely one of the very few that directly compares two different CDK4/6 inhibitors.
====Preceding treatment====
*SONIA: First-line Anastrozole or Letrozole, with progression
====Endocrine therapy====
*Fulvestrant (Faslodex) as follows:
**Cycle 1: 500 mg IM once per day on days 1 & 15
**Cycle 2 onwards: 500 mg IM once on day 1
====Targeted therapy====
*Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21
28-day cycles
===References===
# MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02422615
## Update: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. Epub 2019 Dec 11. link to original article EuroPMC
##HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article EuroPMC
## Update: Slamon DJ, Neven P, Chia S, Jerusalem G, De Laurentiis M, Im S, Petrakova K, Valeria Bianchi G, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Ji Y, Wang C, Deore U, Chakravartty A, Zarate JP, Taran T, Fasching PA. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol. 2021 Aug;32(8):1015-1024. Epub 2021 Jun 5. Erratum in: Ann Oncol. 2021 Oct;32(10):1307. link to original article EuroPMC
#Ahmed Shaaban MH, Elbaiomy MA, Eltantawy A, El-Gilany Abdel-Fattah AH, Shamaa SSA. Comparing Ribociclib versus Palbociclib as a Second Line Treatment in Combination with Fulvestrant in Metastatic Breast Cancer: A Randomised Clinical Trial. Asian Pac J Cancer Prev. 2024 Sep 1;25(9):3039-3049. link to original article contains partial dosing details in abstract EuroPMC
#SONIA: Sonke GS, van Ommen-Nijhof A, Wortelboer N, van der Noort V, Swinkels ACP, Blommestein HM, Guerrero Paez C, Mol L, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van Schaik-van de Mheen C, Tol J, Tromp-van Driel CS, Vrijaldenhoven S, van Leeuwen-Stok AE, Konings IR, Jager A; SONIA Study Consortium. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer. Nature. 2024 Dec;636(8042):474-480. Epub 2024 Nov 27. link to original article does not contain dosing details in manuscript EuroPMC NCT03425838
==Gemcitabine monotherapy==
===Regimen variant #1, 2 out of 3 weeks===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (C)	Dato-DXd 	Shorter PFS (co-primary endpoint)Median PFS: 4.9 vs 6.9 mo(HR 1.59, 95% CI 1.32-1.92)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycles
===Regimen variant #2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02)	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
====Chemotherapy====
*Gemcitabine (Gemzar) 800 to 1200 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
#TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03901339
##Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article EuroPMC
##HRQoL analysis: Rugo HS, Schmid P, Tolaney SM, Dalenc F, Marmé F, Shi L, Verret W, Shah A, Gharaibeh M, Bardia A, Cortes J. Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial. Oncologist. 2024 Sep 6;29(9):768-779. link to original article link to PMC article EuroPMC
#TROPION-Breast01: Bardia A, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Zhang Q, Tsurutani J, Kalinsky K, Rubini Liedke PE, Xu L, Fairhurst RM, Khan S, Denduluri N, Rugo HS, Xu B, Pistilli B; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025 Jan 20;43(3):285-296. Epub 2024 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05104866
#EVER-132-002: Xu B, Wang S, Yan M, Sohn J, Li W, Tang J, Wang X, Wang Y, Im SA, Jiang D, Valdez T, Dasgupta A, Zhang Y, Yan Y, Komatsubara KM, Chung WP, Ma F, Dai MS. Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024 Dec;30(12):3709-3716. Epub 2024 Oct 1. link to original article link to PMC article EuroPMC NCT04639986
==Letrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Dombernowsky et al. 1998 (AR/BC2)	1993-03 to 1994-09 	Phase 3 (E-RT-switch-ic) 	1. Letrozole; 0.5 mg/day	Seems to have longer OS (secondary endpoint)Higher ORR (primary endpoint)
Dombernowsky et al. 1998 (AR/BC2)	1993-03 to 1994-09 	Phase 3 (E-RT-switch-ic) 	2. Megestrol 	Seems to have longer TTTF (secondary endpoint)Seems to have higher ORR (primary endpoint)
Gershanovich et al. 1998 (AR/BC3)	Not reported 	Randomized (E-RT-switch-ic)	1. Letrozole; 0.5 mg/day	Did not meet primary endpoint of ORR
Gershanovich et al. 1998 (AR/BC3)	Not reported 	Randomized (E-RT-switch-ic)	2. Aminoglutethimide 	Might have higher ORR (primary endpoint)
Buzdar et al. 2001 	Not reported 	Phase 3 (E-switch-ic) 	1. Letrozole; 0.5 mg/day	Did not meet primary endpoint of ORR
Buzdar et al. 2001 	Not reported 	Phase 3 (E-switch-ic) 	2. Megestrol 	Did not meet primary endpoint of ORR
Rose et al. 2003 	1997-12 to 1999-11 	Phase 3 (E-swith-ic) 	Anastrozole 	Did not meet primary endpoint of TTP
Bidard et al. 2022 (EMERALD) 	2019-02 to 2020-10 	Phase 3 (C) 	Elacestrant 	Shorter PFSPFS12: 9.4% vs 22.3%(HR 1.43, 95% CI 1.14-1.82)
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
===References===
# AR/BC2: Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998 Feb;16(2):453-61. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# AR/BC3: Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, O'Higgins N, Romieu G, Friederich P, Lassus M; Letrozole International Trial Group. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol. 1998 Jun;9(6):639-45. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X, Brady C. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001 Jul 15;19(14):3357-66. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Rose C, Vtoraya O, Pluzanska A, Davidson N, Gershanovich M, Thomas R, Johnson S, Caicedo JJ, Gervasio H, Manikhas G, Ben Ayed F, Burdette-Radoux S, Chaudri-Ross HA, Lang R. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003 Nov;39(16):2318-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EMERALD: Bidard FC, Kaklamani VG, Neven P, Streich G, Montero AJ, Forget F, Mouret-Reynier MA, Sohn JH, Taylor D, Harnden KK, Khong H, Kocsis J, Dalenc F, Dillon PM, Babu S, Waters S, Deleu I, García Sáenz JA, Bria E, Cazzaniga M, Lu J, Aftimos P, Cortés J, Liu S, Tonini G, Laurent D, Habboubi N, Conlan MG, Bardia A. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022 Oct 1;40(28):3246-3256. Epub 2022 May 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT03778931
==Letrozole & Palbociclib==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bidard et al. 2022 (PADA-1)	2017-2019 	Phase 3 (C)	Fulvestrant & Palbociclib	Shorter PFSMedian PFS: 5.7 vs 11.9 mo(HR 1.64, 95% CI 1.16-2.33)
====Biomarker eligibility criteria====
*PADA-1: ESR1 mutation, detected in blood
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
====Targeted therapy====
*Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21
28-day cycles
===References===
#PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03079011
==Sacituzumab govitecan monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02)	2019-05 to 2021-04 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Capecitabine1b. Eribulin1c. Gemcitabine1d. Vinorelbine	Seems to have longer OS (secondary endpoint)Median OS: 14.4 vs 11.2 mo(HR 0.79, 95% CI 0.65-0.96)Longer PFS (primary endpoint)Median PFS: 5.5 vs 4.0 mo(HR 0.66, 95% CI 0.53-0.83)
Xu et al. 2024 (EVER-132-002)	2020-12-09 to 2022-12-02	Phase 3 (E-switch-ooc) 	Investigator's choice of:1a. Capecitabine1b. Eribulin1c. Gemcitabine1d. Vinorelbine	Longer PFS (primary endpoint)Median PFS: 4.3 vs 4.2 mo(HR 0.67, 95% CI 0.52-0.87)Longer OS (secondary endpoint)Median OS: 21 vs 15.3 mo(HR 0.64, 95% CI 0.47-0.88)
====Antibody-drug conjugate therapy====
*Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8
21-day cycles
===References===
#TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03901339
##Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article EuroPMC
##HRQoL analysis: Rugo HS, Schmid P, Tolaney SM, Dalenc F, Marmé F, Shi L, Verret W, Shah A, Gharaibeh M, Bardia A, Cortes J. Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial. Oncologist. 2024 Sep 6;29(9):768-779. link to original article link to PMC article EuroPMC
#EVER-132-002: Xu B, Wang S, Yan M, Sohn J, Li W, Tang J, Wang X, Wang Y, Im SA, Jiang D, Valdez T, Dasgupta A, Zhang Y, Yan Y, Komatsubara KM, Chung WP, Ma F, Dai MS. Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024 Dec;30(12):3709-3716. Epub 2024 Oct 1. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04639986
==Tamoxifen monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Legha et al. 1979 	1977 	Phase 2 	 	
Tormey et al. 1983 	Not reported 	Randomized (C) 	Fluoxymesterone & Tamoxifen	Shorter TTTF
Bachelot et al. 2012 (TAMRAD)	2008-2009 	Randomized Phase 2 (C)	Everolimus & Tamoxifen 	Shorter OSMedian OS: 32.9 vs NYR mo(HR 2.22, 95% CI 1.23-4.17)
Note: Tormey et al. 1983 specified a wide range of tamoxifen dosing; see paper for details.
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day
Continued indefinitely
===References===
# Legha SS, Buzdar AU, Hortobagyi GN, Wiseman C, Benjamin RS, Blumenschein GR. Tamoxifen: use in treatment of metastatic breast cancer refractory to combination chemotherapy. JAMA. 1979 Jul 6;242(1):49-52. link to original article EuroPMC
# Tormey DC, Lippman ME, Edwards BK, Cassidy JG. Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med. 1983 Feb;98(2):139-44. link to original article EuroPMC
# TAMRAD: Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E; GINECO. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01298713
==Vinorelbine monotherapy==
===Regimen variant #1, qwk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02)	2019-05 to 2021-04 	Phase 3 (C)	Sacituzumab govitecan	Shorter PFSMedian PFS: 4 vs 5.5 mo(HR 1.52, 95% CI 1.20-1.89)Seems to have shorter OSMedian OS: 11.2 vs 14.4 mo(HR 1.27, 95% CI 1.04-1.54)
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once on day 1
7-day cycles
===Regimen variant #2, 2 out of 3 weeks===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bardia et al. 2024 (TROPION-Breast01)	2021-10-18 to 2022-12-26	Phase 3 (C)	Dato-DXd 	Shorter PFS (co-primary endpoint)Median PFS: 4.9 vs 6.9 mo(HR 1.59, 95% CI 1.32-1.92)
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
21-day cycles
===References===
#TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03901339
##Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article EuroPMC
##HRQoL analysis: Rugo HS, Schmid P, Tolaney SM, Dalenc F, Marmé F, Shi L, Verret W, Shah A, Gharaibeh M, Bardia A, Cortes J. Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial. Oncologist. 2024 Sep 6;29(9):768-779. link to original article link to PMC article EuroPMC
#TROPION-Breast01: Bardia A, Jhaveri K, Im SA, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Zhang Q, Tsurutani J, Kalinsky K, Rubini Liedke PE, Xu L, Fairhurst RM, Khan S, Denduluri N, Rugo HS, Xu B, Pistilli B; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025 Jan 20;43(3):285-296. Epub 2024 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05104866
#EVER-132-002: Xu B, Wang S, Yan M, Sohn J, Li W, Tang J, Wang X, Wang Y, Im SA, Jiang D, Valdez T, Dasgupta A, Zhang Y, Yan Y, Komatsubara KM, Chung WP, Ma F, Dai MS. Sacituzumab govitecan in HR+HER2- metastatic breast cancer: the randomized phase 3 EVER-132-002 trial. Nat Med. 2024 Dec;30(12):3709-3716. Epub 2024 Oct 1. link to original article link to PMC article EuroPMC NCT04639986
Category:Breast cancer regimens
Category:Biomarker-specific pages
Category:Malignant breast neoplasm