Breast cancer, ER and HER2 co-expressing

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Note: these are regimens tested in patients with hormone receptor-positive, HER2-positive breast cancer. Please see the main breast cancer page, ER+ breast cancer page, HER2+ breast cancer page, and HER2-low breast cancer page for other regimens.
Last updated on 2024-07-23:19 regimens on this page
21 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/CAP==
*2023: Wolff et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update EuroPMC
**2014: Wolff et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update EuroPMC
**2013: Wolff et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update EuroPMC
**2007: Wolff et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer EuroPMC
*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.
=Neoadjuvant chemotherapy=
==Trastuzumab emtansine monotherapy==
T-DM1: Trastuzumab-DM1 (Trastuzumab emtansine)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harbeck et al. 2017 (WGSG ADAPT)	2012-2015 	Randomized Phase 2 (E-switch-ic)	1. T-DM1 & ET 	Not reported
Harbeck et al. 2017 (WGSG ADAPT)	2012-2015 	Randomized Phase 2 (E-switch-ic)	2. Trastuzumab & ET	Higher pCR rate (primary endpoint)
====Antibody-drug conjugate therapy====
*Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC-TH, unless the patient had pCR in which case adjuvant therapy was optional
===References===
# WGSG ADAPT: Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01817452
==T-DM1 & ET==
T-DM1 & ET: Trastuzumab-DM1 (Trastuzumab emtansine) & Endocrine Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harbeck et al. 2017 (WGSG ADAPT)	2012-2015 	Randomized Phase 2 (E-esc)	1. T-DM1 	Not reported
Harbeck et al. 2017 (WGSG ADAPT)	2012-2015 	Randomized Phase 2 (E-esc)	2. Trastuzumab & ET	Higher pCR rate (primary endpoint)
====Antibody-drug conjugate therapy====
*Trastuzumab emtansine (Kadcyla) 3.6 mg/kg IV once on day 1
====Endocrine therapy====
*One of the following:
**Premenopausal women: Tamoxifen (Nolvadex) recommended
**GnRH analogs were also allowed
**Postmenopausal women: Aromatase inhibitor recommended
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC-TH, unless the patient had pCR in which case adjuvant therapy was optional
===References===
# WGSG ADAPT: Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01817452
==Trastuzumab & ET==
Trastuzumab & ET: Trastuzumab & Endocrine Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harbeck et al. 2017 (WGSG ADAPT)	2012-2015 	Randomized Phase 2 (C)	1. T-DM12. T-DM1 & ET	Lower pCR rate
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycles 2 to 4: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Endocrine therapy by the following criteria:
**Premenopausal women: Tamoxifen (Nolvadex) recommended
***GnRH analogs were also allowed
**Postmenopausal women: Aromatase inhibitor recommended
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery was performed within 3 weeks of the end of therapy. Adjuvant therapy consisted of EC-TH, unless the patient had pCR in which case adjuvant therapy was optional
===References===
# WGSG ADAPT: Harbeck N, Gluz O, Christgen M, Kates RE, Braun M, Küemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, von Schumann R, Liedtke C, Grischke EM, Schumacher J, Wuerstlein R, Kreipe HH, Nitz UA; West German Study Group. De-escalation strategies in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (BC): Final analysis of the West German Study Group Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early BC HER2- and hormone receptor-positive phase II randomized trial-efficacy, safety, and predictive markers for 12 weeks of neoadjuvant trastuzumab emtansine with or without endocrine therapy (ET) versus trastuzumab plus ET. J Clin Oncol. 2017 Sep 10;35(26):3046-3054. Epub 2017 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01817452
=Adjuvant therapy=
==Anastrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (eMonarcHER)	2021-ongoing 	Phase 3 (C)	ET & Abemaciclib	In progress
====Preceding treatment====
*Adjuvant HER2-targeted therapy
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day
28-day cycle for up to 130 cycles (10 years)
===References===
#eMonarcHER: NCT04752332
=Metastatic disease, first-line therapy=
==Anastrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kaufman et al. 2009 (TAnDEM)	2001-2004 	Phase 3 (C)	Anastrozole & Trastuzumab	Shorter PFSMedian PFS: 2.4 vs 4.8 mo(HR 1.59, 95% CI 1.19-2.13)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 28
28-day cycles
===References===
# TAnDEM: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00022672
==Anastrozole & Trastuzumab==
===Regimen variant #1, weekly trastuzumab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kaufman et al. 2009 (TAnDEM)	2001-2004 	Phase 3 (E-esc)	Anastrozole	Longer PFS (primary endpoint)Median PFS: 4.8 vs 2.4 mo(HR 0.63, 95% CI 0.47-0.84)
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 7
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 4 mg/kg IV once on day 1
**Cycle 2 onwards: 2 mg/kg IV once on day 1
7-day cycles
===Regimen variant #2, q3wk trastuzumab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib 1c. Lapatinib & Letrozole 	Did not meet secondary endpoint of PFS
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	2a. Anastrozole, Lapatinib, Trastuzumab2b. Exemestane, Lapatinib, Trastuzumab2c. Lapatinib, Letrozole, Trastuzumab	Shorter PFSMedian PFS: 5.6 vs 11 mo(HR 1.61, 95% CI 1.14-2.22)
Hua et al. 2022 (SYSUCC-002) 	2013-2019 	Phase 3 (E-switch-ooc)	1a. TH (Paclitaxel)1b. TH (Docetaxel)1c. VH1d. XH 	Non-inferior PFS (primary endpoint)Median PFS: 19.2 vs 14.8 mo(HR 0.88, 95% CI 0.71-1.09)
Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. 2022 does not contain dosing instructions for anastrozole.
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 21
21-day cycles
===References===
# TAnDEM: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00022672
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article contains partial protocol link to PMC article EuroPMC NCT01950182
==Anastrozole, Lapatinib, Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib1c. Lapatinib & Letrozole 	Not reported
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	2a. Anastrozole & Trastuzumab2b. Exemestane & Trastuzumab2c. Letrozole & Trastuzumab	Longer PFS (primary endpoint)Median PFS: 11 vs 5.6 mo(HR 0.62, 95% CI 0.45-0.88)
Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.
====Targeted therapy====
*Lapatinib (Tykerb) 1000 mg PO once per day on days 1 to 21
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 21
21-day cycles
===References===
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
==Capecitabine & Trastuzumab (XH)==
XH: Xeloda (Capecitabine) & Herceptin (Trastuzumab)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (C)	1a. Anastrozole & Trastuzumab1b. Exemestane & Trastuzumab1c. Letrozole & Trastuzumab1d. Tamoxifen & Trastuzumab1e. Toremifene & Trastuzumab	Non-inferior PFS (primary endpoint)Median PFS: 14.8 vs 19.2 mo(HR 1.14, 95% CI 0.92-1.41)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01950182
==Docetaxel & Trastuzumab (TH)==
TH: Taxotere (Docetaxel) & Herceptin (Trastuzumab)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (C)	1a. Anastrozole & Trastuzumab1b. Exemestane & Trastuzumab1c. Letrozole & Trastuzumab1d. Tamoxifen & Trastuzumab1e. Toremifene & Trastuzumab	Non-inferior PFS (primary endpoint)Median PFS: 14.8 vs 19.2 mo(HR 1.14, 95% CI 0.92-1.41)
====Chemotherapy====
*Docetaxel (Taxotere) 75 to 100 mg/m2 IV once on day 1
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01950182
==Exemestane & Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib1c. Lapatinib & Letrozole 	Did not meet secondary endpoint of PFS
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	2a. Anastrozole, Lapatinib, Trastuzumab2b. Exemestane, Lapatinib, Trastuzumab2c. Lapatinib, Letrozole, Trastuzumab	Shorter PFSMedian PFS: 5.6 vs 11 mo(HR 1.61, 95% CI 1.14-2.22)
Hua et al. 2022 (SYSUCC-002) 	2013-2019 	Phase 3 (E-switch-ooc)	1a. TH (Paclitaxel)1b. TH (Docetaxel)1c. VH1d. XH 	Non-inferior PFS (primary endpoint)Median PFS: 19.2 vs 14.8 mo(HR 0.88, 95% CI 0.71-1.09)
Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. 2022 does not contain dosing instructions for exemestane.
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Exemestane (Aromasin) 1 mg PO once per day on days 1 to 21
21-day cycles
===References===
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article contains partial protocol link to PMC article EuroPMC NCT01950182
==Exemestane, Lapatinib, Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib1c. Lapatinib & Letrozole 	Not reported
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	2a. Anastrozole & Trastuzumab2b. Exemestane & Trastuzumab2c. Letrozole & Trastuzumab	Longer PFS (primary endpoint)Median PFS: 11 vs 5.6 mo(HR 0.62, 95% CI 0.45-0.88)
Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.
====Targeted therapy====
*Lapatinib (Tykerb) 1000 mg PO once per day on days 1 to 21
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Exemestane (Aromasin) 25 mg PO once per day on days 1 to 21
21-day cycles
===References===
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
==Lapatinib & Letrozole==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Johnston et al. 2009 (EGF30008)	2003-2006 	Phase 3 (E-RT-esc)	Letrozole 	Seems to have longer PFS (primary endpoint)Median PFS: 8.2 vs 3 mo(HR 0.71, 95% CI 0.53-0.96)
====Targeted therapy====
*Lapatinib (Tykerb) 1500 mg PO once per day
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day
28-day cycles
===References===
# EGF30008: Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00073528
==Lapatinib, Letrozole, Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib1c. Lapatinib & Letrozole 	Not reported
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (E-esc)	2a. Anastrozole & Trastuzumab2b. Exemestane & Trastuzumab2c. Letrozole & Trastuzumab	Longer PFS (primary endpoint)Median PFS: 11 vs 5.6 mo(HR 0.62, 95% CI 0.45-0.88)
Note: the original article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published.
====Targeted therapy====
*Lapatinib (Tykerb) 1000 mg PO once per day on days 1 to 21
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 21
21-day cycles
===References===
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
==Letrozole monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2009 (EGF30008)	2003-2006 	Phase 3 (C)	Lapatinib & Letrozole	Seems to have shorter PFSMedian PFS: 3 vs 8.2 mo(HR 1.41, 95% CI 1.04-1.89)
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 28
28-day cycles
===References===
# EGF30008: Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00073528
==Letrozole & Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	1a. Anastrozole & Lapatinib1b. Exemestane & Lapatinib1c. Lapatinib & Letrozole 	Did not meet secondary endpoint of PFS
Johnston et al. 2020 (ALTERNATIVE)	2011-2016 	Phase 3 (C) 	2a. Anastrozole, Lapatinib, Trastuzumab2b. Exemestane, Lapatinib, Trastuzumab2c. Lapatinib, Letrozole, Trastuzumab	Shorter PFSMedian PFS: 5.6 vs 11 mo(HR 1.61, 95% CI 1.14-2.22)
Hua et al. 2022 (SYSUCC-002) 	2013-2019 	Phase 3 (E-switch-ooc)	1a. TH (Paclitaxel)1b. TH (Docetaxel)1c. VH1d. XH 	Non-inferior PFS (primary endpoint)Median PFS: 19.2 vs 14.8 mo(HR 0.88, 95% CI 0.71-1.09)
Note: the original ALTERNATIVE article published in 2018 was retracted due to numeric errors in the analysis, and an update has been published. Hua et al. does not contain dosing instructions for letrozole.
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Letrozole (Femara) 2.5 mg PO once per day on days 1 to 21
21-day cycles
===References===
# ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE. J Clin Oncol. 2021 Jan 1;39(1):79-89. Epub 2020 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01160211
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article contains partial protocol link to PMC article EuroPMC NCT01950182
==Paclitaxel & Trastuzumab (TH)==
TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (C)	1a. Anastrozole & Trastuzumab1b. Exemestane & Trastuzumab1c. Letrozole & Trastuzumab1d. Tamoxifen & Trastuzumab1e. Toremifene & Trastuzumab	Non-inferior PFS (primary endpoint)Median PFS: 14.8 vs 19.2 mo(HR 1.14, 95% CI 0.92-1.41)
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01950182
==Tamoxifen & Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (E-switch-ooc)	1a. TH (Paclitaxel)1b. TH (Docetaxel)1c. VH1d. XH	Non-inferior PFS (primary endpoint)Median PFS: 19.2 vs 14.8 mo(HR 0.88, 95% CI 0.71-1.09)
Note: Hua et al. 2022 does not contain dosing instructions for tamoxifen; this is a commonly used dosage.
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 21
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article contains partial protocol link to PMC article EuroPMC NCT01950182
==Toremifene & Trastuzumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (E-switch-ooc)	1a. TH (Paclitaxel)1b. TH (Docetaxel)1c. VH1d. XH	Non-inferior PFS (primary endpoint)Median PFS: 19.2 vs 14.8 mo(HR 0.88, 95% CI 0.71-1.09)
Note: Hua et al. 2022 does not contain dosing instructions for toremifene; this is a commonly used dosage.
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
====Endocrine therapy====
*Toremifene (Fareston) 60 mg PO once per day on days 1 to 21
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article contains partial protocol link to PMC article EuroPMC NCT01950182
==Vinorelbine & Trastuzumab (VH)==
VH: Vinorelbine & Herceptin (Trastuzumab)
===Regimen variant #1, IV===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (C)	1a. Anastrozole & Trastuzumab1b. Exemestane & Trastuzumab1c. Letrozole & Trastuzumab1d. Tamoxifen & Trastuzumab1e. Toremifene & Trastuzumab	Non-inferior PFS (primary endpoint)Median PFS: 14.8 vs 19.2 mo(HR 1.14, 95% CI 0.92-1.41)
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
===Regimen variant #2, PO===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hua et al. 2022 (SYSUCC-002)	2013-2019 	Phase 3 (C)	1a. Anastrozole & Trastuzumab1b. Exemestane & Trastuzumab1c. Letrozole & Trastuzumab1d. Tamoxifen & Trastuzumab1e. Toremifene & Trastuzumab	Non-inferior PFS (primary endpoint)Median PFS: 14.8 vs 19.2 mo(HR 1.14, 95% CI 0.92-1.41)
====Chemotherapy====
*Vinorelbine (Navelbine) 60 to 80 mg/m2 PO once per day on days 1 & 8
====Targeted therapy====
*Trastuzumab (Herceptin) as follows:
**Cycle 1: 8 mg/kg IV once on day 1
**Cycle 2 onwards: 6 mg/kg IV once on day 1
21-day cycles
===References===
# SYSUCC-002: Hua X, Bi XW, Zhao JL, Shi YX, Lin Y, Wu ZY, Zhang YQ, Zhang LH, Zhang AQ, Huang H, Liu XM, Xu F, Guo Y, Xia W, Hong RX, Jiang KK, Xue C, An X, Zhong YY, Wang SS, Huang JJ, Yuan ZY. Trastuzumab Plus Endocrine Therapy or Chemotherapy as First-line Treatment for Patients with Hormone Receptor-Positive and HER2-Positive Metastatic Breast Cancer (SYSUCC-002). Clin Cancer Res. 2022 Feb 15;28(4):637-645. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01950182
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