Breast cancer, ER-positive - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main ER+ breast cancer page for regimens that include active anticancer treatment.
=Neoadjuvant therapy=
==No neoadjuvant therapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Smith et al. 2020 (POETIC)	2008-2014 	Phase 3 (C)	1a. Anastrozole1b. Letrozole	Did not meet primary endpoint of time to response
No treatment prior to surgical resection.
====Subsequent treatment====
*Surgery
===References===
#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
=Adjuvant therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jensen et al. 2017 (CBC 02) 	1975-1978 	Phase 3 (C)	Tamoxifen x 2 y 	Seems to have shorter OS
Baum et al. 1983 (NATO) 	1977-1981 	Phase 3 (C)	Tamoxifen x 2 y 	Shorter OS
Knoop et al. 2001 (DBCG 77C) 	1977-1982 	Phase 3 (C)	Tamoxifen x 1 y 	Did not meet primary endpoint of DFS
Bianco et al. 1988 (GUN) 	1978-1983 	Phase 3 (C)	Tamoxifen x 2 y 	Seems to have shorter DFS
Stewart et al. 1987 (Scottish Tamoxifen Trial)	1978-1984 	Phase 3 (C)	Tamoxifen x 5 y 	Shorter OS1
Rydén et al. 2005 (SBII:2pre) 	1986-1991 	Phase 3 (C)	Tamoxifen x 2 y 	Shorter RFS
Hutchins et al. 2005 (INT-0102) 	1989-1993 	Phase 3 (C)	Tamoxifen x 5 y 	Did not meet primary endpoint of DFS
Morales et al. 2006 	1991-1999 	Phase 3 (C)	Tamoxifen x 3 y 	Did not meet primary endpoint of OS60
Colleoni et al. 2006 (IBCSG 13-93) 	1993-1999 	Phase 3 (C)	Tamoxifen x 5 y 	Shorter DFS2
Jakesz et al. 2007 (ABCSG-6a) 	Not reported 	Phase 3 (C)	Anastrozole x 3 y	Seems to have shorter RFS
Zdenkowski et al. 2016 (ANZ0501 LATER) 	2007-2012 	Phase 3 (C)	Letrozole x 5 y 	Might have shorter DFS
Iwase et al. 2023 (AERAS) 	2007-11 to 2012-11 	Phase 3 (C)	Anastrozole x 5 y	Shorter DFSDFS60: 86% vs 91%(HR 1.64, 95% CI 1.22-2.17)
1Reported efficacy for the Scottish Tamoxifen Trial is based on the 2001 update.
2Reported efficacy for IBCSG 13-93 is for the ER+ cohort.
Note: No further systemic treatment; many of these trials incorporated RT, however (see individual papers for details). Some of the earlier studies were not exclusively for hormone receptor-positive tumors. Knoop et al. 2001 is a retrospective biomarker analysis; we are not aware of another primary publication for DBCG 77C.
====Preceding treatment====
*INT-0102: Surgery, then adjuvant CAF x 6 versus CMF x 6
*Morales et al. 2006: Adjuvant chemotherapy
*IBCSG 13-93: Surgery, then adjuvant AC-CMF or EC-CMF
*ABCSG-6a: Adjuvant Tamoxifen x 5 y versus Aminoglutethemide & Tamoxifen x 5 y
*ANZ0501 LATER: At least 4 years of any adjuvant endocrine therapy
*AERAS: Adjuvant Anastrozole x 5 y or Tamoxifen-Anastrole; 2-3 y + 2-3 y (5 y total)
===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 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
# 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
# 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
# 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 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
# 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
# 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
# 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 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 EuroPMC NCT00300508
# 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 EuroPMC ACTRN12607000137493
# 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 EuroPMC
# 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
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cummings et al. 1985 (ECOG 1178) 	1978-1982 	Phase 3 (C)	Tamoxifen x 2 y	Shorter DFS
Fisher et al. 1989 (NSABP B-14) 	1982-1987 	Phase 3 (C)	Tamoxifen x 5 y	Shorter OS1
Fisher et al. 2001 (NSABP B-23) 	1991-1998 	Phase 3 (C)	Tamoxifen x 5 y	Did not meet primary endpoint of OS
Bramwell et al. 2009 (NCIC-CTG MA.12)	1993-2000 	Phase 3 (C)	Tamoxifen 	Did not meet primary endpoint of OSOS60: 82% vs 87%(HR 1.28, 95% CI 0.94-1.75)
Goss et al. 2003 (NCIC-CTG MA.17) 	1998-2002 	Phase 3 (C)	Letrozole 	Shorter DFSDFS48: 87% vs 93%(HR 1.75, 95% CI 1.33-2.33)
Mamounas et al. 2008 (NSABP B-33) 	2001-2003 	Phase 3 (C)	Exemestane 	Shorter RFS
Mamounas et al. 2018 (NSABP B-42) 	2006-2010 	Phase 3 (C)	Letrozole x 5 y	Seems to have shorter DFS
1Reported efficacy for NSABP B-14 is based on the 2004 update.
No active antineoplastic treatment within the study design. Used as a comparator arm. Note that some trials do have other ongoing antineoplastic treatments outside of the study design, such as adjuvant radiation therapy.
====Preceding treatment====
*NSABP B-14: Surgery
*NSABP B-23: Adjuvant CMF x 6 versus AC x 4
*NCIC-CTG MA.17: Adjuvant Tamoxifen x 5 y
*NSABP B-33: Adjuvant Tamoxifen x 5 y
*NSABP B-42: Adjuvant AI x 5 y or AI and tamoxifen for a total of 5 y
===References===
# 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 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 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-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
# 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
# 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 EuroPMC NCT00016432
# 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 EuroPMC NCT00002542
# 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
=Advanced or metastatic disease, first-line therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Borner et al. 1994 (SAKK 23/82)	1982-1991 	Phase 3 (C)	Tamoxifen 	Might have shorter DFS1
1Reported efficacy for SAKK 23/82 is based on the 2003 update.
Note: No antineoplastic treatment. Patients in SAKK 23/82 had isolated locoregional recurrence.
===References===
# 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 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
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Category:Null regimens
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