Staging page

Section editor transclusions Note: these are regimens tested in biomarker-specific populations, please see the main breast cancer page for other regimens.

0 regimens on this page 0 variants on this page

Guidelines

ASCO

• 2022: Andre et al. Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update
• 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
• 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline
• 2019: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: ASCO Clinical Practice Guideline focused update

Older

• 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 PubMed
• 2016: Rugo et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology guideline PubMed
• 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
• 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
• 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

NCCN

• 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

Older

• 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017
• 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

Neoadjuvant endocrine therapy, premenopausal

Anastrozole & Goserelin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Masuda et al. 2012 (STAGE)	2007-2009	Phase 3 (E-switch-ic)	Goserelin & Tamoxifen	Superior RR

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Goserelin (Zoladex) 3.6 mg IM depot once per month

24-week course

Subsequent treatment

• Surgery

References

1. 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 contains dosing details in abstract PubMed NCT00605267

Anastrozole, Goserelin, Palbociclib

Regimen

Study	Years of enrollment	Evidence
Ma et al. 2017 (NeoPalAna)	2013-2015	Phase 2

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• 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

1. 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 contains dosing details in manuscript PubMed NCT01723774

Goserelin & Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Masuda et al. 2012 (STAGE)	2007-2009	Phase 3 (C)	Anastrozole & Goserelin	Inferior RR
Kim et al. 2020 (NEST)	2012-2014	Phase 3 (E-switch-ooc)	AC-D	Inconclusive whether non-inferior clinical response

Endocrine therapy

• Goserelin (Zoladex) 3.6 mg IM depot once per month
• Tamoxifen (Nolvadex) 20 mg PO once per day

24-week course

Subsequent treatment

• Surgery

References

1. 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 contains dosing details in abstract PubMed NCT00605267
2. 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 contains dosing details in manuscript PubMed NCT01622361

Neoadjuvant endocrine therapy, postmenopausal

Anastrozole monotherapy

Regimen variant #1, 3-month course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 2005 (IMPACT)	1997-2002	Phase 3 (E-switch-ic)	1. Anastrozole & Tamoxifen 2. 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	NR	Randomized Phase 2 (E-switch-ooc)	Doxorubicin & Paclitaxel (AT)	Did not meet primary endpoint of ORR

Note: while Semiglazov et al. 2007 is 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	Years of enrollment	Evidence	Efficacy
Ellis et al. 2011 (ACOSOG Z1031)	2006-2009	Screening Phase II	cRR: 69% (95% CI, 60-77)

Note: ACOSOG Z1031 was randomized but with the intent to select candidates for phase III trials; efficacy comparisons were not made.

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

16- to 18-week course

Subsequent treatment

• Surgery

References

1. 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 PubMed
2. 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 contains dosing details in abstract PubMed NCT00232661
3. 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 contains dosing details in abstract PubMed
4. 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 contains dosing details in manuscript PubMed NCT00265759
5. 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 PubMed
6. 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 PubMed NCT02338310
7. Alliance A011106: NCT01953588

Anastrozole & Palbociclib

Regimen

Study	Years of enrollment	Evidence
Ma et al. 2017 (NeoPalAna)	2013-2015	Phase 2

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

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

1. 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 contains dosing details in manuscript PubMed NCT01723774

Exemestane monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Semiglazov et al. 2007	NR	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

1. 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 contains dosing details in abstract PubMed
2. 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 PubMed

Letrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ellis et al. 2001	1998-1999	Phase 3 (E-switch-ic)	Tamoxifen	Superior ORR
Eiermann et al. 2001 (P024)	1998-1999	Phase 3 (E-switch-ic)	Tamoxifen	Superior ORR
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

1. 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 contains dosing details in abstract PubMed
2. 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 contains dosing details in abstract PubMed
3. 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 contains dosing details in manuscript PubMed NCT00265759
4. 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 PubMed
5. 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 PubMed NCT02338310

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.

References

1. 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 PubMed

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)

References

1. 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 PubMed

Residual cancer burden (RCB)

• The RCB is calculated as follows: RCB = 1.4 (f_inv*d_prim)^0.17 + [4(1 - 0.75^LN)d_met]^0.17
  • where d_prim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, f_inv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and d_met is the diameter of the largest metastasis in an axillary lymph node.
  • The cut-off points are 1.36 and 3.28.

References

1. 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 PubMed

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.

References

1. 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 PubMed

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

References

1. 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. PubMed

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

References

1. 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 PubMed

ypTNM staging

This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.

Adjuvant therapy, premenopausal

Exemestane & OFS

Exemestane & OFS: Exemestane & Ovarian Function Suppression

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pagani et al. 2014 (TEXT)	2003-2011	Phase 3 (E-switch-ic)	1. Tamoxifen	Superior DFS
			2. Tamoxifen & OFS	Superior DFS
Pagani et al. 2014 (SOFT)	2003-2011	Phase 3 (E-switch-ic)	1. Tamoxifen	Superior DFS
			2. Tamoxifen & OFS	Superior DFS

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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066703
   1. 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 PubMed
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066690
   1. 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 PubMed
   2. 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 PubMed

Goserelin monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Davidson et al. 2005 (ECOG E5188)	1989-1994	Phase 3 (C)	Goserelin & Tamoxifen x 5 y	Inferior DFS
Jonat et al. 2002 (ZEBRA)	1990-1996	Phase 3 (E-switch-ooc)	CMF	Equivalent DFS

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

1. 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 contains dosing details in manuscript PubMed
2. 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 PubMed

Goserelin & Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Davidson et al. 2005 (ECOG E5188)	1989-1994	Phase 3 (E-esc)	Goserelin x 5 y	Superior DFS
Jakesz et al. 2002 (ABCSG 5)	1990-1999	Phase 3 (E-switch-ooc)	CMF	Seems to have superior RFS

Preceding treatment

• ABCSG 5: Surgery
• ECOG E5188: Surgery, then CAF x 6

Endocrine therapy

• Goserelin (Zoladex) 3.6 mg IM depot once per month
  • Note: ABCSG 5 stopped goserelin after 3 years
• Tamoxifen (Nolvadex) 20 mg PO once per day

5-year course (see note)

References

1. 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 PubMed NCT00309478
2. 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 contains dosing details in manuscript PubMed

Leuprolide monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schmid et al. 2007 (TABLE)	1995-1998	Phase 3 (E-switch-ooc)	CMF	Superior OS

Endocrine therapy

• Leuprolide (Lupron) 11.25 mg SC once on day 1

3-month cycle for 8 cycles (2 years)

References

1. 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 contains dosing details in manuscript PubMed

Tamoxifen monotherapy

Regimen variant #1, 2 years of 20 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rydén et al. 2005 (SBII:2pre)	1986-1991	Phase 3 (E-esc)	Observation	Superior RFS

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

2-year course

Regimen variant #2, 5 years

Study	Years 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 primary endpoints of RFS/OS
Bramwell et al. 2009 (NCIC-CTG MA.12)	1993-2000	Phase 3 (C)	Placebo	Might have superior OS OS60: 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 primary endpoints of DFS/OS	Fewer menopausal symptoms
Pagani et al. 2014 (SOFT)	2003-2011	Phase 3 (C)	1. Exemestane & OFS	Inferior DFS
			2. Tamoxifen & OFS	Might have inferior DFS1
Kim et al. 2019 (ASTRRA)	2009-2014	Phase 3 (C)	Tamoxifen & OFS	Inferior OS2

¹Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015.
²In an abstract-only update, overall survival was not significantly different in longer follow-up; awaiting publication of this 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)

5-year course

References

1. 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 contains dosing details in abstract PubMed
   1. 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 PubMed
   2. 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 PubMed
2. 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 PubMed
3. 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 contains dosing details in manuscript PubMed NCT00002582
4. 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 contains dosing details in manuscript PubMed NCT00002542
5. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066690
   1. 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 PubMed
   2. 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 PubMed
6. 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 contains dosing details in manuscript link to PMC article PubMed
7. 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 contains dosing details in manuscript PubMed NCT00912548

Tamoxifen & OFS

Tamoxifen & OFS: Tamoxifen & OFS: Ovarian Function Suppression

Regimen variant #1, 3 years

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gnant et al. 2009 (ABCSG-12)	1999-2006	Phase 3 (C)	Tamoxifen, OFS, Zoledronic acid	Inferior DFS

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	Years 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 primary endpoints of DFS/OS	More menopausal symptoms
Pagani et al. 2014 (TEXT)	2003-2011	Phase 3 (E-esc)	1. Exemestane & OFS	Inferior DFS
			2. Tamoxifen	Might have superior DFS1
Pagani et al. 2014 (SOFT)	2003-2011	Phase 3 (E-esc)	1. Exemestane & OFS	Inferior DFS
			2. Tamoxifen	Might have superior DFS1
Perrone et al. 2019 (HOBOE)	2004-2015	Phase 3 (C)	1. Letrozole & OFS	Might have inferior DFS
			2. ZL & OFS	Inferior DFS	Better tolerated
Kim et al. 2019 (ASTRRA)	2009-2014	Phase 3 (E-esc)	Tamoxifen	Superior OS2 OS60: 99.4% vs 97.8% (HR 0.31, 95% CI 0.10-0.94)

¹Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015.
²In an abstract-only update, overall survival was not significantly different in longer follow-up; awaiting publication of this 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

1. 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 contains dosing details in abstract PubMed NCT00295646
   1. 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 PubMed
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066690
   1. 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 PubMed
   2. 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 PubMed
3. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066703
   1. 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 PubMed
4. 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 contains dosing details in manuscript link to PMC article PubMed
5. 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 contains dosing details in manuscript PubMed NCT00412022
6. 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 contains dosing details in manuscript PubMed NCT00912548

Adjuvant therapy

Abemaciclib & ET

Abemaciclib & ET: Abemaciclib & Endocrine Therapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Johnston et al. 2020 (monarchE)	2017-2019	Phase 3 (E-RT-esc)	Endocrine therapy	Superior IDFS1 IDFS36: 88.8% vs 83.4% (HR 0.70, 95% CI 0.59-0.82)

¹Reported efficacy is based on the 2021 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) 150 mg PO twice per day

2-year course

Endocrine therapy

• Endocrine therapy (clinician choice)

5- to 10-year course

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT03155997
   1. 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 PubMed

Anastrozole monotherapy

Regimen variant #1, 3-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Jakesz et al. 2005 (ARNO 95)	1996-2003	Phase 3 (E-switch-ic)	See link	See link
Jakesz et al. 2005 (ABCSG-8)	1996-2003	Phase 3 (E-switch-ic)	See link	See link
Jakesz et al. 2007 (ABCSG-6a)	NR	Phase 3 (E-esc)	No further treatment	Seems to have superior RFS
Tjan-Heijnen et al. 2017 (DATA)	2006-2009	Phase 3 (C)	Anastrozole x 6 y	Might have inferior DFS	Less toxic
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	See link	See link

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-8, ARNO 95, FATA-GIM3: Tamoxifen x 2 y
• ABCSG-6a: Tamoxifen x 5 y versus Aminoglutethemide & Tamoxifen x 5 y
• DATA: Tamoxifen x 2-3 y

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

3-year course, for a total of 5 to 8 years of hormonal therapy

Regimen variant #2, 5-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baum et al. 2002 (ATAC)	1996-2000	Phase 3 (E-RT-switch-ic)	1. Anastrozole & Tamoxifen	Not reported
			2. Tamoxifen	Superior DFS1 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 EFS60
Smith et al. 2017 (FACE)	2005-2008	Phase 3 (E-switch-ic)	Letrozole	Did not meet primary endpoint of DFS60
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	Tamoxifen x 2 y, then AI x 3 y	Did not meet primary endpoint of DFS
Ruíz-Borrego et al. 2019 (GEICAM/2006-10)	2008-2010	Phase 3 (C)	Anastrozole & Fulvestrant	Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS)	2015-2018	Phase 3 (C)	1. Anastrozole & Palbociclib 2. Exemestane & Palbociclib 3. Letrozole & Palbociclib 4. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFS

¹Reported efficacy for this arm of ATAC is based on the 2010 update for hormone-receptor positive patients.

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

5-year course

Regimen variant #3, 6-year course

Study	Years 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 superior DFS (HR 0.79, 95% CI 0.62-1.02)	More toxic

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

• Tamoxifen x 2-3 y

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

6-year course

Regimen variant #4, 7-year course

Study	Years 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 DFS	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

7-year course

References

1. 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 PubMed NCT00849030
   1. 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 PubMed
   2. 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 PubMed
   3. 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 PubMed
2. 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 PubMed NCT00291759
   1. 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 PubMed
   2. 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 PubMed
3. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
4. 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 contains dosing details in abstract PubMed NCT00300508
5. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066573
6. 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 contains dosing details in abstract PubMed NCT00248170
7. 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 contains dosing details in manuscript PubMed NCT00301457
8. 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 contains dosing details in abstract PubMed NCT00541086
9. 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 PubMed NCT00543127
10. 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 contains dosing details in supplement PubMed NCT02513394
    1. 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 PubMed
11. 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 contains dosing details in manuscript PubMed NCT00295620
12. RxPONDER: NCT01272037

Exemestane monotherapy

Regimen variant #1, 2- to 3-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coombes et al. 2004 (IES)	1998-2003	Phase 3 (E-RT-switch-ic)	See link	See link
van de Velde et al. 2011 (TEAM)	2001-2006	Phase 3 (E-switch-ic)	See link	See link

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. The IES gave a range of 2 to 3 years of therapy. TEAM gave a range of 2 to 2.5 years of therapy.

Preceding treatment

• Tamoxifen x 2-3y

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

2 to 3 years, for a total of 5 years of hormonal therapy

Regimen variant #2, 3-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	See link	See link

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

• Tamoxifen x 2 y

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

3-year course, for a total of 5 years of hormonal therapy

Regimen variant #3, 5-year course

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mamounas et al. 2008 (NSABP B-33)	2001-2003	Phase 3 (E-esc)	Placebo	Superior RFS
Goss et al. 2013 (NCIC-CTG MA.27)	2003-2008	Phase 3 (E-switch-ic)	Anastrozole	Did not meet primary endpoint of EFS60
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	Tamoxifen x 2 y, then AI x 3 y	Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS)	2015-2018	Phase 3 (C)	1. Anastrozole & Palbociclib 2. Exemestane & Palbociclib 3. Letrozole & Palbociclib 4. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFS

Preceding treatment

• NSABP B-33: Tamoxifen x 5 y

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

5-year course

References

1. 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 PubMed NCT00038467
   1. 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 PubMed
   2. 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 PubMed
2. 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 PubMed NCT00016432
3. 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 contains dosing details in manuscript PubMed NCT00279448; NCT00032136; NCT00036270
   1. 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 PubMed
4. 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 contains dosing details in manuscript link to PMC article PubMed NCT00066573
5. 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 contains dosing details in abstract PubMed NCT00541086
6. 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 contains dosing details in supplement PubMed NCT02513394
   1. 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 PubMed

Letrozole monotherapy

Regimen variant #1, 2 years of therapy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98)	1998-2003	Phase 3 (E-RT-switch-ic)	See link	See link

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.

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

2-year course

Subsequent treatment

• Tamoxifen x 3 y

Regimen variant #2, 2 additional years of therapy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Del Mastro et al. 2021 (GIM4)	2005-2010	Phase 3 (C)	Letrozole x 5 y	Inferior iDFS

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: Tamoxifen x 2-3 y

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

2 additional years of endocrine therapy

Regimen variant #3, 2.5 additional years of therapy

Study	Years 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

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 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 #4, 3 additional years of therapy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98)	1998-2003	Phase 3 (E-RT-switch-ic)	See link	See link
Del Mastro et al. 2021 (GIM4)	2005-2010	Phase 3 (C)	Letrozole x 5 y	Inferior iDFS
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	See link	See link

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

• BIG 1-98 & FATA-GIM3: Tamoxifen x 2 y
• GIM4: Tamoxifen x 2-3 y

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

3 additional years of endocrine therapy

Regimen variant #5, 5 years of therapy

Study	Years 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	Did not meet primary endpoint of DFS1
			2. Tamoxifen	Might have superior OS1
			3. Tamoxifen, then Letrozole	Did not meet primary endpoint of DFS1
Goss et al. 2016 (NCIC-CTG MA.17R)	NR-2009	Phase 3 (C)	Letrozole x 10 y	Inferior DFS	No clinical difference in QoL
Smith et al. 2017 (FACE)	2005-2008	Phase 3 (E-switch-ic)	Anastrozole	Did not meet primary endpoint of DFS60
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	Tamoxifen x 2 y, then AI x 3 y	Did not meet primary endpoint of DFS
Loibl et al. 2021 (PENELOPE-B)	2014-2017	Phase 3 (C)	1. Anastrozole & Palbociclib 2. Exemestane & Palbociclib 3. Letrozole & Palbociclib 4. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFS
Mayer et al. 2021 (PALLAS)	2015-2018	Phase 3 (C)	1. Anastrozole & Palbociclib 2. Exemestane & Palbociclib 3. Letrozole & Palbociclib 4. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFS

¹Reported efficacy for BIG 1-98 is based on the 2011 and 2018 updates.
Note: PENELOPE-B did not specify the type of ET, leaving it to local discretion.

Preceding treatment

• PENELOPE-B: Neoadjuvant chemotherapy, then surgery, then RT per local guidelines

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

5-year course

Regimen variant #6, 5 additional years of therapy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Goss et al. 2003 (NCIC-CTG MA.17)	1998-2002	Phase 3 (E-RT-esc)	Placebo	Superior DFS 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	Superior iDFS 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	Might have superior DFS 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	Might have superior DFS
Goss et al. 2016 (NCIC-CTG MA.17R)	NR-2009	Phase 3 (E-esc)	Letrozole x 5 y	Superior DFS 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
Colleoni et al. 2017 (SOLE)	2007-2012	Phase 3 (C)	Letrozole; intermittent	Did not meet primary endpoint of DFS

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 tamoxifen therapy prior to starting letrozole
• GIM4: Tamoxifen x 2-3 y
• ANZ0501 LATER: At least 4 years of any endocrine therapy
• NCIC-CTG MA.17R: Letrozole for 5 years
• IDEAL: Any endocrine therapy for 5 years

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

5 additional years of endocrine therapy

References

1. 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 PubMed NCT00003140
   1. 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 PubMed
   2. 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 PubMed
   3. 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 PubMed
   4. 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 PubMed
   5. 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 PubMed
2. 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 PubMed NCT00004205
   1. 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 PubMed
   2. 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 PubMed
   3. 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 PubMed
   4. 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 PubMed
   5. 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. link to original article link to PMC article PubMed
   6. 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 PubMed
3. 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 contains dosing details in abstract PubMed ACTRN12607000137493
4. 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 contains dosing details in manuscript PubMed NCT00003140; NCT00754845
   1. 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 PubMed
5. 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 contains dosing details in abstract PubMed NCT00248170
6. 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 contains dosing details in manuscript PubMed Eudra-CT 2006-003958-16
7. 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 contains dosing details in abstract PubMed NCT00553410
   1. 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 PubMed
   2. 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 PubMed
8. 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 contains dosing details in abstract PubMed NCT00541086
9. 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 PubMed NCT00382070
10. 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 contains dosing details in supplement PubMed NCT02513394
    1. 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 PubMed
11. 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 PubMed NCT01864746
12. 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 contains dosing details in abstract PubMed NCT01064635

Tamoxifen monotherapy

Regimen variant #1, 1 year

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rydén et al. 1992 (SSBCG II:I)	NR	Phase 3 (C)	1. RT 2. 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. CMFVP 2. CMFVPT	Did not meet primary endpoint of DFS
Overgaard et al. 1999 (DBCG 82C)	1982-1990	Phase 3 (C)	1. CMFT	Inferior DFS1
			2. Tamoxifen & RT	Seems to have inferior OS
Andersen et al. 2008 (DBCG 89C)	1990-1994	Phase 3 (C)	1. Tamoxifen x 2 y 2. 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

1-year course

Regimen variant #2, 2 years of 20 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baum et al. 1983 (NATO)	1977-1981	Phase 3 (E-RT-esc)	Observation	Superior OS
Cummings et al. 1985 (ECOG 1178)	1978-1982	Phase 3 (E-RT-esc)	Placebo	Superior DFS
Bianco et al. 1988 (GUN)	1978-1983	Phase 3 (E-esc)	Observation	Seems to have superior DFS
Rutqvist et al. 1996	1983-1991	Phase 3 (C)	Tamoxifen x 5 y	Seems to have inferior OS
Baum & Odling-Smee 1996 (CRUK Over 50s)	NR-1994	Phase 3 (C)	Tamoxifen x 5 y	Inferior 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	Seems to have inferior RFS
Jakesz et al. 2005 (ARNO 95)	1996-2003	Phase 3 (E-switch-ic)	See link	See link
Jakesz et al. 2005 (ABCSG-8)	1996-2003	Phase 3 (E-switch-ic)	See link	See link
Kimura et al. 2012	1998-2001	Phase 3 (C)	Toremifene	Non-inferior OS
Coombes et al. 2004 (IES)	1998-2003	Phase 3 (E-switch-ic)	See link	See link
Thürlimann et al. 2005 (BIG 1-98)	1998-2003	Phase 3 (E-switch-ic)	See link	See link
De Placido et al. 2018 (FATA-GIM3)	2007-2012	Phase 3 (E-switch-ic)	See link	See link

Note: IES gave a range of 2 to 3 years of therapy.

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

2-year course

Subsequent treatment

• IES: Exemestane
• BIG 1-98: Letrozole
• ABCSG-8 & ARNO 95: Anastrozole x 3 y
• FATA-GIM3: Anastrozole versus Exemestane versus Letrozole

Regimen variant #3, 2 years of 30 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jensen et al. 2017 (CBC 02)	1975-1978	Phase 3 (E-esc)	Observation	Seems to have superior 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

2-year course

Regimen variant #4, 2 years of 40 mg/d, then 3 years of 20 mg/day

Study	Years 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:
  • Years 1 & 2: 40 mg PO once per day
  • Years 3 to 5: 20 mg PO once per day

5-year course

Regimen variant #5, 3 years of 20 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Morales et al. 2006	1991-1999	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of OS60
Thürlimann et al. 2005 (BIG 1-98)	1998-2003	Phase 3 (E-switch-ic)	See link	See link
van de Velde et al. 2011 (TEAM)	2001-2006	Phase 3 (E-switch-ic)	See link	See link

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. TEAM gave a range of 2.5 to 3 years of therapy.

Preceding treatment

• BIG 1-98: Letrozole x 2y
• Morales et al. 2006: Adjuvant chemotherapy

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

3-year course

Subsequent treatment

• TEAM: Exemestane

Regimen variant #6, 3 years of 30 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Namer et al. 2006 (FASG 02)	1986-1990	Phase 3 (C)	FEC50-Tam	Inferior DFS
Namer et al. 2006 (FASG 07)	1991-1998	Phase 3 (C)	FEC50-Tam	Inferior 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

3-year course

Regimen variant #7, 5 years

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Stewart et al. 1987 (Scottish Tamoxifen Trial)	1978-1984	Phase 3 (E-esc)	Observation	Superior OS1
Fisher et al. 1989 (NSABP B-14)	1982-1987	Phase 3 (E-RT-esc)	Placebo	Superior OS2
Tormey et al. 1996 (ECOG E4181/E5181)	1982-NR	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 superior OS
Fisher et al. 1990 (NSABP B-16)	1985-1988	Phase 3 (C)	1. ACT	Seems to have inferior OS
			2. PFT	Seems to have inferior DDFS
Mustacchi et al. 1994 (GRETA)	NR in abstract	Phase 3 (C)	Tamoxifen alone (no surgery)	Did not meet endpoint of OS
Baum & Odling-Smee 1996 (CRUK Over 50s)	NR-1994	Phase 3 (E-esc)	Tamoxifen x 2 y	Superior EFS3
Fisher et al. 1997 (NSABP B-20)	1988-1993	Phase 3 (C)	1. CMFT	Might have inferior OS2
			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 primary endpoint of DFS
			2. Anastrozole	Inferior 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. RT 2. Tamoxifen & RT	Inferior DFS
Fyles et al. 2004	1992-2000	Non-randomized portion of RCT
Hughes et al. 2004 (CALGB 9343)	1994-1999	Non-randomized portion 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 x 2y, then Anastrozole x 3y	Seems to have inferior OS
Jakesz et al. 2005 (ABCSG-8)	1996-2003	Phase 3 (C)	Tamoxifen x 2y, then Anastrozole x 3y	Might have inferior RFS
Davies et al. 2013 (ATLAS)	1996-2005	Phase 3 (C)	Tamoxifen x 10y	Inferior OS
Coombes et al. 2004 (IES)	1998-2003	Phase 3 (C)	Tamoxifen x 2-3y, then Exemestane x 2-3y	Seems to have inferior OS5
Thürlimann et al. 2005 (BIG 1-98)	1998-2003	Phase 3 (C)	1. Letrozole	Might have inferior OS6
			2. Letrozole x 2y, then Tamoxifen x 3y	Not reported
			3. Tamoxifen x 2y, then Letrozole x 3y	Not reported
Mamounas et al. 2008 (NSABP B-33)	2001-2003	Non-randomized portion of RCT
van de Velde et al. 2011 (TEAM)	2001-2006	Phase 3 (C)	Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y	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 portion of RCT
Kalinsky et al. 2021 (RxPONDER)	2011-2017	Non-randomized portion of phase 3 RCT
Mayer et al. 2021 (PALLAS)	2015-2018	Phase 3 (C)	1. Anastrozole & Palbociclib 2. Exemestane & Palbociclib 3. Letrozole & Palbociclib 4. Palbociclib & Tamoxifen	Did not meet primary endpoint of IDFS

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 IES is based on the 2011 update.
⁶Reported 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.

Preceding treatment

• NSABP B-23: Surgery, then CMF x 6 versus AC x 4
• INT-0102: Surgery, then CAF x 6 versus CMF x 6
• SWOG-8814: Surgery versus surgery, then CAF x 6
• TAILORx: Surgery, then AC x 4 or ddAC x 4 or AC x 4, then q3wk T x 4 or ddAC x 4, then ddT x 4 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

5-year course

Subsequent treatment

• NSABP B-33: Exemestane versus Placebo
• TAILORx, post-menopausal at year 6: AI x 5 years

Regimen variant #8, 10 years

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Davies et al. 2013 (ATLAS)	1996-2005	Phase 3 (E-esc)	Tamoxifen x 5 years	Superior OS

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

10-year course

References

1. 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 contains dosing details in abstract PubMed
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
4. 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 PubMed
5. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed
   2. 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 PubMed
   3. 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 PubMed
   4. 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 PubMed
6. 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 PubMed
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7. 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 PubMed
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8. 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. PubMed
   1. 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 PubMed
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9. 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 contains dosing details in abstract PubMed
10. 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 PubMed
    1. 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 PubMed
11. 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 PubMed
12. ECOG E4181/E5181: 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 contains dosing details in abstract PubMed
13. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
14. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
    2. 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 PubMed
15. 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 contains dosing details in abstract PubMed
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16. 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 contains dosing details in abstract PubMed
17. 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 PubMed
    1. 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 PubMed
18. 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 PubMed
19. 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 PubMed NCT00849030
    1. 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 PubMed
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20. 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 contains dosing details in manuscript PubMed
21. 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 contains dosing details in abstract PubMed NCT00309491
22. 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 contains dosing details in abstract PubMed
23. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
24. 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 PubMed NCT00038467
    1. 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 PubMed
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26. 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 contains dosing details in manuscript PubMed
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27. IBCSG 12-93/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 contains dosing details in manuscript PubMed NCT00002529
28. 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 contains dosing details in abstract PubMed
29. 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 PubMed
30. 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 PubMed NCT00291759
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31. 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 PubMed
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32. 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 PubMed
33. 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 PubMed NCT00004205
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34. FASG 02; 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 contains article PubMed
35. 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 contains dosing details in abstract PubMed
36. 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 PubMed
37. 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 PubMed NCT00016432
38. 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 contains dosing details in manuscript PubMed NCT00929591
39. 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 contains dosing details in abstract PubMed UMIN C000000056
40. 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 contains dosing details in manuscript PubMed NCT00002646
41. 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 contains dosing details in manuscript PubMed NCT00279448; NCT00032136; NCT00036270
    1. 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 PubMed
42. 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 PubMed NCT00002864
    1. 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 PubMed
43. 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 contains dosing details in manuscript PubMed
44. 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 contains dosing details in manuscript link to PMC article PubMed NCT00003016
45. 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 contains dosing details in abstract PubMed
46. 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 contains dosing details in manuscript PubMed
47. 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 contains dosing details in abstract PubMed NCT00541086
48. 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 contains dosing details in supplement PubMed NCT00310180
49. 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 contains dosing details in supplement PubMed NCT02513394
    1. 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 PubMed
50. 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 PubMed NCT01272037
51. SWOG S1207: NCT01674140

Toremifene monotherapy

Regimen variant #1, 40 mg/day x 2y

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kimura et al. 2012	1998-2001	Phase 3 (E-switch-ic)	Tamoxifen	Non-inferior OS

Preceding treatment

• Surgery

Endocrine therapy

• Toremifene (Fareston) 40 mg PO once per day

2-year course

Regimen variant #2, 40 mg/day x 5y

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Toi et al. 2021	2012-2016	Phase 3 (C)	S-1 & Toremifene	Inferior IDFS

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

5-year course

Regimen variant #3, 60 mg/day x 5y

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pagani et al. 2004 (IBCSG 12-93/IBCSG 14-93)	1993-1999	Phase 3 (E-switch-ic)	Tamoxifen	Non-inferior DFS1 DFS60: 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.

Preceding treatment

• Surgery

Endocrine therapy

• Toremifene (Fareston) 40 mg PO once per day

5-year course

Regimen variant #4, 120 mg/day x 5y

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Toi et al. 2021	2012-2016	Phase 3 (C)	S-1 & Toremifene	Inferior IDFS

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

5-year course

References

1. IBCSG 12-93/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 contains dosing details in manuscript PubMed NCT00002529
2. 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 contains dosing details in manuscript PubMed
3. 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 contains dosing details in manuscript PubMed UMIN000003969

Metastatic disease, first-line therapy, premenopausal

Anastrozole & Goserelin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (C)	1. Anastrozole, Goserelin, Ribociclib 2. Goserelin, Letrozole, Ribociclib 3. Goserelin, Ribociclib, Tamoxifen	Seems to have inferior OS1

¹Reported efficacy is based on the 2022 update.

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Goserelin (Zoladex) 3.6 mg SC once on day 1

28-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Anastrozole, Goserelin, Ribociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (E-RT-esc)	1. Anastrozole & Goserelin 2. Goserelin & Letrozole 3. Goserelin & Tamoxifen	Seems to have superior OS1 Median OS: 58.7 vs 48 mo (HR 0.76, 95% CI 0.61-0.96)

¹Reported efficacy is based on the 2022 update.

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• 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

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Goserelin & Letrozole

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (C)	1. Anastrozole, Goserelin, Ribociclib 2. Goserelin, Letrozole, Ribociclib 3. Goserelin, Ribociclib, Tamoxifen	Seems to have inferior OS1

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

28-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Goserelin, Letrozole, Ribociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (E-RT-esc)	1. Anastrozole & Goserelin 2. Goserelin & Letrozole 3. Goserelin & Tamoxifen	Seems to have superior OS1 Median OS: 58.7 vs 48 mo (HR 0.76, 95% CI 0.61-0.96)

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

Targeted therapy

• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Goserelin, Ribociclib, Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (E-RT-esc)	1. Anastrozole & Goserelin 2. Goserelin & Letrozole 3. Goserelin & Tamoxifen	Seems to have superior OS1 Median OS: 58.7 vs 48 mo (HR 0.76, 95% CI 0.61-0.96)

¹Reported efficacy 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

Targeted therapy

• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Goserelin & Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7)	2014-2016	Phase 3 (C)	1. Anastrozole, Goserelin, Ribociclib 2. Goserelin, Letrozole, Ribociclib 3. Goserelin, Ribociclib, Tamoxifen	Seems to have inferior OS1

¹Reported efficacy 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

28-day cycles

References

1. 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 contains dosing details in abstract PubMed NCT02278120
   1. 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 PubMed

Tamoxifen monotherapy

Regimen variant #1, 20 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ingle et al. 1986a	1978-1984	Phase 3 (E-RT-switch-ic)	Bilateral oophorectomy	Seems not superior

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buchanan et al. 1986	1979-1983	Phase 3 (E-RT-switch-ic)	Bilateral oophorectomy	Might have superior PFS
Crump et al. 1997	NR	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

1. 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 contains dosing details in abstract PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 PubMed

Metastatic disease, first-line therapy

Abemaciclib & Anastrozole

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Goetz et al. 2017 (MONARCH 3)	2014-2015	Phase 3 (E-RT-esc)	1. Anastrozole 2. Letrozole	Superior PFS Median PFS: NYR vs 14.7 mo (HR 0.54, 95% CI 0.41-0.72)

Targeted therapy

• Abemaciclib (Verzenio) 150 mg PO twice per day

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT02246621

Abemaciclib & Letrozole

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Goetz et al. 2017 (MONARCH 3)	2014-2015	Phase 3 (E-RT-esc)	1. Anastrozole 2. Letrozole	Superior PFS Median PFS: NYR vs 14.7 mo (HR 0.54, 95% CI 0.41-0.72)

Targeted therapy

• Abemaciclib (Verzenio) 150 mg PO twice per day

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT02246621

Anastrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bonneterre et al. 2000 (TARGETBreast)	1995-1998	Phase 3 (E-RT-switch-ic)	Tamoxifen	Equivalent TTP
Nabholtz et al. 2000 (Arimidex Study Group 2000)	1996-1998	Phase 3 (E-RT-switch-ic)	Tamoxifen	Superior TTP
Milla-Santos et al. 2003	1997-1999	Phase 3 (E-switch-ic)	Tamoxifen	Superior OS
Bergh et al. 2012 (FACT)	2004-2008	Phase 3 (C)	Anastrozole & Fulvestrant	Did not meet primary endpoint of TTP
Mehta et al. 2012 (SWOG S0226)	2004-2009	Phase 3 (C)	Anastrozole & Fulvestrant	Seems to have inferior OS
Iwata et al. 2013 (A5991048)	2005-2010	Phase 3 (C)	Exemestane	Inconclusive whether non-inferior TTP
Robertson et al. 2016 (FALCON)	2012-2014	Phase 3 (C)	Fulvestrant	Seems to have inferior PFS
Goetz et al. 2017 (MONARCH 3)	2014-2015	Phase 3 (C)	1. Abemaciclib & Anastrozole 2. Abemaciclib & Letrozole	Inferior PFS

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day

28-day cycles

References

1. TARGET_Breast: 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 contains dosing details in abstract PubMed
2. Arimidex Study Group 2000: Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial; Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67. link to original article PubMed
3. 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 contains dosing details in abstract PubMed
4. 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 contains dosing details in manuscript PubMed NCT00256698
5. 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 contains dosing details in manuscript link to PMC article PubMed NCT00075764
   1. 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 PubMed
6. 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 contains dosing details in abstract PubMed NCT00143390
7. 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 contains dosing details in abstract PubMed NCT01602380
8. 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 contains dosing details in manuscript PubMed NCT02246621
9. DAWNA-2: NCT03966898

Anastrozole & Fulvestrant

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bergh et al. 2012 (FACT)	2004-2008	Phase 3 (E-esc)	Anastrozole	Did not meet primary endpoint of TTP
Mehta et al. 2012 (SWOG S0226)	2004-2009	Phase 3 (E-esc)	Anastrozole	Seems to have superior OS 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
• 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
    • Patients in SWOG S0226 who progressed while on therapy were allowed to receive a higher dose, 500 mg IM once on day 1

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT00256698
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00075764
   1. 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 PubMed

Exemestane monotherapy

Regimen

Study	Years 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)	2003-2004	Phase 3 (C)	Celecoxib & Exemestane	Did not meet primary endpoint of PFS
Iwata et al. 2013 (A5991048)	2005-2010	Phase 3 (C)	Anastrozole	Inconclusive whether non-inferior TTP

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in abstract PubMed NCT00002777
2. 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 contains dosing details in abstract PubMed NCT00525096
3. 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 contains dosing details in abstract PubMed NCT00143390

Fulvestrant monotherapy

Regimen variant #1, 250 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2015 (LEA)	2007-2011	Phase 3 (C)	Fulvestrant & Bevacizumab	Did not meet primary endpoint of PFS

Endocrine therapy

• Fulvestrant (Faslodex) 250 mg IM once on day 1

28-day cycles

Regimen variant #2, 500 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Howell et al. 2004	1998-2000	Phase 3 (E-switch-ic)	Tamoxifen	Might have inferior TTP
Robertson et al. 2016 (FALCON)	2012-2014	Phase 3 (E-RT-switch-ic)	Anastrozole	Seems to have superior PFS Median PFS: 16.6 vs 13.8 mo (HR 0.80, 95% CI 0.64-0.999)
Slamon et al. 2018 (MONALEESA-3)	2015-2016	Phase 3 (C)	Fulvestrant & Ribociclib	Inferior OS1

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

1. 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 PubMed
2. 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 contains dosing details in abstract PubMed NCT00545077
3. 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 contains dosing details in abstract PubMed NCT01602380
4. 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 PubMed NCT02422615
   1. 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 PubMed
   2. 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 PubMed

Fulvestrant & Ribociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3)	2015-2016	Phase 3 (E-RT-esc)	Fulvestrant	Superior OS1 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

1. 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 PubMed NCT02422615
   1. 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 PubMed
   2. 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 PubMed

Goserelin monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jonat et al. 1995	1988-1991	Phase 3 (C)	Goserelin & Tamoxifen	Seems to have inferior TTP

Endocrine therapy

• Goserelin (Zoladex)

References

1. 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 PubMed

Goserelin & Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jonat et al. 1995	1988-1991	Phase 3 (E-esc)	Goserelin	Seems to have superior TTP

Endocrine therapy

• Goserelin (Zoladex)
• Tamoxifen (Nolvadex)

References

1. 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 PubMed

Letrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mouridsen et al. 2001 (ILBCG)	1996-1999	Phase 3 (E-RT-switch-ic)	Tamoxifen	Superior TTP
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 PFS
Martín et al. 2015 (LEA)	2007-2011	Phase 3 (C)	Letrozole & Bevacizumab	Did not meet primary endpoint of PFS
Dickler et al. 2016 (CALGB 40503)	2008-2011	Phase 3 (C)	Letrozole & Bevacizumab	Seems to have inferior PFS
Finn et al. 2015 (PALOMA-1/TRIO-18)	2009-2012	Randomized Phase 2 (C)	Letrozole & Palbociclib	Inferior PFS
Finn et al. 2016 (PALOMA-2)	2013-2014	Phase 3 (C)	Letrozole & Palbociclib	Inferior PFS
Hortobagyi et al. 2016 (MONALEESA-2)	2014-2015	Phase 3 (C)	Letrozole & Ribociclib	Inferior OS1
Goetz et al. 2017 (MONARCH 3)	2014-2015	Phase 3 (C)	1. Abemaciclib & Anastrozole 2. Abemaciclib & Letrozole	Inferior PFS

¹Reported efficacy is based on the 2022 update.
Note: HORIZON is labeled HORIZON_BRCA to distinguish from the study of the same name in multiple myeloma.

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

28-day cycles

References

1. 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 contains dosing details in abstract PubMed
   1. 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 PubMed
2. 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 contains dosing details in abstract PubMed NCT00044291
3. HORIZON_BRCA: 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 contains dosing details in abstract PubMed NCT00083993
4. 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. link to original article contains dosing details in manuscript PubMed NCT00721409
5. 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 contains dosing details in manuscript PubMed NCT00545077
6. 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 contains dosing details in abstract link to PMC article PubMed NCT00601900
7. 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 contains dosing details in manuscript PubMed NCT01958021
   1. 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 PubMed
   2. 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 + 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 PubMed
   3. 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 PubMed
   4. 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 PubMed
8. 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 contains dosing details in manuscript PubMed NCT01740427
   1. 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 PubMed
   2. 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. J Glob Oncol. 2019 May;5:1-19. link to original article link to PMC article PubMed
9. 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 contains dosing details in manuscript PubMed NCT02246621
10. DAWNA-2: NCT03966898

Letrozole & Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2015 (LEA)	2007-2011	Phase 3 (E-esc)	Letrozole	Did not meet primary endpoint of PFS Median 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 superior PFS 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

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT00545077
2. 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 contains dosing details in abstract link to PMC article PubMed NCT00601900

Letrozole & Palbociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18)	2009-2012	Randomized Phase 2 (E-esc)	Letrozole	Superior PFS Median PFS: 20.2 vs 10.2 mo (HR 0.49, 95% CI 0.32-0.75)
Finn et al. 2016 (PALOMA-2)	2013-2014	Phase 3 (E-RT-esc)	Letrozole	Superior PFS Median PFS: 24.8 vs 14.5 mo (HR 0.58, 95% CI 0.46-0.72)

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

Targeted therapy

• Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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. link to original article contains dosing details in manuscript PubMed NCT00721409
2. 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 contains dosing details in manuscript PubMed NCT01740427
   1. 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 PubMed
   2. 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. J Glob Oncol. 2019 May;5:1-19. link to original article link to PMC article PubMed

Letrozole & Ribociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hortobagyi et al. 2016 (MONALEESA-2)	2014-2015	Phase 3 (E-RT-esc)	Letrozole	Superior OS1 Median OS: 63.9 vs 51.4 mo (HR 0.76, 95% CI 0.63-0.93)

¹Reported efficacy is based on the 2022 update.

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

Targeted therapy

• Ribociclib (Kisqali) 600 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT01958021
   1. 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 PubMed
   2. 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 + 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 PubMed
   3. 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 PubMed
   4. 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 PubMed

Tamoxifen monotherapy

Regimen variant #1, 20 mg/day

Study	Years 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-NR	Phase 3 (E-switch-ic)	1. Aminoglutethimide 2. Bilateral adrenalectomy	Did not meet primary endpoints of DOR/TTF/OS
Powles et al. 1984	1979-1983	Phase 3 (C)	TAD	Seems to have inferior ORR
Bratherton et al. 1984	NR	Phase 3 (C)	Tamoxifen; 40 mg/day	Did not meet primary endpoints of ORR/PFS
Ingle et al. 1986	NR	Phase 3 (C)	Aminoglutethemide, Hydrocortisone, Tamoxifen	Did not meet 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 inferior TTP1
Rubens et al. 1988	1981-1986	Phase 3 (C)	Tamoxifen & Prednisolone	Seems to have inferior OS
Castiglione-Gertsch et al. 1993	1982-1985	Phase 3 (C)	MPA	Might have inferior TTP
Gazet et al. 1988	1982-1987	Phase 3 (E-switch-ooc)	Surgery	Seems not superior
Borner et al. 1994 (SAKK 23/82)	1982-1991	Phase 3 (E-esc)	Observation	Might have superior DFS2
Stuart et al. 1996	1985-1988	Phase 3 (C)	Megestrol	Seems not superior
Ingle et al. 1991	1985-1989	Phase 3 (C)	Tamoxifen & Prednisolone	Did not meet primary endpoints of ORR/TTP/OS
Muss et al. 1994	1985-1990	Phase 3 (C)	MPA	Might have inferior OS
Hayes et al. 1995	1988-1991	Phase 3 (C)	1. Toremifene; 60 mg/day	Did not meet primary endpoint of ORR
			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 superior TTTF
Buzdar et al. 2002	1995-1997	Phase 3 (C)	Droloxifene	Superior TTP
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	Inferior TTP
Bajetta et al. 2002	1996-1998	Phase 3 (C)	Octreotide LAR & Tamoxifen	Did not meet primary endpoint of PFS
Mouridsen et al. 2001 (ILBCG)	1996-1999	Phase 3 (C)	Letrozole	Inferior TTP
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 superior TTP
Deshmane et al. 2007	NR	Phase 3 (C)	Arzoxifene	Superior PFS

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
  • Some earlier trials used 10 mg PO twice per day instead

28-day cycles

Regimen variant #2, 30 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gundersen et al. 1990a	NR	Phase 3 (C)	Tamoxifen/MPA	Seems to have inferior ORR

Endocrine therapy

• Tamoxifen (Nolvadex) 30 mg PO once per day

Continued indefinitely

Regimen variant #3, 40 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Morgan et al. 1976	NR	Non-randomized
Kiang et al. 1977	1975-1976	Non-randomized
Bratherton et al. 1984	NR	Phase 3 (E-esc)	Tamoxifen; 20 mg/day	Did not meet primary endpoints of ORR/PFS
Forbes 1986	1978-1981	Randomized (C)	1. AC 2. 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. Megestrol 2. Megestrol & Tamoxifen	Did not meet endpoint of ORR
Pyrhönen et al. 1997	1986-1992	Phase 3 (C)	Toremifene; 60 mg/day	Seems to have superior TTP
Gershanovich et al. 1997	1987-1992	Phase 3 (C)	1. Toremifene; 60 mg/day	Did not meet primary endpoints of ORR/TTP
			2. Toremifene; 240 mg/day	Did not meet primary endpoints of ORR/TTP
Beex et al. 2006 (EORTC 10863)	1987-1997	Phase 3 (C)	1. Tamoxifen; intermittent 2. 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 primary endpoints of ORR/TTP/OS
Milla-Santos et al. 2003	1997-1999	Phase 3 (C)	Anastrozole	Inferior OS

Endocrine therapy

• Tamoxifen (Nolvadex) 40 mg PO once per day
  • Some earlier trials used 20 mg PO twice per day instead

Continued indefinitely

References

1. 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. PubMed
2. Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977 Dec;87(6):687-90. link to original article contains dosing details in abstract PubMed
3. 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 contains dosing details in manuscript PubMed
4. 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 PubMed
5. 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 PubMed
6. 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 contains dosing details in manuscript PubMed
7. 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 contains dosing details in manuscript PubMed
8. 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 contains dosing details in abstract PubMed
9. 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 contains dosing details in abstract PubMed
10. 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 PubMed
11. 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 contains dosing details in abstract PubMed
    1. 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 PubMed
12. 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 contains dosing details in abstract PubMed
13. 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 contains dosing details in abstract PubMed
14. 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 contains dosing details in abstract PubMed
15. 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 contains dosing details in abstract PubMed
16. 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 contains dosing details in abstract PubMed
17. 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 contains dosing details in abstract PubMed
18. 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 PubMed
19. 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 contains dosing details in abstract PubMed
20. 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 contains dosing details in abstract PubMed
    1. 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 PubMed
21. 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 PubMed
22. 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 contains dosing details in abstract PubMed
23. 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 contains dosing details in manuscript PubMed
24. 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 PubMed
25. 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 PubMed
26. TARGET_Breast: 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 contains dosing details in abstract PubMed
27. 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 PubMed
28. 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 contains dosing details in abstract PubMed
29. 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 contains dosing details in abstract PubMed
    1. 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 PubMed
30. 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 contains dosing details in manuscript PubMed
31. 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 contains dosing details in abstract PubMed
32. 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 contains dosing details in abstract PubMed
33. 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 PubMed
34. 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 contains dosing details in abstract PubMed
35. 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 contains dosing details in abstract PubMed
36. 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 contains dosing details in abstract PubMed NCT00002777

Tamoxifen & Prednisolone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rubens et al. 1988	1981-1986	Phase 3 (E-esc)	Tamoxifen	Seems to have superior OS
Ingle et al. 1991	1985-1989	Phase 3 (E-esc)	Tamoxifen	Did not meet 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

1. 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 contains dosing details in abstract PubMed
2. 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 contains dosing details in abstract PubMed

Toremifene monotherapy

Regimen

Study	Years 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 inferior TTP
Gershanovich et al. 1997	1987-1992	Phase 3 (E-RT-switch-ic)	1. Tamoxifen; 40 mg/day	Did not meet primary endpoints of ORR/TTP
			2. Toremifene; 240 mg/day	Did not meet 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
			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 primary endpoints of ORR/TTP/OS

Endocrine therapy

• Toremifene (Fareston) 60 mg PO once per day

Continued indefinitely

References

1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 contains dosing details in abstract PubMed

Metastatic disease, maintenance after first-line therapy

Anastrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019	Phase 3 (C)	1. Anastrozole & Everolimus 2. Everolimus & Exemestane 3. Everolimus & Letrozole	Did not meet primary endpoint of PFS

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

1. 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 contains dosing details in manuscript PubMed EudraCT 2013-004153-24

Exemestane monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019	Phase 3 (C)	1. Anastrozole & Everolimus 2. Everolimus & Exemestane 3. Everolimus & Letrozole	Did not meet primary endpoint of PFS

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

1. 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 contains dosing details in manuscript PubMed EudraCT 2013-004153-24

Letrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Guarneri et al. 2021 (MAIN-A)	2014-2019	Phase 3 (C)	1. Anastrozole & Everolimus 2. Everolimus & Exemestane 3. Everolimus & Letrozole	Did not meet primary endpoint of PFS

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

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed EudraCT 2013-004153-24

Metastatic disease, subsequent lines of therapy

Abemaciclib monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Dickler et al. 2017 (MONARCH 1)	2014-2015	Phase 2 (RT)

Targeted therapy

• Abemaciclib (Verzenio) 200 mg PO twice per day

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT02102490

Abemaciclib & Fulvestrant

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sledge et al. 2017 (MONARCH 2)	2014-2015	Phase 3 (E-RT-esc)	Fulvestrant	Superior OS1 Median OS: 46.7 vs 37.3 mo (HR 0.76, 95% CI 0.61-0.95)

¹Reported efficacy is based on the 2019 update.

Targeted therapy

• Abemaciclib (Verzenio) 150 mg PO twice per day

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

1. 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 contains dosing details in manuscript PubMed NCT02107703
   1. 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 PubMed

Anastrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jonat et al. 1996	1993-1994	Phase 3 (E-RT-switch-ic)	Anastrozole; 10 mg/day	Not reported
			Megestrol	Seems to have superior OS1
Buzdar et al. 1996	NR	Phase 3 (E-RT-switch-ic)	Anastrozole; 10 mg/day	Not reported
			Megestrol	Seems to have superior OS1
Osborne et al. 2002 (Trial 0021)	1997-NR	Phase 3 (C)	Fulvestrant 250 mg	Did not meet primary endpoint of TTP
Howell et al. 2002 (Trial 0020)	NR	Phase 3 (C)	Fulvestrant 250 mg	Seems to have non-inferior TTP
Rose et al. 2003	NR in abstract	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

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

1. 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 contains dosing details in abstract PubMed
   1. 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 PubMed
   2. 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 PubMed
2. 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 PubMed
   1. 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 contains dosing details in abstract PubMed
   2. 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 PubMed
3. 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 contains dosing details in abstract PubMed NCT00635713
   1. 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 PubMed
   2. 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 PubMed
4. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
5. 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 contains dosing details in abstract PubMed
6. 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 PubMed

Anastrozole & Fulvestrant

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Johnston et al. 2013 (SoFEA)	2004-2010	Phase 3 (E-esc)	1. Exemestane 2. Fulvestrant	Did not meet primary endpoint of PFS

Endocrine therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• 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

1. 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 contains dosing details in abstract PubMed NCT00253422; NCT00944918

Capecitabine monotherapy

Regimen variant #1, 1000 mg/m² PO twice per day

Study	Years 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 PFS Median 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 PFS Median PFS: 10 vs 7.5 mo (HR 0.88, 95% CI 0.67-1.18)

Note: this variant was used in patients older than 70 years of age.

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	Years 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 PFS Median 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 PFS Median PFS: 10 vs 7.5 mo (HR 0.88, 95% CI 0.67-1.18)

Note: this variant was used in patients 70 years of age and younger.

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

1. 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 contains dosing details in manuscript PubMed NCT02028507

Capecitabine & Fulvestrant

Regimen

Study	Years of enrollment	Evidence
Schwartzberg et al. 2013 (ALSSMBC0606)	2007-NR	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

1. 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 contains dosing details in manuscript PubMed NCT00534417

Everolimus & Exemestane

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baselga et al. 2011 (BOLERO-2)	2009-2011	Phase 3 (E-RT-esc)	Exemestane	Superior PFS1 Median PFS: 7.8 vs 3.2 mo (HR 0.45, 95% CI 0.38-0.54)

¹Reported efficacy is based on the 2013 update.

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00863655
   1. 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. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to original article link to PMC article PubMed
   2. 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 PubMed

Everolimus & Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bachelot et al. 2012 (TAMRAD)	2008-2009	Randomized Phase 2 (E-esc)	Tamoxifen	Superior OS 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

1. 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 contains dosing details in manuscript PubMed NCT01298713

Exemestane monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kaufmann et al. 2000	1995-1998	Phase 3 (E-RT-switch-ic)	Megestrol	Seems to have superior OS
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 & Fulvestrant 2. Fulvestrant	Did not meet primary endpoint of PFS
Baselga et al. 2011 (BOLERO-2)	2009-2011	Phase 3 (C)	Everolimus & Exemestane	Inferior PFS
Connolly et al. 2021 (ECOG-ACRIN E2112)	2014-2018	Phase 3 (C)	Entinostat & Exemestane	Did not meet primary endpoint of PFS
Jiang et al. 2019 (ACEbrca)	2015-2017	Phase 3 (C)	Exemestane & Tucidinostat	Seems to have inferior PFS

Note: there is a regimen called ACE; the study is labeled as ACE_brca to reduce confusion.

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in abstract PubMed
   1. 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 PubMed
2. 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 PubMed NCT00065325
3. 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 contains dosing details in manuscript link to PMC article PubMed NCT00863655
   1. 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. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to original article link to PMC article PubMed
   2. 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 PubMed
4. 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 contains dosing details in abstract PubMed NCT00253422; NCT00944918
5. ACE: 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 contains dosing details in abstract PubMed NCT02482753
6. 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 contains dosing details in abstract link to PMC article PubMed NCT02115282

Exemestane & Tucidinostat

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jiang et al. 2019 (ACEbrca)	2015-2017	Phase 3 (E-esc)	Exemestane	Seems to have superior PFS 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 ACE_brca to reduce confusion.

Endocrine therapy

• Exemestane (Aromasin) 25 mg PO once per day

Targeted therapy

• Chidamide (Epidaza) 30 mg PO once per day on days 1, 4, 8, 11, 15, 18, 22, 25

28-day cycles

References

1. ACE: 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 contains dosing details in abstract PubMed NCT02482753

Fulvestrant monotherapy

Regimen variant #1, 250 mg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Howell et al. 1995	NR	Phase 1/2, <20 pts
Osborne et al. 2002 (Trial 0021)	1997-NR	Phase 3 (E-RT-switch-ic)	Anastrozole	Did not meet primary endpoint of TTP
Howell et al. 2002 (Trial 0020)	NR	Phase 3 (E-RT-switch-ic)	Anastrozole	Seems to have non-inferior TTP
Perey et al. 2006 (SAKK 21/00)	NR	Phase 2
Di Leo et al. 2010 (CONFIRM)	2005-2007	Phase 3 (C)	Fulvestrant; 500 mg	Seems to have inferior OS1
Xu et al. 2010	2005-2007	Phase 3 (E-switch-ic)	Anastrozole	Did not meet primary endpoint of TTP

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 #2, 250 mg, with loading dose

Study	Years 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 PFS
			2. Anastrozole & Fulvestrant	Did not meet primary endpoint of PFS
Burstein et al. 2014 (CALGB 40302)	2006-2010	Phase 3 (C)	Fulvestrant & Lapatinib	Did not meet primary endpoint of PFS

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

Regimen variant #3, 500 mg

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Di Leo et al. 2010 (CONFIRM)	2005-2007	Phase 3 (E-RT-esc)	Fulvestrant; 250 mg	Seems to have superior OS1 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	Might have inferior OS2
Turner et al. 2015 (PALOMA-3)	2013-2014	Phase 3 (C)	Fulvestrant & Palbociclib	Seems to have inferior OS3
Di Leo et al. 2017 (BELLE-3)	2013-2016	Phase 3 (C)	Buparlisib & Fulvestrant	Inferior PFS
Sledge et al. 2017 (MONARCH 2)	2014-2015	Phase 3 (C)	Abemaciclib & Fulvestrant	Inferior OS4
Slamon et al. 2018 (MONALEESA-3)	2015-2016	Phase 3 (C)	Fulvestrant & Ribociclib	Inferior OS5
Xu et al. 2021 (DAWNA-1)	2019-2020	Phase 3 (C)	Dalpiciclib & Fulvestrant	Inferior PFS
Bidard et al. 2022 (EMERALD)	2019-2020	Phase 3 (C)	Elacestrant	Inferior PFS

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

References

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in abstract PubMed NCT00635713
   1. 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 PubMed
   2. 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 PubMed
3. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
4. 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 contains dosing details in abstract PubMed
5. 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 PubMed NCT00065325
6. 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 PubMed NCT00099437
   1. 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 PubMed
7. 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 PubMed
8. 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 contains dosing details in abstract PubMed NCT00253422; NCT00944918
9. 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 contains dosing details in manuscript PubMed NCT00390455
10. 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 contains dosing details in manuscript PubMed NCT01942135
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed
    4. 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 PubMed
11. 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 contains dosing details in abstract PubMed NCT01610284
    1. 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 PubMed
12. 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 contains dosing details in manuscript PubMed NCT02107703
    1. 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 PubMed
13. 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 contains dosing details in abstract PubMed NCT01633060
14. 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 PubMed NCT02422615
    1. 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 PubMed
    2. 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 PubMed
15. 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 PubMed NCT03927456
16. 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 does not contain dosing details in manuscript PubMed NCT03778931

Fulvestrant & Palbociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Turner et al. 2015 (PALOMA-3)	2013-2014	Phase 3 (E-RT-esc)	Fulvestrant	Seems to have superior OS1 Median OS: 34.8 vs 28 mo (HR 0.81, 95% CI 0.65-0.99)

¹Reported efficacy is based on the 2022 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

• Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed NCT01942135
   1. 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 PubMed
   2. 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 PubMed
   3. 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 PubMed
   4. 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 PubMed

Fulvestrant & Ribociclib

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3)	2015-2016	Phase 3 (E-RT-esc)	Fulvestrant	Superior OS1 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

1. 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 PubMed NCT02422615
   1. 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 PubMed
   2. 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 PubMed

Letrozole monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dombernowsky et al. 1998 (AR/BC2)	1993-1994	Phase 3 (E-RT-switch-ic)	1. Letrozole; 0.5 mg/day	Seems to have superior OS
			2. Megestrol	Seems to have superior TTTF
Gershanovich et al. 1998 (AR/BC3)	NR	Randomized (E-RT-switch-ic)	1. Letrozole; 0.5 mg/day	Did not meet primary endpoint of ORR
			2. Aminoglutethimide	Might have superior ORR
Buzdar et al. 2001	NR	Phase 3 (E-switch-ic)	1. Letrozole; 0.5 mg/day	Did not meet primary endpoint of ORR
			2. Megestrol	Did not meet primary endpoint of ORR
Rose et al. 2003	NR in abstract	Phase 3 (E-swith-ic)	Anastrozole	Did not meet primary endpoint of TTP

Endocrine therapy

• Letrozole (Femara) 2.5 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in abstract PubMed
2. 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 contains dosing details in abstract PubMed
3. 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 contains dosing details in abstract PubMed
4. 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 contains dosing details in abstract PubMed

Tamoxifen monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Legha et al. 1979	1977	Phase 2
Tormey et al. 1983	NR	Randomized (C)	Fluoxymesterone & Tamoxifen	Inferior TTTF
Bachelot et al. 2012 (TAMRAD)	2008-2009	Randomized Phase 2 (C)	Everolimus & Tamoxifen	Inferior OS

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

1. 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 PubMed
2. 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 PubMed
3. 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 contains dosing details in manuscript PubMed NCT01298713