Breast cancer, ER-positive

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 H. Deepika Fernandes, MD, FACP
Virginia G. Piper Cancer Care Network Comprehensive Breast Center of Arizona
Scottsdale, AZ, USA
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: these are regimens typically studied for hormone receptor-positive, HER2-negative tumors, without additional targetable mutations. Please see the main breast cancer page for other regimens, including chemotherapy regimens that might have been evaluated in hormone receptor-positive populations.

73 regimens on this page
98 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

ASCO/CAP

NCCN

St Gallen Breast Guidelines

Neoadjuvant endocrine therapy, premenopausal

Anastrozole & Goserelin

Regimen

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

Endocrine therapy

24-week course

Subsequent treatment

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

Endocrine therapy

Targeted therapy

28-day cycle for 5 cycles

Subsequent treatment

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 Dates 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 (primary endpoint)

Endocrine therapy

24-week course

Subsequent treatment

References

  1. ZIPP: Baum M, Hackshaw A, Houghton J, Rutqvist, Fornander T, Nordenskjold B, Nicolucci A, Sainsbury R; ZIPP International Collaborators Group. Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Eur J Cancer. 2006 May;42(7):895-904. Epub 2006 Mar 20. link to original article PubMed
    1. Update: Hackshaw A, Baum M, Fornander T, Nordenskjold B, Nicolucci A, Monson K, Forsyth S, Reczko K, Johansson U, Fohlin H, Valentini M, Sainsbury R. Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):341-9. Epub 2009 Feb 24. link to original article link to PMC article PubMed
  2. 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
  3. 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
  4. STO-5: Johansson A, Dar H, van 't Veer LJ, Tobin NP, Perez-Tenorio G, Nordenskjöld A, Johansson U, Hartman J, Skoog L, Yau C, Benz CC, Esserman LJ, Stål O, Nordenskjöld B, Fornander T, Lindström LS. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial. J Clin Oncol. 2022 Dec 10;40(35):4071-4082. Epub 2022 Jul 21. link to original article link to PMC article PubMed

Neoadjuvant therapy, postmenopausal

Anastrozole monotherapy

Regimen variant #1, 3-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2005 (IMPACT) 1997-2002 Phase 3 (E-switch-ic) 1. Anastrozole & 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

12-week course

Subsequent treatment


Regimen variant #2, 4-month course

Study Dates of enrollment Evidence Efficacy
Ellis et al. 2011 (ACOSOG Z1031) 2006-2009 Screening Phase 2 cRR: 69% (95% CI, 60-77)

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

Endocrine therapy

16- to 18-week course

Subsequent treatment

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 contains dosing details in manuscript 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 manuscript 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 Dates of enrollment Evidence
Ma et al. 2017 (NeoPalAna) 2013-2015 Phase 2

Endocrine therapy

Targeted therapy

28-day cycle for 5 cycles

Subsequent treatment

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

Doxorubicin & Paclitaxel (AT)

AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Semiglazov et al. 2007 NR Randomized Phase 2 (C) 1a. Anastrozole
1b. Exemestane 		Did not meet primary endpoint of ORR

Note: while this is a technically negative study, it is one of very few that directly compare endocrine therapy to chemotherapy.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

Exemestane monotherapy

Regimen

Study Dates 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

3-month course

Subsequent treatment

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Eiermann et al. 2001 (P024) 1998-03 to 1999-08 Phase 2b/3 (E-switch-ic) Tamoxifen Superior ORR (primary endpoint)
Ellis et al. 2011 (ACOSOG Z1031) 2006-2009 Screening Phase 2 cRR: 75% (95% CI, 66-82)

Note: ACOSOG Z1031 gave a total treatment duration of 16 to 18 weeks, which is approximately 4 months. Also, this trial was randomized but with the intent to select candidates for phase III trials; efficacy comparisons were not made.

Endocrine therapy

4-month course

Subsequent treatment

References

  1. 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 manuscript PubMed
    1. Biomarker analysis: Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15;19(18):3808-16. link to original article contains dosing details in abstract PubMed
  2. 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
  3. 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
  4. 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

Tamoxifen monotherapy

Regimen variant #1, 12 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2005 (IMPACT) 1997-2002 Phase 3 (C) 1. Anastrozole & Tamoxifen
2. Anastrozole 		Did not meet primary endpoint of ORR
Cataliotti et al. 2006 (PROACT) 2000-2002 Phase 3 (C) Anastrozole Did not meet primary endpoint of ORR

Endocrine therapy

12-week course

Subsequent treatment


Regimen variant #2, 4 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eiermann et al. 2001 (P024) 1998-03 to 1999-08 Phase 2b/3 (C) Letrozole Inferior ORR

Endocrine therapy

4-month course

Subsequent treatment

References

  1. 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 manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 manuscript PubMed NCT00232661

Neoadjuvant response criteria

Clinical response rate (cRR)

Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.

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 (finv*dprim)0.17 + [4(1 - 0.75LN)dmet]0.17
    • where dprim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, finv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and dmet is the diameter of the largest metastasis in an axillary lymph node.
    • The cut-off points are 1.36 and 3.28.

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Pagani et al. 2014 (TEXT) 2003-2011 Phase 3 (E-switch-ic) 1. Tamoxifen Superior DFS (primary endpoint)
2. Tamoxifen & OFS Superior DFS (primary endpoint)
DFS60: 91.1% vs 87.3%
(HR 0.72, 95% CI 0.60-0.85)
Pagani et al. 2014 (SOFT) 2003-2011 Phase 3 (E-switch-ic) 1. Tamoxifen Superior DFS (primary endpoint)
2. Tamoxifen & OFS Superior DFS (primary endpoint)
DFS60: 91.1% vs 87.3%
(HR 0.72, 95% CI 0.60-0.85)

Note: Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Endocrine therapy

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. Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article 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. Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article PubMed
    4. Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article PubMed
  3. POSITIVE: Partridge AH, Niman SM, Ruggeri M, Peccatori FA, Azim HA Jr, Colleoni M, Saura C, Shimizu C, Sætersdal AB, Kroep JR, Mailliez A, Warner E, Borges VF, Amant F, Gombos A, Kataoka A, Rousset-Jablonski C, Borstnar S, Takei J, Lee JE, Walshe JM, Ruíz-Borrego M, Moore HCF, Saunders C, Bjelic-Radisic V, Susnjar S, Cardoso F, Smith KL, Ferreiro T, Ribi K, Ruddy K, Kammler R, El-Abed S, Viale G, Piccart M, Korde LA, Goldhirsch A, Gelber RD, Pagani O; International Breast Cancer Study Group; POSITIVE Trial Collaborators. Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. N Engl J Med. 2023 May 4;388(18):1645-1656. link to original article link to PMC article PubMed

Goserelin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davidson et al. 2005 (ECOG E5188) 1989-1994 Phase 3 (C) Goserelin & Tamoxifen x 5 y Inferior DFS
Jonat et al. 2002 (ZEBRA) 1990-1996 Phase 3 (E-switch-ooc) CMF Equivalent DFS1 (co-primary endpoint)
(HR 1.01, 95% CI 0.84-1.20)

1Reported results for ZEBRA are for the ER-positive patients only.

Preceding treatment

Endocrine therapy

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

Note: ABCSG 5 stopped goserelin after 3 years.

Preceding treatment

Endocrine therapy

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

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Rydén et al. 2005 (SBII:2pre) 1986-1991 Phase 3 (E-esc) Observation Superior RFS (primary endpoint)
(RR 0.65, 95% CI 0.48-0.89)

Endocrine therapy

2-year course


Regimen variant #2, 5 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-OAS) 1992-2000 Phase 3 (C) Tamoxifen & OFS Did not meet co-primary endpoints of RFS/OS
Colleoni et al. 2006 (IBCSG 13-93) 1993-1999 Phase 3 (E-esc) Observation Superior DFS1 (primary endpoint)
DFS60: 75% vs 62%
(HR 0.59, 95% CI 0.46-0.75)
Bramwell et al. 2009 (NCIC-CTG MA.12) 1993-2000 Phase 3 (E-esc) Placebo 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 co-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 Seems to have inferior DFS2
Kim et al. 2019 (ASTRRA) 2009-2014 Phase 3 (C) Tamoxifen & OFS Inferior DFS3

Did not meet secondary endpoint of OS3

1Reported efficacy is for the ER+ cohort.
2Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen-only arm; reported efficacy for this arm is based on the 2022 update.
3Reported efficacy for ASTRRA is based on the 2023 update.

Endocrine therapy

  • Tamoxifen (Nolvadex) 20 mg PO once per day or 10 mg PO twice per day (the latter dosing is typical in older trials only)

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
    3. Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article PubMed
    4. Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article 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
    1. Update: Baek SY, Noh WC, Ahn SH, Kim HA, Ryu JM, Kim SI, Lee EG, Im SA, Jung Y, Park MH, Park KH, Kang SH, Jeong J, Park E, Kim SY, Lee MH, Kim LS, Lim W, Kim S, Kim HJ. Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial. J Clin Oncol. 2023 Nov 1;41(31):4864-4871. Epub 2023 Aug 22. link to original article PubMed

Tamoxifen & OFS

Tamoxifen & OFS: Tamoxifen & OFS: Ovarian Function Suppression

Regimen variant #1, 3 years

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

Preceding treatment

Endocrine therapy

28-day cycle for 39 cycles (3 years)


Regimen variant #2, 5 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Tevaarwerk et al. 2014 (ECOG E-3193) 1994-1997 Phase 3 (E-esc) Tamoxifen Did not meet co-primary endpoints of DFS/OS More menopausal symptoms
Pagani et al. 2014 (TEXT) 2003-2011 Phase 3 (E-esc) 1. Exemestane & OFS Inferior DFS (primary endpoint)
2. Tamoxifen Might have superior DFS1 (primary endpoint)
Pagani et al. 2014 (SOFT) 2003-2011 Phase 3 (E-esc) 1. Exemestane & OFS Inferior DFS (primary endpoint)
2. Tamoxifen Seems to have superior DFS1 (primary endpoint)
DFS144: 76.1% vs 71.9%
(HR 0.82, 95% CI 0.69-0.98)

Might have superior OS1 (secondary endpoint)
OS144: 89% vs 86.8%
(HR 0.78, 95% CI 0.60-1.01)
Perrone et al. 2019 (HOBOE) 2004-2015 Phase 3 (C) 1. Letrozole & OFS Might have inferior DFS
2. ZL & OFS Inferior DFS Better tolerated
Kim et al. 2019 (ASTRRA) 2009-2014 Phase 3 (E-esc) Tamoxifen Superior DFS2 (primary endpoint)
DFS96: 85.4% vs 80.2%
(HR 0.67, 95% CI 0.51-0.87)

Did not meet secondary endpoint of OS2

1Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen-only arm; reported efficacy for this arm is based on the 2022 update.
2Reported efficacy for ASTRRA is based on the 2023 update.
Note: These regimens are intended for premenopausal patients. Patients in HOBOE stopped triptorelin if they reached 55 years of age.

Endocrine therapy

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. Update: Francis PA, Fleming GF, Láng I, Ciruelos EM, Bonnefoi HR, Bellet M, Bernardo A, Climent MA, Martino S, Bermejo B, Burstein HJ, Davidson NE, Geyer CE Jr, Walley BA, Ingle JN, Coleman RE, Müller B, Le Du F, Loibl S, Winer EP, Ruepp B, Loi S, Colleoni M, Coates AS, Gelber RD, Goldhirsch A, Regan MM; SOFT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT. J Clin Oncol. 2023 Mar 1;41(7):1370-1375. Epub 2022 Dec 9. Erratum in: J Clin Oncol. 2023 Jul 14;:JCO2301370. link to original article PubMed
    4. Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article 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
    2. Pooled update: Pagani O, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Goetz MP, Ciruelos EM, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Chini C, Puglisi F, Spazzapan S, Ruhstaller T, Winer EP, Ruepp B, Loi S, Coates AS, Gelber RD, Goldhirsch A, Regan MM, Francis PA; SOFT and TEXT Investigators and the International Breast Cancer Study Group (a division of ETOP IBCSG Partners Foundation). Adjuvant Exemestane With Ovarian Suppression in Premenopausal Breast Cancer: Long-Term Follow-Up of the Combined TEXT and SOFT Trials. J Clin Oncol. 2023 Mar 1;41(7):1376-1382. Epub 2022 Dec 15. link to original article link to PMC article 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
    1. Update: Baek SY, Noh WC, Ahn SH, Kim HA, Ryu JM, Kim SI, Lee EG, Im SA, Jung Y, Park MH, Park KH, Kang SH, Jeong J, Park E, Kim SY, Lee MH, Kim LS, Lim W, Kim S, Kim HJ. Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial. J Clin Oncol. 2023 Nov 1;41(31):4864-4871. Epub 2023 Aug 22. link to original article PubMed

Adjuvant therapy

Abemaciclib & ET

Abemaciclib & ET: Abemaciclib & Endocrine Therapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Johnston et al. 2020 (monarchE) 2017-2019 Phase 3 (E-RT-esc) Endocrine therapy Superior IDFS1 (primary endpoint)
IDFS48: 85.8% vs 79.4%
(HR 0.66, 95% CI 0.58-0.76)

1Reported efficacy is based on the 2022 update.
Note: the type and dosage of endocrine therapy was not specified in the protocol and was left to clinician discretion.

Targeted therapy

2-year course

Endocrine therapy

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
    2. PRO analysis: Rugo HS, O'Shaughnessy J, Boyle F, Toi M, Broom R, Blancas I, Gumus M, Yamashita T, Im YH, Rastogi P, Zagouri F, Song C, Campone M, San Antonio B, Shahir A, Hulstijn M, Brown J, Zimmermann A, Wei R, Johnston SRD, Reinisch M, Tolaney SM; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022 Jun;33(6):616-627. Epub 2022 Mar 23. PMID: 35337972. link to original article PubMed
    3. Update: Johnston SRD, Toi M, O'Shaughnessy J, Rastogi P, Campone M, Neven P, Huang CS, Huober J, Jaliffe GG, Cicin I, Tolaney SM, Goetz MP, Rugo HS, Senkus E, Testa L, Del Mastro L, Shimizu C, Wei R, Shahir A, Munoz M, San Antonio B, André V, Harbeck N, Martin M; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023 Jan;24(1):77-90. Epub 2022 Dec 6. link to original article PubMed

Anastrozole monotherapy

Regimen variant #1, 3-year course

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Jakesz et al. 2007 (ABCSG-6a) NR Phase 3 (E-esc) No further treatment Seems to have superior RFS (primary endpoint)
RR120: 7.1% vs 11.8%
(HR 0.62, 95% CI 0.40-0.96)
Tjan-Heijnen et al. 2017 (DATA) 2006-2009 Phase 3 (C) Anastrozole x 6 y Might have inferior DFS Less 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

Endocrine therapy

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


Regimen variant #2, 5-year course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baum et al. 2002 (ATAC) 1996-2000 Phase 3 (E-RT-switch-ic) 1. Anastrozole & Tamoxifen Not reported
2. Tamoxifen Superior DFS1 (co-primary endpoint)
RFS120: 80.3% vs 76%
(HR 0.86, 95% CI 0.78-0.95)
Goss et al. 2013 (NCIC-CTG MA.27) 2003-2008 Phase 3 (C) Exemestane Did not meet primary endpoint of 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) 1. Exemestane
2. Letrozole
3. Tamoxifen-Anastrozole; 2y + 3y
4. Tamoxifen-Exemestane; 2y + 3y
5. Tamoxifen-Letrozole; 2y + 3y 		Did not meet primary endpoint of DFS
Iwase et al. 2023 (AERAS) 2007-11 to 2012-11 Non-randomized part of phase 3 RCT
Ruíz-Borrego et al. 2019 (GEICAM/2006-10) 2008-2010 Phase 3 (C) Anastrozole & Fulvestrant Did not meet primary endpoint of DFS
Bachelot et al. 2022 (UNIRAD) 2013-2020 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Letrozole & Everolimus
1a. Tamoxifen & Everolimus 		Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS) 2015-2018 Phase 3 (C) Patient's choice of:
1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib
1d. 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.
Note: In UNIRAD, the type and total duration of ET were not specified; 19% of patients received anastrozole.

Endocrine therapy

5-year course

Subsequent treatment


Regimen variant #3, 6-year course

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Tjan-Heijnen et al. 2017 (DATA) 2006-2009 Phase 3 (E-esc) Anastrozole x 3 y Might have superior DFS (primary endpoint)
DFS60: 83.1% vs 79.4%
(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

Endocrine therapy

6-year course


Regimen variant #4, 7-year course

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Gnant et al. 2021 (SALSA) 2004-2010 Phase 3 (C) Anastrozole x 10 y Did not meet primary endpoint of 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

7-year course


Regimen variant #5, 5 additional years (10 years total)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Iwase et al. 2023 (AERAS) 2007-11 to 2012-11 Phase 3 (E-esc) Observation Superior DFS (primary endpoint)
DFS60: 91% vs 86%
(HR 0.61, 95% CI 0.46-0.82)

Preceding treatment

Endocrine therapy

5-year course (10 years total)

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-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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. RxPONDER: Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, Lin NU, Perez EA, Goldstein LJ, Chia SKL, Dhesy-Thind S, Rastogi P, Alba E, Delaloge S, Martin M, Kelly CM, Ruiz-Borrego M, Gil-Gil M, Arce-Salinas CH, Brain EGC, Lee ES, Pierga JY, Bermejo B, Ramos-Vazquez M, Jung KH, Ferrero JM, Schott AF, Shak S, Sharma P, Lew DL, Miao J, Tripathy D, Pusztai L, Hortobagyi GN. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021 Dec 16;385(25):2336-2347. Epub 2021 Dec 1. link to original article link to PMC article PubMed NCT01272037
  11. UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article PubMed NCT01805271
  12. AERAS: Iwase T, Saji S, Iijima K, Higaki K, Ohtani S, Sato Y, Hozumi Y, Hasegawa Y, Yanagita Y, Takei H, Tanaka M, Masuoka H, Tanabe M, Egawa C, Komoike Y, Nakamura T, Ohtsu H, Mukai H. Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial. J Clin Oncol. 2023 Jun 20;41(18):3329-3338. Epub 2023 Apr 20. link to original article PubMed UMIN000000818

Exemestane monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mamounas et al. 2008 (NSABP B-33) 2001-2003 Phase 3 (E-esc) Placebo Might have superior DFS (primary endpoint)
DFS48: 91% vs 89%
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) 1. Anastrozole
2. Letrozole
3. Tamoxifen-Anastrozole; 2y + 3y
4. Tamoxifen-Exemestane; 2y + 3y
5. Tamoxifen-Letrozole; 2y + 3y 		Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS) 2015-2018 Phase 3 (C) Patient's choice of:
1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib
1d. Palbociclib & Tamoxifen 		Did not meet primary endpoint of IDFS

Preceding treatment

Endocrine therapy

5-year course

References

  1. 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
  2. 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
  3. 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
  4. 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 additional years of therapy

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

Endocrine therapy

2 additional years of endocrine therapy


Regimen variant #2, 2.5 additional years of therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blok et al. 2017 (IDEAL) 2007-2011 Phase 3 (C) Letrozole x 10 y Did not meet primary endpoint of DFS

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

Endocrine therapy

2.5 additional years of endocrine therapy


Regimen variant #3, 3 additional years of therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Del Mastro et al. 2021 (GIM4) 2005-2010 Phase 3 (C) Letrozole x 5 y 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 upper bound of duration of therapy for GIM4.

Preceding treatment

Endocrine therapy

3 additional years of endocrine therapy


Regimen variant #4, 5 years of therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Thürlimann et al. 2005 (BIG 1-98) 1998-2003 Phase 3 (E-RT-switch-ic) 1. Letrozole, then Tamoxifen; 2y + 3y Did not meet primary endpoint of DFS1
2. Tamoxifen x 5y Might have superior OS1 (secondary endpoint)
3. Tamoxifen, then Letrozole; 2y + 3y 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) 1. Anastrozole
2. Exemestane
3. Tamoxifen-Anastrozole; 2y + 3y
4. Tamoxifen-Exemestane; 2y + 3y
5. Tamoxifen-Letrozole; 2y + 3y 		Did not meet primary endpoint of DFS
Bachelot et al. 2022 (UNIRAD) 2013-2020 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Letrozole & Everolimus
1a. Tamoxifen & Everolimus 		Did not meet primary endpoint of DFS
Loibl et al. 2021 (PENELOPE-B) 2014-2017 Phase 3 (C) 1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib
1d. Palbociclib & Tamoxifen 		Did not meet primary endpoint of IDFS
Mayer et al. 2021 (PALLAS) 2015-2018 Phase 3 (C) Patient's choice of:
1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib
1d. 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. In UNIRAD, the type and total duration of ET were not specified; 32% of patients received letrozole.

Preceding treatment

Endocrine therapy

5-year course


Regimen variant #5, 5 additional years of therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Goss et al. 2003 (NCIC-CTG MA.17) 1998-2002 Phase 3 (E-RT-esc) Placebo Superior DFS (primary endpoint)
DFS48: 93% vs 87%
(HR 0.57, 95% CI 0.43-0.75) 		No clinical difference in QoL
Del Mastro et al. 2021 (GIM4) 2005-2010 Phase 3 (E-esc) Letrozole x 2-3 y Superior iDFS (primary endpoint)
iDFS144: 67% vs 62%
(HR 0.78, 95% CI 0.65-0.93)
Mamounas et al. 2018 (NSABP B-42) 2006-2010 Phase 3 (E-esc) Placebo Seems to have superior DFS (primary endpoint)
DFS84: 85% vs 81%
(HR 0.85, 95% CI 0.73-0.999)
Zdenkowski et al. 2016 (ANZ0501 LATER) 2007-2012 Phase 3 (E-esc) Observation Superior iDFS (primary endpoint)

Might have superior DFS (secondary endpoint)
Goss et al. 2016 (NCIC-CTG MA.17R) NR-2009 Phase 3 (E-esc) Letrozole x 5 y Superior DFS (primary endpoint)
DFS60: 95% vs 91%
(HR 0.66, 95% CI 0.48-0.91) 		No clinical difference in QoL
Blok et al. 2017 (IDEAL) 2007-2011 Phase 3 (E-esc) Letrozole x 7.5 y Did not meet primary endpoint of DFS
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

Endocrine therapy

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. Epub 2011 Oct 20. 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 link to PMC 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 NTR3077
  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
  13. UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article PubMed NCT01805271

Letrozole-Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) 1998-2003 Phase 3 (E-RT-switch-ic) 1. Letrozole x 5y Did not meet primary endpoint of DFS1
2. Tamoxifen x 5y Not reported
3. Tamoxifen, then Letrozole; 2y + 3y Did not meet primary endpoint of DFS1

Endocrine therapy

5-year course

References

  1. 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 contains dosing details in manuscript 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. Epub 2011 Oct 20. 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

Tamoxifen monotherapy

Regimen variant #1, 1 year

Study Dates 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

Endocrine therapy

1-year course


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baum et al. 1983 (NATO) 1977-1981 Phase 3 (E-RT-esc) Observation 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
Kimura et al. 2012 1998-2001 Phase 3 (C) Toremifene Non-inferior OS60

Endocrine therapy

2-year course


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

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

2-year course


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schmid et al. 2003 (ABCSG-6) 1990-1995 Phase 3 (C) Aminoglutethemide & Tamoxifen Did not meet primary endpoint of OS

Endocrine therapy

  • Tamoxifen (Nolvadex) as follows:
    • 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Morales et al. 2006 1991-1999 Phase 3 (E-esc) Observation Did not meet primary endpoint of OS60

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Endocrine therapy

3-year course


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Namer et al. 2006 (FASG 02) 1986-1990 Phase 3 (C) FEC50-Tam 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

3-year course


Regimen variant #7, 5 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Stewart et al. 1987 (Scottish Tamoxifen Trial) 1978-1984 Phase 3 (E-esc) Observation 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) 1982-NR Phase 3 (C) Tamoxifen; indefinitely Did not meet endpoint of OS
Tormey et al. 1996 (ECOG 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 co-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 (secondary endpoint)
Fyles et al. 2004 1992-2000 Non-randomized part of RCT
Pagani et al. 2004 (IBCSG 12-93) 1993-1999 Phase 3 (C) Toremifene Non-inferior DFS
Pagani et al. 2004 (IBCSG 14-93) 1993-1999 Phase 3 (C) Toremifene Non-inferior DFS
Hughes et al. 2004 (CALGB 9343) 1994-1999 Non-randomized part of RCT
Rao et al. 2010 (ECOG EB193) 1995-1999 Phase 3 (C) Fenretinide & Tamoxifen Did not meet primary endpoint of DFS
Pritchard et al. 2011 (NCIC-CTG MA.14) 1996-2000 Phase 3 (C) Tamoxifen & Octreotide LAR Did not meet primary endpoint of EFS
Jakesz et al. 2005 (ARNO 95) 1996-2003 Phase 3 (C) Tamoxifen, then Anastrozole; 2y + 3y Seems to have inferior OS5
Jakesz et al. 2005 (ABCSG-8) 1996-2003 Phase 3 (C) Tamoxifen, then Anastrozole; 2y + 3y Inferior EFS
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-Exemestane; 5 years total Seems to have inferior OS6
Thürlimann et al. 2005 (BIG 1-98) 1998-2003 Phase 3 (C) 1. Letrozole x 5y Might have inferior OS7
2. Letrozole, then Tamoxifen; 2y + 3y Not reported
3. Tamoxifen, then Letrozole; 2y + 3y Not reported
Mamounas et al. 2008 (NSABP B-33) 2001-2003 Non-randomized part of phase 3 RCT
van de Velde et al. 2011 (TEAM) 2001-2006 Phase 3 (C) Tamoxifen-Exemestane; 5 years total Did not meet primary endpoint of DFS60
Aihara et al. 2010 (N-SAS BC03) 2002-2005 Phase 3 (C) Tamoxifen x 1-4y, then Anastrozole x 1-4y (5y total) Did not meet primary endpoint of DFS Similar toxicity
Sparano et al. 2018 (TAILORx) 2006-2010 Non-randomized part of phase 3 RCT
Kalinsky et al. 2021 (RxPONDER) 2011-2017 Non-randomized part of phase 3 RCT
Bachelot et al. 2022 (UNIRAD) 2013-2020 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Letrozole & Everolimus
1a. Tamoxifen & Everolimus 		Did not meet primary endpoint of DFS
Mayer et al. 2021 (PALLAS) 2015-2018 Phase 3 (C) Patient's choice of:
1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib
1d. 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 ARNO 95 is based on the 2007 update.
6Reported efficacy for IES is based on the 2011 update.
7Reported efficacy for BIG 1-98 is based on the 2011 & 2018 updates.
Note: in Fyles et al. 2004 and CALGB 9343, the randomization was to radiation therapy or no radiation therapy; all patients received 5 years of tamoxifen. In UNIRAD, the type and total duration of ET were not specified; 44% of patients received tamoxifen. Tormey et al. 1996 is an update of ECOG E5181 but appears to be the first publication of ECOG E4181.

Preceding treatment

Endocrine therapy

5-year course

Subsequent treatment

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


Regimen variant #8, 10 years

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

Endocrine therapy

10-year course

References

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  32. 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: 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
  33. 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
  34. 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
  35. 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. Epub 2011 Oct 20. 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
  36. FASG 02: Namer M, Fargeot P, Roché H, Campone M, Kerbrat P, Romestaing P, Monnier A, Luporsi E, Montcuquet P, Bonneterre J; French Adjuvant Study Group. Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol. 2006 Jan;17(1):65-73. link to original article contains article PubMed
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. 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
  51. 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
  52. RxPONDER: Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, Lin NU, Perez EA, Goldstein LJ, Chia SKL, Dhesy-Thind S, Rastogi P, Alba E, Delaloge S, Martin M, Kelly CM, Ruiz-Borrego M, Gil-Gil M, Arce-Salinas CH, Brain EGC, Lee ES, Pierga JY, Bermejo B, Ramos-Vazquez M, Jung KH, Ferrero JM, Schott AF, Shak S, Sharma P, Lew DL, Miao J, Tripathy D, Pusztai L, Hortobagyi GN. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021 Dec 16;385(25):2336-2347. Epub 2021 Dec 1. link to original article link to PMC article contains dosing details in supplement PubMed NCT01272037
  53. UNIRAD: Bachelot T, Cottu P, Chabaud S, Dalenc F, Allouache D, Delaloge S, Jacquin JP, Grenier J, Venat Bouvet L, Jegannathen A, Campone M, Del Piano F, Debled M, Hardy-Bessard AC, Giacchetti S, Mouret-Reynier MA, Barthelemy P, Kaluzinski L, Mailliez A, Legouffe E, Sephton M, Bliss J, Canon JL, Penault-Llorca F, Lemonnier J, Cameron D, Andre F. Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. J Clin Oncol. 2022 Nov 10;40(32):3699-3708. Epub 2022 May 23. link to original article PubMed NCT01805271
  54. SWOG S1207: NCT01674140

Tamoxifen-Anastrozole

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jakesz et al. 2005 (ABCSG-8) 1996-2003 Phase 3 (E-switch-ic) Tamoxifen Superior EFS (primary endpoint)
EFS36: 95.8% vs 92.7%
(HR 0.60, 95% CI 0.44-0.81)
Jakesz et al. 2005 (ARNO 95) 1996-2003 Phase 3 (E-switch-ic) Tamoxifen Seems to have superior OS1 (secondary endpoint)
OS60: 96% vs 88%
(HR 0.53, 95% CI 0.28-0.99)

Superior EFS (primary endpoint)
De Placido et al. 2018 (FATA-GIM3) 2007-2012 Phase 3 (C) 1. Anastrozole
2. Exemestane
3. Letrozole
4. Tamoxifen-Exemestane; 2y + 3y
5. Tamoxifen-Letrozole; 2y + 3y 		Did not meet primary endpoint of DFS

1Reported efficacy for ARNO 95 is based on the 2007 update; OS60 is estimated from the KM curve in Figure 2B.

Preceding treatment

Endocrine therapy

5-year course

References

  1. 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: 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
  2. 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
  3. 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

Tamoxifen-Exemestane

Regimen variant #1, 2y + 3y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 2004 (IES) 1998-2003 Phase 3 (E-switch-ic) Tamoxifen x 5 y Superior DFS (primary endpoint)
DFS36: 91.5% vs 86.8%
(HR 0.68, 95% CI 0.56-0.82)

Seems to have superior OS1 (secondary endpoint)
(HR 0.86, 95% CI 0.75-0.99)
De Placido et al. 2018 (FATA-GIM3) 2007-2012 Phase 3 (C) 1. Anastrozole
2. Exemestane
3. Letrozole
4. Tamoxifen-Anastrozole; 2y + 3y
5. Tamoxifen-Letrozole; 2y + 3y 		Did not meet primary endpoint of DFS

1Reported efficacy for IES is based on the 2011 update.
Note: this is the lower bound of tamoxifen treatment duration for IES.

Endocrine therapy

5-year course


Regimen variant #2, 2.5y + 2.5y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van de Velde et al. 2011 (TEAM) 2001-2006 Phase 3 (E-switch-ic) Tamoxifen x 5y Did not meet primary endpoint of DFS60

Note: this is the lower bound of tamoxifen treatment duration for TEAM.

Endocrine therapy

5-year course


Regimen variant #3, 3y + 2y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 2004 (IES) 1998-2003 Phase 3 (E-switch-ic) Tamoxifen x 5 y Superior DFS (primary endpoint)
DFS36: 91.5% vs 86.8%
(HR 0.68, 95% CI 0.56-0.82)

Seems to have superior OS1 (secondary endpoint)
(HR 0.86, 95% CI 0.75-0.99)
van de Velde et al. 2011 (TEAM) 2001-2006 Phase 3 (E-switch-ic) Tamoxifen x 5y Did not meet primary endpoint of DFS60

1Reported efficacy for IES is based on the 2011 update.
Note: this is the upper bound of tamoxifen treatment duration for IES & TEAM.

Endocrine therapy

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. 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
  3. 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

Tamoxifen-Letrozole

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) 1998-2003 Phase 3 (E-RT-switch-ic) 1. Letrozole, then Tamoxifen; 2y + 3y Did not meet primary endpoint of DFS1
2. Tamoxifen x 5y Not reported
3. Letrozole x 5y Did not meet primary endpoint of DFS1
De Placido et al. 2018 (FATA-GIM3) 2007-2012 Phase 3 (C) 1. Anastrozole
2. Exemestane
3. Letrozole
4. Tamoxifen-Anastrozole; 2y + 3y
5. Tamoxifen-Exemestane; 2y + 3y 		Did not meet primary endpoint of DFS

Endocrine therapy

5-year course

References

  1. 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. Epub 2011 Oct 20. 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
  2. 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

Toremifene monotherapy

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kimura et al. 2012 1998-2001 Phase 3 (E-switch-ic) Tamoxifen Non-inferior OS60 (primary endpoint)
OS60: 97% vs 96.9%

Preceding treatment

Endocrine therapy

2-year course


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

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

Note: this is the lower bound of a range specified by Toi et al. 2021.

Preceding treatment

Endocrine therapy

5-year course


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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pagani et al. 2004 (IBCSG 12-93) 1993-1999 Phase 3 (E-switch-ic) Tamoxifen Non-inferior DFS1
DFS60: 72% vs 69%
(RR 0.95, 95% CI 0.76-1.18)
Pagani et al. 2004 (IBCSG 14-93) 1993-1999 Phase 3 (E-switch-ic) Tamoxifen Non-inferior 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. The results are from pooled analysis.

Preceding treatment

Endocrine therapy

5-year course


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

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

Note: this is the upper bound of a range specified by Toi et al. 2021.

Preceding treatment

Endocrine therapy

5-year course

References

  1. IBCSG 12-93: Pagani O, Gelber S, Price K, Zahrieh D, Gelber R, Simoncini E, Castiglione-Gertsch M, Coates AS, Goldhirsch A; International Breast Cancer Study Group. Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. Ann Oncol. 2004 Dec;15(12):1749-59. link to original article contains dosing details in manuscript PubMed NCT00002529
  2. 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
  3. 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
  4. 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) 2014-2016 Phase 3 (C) 1a. Anastrozole, Goserelin, Ribociclib
1b. Goserelin, Letrozole, Ribociclib
1c. Goserelin, Ribociclib, Tamoxifen 		Seems to have inferior OS1

1Reported efficacy is based on the 2022 update.

Endocrine therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Anastrozole, Goserelin, Ribociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) 2014-2016 Phase 3 (E-RT-esc) 1a. Anastrozole & Goserelin
1b. Goserelin & Letrozole
1c. Goserelin & Tamoxifen 		Superior PFS (primary endpoint)
Median PFS: 23.8 vs 13 mo
(HR 0.55, 95% CI 0.44-0.69)

Seems to have superior OS1 (secondary endpoint)
Median OS: 58.7 vs 48 mo
(HR 0.76, 95% CI 0.61-0.96)

1Reported efficacy for OS is based on the 2022 update.

Endocrine therapy

Targeted therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Goserelin & Letrozole

Regimen

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

1Reported efficacy is based on the 2022 update.

Endocrine therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Goserelin, Letrozole, Ribociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) 2014-2016 Phase 3 (E-RT-esc) 1a. Anastrozole & Goserelin
1b. Goserelin & Letrozole
1c. Goserelin & Tamoxifen 		Superior PFS (primary endpoint)
Median PFS: 23.8 vs 13 mo
(HR 0.55, 95% CI 0.44-0.69)

Seems to have superior OS1 (secondary endpoint)
Median OS: 58.7 vs 48 mo
(HR 0.76, 95% CI 0.61-0.96)

1Reported efficacy for OS is based on the 2022 update.

Endocrine therapy

Targeted therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Goserelin, Ribociclib, Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) 2014-2016 Phase 3 (E-RT-esc) 1a. Anastrozole & Goserelin
1b. Goserelin & Letrozole
1c. Goserelin & Tamoxifen 		Superior PFS (primary endpoint)
Median PFS: 23.8 vs 13 mo
(HR 0.55, 95% CI 0.44-0.69)

Seems to have superior OS1 (secondary endpoint)
Median OS: 58.7 vs 48 mo
(HR 0.76, 95% CI 0.61-0.96)

1Reported efficacy for OS is based on the 2022 update.

Endocrine therapy

Targeted therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Goserelin & Tamoxifen

Regimen

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

1Reported efficacy is based on the 2022 update.

Endocrine therapy

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: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. Epub 2019 Jun 4. link to original article PubMed
    2. HRQoL analysis: Harbeck N, Franke F, Villanueva-Vazquez R, Lu YS, Tripathy D, Chow L, Babu GK, Im YH, Chandiwana D, Gaur A, Lanoue B, Rodriguez-Lorenc K, Bardia A. Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7). Ther Adv Med Oncol. 2020 Jul 26;12:1758835920943065. link to original article link to PMC article PubMed
    3. Update: Lu YS, Im SA, Colleoni M, Franke F, Bardia A, Cardoso F, Harbeck N, Hurvitz S, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, O'Regan R, Gasch C, Solovieff N, Wang C, Wang Y, Chakravartty A, Ji Y, Tripathy D. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Cancer Res. 2022 Mar 1;28(5):851-859. link to original article link to PMC article PubMed

Tamoxifen monotherapy

Regimen variant #1, 20 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ingle et al. 1986a 1978-1984 Phase 3 (E-RT-switch-ic) Bilateral oophorectomy Did not meet endpoints

Endocrine therapy

Continued indefinitely


Regimen variant #2, 40 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Buchanan et al. 1986 1979-1983 Phase 3 (E-RT-switch-ic) Bilateral oophorectomy Might have 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

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Goetz et al. 2017 (MONARCH 3) 2014-11-18 to 2015-11-11 Phase 3 (E-RT-esc) 1a. Anastrozole
1b. Letrozole 		Superior PFS1 (primary endpoint)
Median PFS: 28.2 vs 14.8 mo
(HR 0.54, 95% CI 0.42-0.70)

1Reported efficacy is based on the 2019 update.

Targeted therapy

Endocrine therapy

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
    1. Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article PubMed
    2. HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article PubMed

Abemaciclib & Letrozole

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goetz et al. 2017 (MONARCH 3) 2014-11-18 to 2015-11-11 Phase 3 (E-RT-esc) 1a. Anastrozole
1b. Letrozole 		Superior PFS1 (primary endpoint)
Median PFS: 28.2 vs 14.8 mo
(HR 0.54, 95% CI 0.42-0.70)

1Reported efficacy is based on the 2019 update.

Targeted therapy

Endocrine therapy

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
    1. Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article PubMed
    2. HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article PubMed

Anastrozole monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre et al. 2000 (TARGETBreast) 1995-1998 Phase 3 (E-RT-switch-ic) Tamoxifen Equivalent TTP (co-primary endpoint)
Median TTP: 8.2 vs 8.3 mo
(HR 0.99, 95% CI 0.86)
Nabholtz et al. 2000 (Arimidex Study Group 2000) 1996-1998 Phase 3 (E-RT-switch-ic) Tamoxifen Superior TTP (co-primary endpoint)
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 (E-switch-ic) Exemestane Inconclusive whether non-inferior TTP
Robertson et al. 2016 (FALCON) 2012-10-17 to 2014-07-11 Phase 3 (C) Fulvestrant Seems to have inferior PFS
Goetz et al. 2017 (MONARCH 3) 2014-11-18 to 2015-11-11 Phase 3 (C) 1a. Abemaciclib & Anastrozole
1b. Abemaciclib & Letrozole 		Inferior PFS
Zhang et al. 2023 (DAWNA-2) 2019-07-19 to 2020-12-25 Phase 3 (C) 1a. Anastrozole & Dalpiciclib
1b. Dalpiciclib & Letrozole 		Inferior PFS

Endocrine therapy

28-day cycles

References

  1. TARGETBreast: Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000 Nov 15;18(22):3748-57. Erratum in: J Clin Oncol. 2012 Jan 20;30(3):343. link to original article 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; 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
  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 link to PMC 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: Zhang P, Zhang Q, Tong Z, Sun T, Li W, Ouyang Q, Hu X, Cheng Y, Yan M, Pan Y, Teng Y, Yan X, Wang Y, Xie W, Zeng X, Wang X, Hu C, Geng C, Zhang H, Li W, Wu X, Zhong J, Xu J, Shi Y, Wei W, Bayaxi N, Zhu X, Xu B. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Jun;24(6):646-657. Epub 2023 May 11. link to original article contains dosing details in abstract PubMed NCT03966898

Anastrozole & Fulvestrant

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bergh et al. 2012 (FACT) 2004-2008 Phase 3 (E-esc) Anastrozole Did not meet primary endpoint of TTP
Mehta et al. 2012 (SWOG S0226) 2004-2009 Phase 3 (E-esc) Anastrozole Superior PFS (primary endpoint)
Median PFS: 15 vs 13.5 mo
(HR 0.80, 95% CI 0.68-0.94)

Seems to have superior OS (secondary endpoint)
Median OS: 47.7 vs 41.3 mo
(HR 0.81, 95% CI 0.65-1.00)

Endocrine therapy

28-day cycles

Dose and schedule modifications

  • Patients in SWOG S0226 who progressed while on therapy were allowed to receive a higher dose of fulvestrant, 500 mg IM once on day 1

References

  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 link to PMC article PubMed

Exemestane monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paridaens et al. 2008 (EORTC 10951) 1996-2002 Phase 3 (E-switch-ic) Tamoxifen Did not meet primary endpoint of PFS
Falandry et al. 2008 (CELAROM) 2003-09 to 2004-12 Phase 3 (C) Celecoxib & Exemestane Did not meet primary endpoint of PFS
Iwata et al. 2013 (A5991048) 2005-2010 Phase 3 (E-switch-ic) Anastrozole Inconclusive whether non-inferior TTP

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2015 (LEA) 2007-2011 Phase 3 (C) 1a. Fulvestrant & Bevacizumab
1b. Letrozole & Bevacizumab 		Did not meet primary endpoint of PFS

Endocrine therapy

28-day cycles


Regimen variant #2, 500 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Howell et al. 2004 1998-2000 Phase 3 (E-switch-ic) Tamoxifen Might have inferior TTP (primary endpoint)
Median TTP: 6.8 vs 8.3 mo
(HR 1.18, 95% CI 0.98-1.44)
Robertson et al. 2016 (FALCON) 2012-10-17 to 2014-07-11 Phase 3 (E-RT-switch-ic) Anastrozole Seems to have superior PFS (primary endpoint)
Median PFS: 16.6 vs 13.8 mo
(HR 0.80, 95% CI 0.64-0.999)
Slamon et al. 2018 (MONALEESA-3) 2015-06 to 2016-06 Phase 3 (C) Fulvestrant & Ribociclib 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. HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article PubMed
    3. 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3) 2015-06 to 2016-06 Phase 3 (E-RT-esc) Fulvestrant Superior PFS (primary endpoint)
Median PFS: 20.5 vs 12.8 mo
(HR 0.59, 95% CI 0.48-0.73)

Superior OS1 (secondary endpoint)
Median OS: 53.7 vs 41.5 mo
(HR 0.73, 95% CI 0.59-0.90)

1Reported efficacy is based on the 2021 update.

Endocrine therapy

  • Fulvestrant (Faslodex) as follows:
    • Cycle 1: 500 mg IM once per day on days 1 & 15
    • Cycle 2 onwards: 500 mg IM once on day 1

Targeted therapy

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 contains dosing details in manuscript 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. HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article PubMed
    3. 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Jonat et al. 1995 1988-1991 Phase 3 (C) Goserelin & Tamoxifen Seems to have inferior TTP

Endocrine therapy

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

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Mouridsen et al. 2001 (ILBCG) 1996-1999 Phase 3 (E-RT-switch-ic) Tamoxifen Superior TTP (primary endpoint)
Median TTP: 41 vs 26 weeks
(HR 0.70, 95% CI 0.60-0.82)
Goss et al. 2007 (Biomed 777-CLP-29) 2002-2005 Phase 3 (C) Atamestane & Toremifene Did not meet primary endpoint of TTP
Wolff et al. 2012 (HORIZONBRCA) 2004-2006 Phase 3 (C) Letrozole & Temsirolimus Did not meet primary endpoint of PFS
Martín et al. 2015 (LEA) 2007-2011 Phase 3 (C) 1a. Fulvestrant & Bevacizumab
1b. 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. 2014 (PALOMA-1/TRIO-18) 2009-2012 Randomized Phase 2 (C) Letrozole & Palbociclib Inferior PFS
Finn et al. 2016 (PALOMA-2) 2013-02 to 2014-07 Phase 3 (C) Letrozole & Palbociclib Inferior PFS
Hortobagyi et al. 2016 (MONALEESA-2) 2014-01-24 to 2015-03-24 Phase 3 (C) Letrozole & Ribociclib Inferior OS1
Goetz et al. 2017 (MONARCH 3) 2014-11-18 to 2015-11-11 Phase 3 (C) 1a. Abemaciclib & Anastrozole
1b. Abemaciclib & Letrozole 		Inferior PFS
Zhang et al. 2023 (DAWNA-2) 2019-07-19 to 2020-12-25 Phase 3 (C) 1a. Anastrozole & Dalpiciclib
1b. Dalpiciclib & Letrozole 		Inferior PFS

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

Endocrine therapy

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. HORIZONBRCA: Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, Sun Y, Neskovic-Konstantinovic Z, Guimaraes RC, Fumoleau P, Chan A, Hachemi S, Strahs A, Cincotta M, Berkenblit A, Krygowski M, Kang LL, Moore L, Hayes DF. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol. 2013 Jan 10;31(2):195-202. Epub 2012 Dec 10. link to original article link to PMC article 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. Epub 2014 Dec 16. 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 plus letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article 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. PRO analysis: Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, Neven P, Shparyk Y, Mori A, Lu DR, Bhattacharyya H, Bartlett C, Iyer S, Johnston S, Ettl J, Harbeck N. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018 Apr 1;29(4):888-894. link to original article link to PMC article PubMed
    2. 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
    3. 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
    1. Update: Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019 Jan 17;5:5. link to original article link to PMC article PubMed
    2. HRQoL analysis: Goetz MP, Martin M, Tokunaga E, Park IH, Huober J, Toi M, Stoffregen C, Shekarriz S, Andre V, Gainford MC, Price GL, Johnston S. Health-Related Quality of Life in MONARCH 3: Abemaciclib plus an Aromatase Inhibitor as Initial Therapy in HR+, HER2- Advanced Breast Cancer. Oncologist. 2020 Sep;25(9):e1346-e1354. Epub 2020 Jun 24. link to original article link to PMC article PubMed
  10. DAWNA-2: Zhang P, Zhang Q, Tong Z, Sun T, Li W, Ouyang Q, Hu X, Cheng Y, Yan M, Pan Y, Teng Y, Yan X, Wang Y, Xie W, Zeng X, Wang X, Hu C, Geng C, Zhang H, Li W, Wu X, Zhong J, Xu J, Shi Y, Wei W, Bayaxi N, Zhu X, Xu B. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Jun;24(6):646-657. Epub 2023 May 11. link to original article contains dosing details in abstract PubMed NCT03966898

Letrozole & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2015 (LEA) 2007-2011 Phase 3 (E-esc) 1a. Fulvestrant
1b. 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 (primary endpoint)
Median PFS: 20.2 vs 15.6 mo
(HR 0.75, 95% CI 0.59-0.96)

Endocrine therapy

Targeted therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Finn et al. 2014 (PALOMA-1/TRIO-18) 2009-2012 Randomized Phase 2 (E-esc) Letrozole Superior PFS (primary endpoint)
Median PFS: 20.2 vs 10.2 mo
(HR 0.49, 95% CI 0.32-0.75)
Finn et al. 2016 (PALOMA-2) 2013-02 to 2014-07 Phase 3 (E-RT-esc) Letrozole Superior PFS (primary endpoint)
Median PFS: 24.8 vs 14.5 mo
(HR 0.58, 95% CI 0.46-0.72)

Endocrine therapy

Targeted therapy

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. Epub 2014 Dec 16. 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. PRO analysis: Rugo HS, Diéras V, Gelmon KA, Finn RS, Slamon DJ, Martin M, Neven P, Shparyk Y, Mori A, Lu DR, Bhattacharyya H, Bartlett C, Iyer S, Johnston S, Ettl J, Harbeck N. Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol. 2018 Apr 1;29(4):888-894. link to original article link to PMC article PubMed
    2. 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
    3. 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Hortobagyi et al. 2016 (MONALEESA-2) 2014-01-24 to 2015-03-24 Phase 3 (E-RT-esc) Letrozole Superior PFS1 (primary endpoint)
Median PFS: 25.3 vs 16 mo
(HR 0.57, 95% CI 0.46-0.70)

Superior OS2 (secondary endpoint)
Median OS: 63.9 vs 51.4 mo
(HR 0.76, 95% CI 0.63-0.93)

1Reported efficacy is based on the 2018 update.
2Reported efficacy is based on the 2022 update.

Endocrine therapy

Targeted therapy

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 plus letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Ingle et al. 1981 1977-1980 Phase 3 (E-switch-ic) DES Did not meet primary endpoint of ORR
Gale et al. 1994 1977-NR Phase 3 (E-switch-ic) 1. Aminoglutethimide
2. Bilateral adrenalectomy 		Did not meet co-primary endpoints of DOR/TTF/OS
Powles et al. 1984 1979-1983 Phase 3 (C) TAD Seems to have inferior ORR
Bratherton et al. 1984 NR Phase 3 (C) Tamoxifen; 40 mg/day Did not meet co-primary endpoints of ORR/PFS
Ingle et al. 1986 NR Phase 3 (C) Aminoglutethemide, Hydrocortisone, Tamoxifen Did not meet co-primary endpoints of ORR/TTP/OS
Muss et al. 1988 1981-1984 Phase 3 (C) Megestrol Did not meet primary endpoint of ORR
Ingle et al. 1988 1981-1985 Phase 3 (C) Fluoxymesterone & Tamoxifen Seems to have 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 Did not meet endpoint of DFS
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 Did not meet endpoint of ORR
Ingle et al. 1991 1985-1989 Phase 3 (C) Tamoxifen & Prednisolone Did not meet co-primary endpoints of ORR/TTP/OS
Muss et al. 1994 1985-1990 Phase 3 (C) MPA Might have 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 on days 1 to 28
    • Some earlier trials used 10 mg PO twice per day instead

28-day cycles


Regimen variant #2, 30 mg/day

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

Endocrine therapy

Continued indefinitely


Regimen variant #3, 40 mg/day

Study Dates 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 co-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 co-primary endpoints of ORR/TTP
2. Toremifene; 240 mg/day Did not meet co-primary endpoints of ORR/TTP
Beex et al. 2006 (EORTC 10863) 1987-1997 Phase 3 (C) 1. Tamoxifen; 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 co-primary endpoints of ORR/TTP/OS
Milla-Santos et al. 2003 1997-1999 Phase 3 (C) Anastrozole Inferior OS

Endocrine therapy

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 contains dosing details in manuscript 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. TARGETBreast: Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study. J Clin Oncol. 2000 Nov 15;18(22):3748-57. Erratum in: J Clin Oncol. 2012 Jan 20;30(3):343. link to original article 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 Dates 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 co-primary endpoints of ORR/TTP/OS

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Pyrhönen et al. 1997 1986-1992 Phase 3 (E-RT-switch-ic) Tamoxifen; 40 mg/day Seems to have inferior TTP
Gershanovich et al. 1997 1987-1992 Phase 3 (E-RT-switch-ic) 1. Tamoxifen; 40 mg/day Did not meet co-primary endpoints of ORR/TTP
2. Toremifene; 240 mg/day Did not meet co-primary endpoints of ORR/TTP
Hayes et al. 1995 1988-1991 Phase 3 (E-RT-switch-ic) 1. Tamoxifen Did not meet primary endpoint of ORR
2. Toremifene; 200 mg/day Did not meet primary endpoint of ORR
Milla-Santos et al. 2001 1996-1999 Phase 3 (E-switch-ic) Tamoxifen; 40 mg/day Did not meet co-primary endpoints of ORR/TTP/OS

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Guarneri et al. 2021 (MAIN-A) 2014-2019 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Everolimus & Exemestane
1c. 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

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Guarneri et al. 2021 (MAIN-A) 2014-2019 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Everolimus & Exemestane
1c. 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

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Guarneri et al. 2021 (MAIN-A) 2014-2019 Phase 3 (C) 1a. Anastrozole & Everolimus
1b. Everolimus & Exemestane
1c. 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

28-day cycles

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

Targeted therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Sledge et al. 2017 (MONARCH 2) 2014-08 to 2015-12 Phase 3 (E-RT-esc) Fulvestrant Superior PFS (primary endpoint)
Median PFS: 16.4 vs 9.3 mo
(HR 0.55, 95% CI 0.45-0.68)

Superior OS1 (secondary endpoint)
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

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
    2. HRQoL analysis: Kaufman PA, Toi M, Neven P, Sohn J, Grischke EM, Andre V, Stoffregen C, Shekarriz S, Price GL, Carter GC, Sledge GW Jr. Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist. 2020 Feb;25(2):e243-e251. Epub 2019 Oct 24. link to original article link to PMC article PubMed

Anastrozole monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jonat et al. 1996 1993-03 to 1994-09 Phase 3 (E-RT-switch-ic) 1. Anastrozole; 10 mg/day Not reported
2. Megestrol Seems to have superior OS1
Buzdar et al. 1996 NR Phase 3 (E-RT-switch-ic) 1. Anastrozole; 10 mg/day Not reported
2. Megestrol Seems to have superior OS1 (secondary endpoint)
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 1997-12 to 1999-11 Phase 3 (E-swith-ic) Letrozole Did not meet primary endpoint of TTP
Xu et al. 2010 2005-2007 Phase 3 (C) Fulvestrant 250 mg Did not meet primary endpoint of TTP
Bidard et al. 2022 (EMERALD) 2019-02 to 2020-10 Phase 3 (C) Elacestrant Inferior PFS

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

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
  7. 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 contains dosing details in supplement link to PMC article PubMed NCT03778931

Anastrozole & Fulvestrant

Regimen

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

Endocrine therapy

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

Anastrozole & Palbociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bidard et al. 2022 (PADA-1) 2017-2019 Phase 3 (C) Fulvestrant & Palbociclib Inferior PFS

Biomarker eligibility criteria

  • PADA-1: ESR1 mutation, detected in blood

Endocrine therapy

Targeted therapy

28-day cycles

References

  1. PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article contains dosing details in abstract PubMed NCT03079011

Capecitabine monotherapy

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2020 (PEARL cohort 1) 2014-2018 Phase 3 (C) Exemestane & Palbociclib Did not meet primary endpoint of 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)
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Note: this variant was used in patients older than 70 years of age in PEARL, and is the lower bound of dosing in TROPiCS-02.

Biomarker eligibility criteria

  • PEARL cohort 2: ESR1 mutations

Chemotherapy

21-day cycles


Regimen variant #2, 1250 mg/m2 PO twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2020 (PEARL cohort 1) 2014-2018 Phase 3 (C) Exemestane & Palbociclib Did not meet primary endpoint of 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)
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Note: this variant was used in patients 70 years of age and younger in PEARL, and is the upper bound of dosing in TROPiCS-02.

Biomarker eligibility criteria

  • PEARL cohort 2: ESR1 mutations

Chemotherapy

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
  2. TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article PubMed NCT03901339
    1. Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article PubMed

Capecitabine & Fulvestrant

Regimen

Study Dates 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

Capivasertib & Fulvestrant

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Turner et al. 2023 (CAPItello-291) 2020-06-02 to 2021-10-13 Phase 3 (E-RT-esc) Fulvestrant Superior PFS1 (co-primary endpoint)
Median PFS: 7.3 vs 3.1 mo
(HR 0.50, 95% CI 0.38-0.65)

1Reported efficacy is based on the AKT pathway-altered population, which was the subject of FDA approval.

Endocrine therapy

  • Fulvestrant (Faslodex) as follows:
    • Cycle 1: 500 mg IM once per day on days 1 & 15
    • Cycle 2 onwards: 500 mg IM once on day 1

Targeted therapy

28-day cycles

References

  1. CAPItello-291: Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. link to original article contains dosing details in manuscript PubMed NCT04305496

Elacestrant monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bidard et al. 2022 (EMERALD) 2019-02 to 2020-10 Phase 3 (E-RT-switch-ic) 1a. Anastrozole
1b. Exemestane
1c. Fulvestrant
1d. Letrozole 		Superior PFS1 (primary endpoint)
PFS12: 22.3% vs 9.4%
(HR 0.70, 95% CI 0.55-0.88)

1Reported efficacy is for all patients; the FDA approval is only for patients with ESR1 mutations.

Endocrine therapy

Continued indefinitely

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT03778931

Eribulin monotherapy

Regimen variant #1, 1.23 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Note: This is the European dosing in TROPiCS-02.

Chemotherapy

21-day cycles


Regimen variant #2, 1.4 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Note: This is the North American dosing in TROPiCS-02.

Chemotherapy

21-day cycles

References

  1. TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article contains dosing details in manuscript PubMed NCT03901339
    1. Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article PubMed

Everolimus & Exemestane

Regimen

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

Did not meet secondary endpoint of OS2 (secondary endpoint)
Median OS: 31 vs 26.6 mo
(HR 0.89, 95% CI 0.73-1.10)

1Reported efficacy for PFS is based on the 2013 update.
2Reported efficacy for OS is based on the 2014 update.

Targeted therapy

Endocrine therapy

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. Epub 2013 Oct 25. 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 Dates of enrollment Evidence Comparator Comparative Efficacy
Bachelot et al. 2012 (TAMRAD) 2008-2009 Randomized Phase 2 (E-esc) Tamoxifen Superior OS (secondary endpoint)
Median OS: NYR vs 32.9 mo
(HR 0.45, 95% CI 0.24-0.81)

Targeted therapy

Endocrine therapy

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 Dates of enrollment Evidence Comparator Comparative Efficacy
Kaufmann et al. 2000 1995-1998 Phase 3 (E-RT-switch-ic) Megestrol Did not meet primary endpoint of ORR

Seems to have superior OS (secondary endpoint)
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
Bidard et al. 2022 (EMERALD) 2019-02 to 2020-10 Phase 3 (C) Elacestrant Inferior PFS

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

Endocrine therapy

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. Epub 2013 Oct 25. 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
  7. 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 contains dosing details in supplement link to PMC article PubMed NCT03778931

Exemestane & Palbociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bidard et al. 2022 (PADA-1) 2017-2019 Phase 3 (C) Fulvestrant & Palbociclib Inferior PFS

Biomarker eligibility criteria

  • PADA-1: ESR1 mutation, detected in blood

Endocrine therapy

Targeted therapy

28-day cycles

References

  1. PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article contains dosing details in abstract PubMed NCT03079011

Exemestane & Tucidinostat

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jiang et al. 2019 (ACEbrca) 2015-2017 Phase 3 (E-esc) Exemestane Seems to have superior PFS (primary endpoint)
Median PFS: 7.4 vs 3.8 mo
(HR 0.75, 95% CI 0.58-0.98)

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

Endocrine therapy

Targeted therapy

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, 500 mg

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Di Leo et al. 2010 (CONFIRM) 2005-2007 Phase 3 (E-RT-esc) Fulvestrant; 250 mg Superior PFS (primary endpoint)
Median PFS: 6.5 vs 5.5 mo
(HR 0.80, 95% CI 0.68-0.94)

Seems to have superior OS1 (secondary endpoint)
Median OS: 26.4 vs 22.3 mo
(HR 0.81, 95% CI 0.69-0.96)
Baselga et al. 2017 (BELLE-2) 2012-2014 Phase 3 (C) Buparlisib & Fulvestrant Might have inferior OS2
Turner et al. 2015 (PALOMA-3) 2013-10-07 to 2014-08-26 Phase 3 (C) Fulvestrant & Palbociclib Inferior PFS (primary endpoint)

Seems to have inferior OS3 (secondary endpoint)
Di Leo et al. 2017 (BELLE-3) 2013-2016 Phase 3 (C) Buparlisib & Fulvestrant Inferior PFS
Sledge et al. 2017 (MONARCH 2) 2014-08 to 2015-12 Phase 3 (C) Abemaciclib & Fulvestrant Inferior OS4
Slamon et al. 2018 (MONALEESA-3) 2015-06 to 2016-06 Phase 3 (C) Fulvestrant & Ribociclib Inferior OS5
Bidard et al. 2022 (EMERALD) 2019-02 to 2020-10 Phase 3 (C) Elacestrant Inferior PFS
Xu et al. 2021 (DAWNA-1) 2019-06-25 to 2020-09-02 Phase 3 (C) Dalpiciclib & Fulvestrant Inferior PFS
Turner et al. 2023 (CAPItello-291) 2020-06-02 to 2021-10-13 Phase 3 (C) Capivasertib & Fulvestrant 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


Regimen variant #2, 250 mg

Historic variant
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Howell et al. 1995 NR Phase 1/2, fewer than 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 (primary endpoint)
Median TTP: 5.5 vs 5.1 mo
(HR 0.98, 95.14% CI 0.80-1.21)
Perey et al. 2006 (SAKK 21/00) 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

28-day cycles


Regimen variant #3, 250 mg, with loading dose

Historic variant
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chia et al. 2008 (EFECT) 2003-2005 Phase 3 (E-switch-ic) Exemestane Did not meet primary endpoint of TTP
Johnston et al. 2013 (SoFEA) 2004-2010 Phase 3 (E-switch-ic) 1. Exemestane Did not meet primary endpoint of 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

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. PRO analysis: Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, André F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun;27(6):1047-1054. Epub 2016 Mar 30. link to original article link to PMC article PubMed
    3. 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
    4. 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
    5. Update: Cristofanilli M, Rugo HS, Im SA, Slamon DJ, Harbeck N, Bondarenko I, Masuda N, Colleoni M, DeMichele A, Loi S, Iwata H, O'Leary B, André F, Loibl S, Bananis E, Liu Y, Huang X, Kim S, Lechuga Frean MJ, Turner NC. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study. Clin Cancer Res. 2022 Aug 15;28(16):3433-3442. link to original article link to PMC article 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
    2. HRQoL analysis: Kaufman PA, Toi M, Neven P, Sohn J, Grischke EM, Andre V, Stoffregen C, Shekarriz S, Price GL, Carter GC, Sledge GW Jr. Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist. 2020 Feb;25(2):e243-e251. Epub 2019 Oct 24. link to original article link to PMC article 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. HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article PubMed
    3. 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 contains dosing details in supplement link to PMC article PubMed NCT03778931
  17. CAPItello-291: Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. link to original article contains dosing details in manuscript PubMed NCT04305496

Fulvestrant & Palbociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Turner et al. 2015 (PALOMA-3) 2013-10-07 to 2014-08-26 Phase 3 (E-RT-esc) Fulvestrant Superior PFS (primary endpoint)
Median PFS: 9.2 vs 3.8 mo
(HR 0.42, 95% CI 0.32-0.56)

Seems to have superior OS1 (secondary endpoint)
Median OS: 34.8 vs 28 mo
(HR 0.81, 95% CI 0.65-0.99)
Bidard et al. 2022 (PADA-1) 2017-2019 Phase 3 (E-switch-ic) 1a. Anastrozole & Palbociclib
1b. Exemestane & Palbociclib
1c. Letrozole & Palbociclib 		Superior PFS (co-primary endpoint)
Median PFS: 11.9 vs 5.7 mo
(HR 0.61, 95% CI 0.43-0.86)

1Reported efficacy for PALOMA-3 is based on the 2022 update.

Biomarker eligibility criteria

  • PADA-1: ESR1 mutation, detected in blood

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

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. PRO analysis: Harbeck N, Iyer S, Turner N, Cristofanilli M, Ro J, André F, Loi S, Verma S, Iwata H, Bhattacharyya H, Puyana Theall K, Bartlett CH, Loibl S. Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial. Ann Oncol. 2016 Jun;27(6):1047-1054. Epub 2016 Mar 30. link to original article link to PMC article PubMed
    3. 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
    4. 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
    5. Update: Cristofanilli M, Rugo HS, Im SA, Slamon DJ, Harbeck N, Bondarenko I, Masuda N, Colleoni M, DeMichele A, Loi S, Iwata H, O'Leary B, André F, Loibl S, Bananis E, Liu Y, Huang X, Kim S, Lechuga Frean MJ, Turner NC. Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2- ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study. Clin Cancer Res. 2022 Aug 15;28(16):3433-3442. link to original article link to PMC article PubMed
  2. PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article contains dosing details in abstract PubMed NCT03079011

Fulvestrant & Ribociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3) 2015-06 to 2016-06 Phase 3 (E-RT-esc) Fulvestrant Superior PFS (primary endpoint)
Median PFS: 20.5 vs 12.8 mo
(HR 0.59, 95% CI 0.48-0.73)

Superior OS1 (secondary endpoint)
Median OS: 53.7 vs 41.5 mo
(HR 0.73, 95% CI 0.59-0.90)

1Reported efficacy is based on the 2021 update.

Endocrine therapy

  • Fulvestrant (Faslodex) as follows:
    • Cycle 1: 500 mg IM once per day on days 1 & 15
    • Cycle 2 onwards: 500 mg IM once on day 1

Targeted therapy

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 contains dosing details in manuscript 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. HRQoL analysis: Fasching PA, Beck JT, Chan A, De Laurentiis M, Esteva FJ, Jerusalem G, Neven P, Pivot X, Bianchi GV, Martin M, Chandiwana D, Lanoue B, Ridolfi A, Wang Y, Rodriguez Lorenc K, Nusch A. Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study. Breast. 2020 Dec;54:148-154. Epub 2020 Sep 23. link to original article link to PMC article PubMed
    3. 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

Gemcitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Chemotherapy

28-day cycles

References

  1. TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article contains dosing details in manuscript PubMed NCT03901339
    1. Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article PubMed

Letrozole monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dombernowsky et al. 1998 (AR/BC2) 1993-03 to 1994-09 Phase 3 (E-RT-switch-ic) 1. Letrozole; 0.5 mg/day Seems to have superior OS (secondary endpoint)

Superior ORR (primary endpoint)
2. Megestrol Seems to have superior TTTF (secondary endpoint)

Seems to have superior ORR (primary endpoint)
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 (primary endpoint)
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 1997-12 to 1999-11 Phase 3 (E-swith-ic) Anastrozole Did not meet primary endpoint of TTP
Bidard et al. 2022 (EMERALD) 2019-02 to 2020-10 Phase 3 (C) Elacestrant Inferior PFS

Endocrine therapy

28-day cycles

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
  5. 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 contains dosing details in supplement link to PMC article PubMed NCT03778931

Letrozole & Palbociclib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bidard et al. 2022 (PADA-1) 2017-2019 Phase 3 (C) Fulvestrant & Palbociclib Inferior PFS

Biomarker eligibility criteria

  • PADA-1: ESR1 mutation, detected in blood

Endocrine therapy

Targeted therapy

28-day cycles

References

  1. PADA-1: Bidard FC, Hardy-Bessard AC, Dalenc F, Bachelot T, Pierga JY, de la Motte Rouge T, Sabatier R, Dubot C, Frenel JS, Ferrero JM, Ladoire S, Levy C, Mouret-Reynier MA, Lortholary A, Grenier J, Chakiba C, Stefani L, Plaza JE, Clatot F, Teixeira L, D'Hondt V, Vegas H, Derbel O, Garnier-Tixidre C, Canon JL, Pistilli B, André F, Arnould L, Pradines A, Bièche I, Callens C, Lemonnier J, Berger F, Delaloge S; PADA-1 investigators. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022 Nov;23(11):1367-1377. Epub 2022 Sep 29. link to original article contains dosing details in abstract PubMed NCT03079011

Sacituzumab govitecan monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Capecitabine
1b. Eribulin
1c. Gemcitabine
1d. Vinorelbine 		Seems to have superior OS (secondary endpoint)
Median OS: 14.4 vs 11.2 mo
(HR 0.79, 95% CI 0.65-0.96)

Superior PFS (primary endpoint)
Median PFS: 5.5 vs 4.0 mo
(HR 0.66, 95% CI 0.53-0.83)

Antibody-drug conjugate therapy

21-day cycles

References

  1. TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article contains dosing details in manuscript PubMed NCT03901339
    1. Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article PubMed

Tamoxifen monotherapy

Regimen

Study Dates 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

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

Vinorelbine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2022 (TROPiCS-02) 2019-05 to 2021-04 Phase 3 (C) Sacituzumab govitecan Inferior PFS

Chemotherapy

7-day cycles

References

  1. TROPiCS-02: Rugo HS, Bardia A, Marme F, Cortes J, Schmid P, Loirat D, Tredan O, Ciruelos E, Dalenc F, Pardo PG, Jhaveri KL, Delaney R, Fu O, Lin L, Verret W, Tolaney SM. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022 Oct 10;40(29):3365-3376. Epub 2022 Aug 26. link to original article contains dosing details in manuscript PubMed NCT03901339
    1. Update: Rugo HS, Bardia A, Marmé F, Cortés J, Schmid P, Loirat D, Trédan O, Ciruelos E, Dalenc F, Gómez Pardo P, Jhaveri KL, Delaney R, Valdez T, Wang H, Motwani M, Yoon OK, Verret W, Tolaney SM. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 Oct 21;402(10411):1423-1433. Epub 2023 Aug 23. link to original article PubMed
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