Breast cancer, ER/PR-positive

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Hermina Fernandes, MD, FACP
University of North Dakota
Bismarck, ND

Note: these are biomarker-specific regimens, please see the main breast cancer page for other regimens.

46 regimens on this page
67 variants on this page

Contents


Guidelines

ASCO

Older

NCCN


Neoadjuvant endocrine therapy

Anastrozole monotherapy

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Variant #1, 3-month course

Study Evidence Comparator Comparative Efficacy
Smith et al. 2005 (IMPACT) Phase III (E) Anastrozole & Tamoxifen
Tamoxifen
Seems not superior
Cataliotti et al. 2006 (PROACT) Phase III (E) Tamoxifen Seems not superior

Hormonotherapy

12-week course

Subsequent treatment

Variant #2, 4-month course

Study Evidence Efficacy
Ellis et al. 2011 (ACOSOG Z1031) Screening Phase II cRR: 69% (95% CI, 60-77)

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

Hormonotherapy

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 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 protocol PubMed
  3. ACOSOG Z1031: Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article contains verified protocol PubMed

Anastrozole & Goserelin

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Regimen

Study Evidence Comparator Comparative Efficacy
Masuda et al. 2012 (STAGE) Phase III (E) Goserelin & Tamoxifen Superior RR

Hormonotherapy

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 protocol PubMed

Anastrozole & Palbociclib

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Regimen

Study Evidence
Ma et al. 2017 (NeoPalAna) Phase II

Hormonotherapy

Chemotherapy

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 protocol PubMed

Goserelin & Tamoxifen

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Regimen

Study Evidence Comparator Comparative Efficacy
Masuda et al. 2012 (STAGE) Phase III (C) Anastrozole & Goserelin Inferior RR

Hormonotherapy

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 protocol PubMed

Letrozole monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Ellis et al. 2001 Phase III (E) Tamoxifen Superior ORR
Eiermann et al. 2001 (P024) Phase III (E) Tamoxifen Superior ORR
Ellis et al. 2011 (ACOSOG Z1031) Screening Phase II 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.

Hormonotherapy

4-month course

Subsequent treatment

References

  1. Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001 Sep 15;19(18):3808-16. link to original article contains protocol PubMed
  2. P024: Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; 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 protocol PubMed
  3. ACOSOG Z1031: Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson JA. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol. 2011 Jun 10;29(17):2342-9. Epub 2011 May 9. link to original article link to PMC article contains verified protocol PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

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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

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  • 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)

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  • 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)

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  • 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

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  • 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

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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

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

Adjuvant endocrine therapy

Anastrozole monotherapy

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Variant #1, 3-year course

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Jakesz et al. 2005 (ARNO 95) Phase III (E) See link See link
Jakesz et al. 2005 (ABCSG-8) Phase III (E) See link See link
Jakesz et al. 2007 (ABCSG-6a) Phase III (E) No further treatment Seems to have superior RFS
Tjan-Heijnen et al. 2017 (DATA) Phase III (C) 6 y of anastrozole Might have inferior DFS Less toxic
De Placido et al. 2018 (FATA-GIM3) Phase III (E) See link See link

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

Preceding treatment

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

Hormonotherapy

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

Variant #2, 5-year course

Study Evidence Comparator Comparative Efficacy
Baum et al. 2002 (ATAC) Phase III (E) 1. Anastrozole & Tamoxifen Not reported
2. Tamoxifen Seems to have superior DFS
Goss et al. 2013 (NCIC CTG MA.27) Phase III (C) Exemestane Seems not superior
Smith et al. 2017 (FACE) Phase III (E) Letrozole Seems not superior
De Placido et al. 2018 (FATA-GIM3) Phase III (E) Tamoxifen x 2 y, then AI x 3 y Seems not superior

Hormonotherapy

5-year course

Variant #3, 6-year course

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Tjan-Heijnen et al. 2017 (DATA) Phase III (E) 3 y of anastrozole Might have superior DFS 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

Hormonotherapy

6-year course

References

  1. ATAC: Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun 22;359(9324):2131-9. Erratum in: Lancet 2002 Nov 9;360(9344):1520. link to original article PubMed
    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. link to original article PubMed
  2. ABCSG-8; 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 and the GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article PubMed
    1. Update: Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article PubMed
    2. Update: Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. link to original article PubMed
  3. 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; Austrian Breast and Colorectal Cancer Study Group. 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 protocol PubMed
  4. NCIC CTG MA.27: Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol 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 protocol PubMed
  6. 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; Dutch Breast Cancer Research Group (BOOG) for the DATA Investigators. 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 verified protocol PubMed
  7. 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 protocol PubMed

Exemestane monotherapy

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Variant #1, 2- to 3-year course

Study Evidence Comparator Comparative Efficacy
Coombes et al. 2004 (IES) Phase III (E) See link See link
van de Velde et al. 2011 (TEAM) Phase III (E) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. The IES gave a range of 2 to 3 years of therapy. TEAM gave a range of 2 to 2.5 years of therapy.

Preceding treatment

Hormonotherapy

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

Variant #2, 3-year course

Study Evidence Comparator Comparative Efficacy
De Placido et al. 2018 (FATA-GIM3) Phase III (E) See link See link

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

Preceding treatment

Hormonotherapy

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

Variant #3, 5-year course

Study Evidence Comparator Comparative Efficacy
Mamounas et al. 2008 (NSABP B-33) Phase III (E) Placebo Superior RFS
Goss et al. 2013 (NCIC CTG MA.27) Phase III (E) Anastrozole Seems not superior
De Placido et al. 2018 (FATA-GIM3) Phase III (E) Tamoxifen x 2 y, then AI x 3 y Seems not superior

Preceding treatment

Hormonotherapy

5-year course

Variant #4, 5 years, with OFS

Study Evidence Comparator Comparative Efficacy
Pagani et al. 2014 (TEXT) Phase III (E) 1. Tamoxifen Superior DFS
2. Tamoxifen & OFS Superior DFS
Pagani et al. 2014 (SOFT) Phase III (E) 1. Tamoxifen Superior DFS
2. Tamoxifen & OFS Superior DFS

OFS: Ovarian Function Suppression These regimens are intended for premenopausal patients. Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Hormonotherapy

Supportive medications

28-day cycle for 65 cycles (5 years)

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
    1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
    2. Update: Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, van de Velde CJ, Lønning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. J Clin Oncol. 2012 Mar 1;30(7):709-17. Epub 2011 Oct 31. link to original article PubMed
  2. NSABP B-33: Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed
  3. TEAM: van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article contains verified protocol PubMed
    1. Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article PubMed
  4. NCIC CTG MA.27: Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol link to PMC article PubMed
  5. TEXT/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 verified protocol link to PMC article PubMed
  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 protocol PubMed

Goserelin monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Jonat et al. 2002 (ZEBRA) Phase III (E) CMF Equivalent DFS
Davidson et al. 2005 (ECOG E5188) Phase III (C) Goserelin & Tamoxifen x 5 y Inferior DFS

Preceding treatment

Hormonotherapy

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 verified protocol 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

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Regimen

Study Evidence Comparator Comparative Efficacy
Jakesz et al. 2002 (ABCSG 5) Phase III (E) CMF Seems to have superior RFS
Davidson et al. 2005 (ECOG E5188) Phase III (E) Goserelin x 5 y Superior DFS

Preceding treatment

Hormonotherapy

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; Austrian Breast and Colorectal Cancer Study Group Trial 5. 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
  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 verified protocol PubMed

Letrozole monotherapy

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Variant #1, 2 years of therapy

Study Evidence Comparator Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) Phase III (E) See link See link

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

Hormonotherapy

2-year course

Subsequent treatment

Variant #2, 2.5 additional years of therapy

Study Evidence Comparator Comparative Efficacy
Blok et al. 2017 (IDEAL) Phase III (E) Letrozole x 10 y Seems not superior

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.

Preceding treatment

  • Any endocrine therapy for 5 years

Hormonotherapy

2.5-year course, for a total of 7.5 years of hormonal therapy

Variant #3, 3 additional years of therapy

Study Evidence Comparator Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) Phase III (E) See link See link
De Placido et al. 2018 (FATA-GIM3) Phase III (E) See link See link

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

Preceding treatment

Hormonotherapy

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

Variant #4, 5 years of therapy

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Thürlimann et al. 2005 (BIG 1-98) Phase III (E) 1. Letrozole, then Tamoxifen Seems not superior (*)
2. Tamoxifen Might have superior OS (*)
3. Tamoxifen, then Letrozole Seems not superior (*)
Goss et al. 2016 (NCIC CTG MA.17R) Phase III (C) Letrozole x 10 y Inferior DFS No clinical difference in QoL
Smith et al. 2017 (FACE) Phase III (E) Anastrozole Seems not superior
De Placido et al. 2018 (FATA-GIM3) Phase III (E) Tamoxifen x 2 y, then AI x 3 y Seems not superior

Efficacy reported for BIG 1-98 is based on the 2011 and 2018 updates.

Hormonotherapy

5-year course

Variant #5, 5 additional years of therapy

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Goss et al. 2003 (NCIC CTG MA.17) Phase III (E) Placebo Superior DFS No clinical difference in QoL
Zdenkowski et al. 2016 (ANZ0501 LATER) Phase III (E) Observation Might have superior DFS
Goss et al. 2016 (NCIC CTG MA.17R) Phase III (E) Letrozole x 5 y Superior DFS No clinical difference in QoL
Blok et al. 2017 (IDEAL) Phase III (E) Letrozole x 7.5 y Seems not superior
Colleoni et al. 2017 (SOLE) Phase III (C) Intermittent Letrozole Seems not superior
Mamounas et al. 2018 (NSABP B-42) Phase III (E) Placebo Might have superior 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.

Preceding treatment

  • NCIC CTG MA.17: Most patients received 5 years of tamoxifen therapy prior to starting letrozole
  • ANZ0501 LATER: At least 4 years of any endocrine therapy
  • NCIC CTG MA.17R: Letrozole for 5 years
  • IDEAL: Any endocrine therapy for 5 years

Hormonotherapy

5 additional years for a total 10-year course of hormonal 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
    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. QoL 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; Breast International Group (BIG) 1-98 Collaborative Group. 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
    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 1-98 Collaborative and International Breast Cancer Study Groups. 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 1-98 Collaborative Group. 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 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
    6. Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; members of the BIG 1-98 Collaborative Group and the 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. 2018 Nov 26:JCO1800440. [Epub ahead of print] link to original 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 protocol PubMed
  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 verified protocol PubMed
    1. QoL analysis: Lemieux J, Brundage MD, Parulekar WR, Goss PE, Ingle JN, Pritchard KI, Celano P, Muss H, Gralow J, Strasser-Weippl K, Whelan K, Tu D, Whelan TJ. Quality of life from Canadian Cancer Trials Group MA.17R: a randomized trial of extending adjuvant letrozole to 10 years. J Clin Oncol. 2018 Feb 20;36(6):563-571. Epub 2018 Jan 12. link to original article PubMed
  5. FACE: Smith I, Yardley D, Burris H, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Comarella L, Salomon H, Wamil B, O'Shaughnessy J. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol. 2017 Apr 1;35(10):1041-1048. Epub 2017 Jan 23. link to original article contains protocol PubMed
  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 verified protocol PubMed
  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 protocol PubMed
    1. QoL 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 Apr 10. [Epub ahead of print] 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 protocol PubMed
  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. 2018 Nov 30. [Epub ahead of print] link to original article PubMed

Leuprolide monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Schmid et al. 2007 (TABLE) Phase III (E) CMF Superior OS

Hormonotherapy

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 verified protocol PubMed

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Baum et al. 1983 (NATO) Phase III (C) Tamoxifen x 2 y Inferior OS
Stewart et al. 1987 (Scottish Tamoxifen Trial) Phase III (C) Tamoxifen x 5 y Inferior OS (*)
Rydén et al. 2005 (SBII:2pre) Phase III (C) Tamoxifen x 2 y Inferior RFS
Hutchins et al. 2005 (INT-0102) Phase III (C) Tamoxifen x 5 y Seems not superior
Colleoni et al. 2006 (IBCSG 13-93) Phase III (C) Tamoxifen x 5 y Superior DFS
Zdenkowski et al. 2016 (ANZ0501 LATER) Phase III (C) Letrozole x 5 y Might have inferior DFS
Jensen et al. 2017 (CBC 02) Phase III (C) Tamoxifen x 2 y Seems to have inferior OS

No further treatment. Efficacy for the Scottish Tamoxifen Trial is based on the 2001 update.

Preceding treatment

  • INT-0102: Surgery, then CAF x 6 versus CMF x 6
  • IBCSG 13-93: Surgery, then AC x 4 or EC x 4, then CMF x 3
  • ANZ0501 LATER: At least 4 years of any endocrine therapy

References

  1. NATO: Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet. 1983 Feb 5;1(8319):257-61. link to original article contains protocol PubMed
    1. Update: Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Richards D, Ellis SH. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: analysis at six years by Nolvadex Adjuvant Trial Organisation. Lancet. 1985 Apr 13;1(8433):836-40. link to original article PubMed
  2. Scottish Tamoxifen Trial: Stewart HJ, Taylor W, Forrest P. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial: report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet. 1987 Jul 25;2(8552):171-5. link to original article PubMed
    1. Update: Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, Prescott RJ, George WD; The Scottish Cancer Trials Breast Group. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. Br J Cancer. 1996 Jul;74(2):297-9. link to original article link to PMC article PubMed
    2. Update: Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001 Mar 21;93(6):456-62. link to original article PubMed
  3. 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 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
  4. 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
  5. 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 contains verified protocol PubMed
  6. 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 PubMed
  7. 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 PubMed

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Fisher et al. 1989 (NSABP B-14) Phase III (C) Tamoxifen Inferior OS (*)
Fisher et al. 2001 (NSABP B-23) Phase III (C) Tamoxifen Seems not superior
Goss et al. 2003 (NCIC CTG MA.17) Phase III (C) Letrozole Inferior DFS
Mamounas et al. 2008 (NSABP B-33) Phase III (C) Exemestane Inferior RFS

No active treatment. Used as a comparator arm. Efficacy for NSABP B-14 based on the 2004 update.

Preceding treatment

References

  1. NSABP B-14: Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, Margolese R, Robidoux A, Shibata H, Terz J, Peterson AHG, Feldman MI, Farrar W, Evans J, Lickley HL, Ketner M. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84. link to original article contains verified protocol PubMed
    1. Update: Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschênes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AH, Feldman MI, Farrar W, Evans J, Lickley HL. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42. link to original article PubMed
    2. Update: Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001 May 2;93(9):684-90. link to original article PubMed
    3. Update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article PubMed
    4. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
  2. NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
    1. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
  3. 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
    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. QoL 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
  4. 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

Tamoxifen monotherapy

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Variant #1, 1 year

Study Evidence Comparator Comparative Efficacy
Rydén et al. 1992 (SSBCG II:I) Phase III (C) 1. RT
2. Tamoxifen & RT
Seems not superior
Rivkin et al. 1994 (SWOG S7827) Phase III (C) 1. CMFVP
2. CMFVPT
Seems not superior
Overgaard et al. 1999 (DBCG 82C) Phase III (C) 1. CMFT Inferior DFS (*)
2. Tamoxifen & RT Seems to have inferior OS
Knoop et al. 2001 (DBCG 77C) Phase III (E) Observation Seems not superior
Andersen et al. 2008 (DBCG 89C) Phase III (C) 1. Tamoxifen x 2 y
2. TAM/MA
Seems not superior

Note: efficacy for this arm of DBCG 82C versus CMFT is based on the 2013 update. Knoop et al. 2001 is a retrospective biomarker analysis; we are not aware of another primary publication for DBCG 77C.

Preceding treatment

Hormonotherapy

1-year course

Variant #2, 2 years of 20 mg/day

Study Evidence Comparator Comparative Efficacy
Baum et al. 1983 (NATO) Phase III (E) Observation Superior OS
Bianco et al. 1988 (GUN) Phase III (E) Observation Seems to have superior DFS
Rutqvist et al. 1996 Phase III (C) Tamoxifen x 5 y Seems to have inferior OS
Baum & Odling-Smee 1996 (CRUK Over 50s) Phase III (C) Tamoxifen x 5 y Inferior EFS
Jakesz et al. 1999 Phase III (C) AV-CMF-TAM Seems not superior
Coombes et al. 2004 (IES) Phase III (E) See link See link
Rydén et al. 2005 (SBII:2pre) Phase III (E) Observation Superior RFS
Thürlimann et al. 2005 (BIG 1-98) Phase III (E) See link See link
Jakesz et al. 2005 (ARNO 95) Phase III (E) See link See link
Jakesz et al. 2005 (ABCSG-8) Phase III (E) See link See link
Shien et al. 2014 (JCOG9401) Phase III (C) ACT Seems to have inferior RFS
De Placido et al. 2018 (FATA-GIM3) Phase III (E) See link See link

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

Hormonotherapy

2-year course

Subsequent treatment

Variant #3, 2 years of 30 mg/day

Study Evidence Comparator Comparative Efficacy
Pritchard et al. 1997 Phase III (C) CMFT Seems not superior
Jensen et al. 2017 (CBC 02) Phase III (E) Observation Seems to have superior OS

Hormonotherapy

2-year course

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

Study Evidence Comparator Comparative Efficacy
Schmid et al. 2003 (ABCSG-6) Phase III (C) Aminoglutethemide & Tamoxifen Seems not superior

Hormonotherapy

  • 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

Variant #5, 3 years of 20 mg/day

Study Evidence Comparator Comparative Efficacy
Thürlimann et al. 2005 (BIG 1-98) Phase III (E) See link See link
Morales et al. 2006 Phase III (E) Observation Seems not superior
van de Velde et al. 2011 (TEAM) Phase III (E) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. TEAM gave a range of 2.5 to 3 years of therapy.

Preceding treatment

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

Hormonotherapy

3-year course

Subsequent treatment

Variant #6, 3 years of 30 mg/day

Study Evidence Comparator Comparative Efficacy
Fargeot et al. 2004 (FASG 08) Phase III (C) Epirubicin & Tamoxifen Seems not superior
Namer et al. 2006 (FASG 02) Phase III (C) FEC50-Tam Inferior DFS
Namer et al. 2006 (FASG 07) Phase III (C) FEC50-Tam Inferior DFS

Hormonotherapy

3-year course

Variant #7, 5 years

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Stewart et al. 1987 (Scottish Tamoxifen Trial) Phase III (E) Observation Superior OS (*)
Fisher et al. 1989 (NSABP B-14) Phase III (E) Placebo Superior OS (*)
Fisher et al. 1990 (NSABP B-16) Phase III (C) 1. ACT Seems to have inferior OS
2. PFT Seems to have inferior DDFS
Mustacchi et al. 1994 (GRETA) Phase III (C) Tamoxifen alone (no surgery) Seems not superior
Rutqvist et al. 1996 Phase III (E) Tamoxifen x 2 y Seems to have superior OS
Tormey et al. 1996 (ECOG E4181/E5181) Phase III (C) Tamoxifen indefinitely Seems not superior
Baum & Odling-Smee 1996 (CRUK Over 50s) Phase III (E) Tamoxifen x 2 y Superior EFS (*)
Fisher et al. 1997 (NSABP B-20) Phase III (C) 1. CMFT Might have inferior OS (*)
2. MFT Not reported (*)
Fisher et al. 2001 (NSABP B-23) Phase III (E) Placebo Seems not superior
Baum et al. 2002 (ATAC) Phase III (C) 1. Anastrozole & Tamoxifen Seems not superior
2. Anastrozole Seems to have inferior DFS
Fisher et al. 2002 (NSABP B-21) Phase III (E) RT
Tamoxifen & RT
Inferior DFS
Assikis et al. 2003 Phase III (E) FAC, then MV Seems not superior
Coombes et al. 2004 (IES) Phase III (C) Tamoxifen x 2-3y, then Exemestane x 2-3y Seems to have inferior OS (*)
Fyles et al. 2004 Non-randomized portion of RCT
Hughes et al. 2004 (CALGB 9343) Non-randomized portion of RCT
Hutchins et al. 2005 (INT-0102) Phase III (E) Observation Seems not superior
Thürlimann et al. 2005 (BIG 1-98) Phase III (C) 1. Letrozole Might have inferior OS (*)
2. Letrozole x 2y, then Tamoxifen x 3y Not reported
3. Tamoxifen x 2y, then Letrozole x 3y Not reported
Jakesz et al. 2005 (ARNO 95) Phase III (C) Tamoxifen x 2y, then Anastrozole x 3y Seems to have inferior OS
Jakesz et al. 2005 (ABCSG-8) Phase III (C) Tamoxifen x 2y, then Anastrozole x 3y Might have inferior RFS
Mamounas et al. 2008 (NSABP B-33) Non-randomized portion of RCT
Albain et al. 2009 (SWOG-8814) Phase III (*) See link See link
Aihara et al. 2010 (N-SAS BC03) Phase III (C) Tamoxifen x 1-4y, then Anastrozole x 1-4y (5y total) Seems not superior Similar toxicity
Rao et al. 2010 (ECOG EB193) Phase III (C) Fenretinide & Tamoxifen Seems not superior
van de Velde et al. 2011 (TEAM) Phase III (C) Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y Seems not superior
Pritchard et al. 2011 (NCIC CTG MA.14) Phase III (C) Tamoxifen & Octreotide LAR Seems not superior
Davies et al. 2013 (ATLAS) Phase III (C) Tamoxifen x 10 years Inferior OS
Pagani et al. 2014 (SOFT) Phase III (C) 1. Exemestane & OFS Inferior DFS
2. Tamoxifen & OFS Might have inferior DFS (*)
Tevaarwerk et al. 2014 (ECOG E-3193) Phase III (C) Tamoxifen & OFS Seems not superior Fewer menopausal symptoms
Sparano et al. 2018 (TAILORx) Non-randomized portion of RCT

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. Reported efficacy for the Scottish Tamoxifen Trial is based on the 2001 update. Reported efficacy for NSABP B-14 & NSABP B-20 is based on the 2004 update. Efficacy for CRUK Over 50s is based on the 2011 update. Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015. Reported efficacy for IES is based on the 2011 update. Reported efficacy for BIG 1-98 is based on the 2011 & 2018 updates.

Preceding treatment

Hormonotherapy

5-year course

Subsequent treatment

Variant #8, 10 years

Study Evidence Comparator Comparative Efficacy
Davies et al. 2013 (ATLAS) Phase III (E) Tamoxifen x 5 years Superior OS

Hormonotherapy

10-year course

References

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  5. NSABP B-16: Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. link to original article PubMed
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  6. SSBCG II:I: Rydén S, Fernö M, Möller T, Aspegren K, Bergljung L, Killander D, Landberg T. Long-term effects of adjuvant tamoxifen and/or radiotherapy: the South Sweden Breast Cancer Trial. Acta Oncol. 1992;31(2):271-4. link to original article PubMed
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  7. GRETA: Mustacchi G, Milani S, Pluchinotta A, De Matteis A, Rubagotti A, Perrota A; Group for Research on Endocrine Therapy in the Elderly. Tamoxifen or surgery plus tamoxifen as primary treatment for elderly patients with operable breast cancer: the GRETA trial. Anticancer Res. 1994 Sep-Oct;14(5B):2197-200. PubMed
    1. Update: Mustacchi G, Ceccherini R, Milani S, Pluchinotta A, De Matteis A, Maiorino L, Farris A, Scanni A, Sasso F; Italian Cooperative Group GRETA. Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol. 2003 Mar;14(3):414-20. link to original article PubMed
    2. Update: Mustacchi G, Scanni A, Capasso I, Farris A, Pluchinotta A, Isola G. Update of the phase III trial 'GRETA' of surgery and tamoxifen versus tamoxifen alone for early breast cancer in elderly women. Future Oncol. 2015;11(6):933-41. Epub 2014 Nov 10. link to original article PubMed
  8. SWOG S7827: Rivkin SE, Green S, Metch B, Cruz AB, Abeloff MD, Jewell WR, Costanzi JJ, Farrar WB, Minton JP, Osborne CK. Adjuvant CMFVP versus tamoxifen versus concurrent CMFVP and tamoxifen for postmenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1994 Oct;12(10):2078-85. link to original article contains protocol PubMed
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  10. ECOG E4181/E5181: Tormey DC, Gray R, Falkson HC; Eastern Cooperative Oncology Group. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst. 1996 Dec 18;88(24):1828-33. link to original article contains protocol PubMed
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    1. Update: Hackshaw A, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer. J Clin Oncol. 2011 May 1;29(13):1657-63. Epub 2011 Mar 21. link to original article PubMed
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  13. NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article contains verified protocol PubMed
    1. Update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article PubMed
    2. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
  14. DBCG 82C: Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. link to original article contains protocol PubMed
    1. Update: Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article contains verified protocol PubMed
  15. Jakesz R, Hausmaninger H, Haider K, Kubista E, Samonigg H, Gnant M, Manfreda D, Tschurtschenthaler G, Kolb R, Stierer M, Fridrik M, Mlineritsch B, Steindorfer P, Mittlböck M, Steger G; ABCSG. Randomized trial of low-dose chemotherapy added to tamoxifen in patients with receptor-positive and lymph node-positive breast cancer. J Clin Oncol. 1999 Jun;17(6):1701-9. link to original article contains protocol PubMed
  16. NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
    1. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
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  18. 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
    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. link to original article PubMed
  19. NSABP B-21: Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, Margolese RG, Nesbitt L, Paik S, Pisansky TM, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002 Oct 15;20(20):4141-9. link to original article contains verified protocol PubMed
  20. ABCSG-6: Schmid M, Jakesz R, Samonigg H, Kubista E, Gnant M, Menzel C, Seifert M, Haider K, Taucher S, Mlineritsch B, Steindorfer P, Kwasny W, Stierer M, Tausch C, Fridrik M, Wette V, Steger G, Hausmaninger H; ABCSG. Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjuvant treatment in postmenopausal breast cancer patients with hormone receptor-positive disease: Austrian breast and colorectal cancer study group trial 6. J Clin Oncol. 2003 Mar 15;21(6):984-90. link to original article contains protocol PubMed
  21. Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains protocol PubMed
  22. 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
    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
  23. Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, Weir LM, Olivotto IA. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):963-70. link to original article PubMed
  24. CALGB 9343: Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, Wheeler J, Champion LA, Smith TJ, Smith BL, Shapiro C, Muss HB, Winer E, Hudis C, Wood W, Sugarbaker D, Henderson IC, Norton L; Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):971-7. link to original article contains verified protocol PubMed
    1. Update: Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, Muss HB, Smith BL, Hudis CA, Winer EP, Wood WC. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013 Jul 1;31(19):2382-7. Epub 2013 May 20. link to PMC article PubMed
  25. FASG 08: Fargeot P, Bonneterre J, Roché H, Lortholary A, Campone M, Van Praagh I, Monnier A, Namer M, Schraub S, Barats JC, Guastalla JP, Goudier MJ, Chapelle-Marcillac I. Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial. J Clin Oncol. 2004 Dec 1;22(23):4622-30. Epub 2004 Oct 25. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248. link to original article contains protocol PubMed
  26. 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 protocol 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
  27. Review: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. link to original article PubMed
  28. ABCSG-8; 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 and the GABG. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article PubMed
    1. Update: Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article PubMed
    2. Update: Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. link to original article PubMed
  29. 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
  30. 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 contains verified protocol PubMed
  31. 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; Breast International Group (BIG) 1-98 Collaborative Group. 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
    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 1-98 Collaborative and International Breast Cancer Study Groups. 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 1-98 Collaborative Group. 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 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
    6. Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; members of the BIG 1-98 Collaborative Group and the 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. 2018 Nov 26:JCO1800440. [Epub ahead of print] link to original article PubMed
  32. FASG 02; FASG 07: Namer M, Fargeot P, Roché H, Campone M, Kerbrat P, Romestaing P, Monnier A, Luporsi E, Montcuquet P, Bonneterre J; French Adjuvant Study Group. Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials. Ann Oncol. 2006 Jan;17(1):65-73. link to original article contains article PubMed
  33. Morales L, Canney P, Dyczka J, Rutgers E, Coleman R, Cufer T, Welnicka-Jaskiewicz M, Nortier J, Bogaerts J, Therasse P, Paridaens R; European Organisation for Research and Treatment of Cancer 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 protocol PubMed
  34. 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
  35. 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
  36. 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 verified protocol PubMed
  37. 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 protocol PubMed
  38. 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 verified protocol PubMed
  39. 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 verified protocol PubMed
    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
  40. 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
    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
  41. 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 verified protocol link to PMC article PubMed
  42. 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 protocol PubMed
  43. TEXT/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 verified protocol link to PMC article PubMed
    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
  44. 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 verified protocol link to PMC article PubMed
  45. 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 verified protocol PubMed
  46. 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 protocol PubMed
  47. 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 verified protocol in supplement PubMed

Tamoxifen & OFS

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Tamoxifen & OFS: Tamoxifen & OFS: Ovarian Function Suppression

Variant #1, 3 years

Study Evidence Comparator Comparative Efficacy
Gnant et al. 2009 (ABCSG-12) Phase III (C) Tamoxifen, OFS, Zoledronic acid Inferior DFS

Preceding treatment

Hormonotherapy

Supportive medications

28-day cycle for 39 cycles (3 years)

Variant #2, 5 years

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Pagani et al. 2014 (TEXT) Phase III (E) 1. Exemestane & OFS Inferior DFS
2. Tamoxifen Might have superior DFS (*)
Pagani et al. 2014 (SOFT) Phase III (E) 1. Exemestane & OFS Inferior DFS
2. Tamoxifen Might have superior DFS (*)
Tevaarwerk et al. 2014 (ECOG E-3193) Phase III (E) Tamoxifen Seems not superior More menopausal symptoms

These regimens are intended for premenopausal patients. Pagani et al. 2014 reports on two trials, but only SOFT had the tamoxifen only arm; efficacy for this arm is as reported in Francis et al. 2015.

Hormonotherapy

Supportive medications

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-12 Trial Investigators. 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 protocol PubMed
    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; Austrian Breast and Colorectal Cancer Study Group. 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. TEXT/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 verified protocol link to PMC article PubMed
    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
  3. 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 verified protocol link to PMC article PubMed

Toremifene monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kimura et al. 2012 Phase III (E) Tamoxifen Non-inferior OS

Preceding treatment

Hormonotherapy

2-year course

References

  1. 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 verified protocol PubMed

Metastatic disease, first-line endocrine therapy

Abemaciclib & Anastrozole

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Goetz et al. 2017 (MONARCH 3) Phase III (E) Anastrozole Superior PFS

Chemotherapy

Hormonotherapy

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 verified protocol PubMed

Abemaciclib & Letrozole

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Goetz et al. 2017 (MONARCH 3) Phase III (E) Letrozole Superior PFS

Chemotherapy

Hormonotherapy

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 verified protocol PubMed

Anastrozole monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Bonneterre et al. 2000 (TARGET) Phase III (E) Tamoxifen Equivalent TTP
Nabholtz et al. 2000 (Arimidex Study Group 2000) Phase III (E) Tamoxifen Superior TTP
Milla-Santos et al. 2003 Phase III (E) Tamoxifen Superior OS
Kaufman et al. 2009 (TAnDEM) Phase III (C) Anastrozole & Trastuzumab Inferior PFS
Bergh et al. 2012 (FACT) Phase III (C) Anastrozole & Fulvestrant Seems not superior
Mehta et al. 2012 (SWOG S0226) Phase III (C) Anastrozole & Fulvestrant Seems to have inferior OS
Iwata et al. 2013 Phase III (C) Exemestane Inconclusive whether non-inferior
Robertson et al. 2016 (FALCON) Phase III (C) Fulvestrant Seems to have inferior PFS
Goetz et al. 2017 (MONARCH 3) Phase III (C) Abemaciclib & Anastrozole Inferior PFS
Tripathy et al. 2018 (MONALEESA-7) Phase III (C) Anastrozole & Ribociclib Inferior PFS

Note: TAnDEM enrolled patients who were HER2+ and ER/PR-positive.

Hormonotherapy

Supportive medications

28-day cycles

References

  1. TARGET: 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 protocol PubMed
  2. Arimidex Study Group 2000: Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial; Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67. link to original article PubMed
  3. Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, Casanovas J, Puig-Gali M. Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer: a prospective, randomized, phase III study. Am J Clin Oncol. 2003 Jun;26(3):317-22. link to original article contains protocol PubMed
  4. TAnDEM: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. link to original article contains protocol PubMed
  5. 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 verified protocol PubMed
  6. 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 verified protocol link to PMC article PubMed
    1. Update: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234. Erratum in: N Engl J Med. 2019 Jun 6;380(23):2282. link to original article PubMed
  7. 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 protocol PubMed
  8. 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 protocol 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 verified protocol PubMed
  10. 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 protocol PubMed

Anastrozole & Fulvestrant

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Regimen

Study Evidence Comparator Comparative Efficacy
Bergh et al. 2012 (FACT) Phase III (E) Anastrozole Seems not superior
Mehta et al. 2012 (SWOG S0226) Phase III (E) Anastrozole Seems to have superior OS

Hormonotherapy

  • Anastrozole (Arimidex) 1 mg PO once per day
  • Fulvestrant (Faslodex) as follows:
    • Cycle 1: 500 mg IM once on day 1, then 250 mg IM once on day 15
    • Cycle 2 onwards: 250 mg IM once on day 1
      • Patients in SWOG S0226 who progressed while on therapy were allowed to receive a higher dose, 500 mg IM once on day 1

28-day cycles

References

  1. FACT: Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, Lindemann JP, Wiklund F, Henriksson R. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012 Jun 1;30(16):1919-25. Epub 2012 Feb 27. link to original article contains verified protocol PubMed
  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 verified protocol link to PMC article PubMed
    1. Update: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Linden HH, Livingston RB, Hortobagyi GN. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. N Engl J Med. 2019 Mar 28;380(13):1226-1234. Erratum in: N Engl J Med. 2019 Jun 6;380(23):2282. link to original article PubMed

Anastrozole & Ribociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) Phase III (E) Anastrozole Superior PFS

Hormonotherapy

Chemotherapy

Supportive medications

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 protocol PubMed

Exemestane monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Paridaens et al. 2008 Phase III (E) Tamoxifen Seems not superior
Iwata et al. 2013 Phase III (C) Anastrozole Inconclusive whether non-inferior

Hormonotherapy

Continued indefinitely

References

  1. Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P. 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 protocol PubMed
  2. 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 protocol PubMed

Fulvestrant monotherapy

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Variant #1, 250 mg

Study Evidence Comparator Comparative Efficacy
Martín et al. 2015 (LEA) Phase III (C) Fulvestrant & Bevacizumab Seems not superior

Hormonotherapy

28-day cycles

Variant #2, 500 mg

Study Evidence Comparator Comparative Efficacy
Howell et al. 2004 Phase III (E) Tamoxifen Might have inferior TTP
Slamon et al. 2018 (MONALEESA-3) Phase III (C) Fulvestrant & Ribociclib Inferior PFS

Hormonotherapy

  • 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 protocol PubMed
  3. 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

Fulvestrant & Ribociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3) Phase III (E) Fulvestrant Superior PFS

Hormonotherapy

  • 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

Chemotherapy

28-day cycles

References

  1. MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article PubMed

Goserelin monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Jonat et al. 1995 Phase III (C) Goserelin & Tamoxifen Seems to have inferior TTP

Hormonotherapy

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

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Regimen

Study Evidence Comparator Comparative Efficacy
Jonat et al. 1995 Phase III (E) Goserelin Seems to have superior TTP

Hormonotherapy

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

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Regimen

Study Evidence Comparator Comparative Efficacy
Mouridsen et al. 2001 (ILBCG) Phase III (E) Tamoxifen Superior TTP
Goss et al. 2007 Phase III (C) Atamestane & Toremifene Seems not superior
Johnston et al. 2009 (EGF30008) Phase III (C) Lapatinib & Letrozole Seems to have inferior PFS
Wolff et al. 2012 (HORIZON) Phase III (C) Letrozole & Temsirolimus Seems not superior
Finn et al. 2015 (PALOMA-1/TRIO-18) Randomized Phase II (C) Letrozole & Palbociclib Inferior PFS
Martín et al. 2015 (LEA) Phase III (C) Letrozole & Bevacizumab Seems not superior
Dickler et al. 2016 (CALGB 40503) Phase III (C) Letrozole & Bevacizumab Seems to have inferior PFS
Hortobagyi et al. 2016 (MONALEESA-2) Phase III (C) Letrozole & Ribociclib Inferior PFS
Finn et al. 2016 (PALOMA-2) Randomized Phase II (C) Letrozole & Palbociclib Inferior PFS
Goetz et al. 2017 (MONARCH 3) Phase III (C) Abemaciclib & Letrozole Inferior PFS
Tripathy et al. 2018 (MONALEESA-7) Phase III (C) Letrozole & Ribociclib Inferior PFS

Note: EGF30008 enrolled patients who were HER2+ and ER/PR-positive.

Hormonotherapy

Supportive medications

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 protocol 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. 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 protocol PubMed
  3. EGF30008: Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. link to original article contains protocol PubMed
  4. HORIZON: 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 protocol PubMed
  5. PALOMA-1/TRIO-18: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
  6. 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 verified protocol PubMed
  7. 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 protocol link to PMC article PubMed
  8. 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 verified protocol PubMed
    1. Subgroup analysis: Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, Villanueva C, Jakobsen E, Alba E, Wist E, Favret AM, Bachelot T, Hegg R, Wheatley-Price P, Souami F, Sutradhar S, Miller M, Germa C, Burris HA. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018 Feb;167(3):659-669. Epub 2017 Oct 22. link to original article link to PMC article PubMed
    2. HRQoL analysis: Verma S, O'Shaughnessy J, Burris HA, Campone M, Alba E, Chandiwana D, Dalal AA, Sutradhar S, Monaco M, Janni W. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article PubMed
    3. Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. link to original article PubMed
  9. 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 verified protocol PubMed
    1. Update: Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, Harbeck N, Castrellon A, Iyer S, Lu DR, Mori A, Gauthier ER, Bartlett CH, Gelmon KA, Slamon DJ. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr;174(3):719-729. Epub 2019 Jan 10. link to original article link to PMC article PubMed
  10. 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 verified protocol PubMed
  11. 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 protocol PubMed

Letrozole & Bevacizumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Martín et al. 2015 (LEA) Phase III (E) Letrozole Seems not superior
Dickler et al. 2016 (CALGB 40503) Phase III (E) Letrozole Seems to have superior PFS

Hormonotherapy

Chemotherapy

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 verified protocol PubMed
  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 protocol link to PMC article PubMed

Letrozole & Palbociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18) Randomized Phase II (E) Letrozole Superior PFS
Finn et al. 2016 (PALOMA-2) Phase III (E) Letrozole Superior PFS

Hormonotherapy

Chemotherapy

28-day cycles

References

  1. PALOMA-1/TRIO-18: Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
  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 verified protocol PubMed
    1. Update: Rugo HS, Finn RS, Diéras V, Ettl J, Lipatov O, Joy AA, Harbeck N, Castrellon A, Iyer S, Lu DR, Mori A, Gauthier ER, Bartlett CH, Gelmon KA, Slamon DJ. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat. 2019 Apr;174(3):719-729. Epub 2019 Jan 10. link to original article link to PMC article PubMed

Letrozole & Ribociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Hortobagyi et al. 2016 (MONALEESA-2) Phase III (E) Letrozole Superior PFS
Tripathy et al. 2018 (MONALEESA-7) Phase III (E) Letrozole Superior PFS

Hormonotherapy

Chemotherapy

Supportive medications

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 verified protocol PubMed
    1. Subgroup analysis: Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, Villanueva C, Jakobsen E, Alba E, Wist E, Favret AM, Bachelot T, Hegg R, Wheatley-Price P, Souami F, Sutradhar S, Miller M, Germa C, Burris HA. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018 Feb;167(3):659-669. Epub 2017 Oct 22. link to original article link to PMC article PubMed
    2. HRQoL analysis: Verma S, O'Shaughnessy J, Burris HA, Campone M, Alba E, Chandiwana D, Dalal AA, Sutradhar S, Monaco M, Janni W. Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2. Breast Cancer Res Treat. 2018 Aug;170(3):535-545. Epub 2018 Apr 13. link to original article link to PMC article PubMed
    3. Update: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. link to original article PubMed
  2. 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 protocol PubMed

Ribociclib & Tamoxifen

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Regimen

Study Evidence Comparator Comparative Efficacy
Tripathy et al. 2018 (MONALEESA-7) Phase III (E) Tamoxifen Superior PFS

Hormonotherapy

Chemotherapy

Supportive medications

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 protocol PubMed

Tamoxifen monotherapy

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Variant #1, 20 mg/day

Study Evidence Comparator Comparative Efficacy
Ingle et al. 1981 Phase III (E) DES Seems not superior
Bratherton et al. 1984 Phase III (C) Tamoxifen 40 mg/d Seems not superior
Ingle et al. 1986 Phase III (C) Aminoglutethemide, Hydrocortisone, Tamoxifen Seems not superior
Gazet et al. 1988 Phase III (E) Surgery Seems not superior
Ingle et al. 1988 Phase III (C) Fluoxymesterone & Tamoxifen Seems to have inferior TTP (*)
Muss et al. 1988 Phase III (C) Megestrol Seems not superior
Rubens et al. 1988 Phase III (C) Tamoxifen & Prednisolone Seems to have inferior OS
Ingle et al. 1991 Phase III (C) Tamoxifen & Prednisolone Seems not superior
Castiglione-Gertsch et al. 1993 Phase III (C) Megestrol Might have inferior TTP
Borner et al. 1994 (SAKK 23/82) Phase III (E) Observation Might have superior DFS (*)
Hayes et al. 1995 Phase III (C) 1. Toremifene 60 mg per day Seems not superior
2. Toremifene 200 mg per day Seems not superior
Thürlimann et al. 1996 (SAKK 20/88) Phase III (C) Fadrozole Might have superior TTTF
Bonneterre et al. 2000 (TARGET) Phase III (C) Anastrozole Equivalent TTP
Nabholtz et al. 2000 (Arimidex Study Group 2000) Phase III (C) Anastrozole Inferior TTP
Mouridsen et al. 2001 (ILBCG) Phase III (C) Letrozole Inferior TTP
Bajetta et al. 2002 Phase III (C) Octreotide LAR & Tamoxifen Seems not superior
Buzdar et al. 2002 Phase III (C) Droloxifene Superior TTP
Howell et al. 2004 Phase III (C) Fulvestrant Might have superior TTP
Deshmane et al. 2007 Phase III (C) Arzoxifene Superior PFS
Paridaens et al. 2008 Phase III (C) Exemestane Seems not superior
Tripathy et al. 2018 (MONALEESA-7) Phase III (C) Ribociclib & Tamoxifen Inferior PFS

Note: patients in Gazet et al. 1988 had resectable disease but did not undergo surgery in this arm. Reported efficacy for Ingle et al. 1988 is based on the 1991 update. Patients in SAKK 23/82 had isolated locoregional recurrence; reported efficacy is based on the 2003 update.

Hormonotherapy

Supportive medications

28-day cycles

Variant #2, 30 mg/day

Study Evidence Comparator Comparative Efficacy
Gundersen et al. 1990a Phase III (C) Tamoxifen/MPA Seems to have inferior ORR

Hormonotherapy

Continued indefinitely

Variant #3, 40 mg/day

Study Evidence Comparator Comparative Efficacy
Morgan et al. 1976 Non-randomized
Kiang et al. 1977 Non-randomized
Bratherton et al. 1984 Phase III (E) Tamoxifen 20 mg/d Seems not superior
van Veelen et al. 1986 Phase III (E) MPA Seems not superior
Buchanan et al. 1986 Phase III (E) Oophorectomy Might have superior PFS
Kellokumpu-Lehtinen et al. 1987 Phase III (C) Nandrolone Seems not superior
Gill et al. 1993 Phase III (C) 1. Megestrol
2. Megestrol & Tamoxifen
Seems not superior
Gershanovich et al. 1997 Phase III (C) 1. Toremifene 60 mg per day Seems not superior
2. Toremifene 240 mg per day Seems not superior
Pyrhönen et al. 1997 Phase III (C) Toremifene 60 mg per day Seems to have superior TTP
Beex et al. 2006 (EORTC 10863) Phase III (C) 1. Intermittent Tamoxifen
2. Intermittent Tamoxifen/MPA
Seems not superior

Hormonotherapy

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 protocol 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 verified protocol PubMed
  4. 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 PubMed
  5. 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 verified protocol PubMed
  6. 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 protocol PubMed
  7. 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 verified protocol PubMed
  8. 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 protocol PubMed
  9. 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
  10. 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 protocol 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
  11. 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 protocol PubMed
  12. 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 PMC article contains protocol PubMed
  13. 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 protocol PubMed
  14. 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. 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 protocol PubMed
  15. 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 protocol PubMed
  16. 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 protocol PubMed
  17. 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 protocol PubMed
    1. Update: Waeber M, Castiglione-Gertsch M, Dietrich D, Thürlimann B, Goldhirsch A, Brunner KW, Borner MM; Swiss Group for Clinical Cancer Research (SAKK). 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
  18. 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
  19. 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 protocol PubMed
  20. 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
  21. 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 PMC article PubMed
  22. TARGET: 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 protocol PubMed
  23. 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
  24. 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 protocol 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
  25. 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 verified protocol PubMed
  26. 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 protocol PubMed
  27. 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
  28. 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 protocol PubMed
  29. 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 protocol PubMed
  30. Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P. 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 protocol PubMed
  31. 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 protocol PubMed

Tamoxifen & Prednisolone

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Regimen

Study Evidence Comparator Comparative Efficacy
Rubens et al. 1988 Phase III (E) Tamoxifen Seems to have superior OS
Ingle et al. 1991 Phase III (E) Tamoxifen Seems not superior

Hormonotherapy

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 PMC article contains protocol 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. 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 protocol PubMed

Toremifene monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Hayes et al. 1995 Phase III (E) 1. Tamoxifen Seems not superior
2. Toremifene 200 mg per day Seems not superior
Gershanovich et al. 1997 Phase III (E) 1. Tamoxifen 40 mg per day Seems not superior
2. Toremifene 240 mg per day Seems not superior
Pyrhönen et al. 1997 Phase III (E) Tamoxifen 40 mg per day Seems to have inferior TTP
Milla-Santos et al. 2001 Phase III (E) Tamoxifen 40 mg per day Seems not superior

Hormonotherapy

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 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 protocol PubMed

Metastatic disease, first-line endocrine therapy, HER2 co-expressing

Anastrozole & Trastuzumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Kaufman et al. 2009 (TAnDEM) Phase III (E) Anastrozole Superior PFS

Hormonotherapy

Chemotherapy

  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
    • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

28-day cycles

References

  1. TAnDEM: Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Révil C, Jones A. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009 Nov 20;27(33):5529-37. Epub 2009 Sep 28. link to original article contains protocol PubMed

Lapatinib & Letrozole

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Regimen

Study Evidence Comparator Comparative Efficacy
Johnston et al. 2009 (EGF30008) Phase III (E) Letrozole Seems to have superior PFS

Chemotherapy

Hormonotherapy

Continued indefinitely

References

  1. EGF30008: Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. Epub 2009 Sep 28. link to original article contains protocol PubMed

Lapatinib, Letrozole, Trastuzumab

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Regimen

Study Evidence Comparator Comparative Efficacy
Johnston et al. 2017 (ALTERNATIVE) Phase III (E) 1. Lapatinib & Letrozole Not reported
2. Letrozole & Trastuzumab Superior PFS

Chemotherapy

Hormonotherapy

21-day cycles

References

  1. ALTERNATIVE: Johnston SRD, Hegg R, Im SA, Park IH, Burdaeva O, Kurteva G, Press MF, Tjulandin S, Iwata H, Simon SD, Kenny S, Sarp S, Izquierdo MA, Williams LS, Gradishar WJ. Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. J Clin Oncol. 2018 Mar 10;36(8):741-748. Epub 2017 Dec 15. link to original article contains verified protocol PubMed

Metastatic disease, subsequent lines of endocrine therapy

Abemaciclib & Fulvestrant

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Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Sledge et al. 2017 (MONARCH 2) Phase III (E) Fulvestrant Superior PFS

Chemotherapy

Hormonotherapy

  • 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 verified protocol PubMed

Anastrozole monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Jonat et al. 1996 Phase III (E) Anastrozole 10 mg/d Not reported
Megestrol Seems to have superior OS (*)
Buzdar et al. 1997 (Arimidex Study Group 1997) Phase III (E) Anastrozole 10 mg/d Not reported
Megestrol Seems to have superior OS (*)
Osborne et al. 2002 (Trial 0021) Phase III (C) Fulvestrant 250 mg Seems not superior
Howell et al. 2002 (Trial 0020) Phase III (C) Fulvestrant 250 mg Seems to have non-inferior TTP
Xu et al. 2010 Phase III (C) Fulvestrant 250 mg Seems not superior
Robertson et al. 2016 (FALCON) Phase III (C) Fulvestrant 500 mg Seems to have inferior PFS

Note: reported efficacy for Jonat et al. 1996 and Arimidex Study Group 1997 is based on the 1998 pooled update.

Hormonotherapy

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 protocol PubMed
    1. 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. Arimidex Study Group 1997: 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 protocol PubMed
    1. 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 protocol PubMed
    1. 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: 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. 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
  6. 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 protocol PubMed

Anastrozole & Fulvestrant

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Regimen

Study Evidence Comparator Comparative Efficacy
Johnston et al. 2013 (SoFEA) Phase III (E) Fulvestrant Seems not superior

Hormonotherapy

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 protocol PubMed

Capecitabine & Fulvestrant

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Regimen

Study Evidence
Schwartzberg et al. 2013 Phase II

Chemotherapy

  • Capecitabine (Xeloda) as follows:
    • 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

Hormonotherapy

  • 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. 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 verified protocol PubMed

Everolimus & Exemestane

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Regimen

Study Evidence Comparator Comparative Efficacy
Baselga et al. 2011 (BOLERO-2) Phase III (E) Exemestane Superior PFS

Chemotherapy

Hormonotherapy

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 verified protocol PubMed
    1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to 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 PubMed

Everolimus & Tamoxifen

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Regimen

Study Evidence Comparator Comparative Efficacy
Bachelot et al. 2012 (TAMRAD) Randomized Phase II (E) Tamoxifen Superior OS

Chemotherapy

Hormonotherapy

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 verified protocol PubMed

Exemestane monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kaufmann et al. 2000 Phase III (E) Megestrol Seems to have superior OS
Chia et al. 2008 (EFECT) Phase III (E) Fulvestrant Seems not superior
Baselga et al. 2011 (BOLERO-2) Phase III (C) Everolimus & Exemestane Inferior PFS
Jiang et al. 2019 (ACEbrca) Phase III (C) Exemestane & Tucidinostat Seems to have inferior PFS

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

Hormonotherapy

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; The 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 protocol 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
  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 verified protocol PubMed
    1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to 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 PubMed
  4. 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 protocol PubMed

Exemestane & Tucidinostat

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Regimen

Study Evidence Comparator Comparative Efficacy
Jiang et al. 2019 (ACEbrca) Phase III (E) Exemestane Seems to have superior PFS

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

Hormonotherapy

Chemotherapy

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 protocol PubMed

Fulvestrant monotherapy

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Variant #1, 250 mg

Study Evidence Comparator Comparative Efficacy
Howell et al. 1995 Phase I/II, <20 pts
Osborne et al. 2002 (Trial 0021) Phase III (E) Anastrozole Seems not superior
Howell et al. 2002 (Trial 0020) Phase III (E) Anastrozole Seems to have non-inferior TTP
Perey et al. 2006 (SAKK 21/00) Phase II
Di Leo et al. 2010 (CONFIRM) Phase III (C) Fulvestrant 500 mg Seems to have inferior OS (*)
Xu et al. 2010 Phase III (E) Anastrozole Seems not superior

Note: reported efficacy for CONFIRM is based on the 2013 update.

Hormonotherapy

28-day cycles

Variant #2, 250 mg, with loading dose

Study Evidence Comparator Comparative Efficacy
Chia et al. 2008 (EFECT) Phase III (E) Exemestane Seems not superior
Johnston et al. 2013 (SoFEA) Phase III (E) 1. Exemestane Seems not superior
2. Anastrozole & Fulvestrant Seems not superior
Burstein et al. 2014 (CALGB 40302) Phase III (C) Fulvestrant & Lapatinib Seems not superior

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.

Hormonotherapy

  • 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

Variant #3, 500 mg

Study Evidence Comparator Comparative Efficacy
Di Leo et al. 2010 (CONFIRM) Phase III (E) Fulvestrant 250 mg Seems to have superior OS (*)
Turner et al. 2015 (PALOMA-3) Phase III (C) Fulvestrant & Palbociclib Inferior PFS
Robertson et al. 2016 (FALCON) Phase III (E) Anastrozole Seems to have superior PFS
Baselga et al. 2017 (BELLE-2) Phase III (C) Buparlisib & Fulvestrant Might have inferior OS
Sledge et al. 2017 (MONARCH 2) Phase III (C) Abemaciclib & Fulvestrant Inferior PFS
Di Leo et al. 2017 (BELLE-3) Phase III (C) Buparlisib & Fulvestrant Inferior PFS
Slamon et al. 2018 (MONALEESA-3) Phase III (C) Fulvestrant & Ribociclib Inferior PFS

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]." Reported efficacy for CONFIRM is based on the 2013 update. Reported efficacy for BELLE-2 is based on the 2018 update.

Hormonotherapy

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

28-day cycles

References

  1. Howell A, DeFriend D, Robertson J, Blamey R, Walton P. Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet. 1995 Jan 7;345(8941):29-30. link to original article contains verified protocol 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 protocol PubMed
    1. 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: 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 protocol 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
  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
    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 protocol PubMed
  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 verified protocol PubMed
  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 verified protocol PubMed
    1. Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original article PubMed
    2. Subgroup analysis: Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im SA, Masuda N, Loi S, André F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017 Sep;22(9):1028-1038. Epub 2017 Jun 26. link to original article link to PMC article PubMed
    3. Update: Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. Epub 2018 Oct 20. link to original article PubMed
  11. 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 protocol PubMed
  12. 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 protocol PubMed
    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
  13. 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 verified protocol PubMed
  14. 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 protocol PubMed
  15. 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

Fulvestrant & Palbociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Turner et al. 2015 (PALOMA-3) Phase III (E) Fulvestrant Superior PFS

Hormonotherapy

  • 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

Chemotherapy

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 verified protocol PubMed
    1. Update: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39. Epub 2016 Mar 3. link to original article PubMed
    2. Subgroup analysis: Loibl S, Turner NC, Ro J, Cristofanilli M, Iwata H, Im SA, Masuda N, Loi S, André F, Harbeck N, Verma S, Folkerd E, Puyana Theall K, Hoffman J, Zhang K, Bartlett CH, Dowsett M. Palbociclib combined with fulvestrant in premenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017 Sep;22(9):1028-1038. Epub 2017 Jun 26. link to original article link to PMC article PubMed
    3. Update: Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, André F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. Epub 2018 Oct 20. link to original article PubMed

Fulvestrant & Ribociclib

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Regimen

Study Evidence Comparator Comparative Efficacy
Slamon et al. 2018 (MONALEESA-3) Phase III (E) Fulvestrant Superior PFS

Hormonotherapy

  • 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

Chemotherapy

28-day cycles

References

  1. MONALEESA-3: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martín M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. Epub 2018 Jun 3. link to original article PubMed

Letrozole monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Buzdar et al. 2001 Phase III (E) Letrozole 0.5 mg/d Seems not superior
Megestrol Seems not superior

Hormonotherapy

Continued indefinitely

References

  1. 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 protocol PubMed

Tamoxifen monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Legha et al. 1979 Phase II
Tormey et al. 1983 Randomized (C) Fluoxymesterone & Tamoxifen Inferior TTTF
Bachelot et al. 2012 (TAMRAD) Randomized Phase II (C) Everolimus & Tamoxifen Inferior OS

Note: Tormey et al. 1983 specified a wide range of tamoxifen dosing; see paper for details.

Hormonotherapy

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. 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 verified protocol PubMed