Breast Cancer Research and Treatment

, Volume 167, Issue 3, pp 607–614 | Cite as

Efficacy and safety in older patient subsets in studies of endocrine monotherapy versus combination therapy in patients with HR+/HER2− advanced breast cancer: a review




Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population.


We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer treated with ET ± targeted agents.


We identified 19 studies reporting 10 clinical trials. Efficacy was similar in age-stratified subsets. There was a reduced disease progression risk for ET + everolimus, palbociclib, or ribociclib versus ET alone. In the first-line setting, median progression-free survival (mPFS) in older patients was 8.5, 26.2 months, and not reached with letrozole + temsirolimus, palbociclib, and ribociclib, respectively, and in younger patients was 9.0, 18.8 months, and not reached, respectively. In the second-line setting, older patients had mPFS of 6.8 and 9.9 months with everolimus + exemestane and palbociclib + fulvestrant, respectively, and younger patients had mPFS of 8.1 and 9.5 months, respectively. Tolerability was worse for combination therapy versus monotherapy. No age-related differences in discontinuations were observed for CDK4/6 inhibitors, although a higher rate of treatment discontinuation was observed for patients ≥ 70 years receiving everolimus + exemestane. Adverse event rates were similar in age-stratified subsets.


ET + CDK4/6 or mTOR inhibitors are likely safe and effective in older patients with HR+, HER2− advanced breast cancer.


Elderly Breast cancer Geriatric CDK4/6 inhibitor Ribociclib Palbociclib 



Editorial assistance was provided under the direction of the authors by Jonathan Morgan, Ph.D., and David Boffa, ELS, MedThink SciCom.


This study was funded by Novartis Pharmaceuticals Corporation. Rachel Freedman receives funding from Susan G. Komen and the American Cancer Society.

Compliance with ethical standards

Conflict of interest

Rachel Freedman receives research funding (institutional) from Eisai and Puma Biotechnology. Sara Tolaney receives research funding (institutional) from Novartis Pharmaceuticals Corporation, Eli Lilly and Co, Pfizer, Exelixis, Eisai, Merck, Genentech, AstraZeneca, Cyclacel, and Nektar Therapeutics, and she serves as a consultant to Eli Lilly and Co, Novartis Pharmaceuticals Corporation, Pfizer, Eisai, Sanofi, Merck, AstraZeneca, and Nektar Therapeutics. This study was supported by Novartis Pharmaceuticals Corporation.

Informed consent

Not applicable.

Research involving human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    National Comprehensive Cancer Network (2017) NCCN clinical practice guidelines in oncology: breast cancer. Accessed 12 July 2017
  2. 2.
    Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F et al (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Breast 23(5):489–502. CrossRefPubMedGoogle Scholar
  3. 3.
    Baselga J, Campone M, Piccart M, Burris HA III, Rugo HS, Sahmoud T et al (2012) Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med 366(6):520–529CrossRefPubMedGoogle Scholar
  4. 4.
    Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K et al (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375(20):1925–1936. CrossRefPubMedGoogle Scholar
  5. 5.
    Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375(18):1738–1748. CrossRefPubMedGoogle Scholar
  6. 6.
    Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X et al (2017) 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 35(25):2875–2884CrossRefPubMedGoogle Scholar
  7. 7.
    SEER Cancer Stat Facts: female breast cancer. National Cancer Institute. Bethesda, MD. Accessed 25 April 2017
  8. 8.
    Aapro MS, Köhne C-H, Cohen HJ, Extermann M (2005) Never too old? Age should not be a barrier to enrollment in cancer clinical trials. Oncologist 10(3):198–204CrossRefPubMedGoogle Scholar
  9. 9.
    Freedman RA, Foster JC, Seisler DK, Lafky JM, Muss HB, Cohen HJ et al (2016) Accrual of older patients with breast cancer to alliance systemic therapy trials over time: protocol A151527. J Clin Oncol 35(4):421–431CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA et al (2014) US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 106(5).
  11. 11.
    Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N et al (2016) 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 17(4):425–439. CrossRefPubMedGoogle Scholar
  12. 12.
    Finn RS, Crown JP, Ettl J, Schmidt M, Bondarenko IM, Lang I et al (2016) Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res 18(1):67. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hart LL, Souami F, Sutradhar S, Miller M, Germa C, Burris HA (2017) Efficacy and safety of ribociclib (LEE011) + letrozole in elderly patients with hormone receptor–positive, HER2-Negative advanced breast cancer in MONALEESA-2 study. Poster presented at the 34th Annual Miami Breast Cancer Conference, Miami Beach, FL, March 9–12Google Scholar
  14. 14.
    Johnston SR, Kilburn LS, Ellis P, Dodwell D, Cameron D, Hayward L et al (2013) 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 14(10):989–998. CrossRefPubMedGoogle Scholar
  15. 15.
    Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR et al (2012) Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 367(5):435–444. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    O’Shaughnessy J, Campone M, Brain E, Neven P, Hayes D, Bondarenko I et al (2016) Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Ann Oncol 27(1):106–113. CrossRefPubMedGoogle Scholar
  17. 17.
    Pritchard KI, Burris HA 3rd, Ito Y, Rugo HS, Dakhil S, Hortobagyi GN et al (2013) Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clin Breast Cancer 13(6):421–432. CrossRefPubMedGoogle Scholar
  18. 18.
    Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N et al (2016) Palbociclib in combination with endocrine therapy in treatment-naive and previously treated elderly women with HR+, HER2− advanced breast cancer: a pooled analysis from randomized phase 2 and 3 studies. Poster presented at the 2016 San Antonio Breast Cancer Symposium, San Antonio, TX, December 6–10Google Scholar
  19. 19.
    Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S et al (2017) Efficacy and safety of ribociclib + letrozole in elderly patients with HR+, HER2- advanced breast cancer in MONALEESA-2. Paper presented at the European Cancer Congress, Amsterdam, The Netherlands, January 27–30Google Scholar
  20. 20.
    Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H (2015) Palbociclib in Hormone-receptor-positive advanced breast cancer. N Engl J Med 373(3):209–219. CrossRefPubMedGoogle Scholar
  21. 21.
    Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L et al (2013) 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 31(2):195–202. CrossRefPubMedGoogle Scholar
  22. 22.
    Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M et al (2013) Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30(10):870–884. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S et al (2017) Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2−), advanced breast cancer (ABC). J Clin Oncol 35:1038Google Scholar
  24. 24.
    Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA (2009) Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 27(17):2758–2765CrossRefPubMedGoogle Scholar
  25. 25.
    Braithwaite D, Satariano WA, Sternfeld B, Hiatt RA, Ganz PA, Kerlikowske K et al (2010) Long-term prognostic role of functional limitations among women with breast cancer. J Natl Cancer Inst 102(19):1468–1477CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Land L, Dalton S, Jensen M, Ewertz M (2012) Influence of comorbidity on the effect of adjuvant treatment and age in patients with early-stage breast cancer. Br J Cancer 107(11):1901–1907CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738–1748. Accessed 13 July 2017
  28. 28.
    Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al (2016) Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375(20):1925–1936. Accessed 13 July 2017
  29. 29.
    Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X et al (2017) MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR +/HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol 35(25):2875–2884. Accessed 18 July 2017
  30. 30.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al (2012) Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med 366(6):520–529 Accessed 13 July 2017
  31. 31.
    US National Institutes of Health Palbociclib (PD-0332991) Combined with fulvestrant in hormone receptor + HER2-negative metastatic breast cancer after endocrine failure (PALOMA-3). Accessed 13 July 2017
  32. 32.
    US National Institutes of Health study of Letrozole with or without Palbociclib (PD-0332991) for the first-line treatment of hormone-receptor positive advanced breast cancer. Accessed 13 July 2017
  33. 33.
    US National Institutes of Health study to assess the safety and efficacy of Ribociclib (LEE011) in combination with letrozole for the treatment of men and pre/postmenopausal women with HR+ HER2− aBC. Accessed 13 July 2017
  34. 34.
    US National Institutes of Health study of efficacy and safety of LEE011 in men and postmenopausal women with advanced breast cancer. (MONALEESA-3). Accessed 13 July 2017
  35. 35.
    Hurria A, Dale W, Mooney M, Rowland JH, Ballman KV, Cohen HJ et al (2014) Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 32(24):2587–2594CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Breast Oncology Program, Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA

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