Top

04-11-2017 | Breast cancer | Article

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

Journal: Breast Cancer Research and Treatment

Authors: Rachel A. Freedman, Sara M. Tolaney

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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

National Comprehensive Cancer Network (2017) NCCN clinical practice guidelines in oncology: breast cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 12 July 2017

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. https://doi.org/10.1016/j.breast.2014.08.009 CrossRefPubMed

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):520–529CrossRefPubMed

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. https://doi.org/10.1056/NEJMoa1607303 CrossRefPubMed

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. https://doi.org/10.1056/NEJMoa1609709 CrossRefPubMed

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):2875–2884CrossRefPubMed

SEER Cancer Stat Facts: female breast cancer. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/statfacts/html/breast.html. Accessed 25 April 2017

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):198–204CrossRefPubMed

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):421–431CrossRefPubMedPubMedCentral

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). https://doi.org/10.1093/jnci/dju055

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. https://doi.org/10.1016/S1470-2045(15)00613-0 CrossRefPubMed

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. https://doi.org/10.1186/s13058-016-0721-5 CrossRefPubMedPubMedCentral

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 9–12

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. https://doi.org/10.1016/S1470-2045(13)70322-X CrossRefPubMed

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. https://doi.org/10.1056/NEJMoa1201622 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1093/annonc/mdv487 CrossRefPubMed

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. https://doi.org/10.1016/j.clbc.2013.08.011 CrossRefPubMed

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 6–10

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 27–30

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. https://doi.org/10.1056/NEJMoa1505270 CrossRefPubMed

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. https://doi.org/10.1200/JCO.2011.38.3331 CrossRefPubMed

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. https://doi.org/10.1007/s12325-013-0060-1 CrossRefPubMedPubMedCentral

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 35:1038

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):2758–2765CrossRefPubMed

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):1468–1477CrossRefPubMedPubMedCentral

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):1901–1907CrossRefPubMedPubMedCentral

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. https://doi.org/10.1056/NEJMoa1609709. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1609709/suppl_file/nejmoa1609709_protocol.pdf. Accessed 13 July 2017

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. https://doi.org/10.1056/NEJMoa1607303. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1607303/suppl_file/nejmoa1607303_protocol.pdf. Accessed 13 July 2017

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. https://doi.org/10.1200/JCO.2017.73.7585. https://ascopubs.org/doi/suppl/10.1200/JCO.2017.73.7585/suppl_file/protocol_2017.737585.pdf. Accessed 18 July 2017

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 https://doi.org/10.1056/NEJMoa1109653. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1109653/suppl_file/nejmoa1109653_protocol.pdf. Accessed 13 July 2017

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). https://clinicaltrials.gov/ct2/show/NCT01942135. Accessed 13 July 2017

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. https://clinicaltrials.gov/ct2/show/NCT00721409. Accessed 13 July 2017

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. https://clinicaltrials.gov/ct2/show/NCT02941926. Accessed 13 July 2017

34.

US National Institutes of Health study of efficacy and safety of LEE011 in men and postmenopausal women with advanced breast cancer. (MONALEESA-3). https://clinicaltrials.gov/ct2/show/NCT02422615. Accessed 13 July 2017

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):2587–2594CrossRefPubMedPubMedCentral