Postmenopausal breast cancer: a best endocrine strategy?
Authors: Erica L Mayer, Harold J Burstein
Journal: The Lancet (2015)

Postmenopausal, oestrogen receptor (ER)-positive breast cancers account for the majority of the 1·7 million breast cancers diagnosed annually worldwide. Adjuvant endocrine therapy dramatically improves survival among such patients, making it vital to understand the best treatment strategies. For decades, the Early Breast Cancer Trialists' Collaborative Group meta-analyses have informed clinical practice in early-stage breast cancer, and the present report1Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; (published online July 24.)http://dx.doi.org/10.1016/S0140-6736(15)61074-1Google Scholar in The Lancet on over 30 000 women treated with adjuvant tamoxifen, aromatase inhibitors, or a sequence of those agents continues that tradition. The meta-analysis confirms that, in comparison with tamoxifen alone, aromatase inhibitor-based therapy in the first 5 years reduces the risk of recurrence (rate ratio 0·64, 95% CI 0·52–0·78, during years 0–1; 0·80, 0·68–0·93, during years 2–4) and improves overall survival at 10 years (0·89, 0·81–0·97). Sequential therapy with tamoxifen and then an aromatase inhibitor during the first 5 years yielded recurrence rates that were nearly the same as those achieved with upfront aromatase inhibitor therapy, with average recurrence rates differing by less than 1% through 7 years of follow-up and without a survival difference. Because of the enormous size of the individual trials that comprised the meta-analysis—most of the primary studies enrolled between 5000 and 10 000 women—recurrence reductions were already well established,2Cuzick J Sestak I Baum M et al.Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial.Lancet Oncol. 2010; 11: 1135-1141Summary Full Text Full Text PDF PubMed Scopus (698) Google Scholar, 3Regan MM Neven P Giobbie-Hurder A et al.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; 12: 1101-1108Summary Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 4Van de Velde CJ Rea D Seynaeve C et al.Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.Lancet. 2011; 377: 321-331Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar and clinical guidelines recommend that postmenopausal women consider aromatase inhibitor-based therapy within the first 5 years of their adjuvant treatment course, either up front or sequentially after tamoxifen.5Burstein HJ Prestrud AA Seidenfeld J et al.American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor positive breast cancer.J Clin Oncol. 2010; 28: 3784-3796Crossref PubMed Scopus (583) Google Scholar, 6Coates AS Winer EP Goldhirsh A et al.Tailoring therapies—improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015.Ann Oncol. 2015; (published online May 4.)https://doi.org/10.1093/annonc/mdv221Crossref Scopus (1289) Google Scholar, 7National Comprehensive Cancer NetworkBreast cancer guidelines.http://www.nccn.org/professionals/physician_gls/pdf/breast.pdfDate: 2015Google Scholar Pooled data in the overview could facilitate subset analyses when low numbers of events in individual trials might otherwise make it hard to spot benefits. The advantage of aromatase inhibitor-based treatment over tamoxifen alone for postmenopausal, ER-positive cancers extended across all commonly tested tumour biomarkers (ie, grade, progesterone receptor [PR] status, HER2 status), tumour stage (size and nodal status), and patient characteristics such as body-mass index and age. What stands out most is the absence of any single prognostic marker that identifies patients or tumours that would benefit selectively from an aromatase inhibitor or tamoxifen. As would be expected, higher risk cancers defined by stage or HER2 status show greater numerical advantage for aromatase inhibitor treatment over tamoxifen, whereas lower risk tumours show smaller numerical advantage for aromatase inhibitors. Comparisons between drugs show that the benefits of aromatase inhibitor treatment are a class effect: there is nothing to distinguish one brand from another. These new data challenge clinicians to ask two important questions. First, should all postmenopausal women with ER-positive breast cancer be offered upfront aromatase inhibitor therapy as opposed to sequential treatment, and, if not, can clinical factors be identified that might enable clinicians to tailor therapy? Second, how might the longer durations of endocrine therapy that are now being recommended bear on the understanding of these data? When the trials included in this meta-analysis were done, the standard duration of adjuvant endocrine therapy was 5 years. Since then, we have learned that extending adjuvant treatment beyond 5 years out to 10 years with either ongoing tamoxifen8Davies C Pan H Godwin J et al.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; 381: 805-816Summary Full Text Full Text PDF PubMed Scopus (1373) Google Scholar or by switching to an aromatase inhibitor9Goss PE Ingle JN Martino S et al.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; 16: 707-715Google Scholar can further reduce breast cancer recurrences. These findings invite speculation that longer treatment duration with an aromatase inhibitor—longer than the 5 years studied in the meta-analysis—or a longer sequential programme would be of benefit to patients. But, at present, there are no data from randomised trials assessing the efficacy of these approaches. Despite extensive efforts, there is currently no validated marker that can be used to specifically predict which patients will benefit from a longer duration of adjuvant endocrine treatment. The same prognostic markers that stratify patients for risk of early recurrence—stage, grade, quantitative hormone receptor expression, Ki67, intrinsic subtype, 21-gene recurrence score, and other molecular profiling assays—are, however, also prognostic for late recurrence.10Sestak I Dowsett M Zabaglo L et al.Factors predicting late recurrence for estrogen receptor-positive breast cancer.J Natl Cancer Inst. 2013; 105: 1504-1511Crossref PubMed Scopus (174) Google Scholar Since the inception of adjuvant trials of aromatase inhibitor therapy, we have learned how to integrate clinical stage with many prognostic marker analyses, including molecular profiles to risk stratify patients with ER-positive breast cancers. We have also altered the natural history of ER-positive, HER2-positive tumours—historically and in this meta-analysis1Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; (published online July 24.)http://dx.doi.org/10.1016/S0140-6736(15)61074-1Google Scholar among the most aggressive of ER-positive breast cancers—with use of adjuvant trastuzumab. In contemporary breast cancer management, clinicians use these well known factors to assign most women with postmenopausal ER-positive breast cancers into lower-risk or higher-risk groups. For women whose tumour stage and biology put them at the lower end of the risk recurrence spectrum—typically node-negative cancers with lower grade or proliferation features, strong expression of ER and PR, and lack of HER2 expression, usually associated with luminal A phenotype or low recurrence score molecular profiles—the differences in outcomes between tamoxifen-based and aromatase inhibitor-based therapy are lower.11Viale G Regan MM Dell'Orto P et al.Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial.Ann Oncol. 2011; 22: 2201-2207Crossref PubMed Scopus (82) Google Scholar Prospective studies, not included in the meta-analysis,1Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; (published online July 24.)http://dx.doi.org/10.1016/S0140-6736(15)61074-1Google Scholar comparing tamoxifen and aromatase inhibitor therapy among premenopausal women with lower-risk tumours, who were offered ovarian suppression with an aromatase inhibitor or with tamoxifen but not given chemotherapy, showed small differences between aromatase inhibitor-based or tamoxifen-based treatment.12Gnant M Mlineritsch B Schippinger W et al.Endocrine therapy plus zoledronic acid in premenopausal breast cancer.N Engl J Med. 2009; 360: 679-691Crossref PubMed Scopus (936) Google Scholar, 13Francis PA Regan MM Fleming GF et al.Adjuvant ovarian suppression in premenopausal breast cancer.N Engl J Med. 2015; 372: 436-446Crossref PubMed Scopus (453) Google Scholar For women with tumours bearing lower recurrence risk, consideration of the side-effect profile and preferences of the patient are critical for choosing the initial endocrine drug. By contrast, among women at greater risk of recurrence, typically those with larger or node-positive tumours by stage, or because of adverse pathological or molecular features, it is more important to capture the relative gains of early aromatase inhibitor therapy, making it preferable to start treatment with an aromatase inhibitor. This risk-tailored approach has been specifically endorsed by expert consensus guidelines.6Coates AS Winer EP Goldhirsh A et al.Tailoring therapies—improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015.Ann Oncol. 2015; (published online May 4.)https://doi.org/10.1093/annonc/mdv221Crossref Scopus (1289) Google Scholar Those caring for women with breast cancer realise that the accompanying meta-analysis1Early Breast Cancer Trialists' Collaborative GroupAromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.Lancet. 2015; (published online July 24.)http://dx.doi.org/10.1016/S0140-6736(15)61074-1Google Scholar is missing a key set of data: the patient experience. Women on anti-oestrogen treatments endure substantial side-effects, including menopausal symptoms such as hot flashes and night sweats. Aromatase inhibitors, in particular, are also associated with bone pain and arthralgias, vaginal dryness, sexual dysfunction, osteoporosis, bone fracture, and hair thinning. Some of these symptoms can be addressed with specific interventions; others prove resistant and markedly affect quality of life. Treatment-related symptoms are a primary determinant of patient compliance with adjuvant endocrine therapy.14Aiello Bowles EJ Boudreau DM Chubak J et al.Patient-reported discontinuation of endocrine therapy and related adverse effects among women with early-stage breast cancer.J Oncol Pract. 2012; 8: 149-157Crossref PubMed Scopus (79) Google Scholar, 15Hadji P Jackisch C Bolten W et al.COMPliance and Arthralgia in Clinical Therapy: the COMPACT trial, assessing the incidence of arthralgia, and compliance within the first year of adjuvant anastrozole therapy.Ann Oncol. 2014; 25: 372-377Crossref PubMed Scopus (48) Google Scholar Anecdotal experience suggests that some patients tolerate aromatase inhibitors better than tamoxifen, and vice versa, and that patients intolerant of one aromatase inhibitor might tolerate another, especially after a short treatment hiatus to reset their symptom profile. Ultimately, the best choice for adjuvant endocrine therapy is a treatment the patient is willing to take. For most patients, especially as we envision an era of longer durations of endocrine therapy, it will be more important to assure that they are on a tolerable medication than to be unyielding over prescribing a specific bottle that sits untouched in the medicine cabinet. ELM has received research funding from Eisai, Myriad, and Pfizer. HJB declares no competing interests. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trialsAromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. Full-Text PDF Open Access