Reply to the letter to the editor 'duration of endocrine therapy and its impact on the results of adjuvant trials in premenopausal breast cancer patients' by Fouad et al.

Abstract

We appreciate the interest of Fouad et al. [1.Fouad T.M. de Azambuja E. Azim Jr, H.A. Duration of endocrine therapy and its impact on the results of adjuvant trials in premenopausal breast cancer patients.Ann Oncol. 2015; 26: 1511Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] in ABCSG-12. However, several comments have to be made: despite looking closely, we were unable to identify comments of Fouad et al. with respect to the claimed ‘various shortcomings’ of ABCSG-12—instead, we note a single concern only: protocol-violating treatment extension in the ovarian function suppression (OFS) plus tamoxifen (TAM) arm may have confounded trial results. Treatment continuation outside of an adjuvant protocol would indeed constitute a potential confounder, however did not occur in ABCSG 12: clearly, such a confounder would lead to a difference in disease-free survival (DFS), not in postrelapse overall survival (OS). The TAM–Anastrozol DFS outcome in ABCSG-12 was always similar throughout the long-term follow-up of the trial, with superimposable curves in all respective publications [2.Gnant 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 (939) Google Scholar, 3.Gnant M. Mlineritsch B. Stoeger H. et al.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; 12: 631-641Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 4.Gnant M. Mlineritsch B. Stoeger H. et al.Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12.Ann Oncol. 2015; 26: 313-320Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar]. The claims by our colleagues are thus not supported by the data, which up to a median of almost 95 months have matured remarkably well; all hazard ratios (HRs) of DFS and OS have been highly stable at all times of analysis. On a further note, although the existence of a confounder can never be completely ruled out, it does seem highly unlikely in light of the accurate documentation about any postprotocol therapy received in this FDA-inspected trial database. While intertrial comparisons between SOFT and ABCSG 12 should be (as always) interpreted with great caution, Fouad et al. also err in stating that ABCSG-12 contradicts the analysis of the SOFT trial: in the subgroup of SOFT patients who did not receive adjuvant chemotherapy, there is no significant DFS difference between TAM and exemestane [5.Francis P.A. Regan M.M. Fleming G.F. et al.Adjuvant ovarian suppression in premenopausal breast cancer.N Engl J Med. 2015; 372: 436-446Crossref PubMed Scopus (468) Google Scholar], a result that is highly similar to ABCSG-12. Likewise, the striking deterioration of postrelapse survival in patients who had adjuvant OFS and aromatase inhibitors (AIs) is both present in ABCSG-12 and the combined SOFT/TEXT analysis, with respective HRs of 0.72 for DFS and 1.14 for OS [6.Pagani O. Regan M.M. Walley B.A. et al.Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.N Engl J Med. 2014; 371: 107-118Crossref PubMed Scopus (448) Google Scholar]. As a result, many international opinion leaders have recently voiced their concerns about potential long-term adverse effects of the OFS+AI combination at the occasion of the recent St Gallen Breast Cancer Consensus in Vienna [7.Coates A.S. Winer E.P. Goldhirsch 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; 26: 1533-1546Abstract Full Text Full Text PDF PubMed Scopus (1311) Google Scholar]. Finally, it remains less than clear that 5 years are in fact an inevitable ‘standard’ duration in premenopausal breast cancer: treatment durations within pivotal clinical trials of OFS have increased over time [8.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; 365: 1687-1717Abstract Full Text Full Text PDF PubMed Scopus (6441) Google Scholar], starting historically with 6 months, 18 months [9.Castiglione-Gertsch M. O'Neill A. International Breast Cancer Study Group (IBCSG) et al.Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial.J Natl Cancer Inst. 2003; 95: 1833-1846Crossref PubMed Scopus (259) Google Scholar], 2 years [10.Jonat W. Kaufmann M. Sauerbrei W. et al.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; 20: 4628-4635Crossref PubMed Scopus (310) Google Scholar], 3 years [11.Jakesz R. Hausmaninger H. Kubista E. et al.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; 20: 4621-4627Crossref PubMed Scopus (263) Google Scholar] to 5 years. While in general adjuvant endocrine treatment durations increase particularly for postmenopausal breast cancer [12.Burstein H.J. Temin S. Anderson H. et al.Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline focused update.J Clin Oncol. 2014; 32: 2255-2269Crossref PubMed Scopus (565) Google Scholar], there is considerable concern that extending endocrine therapy severely impairs patients' quality of life, particularly in younger patients [13.Colleoni M. Giobbie-Hurder A. Benefits and adverse effects of endocrine therapy.Ann Oncol. 2010; 21: vii107-vii111Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. Dramatic side-effects on bone have been well described even after only 3 years of endocrine therapy [14.Gnant M. Mlineritsch B. Luschin-Ebengreuth G. et al.Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy.Lancet Oncol. 2008; 9: 840-849Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar], and the true impact of hormonal treatments in young women with active personal and professional lives may be well hidden between the lines of clinical trial data, but can loudly be heard by clinicians who take an active interest during patient follow-up. Identifying better selection criteria, either based on molecular or clinical parameters [15.Pfeiler G. Königsberg R. Fesl C. et al.Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial.J Clin Oncol. 2011; 29: 2653-2659Crossref PubMed Scopus (179) Google Scholar], to avoid highly displeasing overtreatment, is the task at hand [16.Gnant M. Steger G.G. Fighting overtreatment in adjuvant breast cancer therapy.Lancet. 2009; 374: 2029-2030Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. The authors declare no conflicts of interest with respect to this letter. Outside this work, MG reports receiving institutional grants from: Sanovi Aventis, Novartis, Roche, GlaxoSmithKline, Pfizer and Smith Medical, and personal fees from: Novartis, Roche, GlaxoSmithKline, AstraZeneca, Nanostring Technologies and Accelsiors; PCD reports receiving personal fees from: Roche, AstraZeneca and Pfizer, and travel/accommodations expenses reimbursement from: Novartis.