Abstract IA23: Lessons for ER+ breast cancer from neoadjuvant endocrine therapy trials

For postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer, neoadjuvant endocrine therapy (NET) is an underutilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates (1). Several studies from a decade or more ago showed marked improvements in breast conservation after 3 to 4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation. More recently the American College of Surgeons Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast-conserving surgery after 16 to 18 weeks of AI treatment (2). Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to NET such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET (3). Z1031 therefore provided an opportunity to further evaluate the PEPI. This study was run in two phases, Z1031A enrolled postmenopausal women with stage II/III ER+ (Allred 6 to 8) breast cancer (BC) whose treatment was randomized to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For Z1031B the protocol was amended to include a tumor Ki67 determination after 2-4 weeks of AI. If the Ki67 was >10%, patients were switched to neoadjuvant chemotherapy because the chance of a PEPI=0 score (best prognostic group) is very low in this subpopulation. A pCR rate of >20% was the predefined efficacy threshold. Only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7-19.1%). After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI=0 score relapsed versus 49 of 341 (14.4%) PEPI>0 patients, recurrence hazard ratio (PEPI=0/PEPI>0) = 0.27 (p=0.014; 95%CI: 0.092-0.764). Chemotherapy efficacy was therefore lower than expected in ER+ tumors exhibiting AI-resistant proliferation. For patients with PEPI=0 disease the relapse risk over 5 years was only 3.6% without chemotherapy supporting the study of adjuvant endocrine monotherapy in this group (4). These Ki67 and PEPI triage approaches are being definitively studied in new studies. In particular, new approaches are needed for the poor responders given the low efficacy of chemotherapy. Preliminary studies demonstrate that tumors that exhibit AI-resistant proliferation in the neoadjuvant setting often remain sensitive to CDK4/6 inhibition (5). Serial Ki67 monitoring could logically be considered as an approach to tailored use of adjuvant CDK4/6i treatment. Finally, serial sampling of the tumor inherent in the PEPI approach allows us to study of the genomic evolution of the tumor and to identify new therapeutic targets (6) and monitor tumor evolution in response to AI therapy (7). References: 1. Goncalves R, Ma C, Luo J, Suman V, Ellis M. J. Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol 2012;9:223-9; doi:10.1038/nrclinonc.2012.21. 2. Ellis MJ et al. 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;29:2342-9; doi:10.1200/JCO.2010.31.6950. 3. Ellis MJ et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 2008;100:1380-8; doi:10.1093/jnci/djn309. 4. Ellis MJ et al. Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: Results from the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol 2017;JCO2016694406. 5. Ma CX et al. 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;doi:10.1158/1078-0432.CCR-16-3206. 6. Ellis MJ et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012;486:353-60; doi:10.1038/nature11143. 7. Miller CA et al. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun 2016;7:12498; doi:10.1038/ncomms12498. Citation Format: Matthew J. Ellis. Lessons for ER+ breast cancer from neoadjuvant endocrine therapy trials [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; Sao Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA23.