BACKGROUND: Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)–positive, postmenopausal patients not eligible for primary breast‐conserving surgery (BCS).METHODS: This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR‐positive/human epidermal growth factor receptor 2 (HER2)–negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse‐free survival (RFS), and predictive markers of responses and outcomes.RESULTS: From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2‐T4, N0‐N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%‐64%) in arm A and 36.8% (95% CI, 25%‐49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated.CONCLUSIONS: Both drugs are effective and well tolerated as NET in postmenopausal women with HR‐positive/HER2‐negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032‐3040. © 2016 American Cancer Society.

Postmenopausal women with large, hormone receptor (HR)-positive/HER2-negative and low-proliferative breast cancer derived a benefit from neoadjuvant endocrine therapy (NET) in the CARMINA02 trial. This study was designed to correlate gene expression and mutation profiles with both response to NET and prognosis. Gene expression profiling using RNA sequencing was performed in 86 pre-NET and post-NET tumor samples. Targeted next-generation sequencing of 91 candidate breast cancer-associated genes was performed on DNA samples from 89 patients. Molecular data were correlated with radiological response and relapse-free survival. The transcriptional profile of tumors to NET in responders involved immune-associated genes enriched in activated Th1 pathway, which remained unchanged in non-responders. Immune response was confirmed by analysis of tumor-infiltrating lymphocytes (TILs). The percentage of TILs was significantly increased post-NET compared to pre-NET samples in responders (p = 0.0071), but not in non-responders (p = 0.0938). Gene expression revealed that lipid metabolism was the main molecular function related to prognosis, while PPARγ is the most important upstream regulator gene. The most frequently mutated genes were PIK3CA (48.3%), CDH1 (20.2%), PTEN (15.7%), TP53 (10.1%), LAMA2 (10.1%), BRCA2 (9.0%), MAP3K1 (7.9%), ALK (6.7%), INPP4B (6.7%), NCOR1 (6.7%), and NF1 (5.6%). Cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway were altered significantly more frequently in non-responders than in responders (p = 0.0017 and p = 0.0094, respectively). The average number of mutations per sample was significantly higher in endocrine-resistant tumors (2.88 vs. 1.64, p = 0.03), but no difference was observed in terms of prognosis. ESR1 hotspot mutations were detected in 3.4% of treatment-naive tumors. The Th1-related immune system and lipid metabolism appear to play key roles in the response to endocrine therapy and prognosis in HR-positive/HER2-negative breast cancer. Deleterious somatic mutations in the cell cycle and apoptosis pathway and PIK3CA/AKT/mTOR pathway may be relevant for clinical management. This trial is registered with ClinicalTrials.gov ( NCT00629616 ) on March 6, 2008, retrospectively registered.

Return to work (RTW) after breast cancer is associated with improved quality of life. The link between household characteristics and RTW remains largely unknown. The aim of this study was to examine the effect of the family situation on women’s RTW two years after breast cancer. We used data of a French prospective cohort of women diagnosed with stage I-III, primary breast cancer (CANTO, NCT01993498). Among women employed at diagnosis and under 57 years old, we assessed the association between household characteristics (living with a partner, marital status, number and age of economically dependent children, support by the partner) and RTW. Logistic regression models were adjusted for age, household income, stage, comorbidities, treatments and their side effects. Analyzes stratified by age and household income were performed to assess the association between household characteristics and RTW in specific subgroups. Among the 3004 patients included, women living with a partner returned less to work (OR = 0.63 [0.47–0.86]) and decreased their working time after RTW. Among the 2305 women living with a partner, being married was associated with decreased RTW among women aged over 50 (OR = 0.57 [0.34–0.95]). Having three or more children (vs. none) was associated with lower RTW among women with low household income (OR = 0.28 [0.10–0.80]). Household characteristics should be considered in addition to clinical information to identify vulnerable women, reduce the social consequence of cancer and improve their quality of life.

Background: Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). Methods: This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. Results: In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)). Conclusions: Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

Endocrine therapy is the mainstay of treatment in HR+/HER2- breast cancers, which represent about 70% of all breast cancers. Neoadjuvant therapy has been developed since the 1990s to address several issues, including breast-conserving surgery (BCS) and improvement of survival rates. For a long time, neoadjuvant endocrine therapy (NET) was confined to frail patients in order to improve surgery outcome. Since the 2000s, NET now plays a central role as a research tool for predictive endocrine sensitivity biomarkers and targeted therapies. One of the major issues in early HR+/HER2- breast cancer is to identify patients in whom chemotherapy can be safely withheld. In vivo assessment of response to NET might be the best treatment strategy to address this issue.