Abstract PO4-15-07: ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact

Abstract Background Neoadjuvant endocrine therapy (NET) is currently used in several clinical trials to select patients for chemotherapy de-escalation. However, exposure to NET may induce/select endocrine-resistant tumor cell clones harboring ESR1 mutations (ESR1mut), which are well known to confer poor prognosis and ET resistance to aromatase inhibitors in the metastatic setting. In this study, we sought to determine the frequency and prognostic significance of ESR1mut after NET in postmenopausal patients with HR+/HER2- early breast cancer. Materials and methods We conducted a retrospective study in postmenopausal patients with ER+/HER2-early breast cancer diagnosed between 2000 and 2012 and treated with NET for at least three months at Institut Curie Hospitals (Paris and Saint Cloud, France). Exclusion criteria were: stage IV breast cancer, no surgery of the primary tumor, neoadjuvant radiation therapy, chemotherapy or targeted therapies. DNA from post-NET surgical samples was extracted using the phenol-chloroform DNA isolation method. ESR1mut were detected with multiplex drop-off ddPCR assay previously used in the PADA-1 trial (targeting clustered hotspot mutations in exon 8 and 5, using a BioRad QX100 system and analyzed with QuantaSoft v.1.7.4 software). Associations between ESR1mut detection and patient outcomes, distant relapse-free interval (DRFI) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results N=143 patients treated with NET were eligible for this study, of whom N=136 had interpretable ESR1mut detection results. Median age at NET initiation was 75.4 (IQR 66.6-81.3) years. The median duration of NET was 6.6 months (IQR 5.8 – 7.6). Most patients were treated with aromatase inhibitors (n=107, 75.9%), while 24.1% (n=34) received tamoxifen. The median time between diagnosis and surgery was 7.6 (IQR 6.4 – 8.7) months. ESR1mut were detected in post-NET surgical samples in N=7 patients (5.2%). Baseline clinicopathological characteristics were not associated with post-NET ESR1mut detection status. The median follow-up for DRFI and OS was 11.0 (IQR 7.7 – 13.8) and 18.7 (IQR 13.3 – 18.7) years, respectively. The median DRFI was 6.7 (95%CI [4.9-NR]) vs 14.0 [10.7-NR] years in ESR1mut and ESR1wt patients, respectively (HR=1.9 [0.6-6.2], p=0.29). Similarly, median OS was numerically shorter in patients with post-NET ESR1mut (6.8 [3.7-NR] vs 9.8 [8.5-NR]; HR=2.0 [0.9-4.7], p=0.09). Conclusions Post-NET tumors are enriched in ESR1mut subclones, which represent a potentially lethal threat in the context of aromatase inhibitor-based adjuvant endocrine therapy. Although the limited sample size of our study did not allow reaching statistical significance, our results suggest, for the first time, worse survival outcomes for patients with a ESR1mut detected in post-NET primary tumors. The role of next-generation oral SERDs as neoadjuvant or adjuvant endocrine therapy to prevent ESR1mut-related relapses remains to be determined. Citation Format: José Luis Sandoval, Helene Salaun, Shufang Renault, Marcela Carausu, Aurore Rampanou, Caroline Hego, Matthieu Carton, Luc Cabel, Jean-Yves Pierga, Romain Geiss, Francois-Clement Bidard, Florence Lerebours. ESR1 mutations emerging during neoadjuvant endocrine therapy in postmenopausal ER+/HER2- early breast cancer patients: prevalence and prognostic impact [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-07.