226P Prevalence and characteristics of HR+/HER2- MBC with ESR1 mutations post-CDK inhibitor therapy

Activating mutations of the ESR1 gene can be detected in up to 40% of endocrine therapy (ET)-resistant hormone receptor-positive, HER2-negative (HR+/ HER2-) metastatic breast cancer (MBC). Our aim was to investigate the role of ESR1mut in HR+/HER2- MBC patients (pts) who have developed resistance to ET in combination with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). We retrospectively collected data and/or samples from pts with HR+/HER2- MBC treated at 4 institutions in Italy who had undergone a biopsy upon progression to first or second-line CDK4/6i plus ET prior to initiating a new treatment or within one month of beginning it. We assessed the presence of ESR1mut in the biopsy samples using NGS and/or ddPCR panels assays targeting all the hotspot regions. The time to treatment failure (TTF) was calculated as the interval from the initiation of CDK4/6i therapy to its conclusion. A significance level of p<0.05 was established for correlative analyses. Of the 39 pts enrolled in the study (age 45-58, median 51 years), 26 (67%) had ESR1mut in their metastatic sites. 57% of these pts had visceral metastases. After progression to CDK4/6i, 7 pts received ET (monotherapy or in combination treatments), while 17 received other therapies (including chemotherapy and PARP inhibitors). p.D538G and p.Y537S ESR1 activating mutations were the most prevalent mutations, present in 35% and 27% of the pts, respectively. The prevalence of liver metastases was similar in ESR1mut and ESR1WT tumors (70% vs 65%). There were no significant differences in TTF based on the type of therapy received after CDK4/6i, nor according to the duration of prior CDK4/6i (cutoff of 12 months). Additionally, the type of ESR1mut did not affect the clinical outcome (p=0.16). Pts with concurrent mutations in both ESR1 and PIK3CA (n=4) exhibit a worse survival compared to the non-mutated counterpart, although the difference was not statistically significant (p=0.40). This real-world study illuminates on the clinical characteristics and outcomes of pts with HR+/HER2- MBC according to the presence and type of ESR1mut. We are expanding the cohort to include a broader spectrum of pts, enhancing the clinical relevance of our findings.