Abstract A014: Comprehensive genomic and clinicopathologic characterization of <i>ESR1</i> mutations in Chinese breast cancer patients reveals distinct molecular features and metastasis-associated enrichment

Abstract Background: Estrogen receptor 1 (ESR1) mutations represent a key mechanism of acquired endocrine resistance in hormone receptor-positive (HR+) breast cancer, especially in advanced and metastatic disease. However, their clinical and genomic characteristics remain underexplored in real-world Asian populations. This study aimed to characterize the clinicopathologic and molecular features of ESR1-mutant breast cancer using a large Chinese patient cohort. Methods: We performed targeted deep sequencing on tumor and matched blood samples from 1,030 Chinese breast cancer patients using a CAP/CLIA-certified panel covering SNVs, indels, copy number variations (CNVs), and gene rearrangements. Clinical, pathological, and molecular data were integrated for comparative analysis between ESR1-mutant and wild-type groups. Results: ESR1 mutations were identified in 4.9% of patients (50/1030), with 62 total ESR1 alterations including canonical hotspot SNVs, including Y537S/C/N (14), E380Q (6), D538G (5), K449R (1), also ESR1 amplifications (10), and 5 rearrangements (2 ESR1-MTHFD1L). Of the 50 patients, 10 (20%) carried multiple ESR1 alterations, including one with E380Q, L536P, and Y537N. ESR1-mutant patients were significantly older (mean age 54.6 vs. 49.6 years, P=0.004), and enriched in the HR+/HER2- subtype (6.4% vs. 1.7% in TNBC and 4.4% in HER2+, P=0.014). ESR1 mutations were more prevalent in metastatic lesions than primary tumors (10.7% vs. 3.3%, P&amp;lt;0.001), and in stage IV disease compared to stages I–III (8.6% vs. 3.3%, P&amp;lt;0.001). Notably, ER or PR positivity strongly correlated with ESR1 mutation presence (6.3% vs. 1.8%, P=0.002), underscoring continued hormone receptor dependence. Genomic co-alteration analysis revealed higher frequencies of ZNF703 (24.0% vs. 6.5%), FGFR1 (26.0% vs. 8.7%), and MYC (18.0% vs. 7.7%) mutations in ESR1-mutant tumors, suggesting activation of proliferative and endocrine resistance pathways. Although the overall PIK3CA mutation rate in ESR1-mutant cases reached 44%, it was not significantly different from wild-type tumors (44.0% vs. 39.6%, P=0.64), indicating mechanistic independence. While preliminary survival analysis showed lower survival probability trends in ESR1-mutant cases, extensive data censoring limited interpretability. Conclusions: This study provides the first comprehensive genomic and clinicopathologic landscape of ESR1 mutations in a large Chinese breast cancer cohort. ESR1 mutations preferentially occur in HR+/HER2− tumors, are enriched in metastatic and advanced-stage cases, and co-occur with ZNF703, FGFR1, and MYC alterations. These findings support the hypothesis that ESR1 mutations arise as acquired resistance events and may cooperate with additional oncogenic pathways to drive tumor progression. Future studies with more complete longitudinal data are warranted to evaluate the prognostic and therapeutic relevance of ESR1 mutations in breast cancer. Citation Format: Qing Hao, Shaohua Yuan, Chengyi Wang, Kai Wang. Comprehensive genomic and clinicopathologic characterization of ESR1 mutations in Chinese breast cancer patients reveals distinct molecular features and metastasis-associated enrichment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A014.