35P Genomic and clinical landscape of metastatic hormone receptor-positive breast cancers carrying ESR1 alterations

Genomic alterations in ESR1 are enriched in endocrine therapy (ET)-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). In the present analysis, we investigated clinical and genomic differences among ESR1 wild type (ESR1WT) and ESR1-mutated (ESR1MUT) ER+ mBCs. Clinical and genomic data was retrieved from cBioPortal using the MSK MetTropism dataset. Metastatic, post-ET ER+/HER2- tumor samples were included in the analysis. Oncogenic and likely oncogenic alterations according to OncoKB were included in the analysis. False discovery rate (FDR) correction was applied for multiple hypothesis testing. Among 707 ER+/HER2- mBCs, 136 ESR1MUT in 131 tumors were found, of whom 85.29% (116/136) consisted in alterations located in helices 11 and 12 (H11-12), 10.29% (14/136) in H5 (E380X), and 4.41% (6/136) in other domains of the ESR1 gene. The frequency of ESR1MUT was higher in ductal vs. lobular mBC (20.1% vs. 13.2%; P=0.04) and enriched in liver metastasis compared to other sites (22.5% vs. 12.7%; q=0.02). ESR1MUT tumors showed higher fraction of genome altered (FGA) (0.28 IQR 0.15 0.43 vs. 0.22 0.11-0.38; P=0.04) and tumor mutational burden (TMB) (4.89 IQR 3.46-6.85 vs. 3.92 2.59-6.05 mut/Mb; P=0.001) compared to ESR1WT mBC. Tumors harboring E380X alterations had higher TMB compared to those with H11-12 alterations (8.24 IQR 5.06-15.3 vs. 4.89 3.46-6.75 mut/Mb; P=0.01). In both ESR1MUT and ESR1WT tumors, PIK3CA represented the most common altered gene (38% and 42%). TP53 gene alterations were enriched in ESR1WT tumors (36% vs. 14%) (Odd Ratio (OR) 3.17, 95% CI 1.88-5.64, q=0.001). Considering signaling pathways, ESR1MUT tumors showed a lower occurrence of TP53-pathway (OR 0.48, 95%CI 0.30-0.74; q=0.003) and MAPK (OR 0.29, 95%CI 0.11-0.65; q=0.009) alterations. TP53 (q<0.001), CDH1 (q<0.001) and ERBB2 (q<0.001) demonstrated mutual exclusivity with ESR1MUT. ER+/HER2- mBCs carrying ESR1MUT exhibit a divergent genomic background, such as a low number of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with high TMB, deserving further investigation to understand their real actionability.