Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations

• Published in: ESMO open Vol. 9; no. 10; p. 103731
• Main Authors: Boscolo Bielo, L., Guerini Rocco, E., Trapani, D., Zagami, P., Taurelli Salimbeni, B., Esposito, A., Belli, C., Crimini, E., Venetis, K., Munzone, E., Fusco, N., Criscitiello, C., Marra, A., Curigliano, G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2024; Elsevier
• Subjects: breast cancer; ESR1; genomic analysis; next-generation sequencing; Original Research; precision medicine; breast cancer; precision medicine; next-generation sequencing; ESR1; genomic analysis
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2024.103731

Somatic genetic alterations of the estrogen receptor 1 gene (ESR1) are enriched in endocrine therapy-resistant, estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Herein, we investigated and compared the clinical and genomic landscape of ESR1-mutant (ESR1MUT) and ESR1 wild type (ESR1WT) ER+/ human epidermal growth factor receptor 2 (HER2)− mBCs. Clinical and genomic data were retrieved from cBioPortal using the publicly-available MSK MetTropism dataset. Metastatic, ER+/HER2− mBC samples were included in the analysis. Only oncogenic and likely oncogenic alterations according to OncoKB were included. Statistical analyses were carried out using alpha level of 0.05, with a false discovery rate threshold of 10% for multiple comparisons using the Benjamini–Hochberg method. Among 679 samples, 136 ESR1MUT among 131 tumors were found (19.2%). The frequency of ESR1MUT was higher in ductal versus lobular mBC (21.2% versus 13.8%, P = 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; q = 0.02). Compared with ESR1WT mBC, ESR1MUT tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); P = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; P = 0.001]. Tumors harboring p.E380X alterations showed higher TMB compared with those with H11-12 alterations [8.24 (IQR 5.06-15.3) versus 4.89 (IQR 3.46-6.75) mut/Mb; P = 0.01]. Genetic alterations of TP53 were enriched in ESR1WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1MUT tumors showed a lower occurrence of TP53 (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, characterized by a lower prevalence of TP53 and MAPK pathway alterations. Less common ESR1 alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability. •Distinct genomic mechanisms promote endocrine resistance among ESR1-mutant and ESR1 wild-type ER+/HER2− breast cancer.•ESR1-mutant ER+/HER2− breast cancer displays peculiar genetic landscape and genomic signatures.•Potentially actionable genetic alterations are differently distributed according to the presence of ESR1 alterations.•ER+/HER2− breast cancer carrying ESR1 p.E380Q might be particularly susceptible to the use of immunotherapy.