Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations
Luca Boscolo Bielo, E. Guerini Rocco, Dario Trapani, Paola Zagami, Beatrice Taurelli Salimbeni, Anna Esposito, Carmen Belli, Edoardo Crimini, Konstantinos Venetis, Elisabetta Munzone, Nicola Fusco, Carmen Criscitiello, Antonio Marra, Giuseppe Curigliano
Abstract
Background 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 ( ESR1 MUT ) and ESR1 wild type ( ESR1 WT ) ER+/ human epidermal growth factor receptor 2 (HER2)− mBCs. Methods 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. Results Among 679 samples, 136 ESR1 MUT among 131 tumors were found (19.2%). The frequency of ESR1 MUT 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 ESR1 WT mBC, ESR1 MUT 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 ESR1 WT tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, q = 0.001]. Considering signaling pathways, ESR1 MUT 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 ESR1 MUT . Conclusions ER+/HER2− mBCs carrying ESR1 MUT 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.