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

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.

Keywords: ESR1; breast cancer; genomic analysis; next-generation sequencing; precision medicine.

Figure 1

Proportion of ESR1^MUTaccording to metastatic site, type of ESR1 mutations, and driver genes among ESR1-mutated and ESR1 wild-type tumors. (A) Sampled sites with proportion of ESR1^MUT detected by each site (shown in red). (B) Spectrum of ESR1^MUT detected among 679 ER+ mBC. (C) Oncoprints of driver genes in breast cancer among ESR1^WT and ESR1^MUT tumors. CTD, C-terminal domain; DBD, DNA-binding domain; ER, estrogen receptor; FGA, fraction of genome altered; LBD, ligand binding domain; mBC, metastatic breast cancer; MUT, mutant; NTD, N-terminal domain; TMB, tumor mutational burden; WT, wild-type.

Figure 2

Enrichment gene alteration analysis among ESR1-mutated and ESR1 wild-type tumors. (A) Different distribution of gene-level genomic alterations among ESR1^MUT and ESR1^WT tumors. (B) Different distribution of pathway-level genetic alterations among ESR1^MUT and ESR1^WT tumors. (C) Groupwise comparisons of mutual exclusivity of selected list of genes from included in the MAPK, RTK, PI3K-AKT-mTOR, and transcription factors pathways. (D) Proportion of detected genetic biomarkers with approved biomarker-matched targeted therapy available among ESR1^MUT (in yellow) and ESR1^WT (in gray) tumors. NTRK1/2/3 fusions, RET fusions and MSI-H not displayed as no case was observed. MUT, mutant; WT, wild-type.

Figure 3

Genomic signatures among ESR1-mutated and ESR1 wild-type tumors, and across classes of ESR1 mutations. (A) Comparison of tumor mutational burden and (B) fraction genome altered among ESR1^MUT and ESR1^WT tumors. Comparison of tumor mutational burden (C) and fraction genome altered (D) across different class of ESR1 mutations. MUT, mutant; WT, wild-type.