携带ESR1突变的转移性激素受体阳性乳腺癌的基因组和临床特征

体细胞遗传变异，尤其是雌激素受体1基因（ESR1）的突变，在耐内分泌治疗、ER阳性（ER+）转移性乳腺癌（mBC）中呈现出富集。本研究探讨并比较了ESR1突变（ESR1MUT）与野生型（ESR1WT）ER+/HER2- mBC的临床和基因组特征。数据来源于cBioPortal的公开MSK MetTropism数据集，分析包括转移性ER+/HER2- mBC样本，仅包括根据OncoKB定义的致癌或可能致癌的变异。采用Benjamini-Hochberg方法，在α=0.05的显著性水平下进行多重比较校正。共分析679个样本，其中发现136个ESR1MUT（占19.2%），分布在131个肿瘤中。ESR1MUT在导管癌比腺泡癌中比例更高（21.2%对13.8%，P=0.052），且在肝转移中更为丰富（22.5%对12.7%，q=0.02）。与ESR1WT肿瘤相比，ESR1MUT肿瘤表现出更高的基因组变异比例（FGA）（中位值0.28[四分位距0.15-0.43]对0.22[0.11-0.38]，P=0.04）及肿瘤突变负荷（TMB）（中位值4.89[3.46-6.85]对3.92[2.59-6.05]突变/兆碱基，P=0.001）。携带p.E380X变异的肿瘤TMB明显高于H11-12区域的变异（8.24[5.06-15.3]对4.89[3.46-6.75]突变/兆碱基，P=0.01）。TP53基因变异在ESR1WT肿瘤中更为丰富（36%对14%，OR=3.17，95% CI 1.88-5.64，q=0.001）。在信号通路分析中，ESR1MUT肿瘤较少出现TP53（OR=0.48，95% CI 0.30-0.74，q=0.003）和MAPK（OR=0.29，95% CI 0.11-0.65，q=0.009）途径变异。TP53（q<0.001）、CDH1（q<0.001）和ERBB2（q<0.001）与ESR1MUT呈相互排斥。携带ESR1MUT的ER+/HER2- mBC表现出不同的基因组背景，TP53和MAPK途径变异的发生率较低。少见的位于H11-H12区域之外的ESR1变异似乎在具有更高TMB的肿瘤中更常见，有待进一步研究其潜在的治疗靶向性。

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.