雌激素受体 1 基因 (ESR1) 的体细胞遗传改变在内分泌治疗耐药、雌激素受体阳性 (ER) 转移性乳腺癌 (mBC) 中丰富。在此，我们研究并比较了 ESR1 突变体 (ESR1MUT) 和 ESR1 野生型 (ESR1WT) ER/人表皮生长因子受体 2 (HER2)-mBC 的临床和基因组情况。临床和基因组数据使用公开的 cBioPortal 检索- 可用的 MSK MetTropism 数据集。分析中包括转移性 ER/HER2-mBC 样本。仅包括根据 OncoKB 的致癌和可能致癌改变。使用0.05的α水平进行统计分析，使用Benjamini-Hochberg方法进行多重比较的错误发现率阈值为10%。在679个样本中，在131个肿瘤中发现了136个ESR1MUT（19.2%）。与小叶 mBC 相比，ESR1MUT 的频率在导管型 mBC 中较高（21.2% 对 13.8%，P = 0.052），并且与其他部位相比，在肝转移中富集（22.5% 对 12.7%；q = 0.02）。与 ESR1WT mBC 相比，ESR1MUT 肿瘤显示出更高的基因组改变比例 (FGA) {[0.28 四分位距 (IQR)，0.15-0.43] 与 0.22 (0.11-0.38) 相比； P = 0.04}和肿瘤突变负荷 (TMB) [4.89 (IQR 3.46-6.85) 对比 3.92 (2.59-6.05) mut/Mb； P = 0.001]。与具有 H11-12 突变的肿瘤相比，携带 p.E380X 突变的肿瘤显示出更高的 TMB [8.24 (IQR 5.06-15.3) vs 4.89 (IQR 3.46-6.75) mut/Mb； P = 0.01]。 TP53 的遗传改变在 ESR1WT 肿瘤中丰富（36% 对比 14%）[比值比 (OR) 3.17，95% 置信区间 (CI) 1.88-5.64，q = 0.001]。考虑到信号通路，ESR1MUT 肿瘤显示 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）改变的发生率较低。 TP53 (q < 0.001)、CDH1 (q < 0.001) 和 ERBB2 (q < 0.001) 与 ESR1MUT 表现出相互排他性。携带 ESR1MUT 的 ER /HER2- mBC 表现出不同的基因组背景，其特征是 TP53 和 MAPK 通路的患病率较低变更。 H11-H12 区域之外的不太常见的 ESR1 改变似乎发生在 TMB 较高的肿瘤中，值得进一步研究以了解其潜在的可操作性。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.