携带ESR1改变的转移性激素受体阳性乳腺癌的基因组和临床景观

雌激素受体1基因（ESR1）的体细胞遗传改变富含内分泌治疗，抗雌激素受体阳性（ER+）转移性乳腺癌（MBC）。在此，我们调查并比较了ESR1突变剂（ESR1MUT）和ESR1野生型（ESR1WT）ER+/人类表皮生长因子受体2（HER2）-MBCS.Clinical和Genomic数据的临床和基因组生长因子受体2（HER2）和基因组数据，使用公共cbioportal使用公共利用的MSK MSK MSK MSK MSK gettropset。分析中包括转移性ER+/HER2-MBC样品。仅包括Oncokb的致癌性和可能的致癌改变。使用alpha水平为0.05进行统计分析，使用Benjamini-Hochberg方法进行多次比较的错误发现率阈值为10％。在679个样本中，发现136个ESR1MUT在131个肿瘤中（19.2％）。与其他部位相比，导管与小叶MBC的ESR1MUT频率较高（21.2％对13.8％，P = 0.052），并且在肝转移中富集（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（FGA）{[[0.28四分位间范围（IQR），0.15-0.43]，而0.22（0.11-0.38）； p = 0.04}和肿瘤突变负担（TMB）[4.89（IQR 3.46-6.85）与3.92（2.59-6.05）mut/mb; p = 0.001]。与H11-12变化的肿瘤相比，具有P.E380X改变的肿瘤显示出更高的TMB [8.24（IQR 5.06-15.3），而4.89（IQR 3.46-6.75）MUT/MB； p = 0.01]。 TP53的遗传改变富含ESR1WT肿瘤（36％和14％）[优势比（OR）3.17，95％置信区间（CI）1.88-5.64，Q = 0.001]。考虑信号通路，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）的发生率较低。 TP53（Q <0.001），CDH1（Q <0.001）和ERBB2（Q <0.001）表现出具有ESR1MUT.ER+/HER2- MBC的相互排他性，携带ESR1MUT的MBC表现出不同的基因组背景，其特征是TP53和MAPK PATHERAGE PATHEARKE FATERACTIONS较低的出现。不太常见的ESR1改变落在H11-H12区域以外的肿瘤中似乎发生了，应进一步研究以了解其潜在的可行性。

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.