携带 ESR1 基因改变的激素受体阳性转移性乳腺癌的基因组和临床情况。

IF 7.1 2区医学 Q1 ONCOLOGY

ESMO Open Pub Date : 2024-10-01 DOI:10.1016/j.esmoop.2024.103731

{"title":"携带 ESR1 基因改变的激素受体阳性转移性乳腺癌的基因组和临床情况。","authors":"","doi":"10.1016/j.esmoop.2024.103731","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Somatic genetic alterations of the estrogen receptor 1 gene (<em>ESR1</em><em>)</em> 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 <em>ESR1</em>-mutant (<em>ESR1</em><sup><em>MUT</em></sup>) and <em>ESR1</em> wild type (<em>ESR1</em><sup><em>WT</em></sup>) ER+/ human epidermal growth factor receptor 2 (HER2)− mBCs.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Among 679 samples, 136 <em>ESR1</em><sup><em>MUT</em></sup> among 131 tumors were found (19.2%). The frequency of <em>ESR1</em><sup><em>MUT</em></sup> was higher in ductal versus lobular mBC (21.2% versus 13.8%, <em>P =</em> 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; <em>q =</em> 0.02). Compared with <em>ESR1</em><sup><em>WT</em></sup> mBC, <em>ESR1</em><sup>MUT</sup> tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); <em>P</em> = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; <em>P</em> = 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<em>; P</em> = 0.01]. Genetic alterations of <em>TP53</em> were enriched in <em>ESR1</em><sup><em>WT</em></sup> tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, <em>q</em> = 0.001]. Considering signaling pathways, <em>ESR1</em><sup><em>MUT</em></sup> tumors showed a lower occurrence of <em>TP53</em> (OR 0.48, 95% CI 0.30-0.74; <em>q</em> = 0.003) and <em>MAPK</em> (OR 0.29, 95% CI 0.11-0.65; <em>q</em> = 0.009) alterations. <em>TP53</em> (<em>q</em> < 0.001), <em>CDH1</em> (<em>q</em> < 0.001), and <em>ERBB2</em> (<em>q</em> < 0.001) demonstrated mutual exclusivity with <em>ESR1</em><sup><em>MUT</em></sup>.</div></div><div><h3>Conclusions</h3><div>ER+/HER2− mBCs carrying <em>ESR1</em><sup><em>MUT</em></sup> exhibit a divergent genomic background, characterized by a lower prevalence of <em>TP53</em> and <em>MAPK</em> pathway alterations. Less common <em>ESR1</em> alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.</div></div>","PeriodicalId":11877,"journal":{"name":"ESMO Open","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genomic and clinical landscape of metastatic hormone receptors-positive breast cancers carrying ESR1 alterations\",\"authors\":\"\",\"doi\":\"10.1016/j.esmoop.2024.103731\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Somatic genetic alterations of the estrogen receptor 1 gene (<em>ESR1</em><em>)</em> 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 <em>ESR1</em>-mutant (<em>ESR1</em><sup><em>MUT</em></sup>) and <em>ESR1</em> wild type (<em>ESR1</em><sup><em>WT</em></sup>) ER+/ human epidermal growth factor receptor 2 (HER2)− mBCs.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Among 679 samples, 136 <em>ESR1</em><sup><em>MUT</em></sup> among 131 tumors were found (19.2%). The frequency of <em>ESR1</em><sup><em>MUT</em></sup> was higher in ductal versus lobular mBC (21.2% versus 13.8%, <em>P =</em> 0.052) and enriched in liver metastasis compared with other sites (22.5% versus 12.7%; <em>q =</em> 0.02). Compared with <em>ESR1</em><sup><em>WT</em></sup> mBC, <em>ESR1</em><sup>MUT</sup> tumors showed higher fraction of genome altered (FGA) {[0.28 interquartile range (IQR), 0.15-0.43] versus 0.22 (0.11-0.38); <em>P</em> = 0.04} and tumor mutational burden (TMB) [4.89 (IQR 3.46-6.85) versus 3.92 (2.59-6.05) mut/Mb; <em>P</em> = 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<em>; P</em> = 0.01]. Genetic alterations of <em>TP53</em> were enriched in <em>ESR1</em><sup><em>WT</em></sup> tumors (36% versus 14%) [odds ratio (OR) 3.17, 95% confidence interval (CI) 1.88-5.64, <em>q</em> = 0.001]. Considering signaling pathways, <em>ESR1</em><sup><em>MUT</em></sup> tumors showed a lower occurrence of <em>TP53</em> (OR 0.48, 95% CI 0.30-0.74; <em>q</em> = 0.003) and <em>MAPK</em> (OR 0.29, 95% CI 0.11-0.65; <em>q</em> = 0.009) alterations. <em>TP53</em> (<em>q</em> < 0.001), <em>CDH1</em> (<em>q</em> < 0.001), and <em>ERBB2</em> (<em>q</em> < 0.001) demonstrated mutual exclusivity with <em>ESR1</em><sup><em>MUT</em></sup>.</div></div><div><h3>Conclusions</h3><div>ER+/HER2− mBCs carrying <em>ESR1</em><sup><em>MUT</em></sup> exhibit a divergent genomic background, characterized by a lower prevalence of <em>TP53</em> and <em>MAPK</em> pathway alterations. Less common <em>ESR1</em> alterations falling outside the H11-H12 region seem to occur in tumors with higher TMB, deserving further investigation to understand their potential actionability.</div></div>\",\"PeriodicalId\":11877,\"journal\":{\"name\":\"ESMO Open\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.1000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ESMO Open\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2059702924015011\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ESMO Open","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2059702924015011","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

背景：雌激素受体1基因（ESR1）的体细胞基因改变富集于内分泌治疗耐药的雌激素受体阳性（ER+）转移性乳腺癌（mBC）中。在此，我们研究并比较了ESR1突变型（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：使用公开的MSK MetTropism数据集从cBioPortal检索临床和基因组数据。转移性、ER+/HER2- mBC 样本被纳入分析。根据 OncoKB，仅纳入致癌和可能致癌的改变。统计分析采用 Benjamini-Hochberg 方法，以 0.05 为阿尔法水平，多重比较的假发现率阈值为 10%：在679个样本中，131个肿瘤中发现了136个ESR1MUT（19.2%）。ESR1MUT在导管型与小叶型mBC中的频率更高（21.2%对13.8%，P = 0.052），在肝转移瘤中的富集率也高于其他部位（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率（FGA）{[0.28 四分位数间距（IQR），0.15-0.43] 对 0.22（0.11-0.38）；P = 0.04}和肿瘤突变负荷（TMB）[4.89（IQR 3.46-6.85）对 3.92（2.59-6.05）mut/Mb；P = 0.001]。与 H11-12 基因改变的肿瘤相比，携带 p.E380X 基因改变的肿瘤显示出更高的 TMB [8.24 (IQR 5.06-15.3) 对 4.89 (IQR 3.46-6.75) mut/Mb；P = 0.01]。TP53的基因改变在ESR1WT肿瘤中更为常见（36%对14%）[几率比（OR）3.17，95%置信区间（CI）1.88-5.64，q = 0.001]。考虑到信号通路，ESR1MUT 肿瘤的 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）改变发生率较低。TP53（q < 0.001）、CDH1（q < 0.001）和ERBB2（q < 0.001）与ESR1MUT具有互斥性：结论：携带ESR1MUT的ER+/HER2- mBC表现出不同的基因组背景，其特点是TP53和MAPK通路改变的发生率较低。在H11-H12区域外较少见的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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

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

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.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

ESMO Open Medicine-Oncology

CiteScore

11.70

自引率

2.70%

发文量

255

审稿时长

10 weeks

期刊介绍： ESMO Open is the online-only, open access journal of the European Society for Medical Oncology (ESMO). It is a peer-reviewed publication dedicated to sharing high-quality medical research and educational materials from various fields of oncology. The journal specifically focuses on showcasing innovative clinical and translational cancer research. ESMO Open aims to publish a wide range of research articles covering all aspects of oncology, including experimental studies, translational research, diagnostic advancements, and therapeutic approaches. The content of the journal includes original research articles, insightful reviews, thought-provoking editorials, and correspondence. Moreover, the journal warmly welcomes the submission of phase I trials and meta-analyses. It also showcases reviews from significant ESMO conferences and meetings, as well as publishes important position statements on behalf of ESMO. Overall, ESMO Open offers a platform for scientists, clinicians, and researchers in the field of oncology to share their valuable insights and contribute to advancing the understanding and treatment of cancer. The journal serves as a source of up-to-date information and fosters collaboration within the oncology community.