{"title":"肠道亚型作为局部晚期胃腺癌新辅助免疫化疗反应的生物标志物：一项前瞻性II期试验的启示。","authors":"Lei Wang, Mengting Sun, Jinyang Li, Linghong Wan, Yuting Tan, Shuoran Tian, Yongying Hou, Linyu Wu, Ziyi Peng, Xiao Hu, Qihua Zhang, Zening Huang, Mengyi Han, Shiyin Peng, Yuwei Pan, Yuanfeng Ren, Mengsi Zhang, Dongfeng Chen, Qin Liu, Xianfeng Li, Zhong-Yi Qin, Junyv Xiang, Mengxia Li, Jianwu Zhu, Qiyue Chen, Huiyan Luo, Shunan Wang, Tao Wang, Fan Li, Xiu-Wu Bian, Bin Wang","doi":"10.1158/1078-0432.CCR-24-2436","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC.</p><p><strong>Patients and methods: </strong>A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses.</p><p><strong>Results: </strong>The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts.</p><p><strong>Conclusions: </strong>Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.\",\"authors\":\"Lei Wang, Mengting Sun, Jinyang Li, Linghong Wan, Yuting Tan, Shuoran Tian, Yongying Hou, Linyu Wu, Ziyi Peng, Xiao Hu, Qihua Zhang, Zening Huang, Mengyi Han, Shiyin Peng, Yuwei Pan, Yuanfeng Ren, Mengsi Zhang, Dongfeng Chen, Qin Liu, Xianfeng Li, Zhong-Yi Qin, Junyv Xiang, Mengxia Li, Jianwu Zhu, Qiyue Chen, Huiyan Luo, Shunan Wang, Tao Wang, Fan Li, Xiu-Wu Bian, Bin Wang\",\"doi\":\"10.1158/1078-0432.CCR-24-2436\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC.</p><p><strong>Patients and methods: </strong>A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses.</p><p><strong>Results: </strong>The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts.</p><p><strong>Conclusions: </strong>Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.</p>\",\"PeriodicalId\":10279,\"journal\":{\"name\":\"Clinical Cancer Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":10.0000,\"publicationDate\":\"2024-11-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1078-0432.CCR-24-2436\",\"RegionNum\":1,\"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":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.CCR-24-2436","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.
Purpose: Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC.
Patients and methods: A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses.
Results: The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts.
Conclusions: Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.
期刊介绍：
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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