The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Caris Life Sciences, Phoenix, AZ, USA.
Br J Cancer. 2024 Nov;131(8):1328-1339. doi: 10.1038/s41416-024-02826-0. Epub 2024 Sep 4.
We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).
The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant).
CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer TOT with anti-EGFR antibodies (cetuximab and panitumumab). When restricting to only CMS2, there was no significant difference in TOT between right- versus left-sided tumors. CMS1 tumors were associated with a longer median TOT with pembrolizumab relative to other CMS groups, even when analyzing only microsatellite stable (MSS) tumors.
A WTS-based CMS classifier allowed investigation of a large multi-institutional clinico-genomic mCRC cohort, suggesting anti-EGFR therapy benefit for right-sided RAS-WT CMS2 tumors and immune checkpoint inhibitor benefit for MSS CMS1. Routine CMS classification of CRC provides important treatment associations that should be further investigated.
我们使用 FFPE 组织开发了一种基于全转录组测序（WTS）的共识分子亚型（CMS）分类器，并在一个大型结直肠癌患者临床基因组数据库（n=24939）中研究了其预后和预测效用。
该分类器使用 SVM 模型针对原始 CMS 数据集进行了训练，并在独立的 TCGA 数据集（88.0%的准确率）中进行了验证。为每个 CMS 计算了总生存期（OS）和治疗时间（TOT）的 Kaplan-Meier 估计值（p<0.05 被认为具有统计学意义）。
CMS2 肿瘤在结肠左侧富集，并提供了最长的中位 OS。在 RAS 野生型 mCRC 中，左侧肿瘤和 CMS2 分类与抗 EGFR 抗体（西妥昔单抗和帕尼单抗）的更长 TOT 相关。当仅限制在 CMS2 时，右侧与左侧肿瘤之间的 TOT 无显著差异。与其他 CMS 组相比，CMS1 肿瘤与 pembrolizumab 的中位 TOT 更长，即使仅分析微卫星稳定（MSS）肿瘤也是如此。
基于 WTS 的 CMS 分类器允许对大型多机构临床基因组 mCRC 队列进行研究，提示抗 EGFR 治疗对右侧 RAS-WT CMS2 肿瘤有益，免疫检查点抑制剂对 MSS CMS1 有益。CRC 的常规 CMS 分类提供了重要的治疗关联，应进一步研究。
