Faculty, Staff and Student Publications

Language

English

Publication Date

11-1-2024

Journal

British Journal of Cancer

DOI

10.1038/s41416-024-02826-0

PMID

39227409

PMCID

PMC11473766

PubMedCentral® Posted Date

9-4-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Background: 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).

Methods: 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).

Results: 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.

Discussion: 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.

Keywords

Humans, Colorectal Neoplasms, Biomarkers, Tumor, Female, Male, Prognosis, Cetuximab, Panitumumab, Aged, Antibodies, Monoclonal, Humanized, Middle Aged, Kaplan-Meier Estimate, Neoplasm Metastasis, Consensus

Published Open-Access

yes

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