Consensus molecular subtyping of colorectal cancer to demonstrate cetuximab benefit in right-sided CMS2 tumors, and pembrolizumab benefit in MSS CMS1 tumors.
Authors: Shen John Paul Y.C. , Xiu Joanne , Nicolaides Theodore , Zhang Jian , Chowdhury Saikat , Korn W. Michael , Poorman Kelsey Anne , Lenz Heinz-Josef , Marshall John , Oberley Matthew James , Sledge George W. , Spetzler David , Kopetz Scott 
Published: June 2023

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Background: Consensus Molecular Subtypes (CMS) of colorectal cancer (CRC) were first developed in 2015 using microarray-based assays but are not widely used clinically. We developed a Caris CMS classifier on whole transcriptome sequencing data (WTS) with high concordance with the previously established CMS pipeline (Guinney et al 2015), and applied to a large clinic-genomic database of CRC to investigate the utility of CMS classification in identifying patients that may respond well to therapies commonly used in CRC. Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and WTS was tested on CRC patient samples (n = 12,788) at a CLIA-certified lab (Caris Life Sciences, Phoenix, AZ). Caris CMS classifier was trained against the original CMS datasets using a classic SVM model and cross-validated for optimization of the SVM parameters. Possible overtraining was evaluated by predicting CMS from an independent blinded dataset (TCGA, N = 512) with an accuracy of 88.3%. Real-world overall survival was obtained from insurance claims and calculated from tissue collection to last contact (OS); time on treatment (TOT) was from first to last of treatment time. Kaplan-Meier estimates were calculated for molecularly defined cohorts. Significance was determined as p of < 0.05. Results: Among all patients, CMS1 was seen in 16%, CMS2 in 32%, CMS3 in 17% and CMS4 in 35%. MSI-H/MMRd (31%) and BRAF mut (33%) were most prevalent in CMS1 with KRAS mt the highest in CMS3 (66%). CMS2 was associated with the longest mOS (33m; 95% CI: 31m-35m), followed by CMS4 (29m; 28-31m), CMS3 (27m; 25-29m) and CMS1 (22m; 20-23m). In the microsatellite stable (MSS) tumors treated with pembrolizumab, CMS1 (N = 22, mTOT: 4.2m; 2.8-9.1m) had longer TOT than CMS2 (N = 45, mTOT: 2.1m; 1.4-3.1m), CMS3 (N = 21, 2.1m; 1.4m-3.0m) and CMS4 (N = 40; 2.1m; 1.4m-2.8m); CMS1 vs. CMS2-4 in MSS (HR: 0.58; CI: 0.34-0.97, p = 0.035). When investigating cetuximab, CMS2 had the longest mTOT (N = 189, mTOT: 6.3m; 5.4m-7.7m) among the four groups. Interestingly, although among all Ras WT tumors left-sided CRC showed longer mTOT on cetuximab (n = 457, mTOT: 5.4m; 4.7m-6.3m) than right-sided (n = 151, mTOT: 3.8m; 3.3m-4.5m), CMS2 showed similar mTOT from the left (n = 128) and the right (n = 16, mOT: 6.3m vs. 5.6m, HR = 0.896, 95% CI: 0.501-1.604, p = 0.722). Notably, CMS2 comprises 49% of left- and 15% of right-sided tumors, potentially underlying the TOT difference seen between left and right. Conclusions: A WTS based CMS classifier allows for investigation in a large real-world clinic-genomic database. We found that MSS CMS1 CRC’s may derive benefit from immunotherapy. Additionally, CMS2 subgroup of right-sided tumors may derive benefit from cetuximab. Routine CMS subgrouping of CRC provides important treatment associations that should be further investigated.