Abstract

3535 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.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call