Association of consensus molecular subtypes (CMS) with time to progression (TTP), progression free survival (PFS), and overall survival (OS) with second-line FOLFIRI ± regorafenib in metastatic colorectal cancer (mCRC).

Abstract

597 Background: LCCC1029 was a 2:1 randomized phase II trial of second-line FOLFIRI plus either regorafenib or placebo in mCRC that showed no statistically significant difference in PFS or OS. CMS, defined using gene expression, is prognostic for PFS and OS in previously untreated mCRC, but the impact of CMS in second-line treatment is unclear, as well as its impact on regorafenib efficacy. Methods: RNAseq on archival tumor tissue was successfully performed in 68 LCCC1029 patients (49 on regorafenib, 19 on placebo). A multinomial elastic net CMS classifier was trained using 6 CRC gene expression data sets with known CMS classification. We built our model with only CMS1-4 classified samples and then applied it to normalized and median adjusted RNASeq from LCCC1029 to classify all samples into CMS1-4. TTP, PFS, and OS were compared using Kaplan-Meier method and log-rank tests, and hazard ratios were estimated using Cox proportional hazards method. Results: Our model had > 93% sensitivity and specificity for CMS1-4 in the training data set; the 17% of non-consensus samples in the training data were predominantly labeled CMS2. We classified the LCCC1029 samples as CMS1 (12%), CMS2 (63%), CMS3 (4%), and CMS4 (21%). CMS was prognostic for TTP (log-rank p=0.03), with median for CMS1 of 2.0 months (95% CI 0.0-4.8) versus 5.6 months (5.3-5.9) for CMS2 and 7.8 months (5.5-10.1) for CMS4. There was a trend toward association between CMS and either PFS (log-rank p = 0.11) or OS (log-rank p = 0.085). CMS2 had superior OS compared to CMS1 (HR 0.39, 95% CI 0.17-0.87, p = 0.02). With our limited sample size, we found no significant interaction between CMS and treatment arm for TTP, PFS, or OS. Conclusions: CMS is associated with significant differences in TTP in second-line treatment of mCRC in LCCC1029, and specific CMS types also have differences in OS. Thus, the prognostic impact of CMS extends to second-line treatment in mCRC, meriting further study of CMS classification in additional non-first-line studies.

Clinical Value of Consensus Molecular Subtypes in Colorectal Cancer: A Systematic Review and Meta-Analysis

“…Among the 35 eligible studies were 27 full-text articles ( 6 , 11 , 12 , 15 , 55–77 ) and 8 conference abstracts ( 78–85 ). Prognostic data were extracted from 21 studies, of which 2 were conference abstracts ( 6 , 11 , 15 , 57 , 58 , 60 , 61 , 63 , 64 , 66–73 , 75 , 77 , 80 , 81 ). The predictive value of the CMSs was assessed in 16 studies and 6 conference abstracts ( 12 , 15 , 55–57 , 59 , 62 , 64–67 , 69 , 72–74 , 76 , 78 , 79 , 82–85 ).…”

“…Pairwise CMS comparisons in the metastatic setting included patients from 9 unique cohorts and showed that CMS1 consistently had worse OS and PFS than CMS2, CMS3, and CMS4 (OS HR range = 0.33-0.55; PFS HR range = 0.53-0.89) ( 57 , 64 , 67 , 69 , 70 , 81 ) ( Figure 2, A and C ; Supplementary Figure 1, A , available online). This is in line with the reported mOS times.…”

Consensus molecular subtypes of colorectal cancer in clinical practice: A translational approach

“…The authors theorized that the combination of irinotecan and cetuximab in all CMS classification, when patients have received oxaliplatin, has a synergic effect in CMS2 and CMS3, but in CMS1 and CMS4 it has an antagonistic effect due to the poor efficacy of oxaliplatin in a fibroblast-rich microenvironment[ 49 ]. Recently, different retrospective studies of clinical trials have shown associations between CMS and the prognosis of different chemotherapy regimens[ 43 , 50 ]. However, these results must be confirmed using clinical trials with prospective designs that include different CMS patients.…”