CMS is a transcriptome-based classification of colorectal cancer (CRC) with prognostic implications, but its association with treatment outcomes, especially in the metastatic setting, remains unknown. We investigated whether CMS classification was predictive of bevacizumab treatment benefit using data from the phase 3 MAX trial. MAX previously reported progression-free survival (PFS) benefit for the addition of bevacizumab (B) to chemotherapy (capecitabine (C) +/- mitomycin (M)) in first line treatment of metastatic CRC.
Archival tumours from 256 patients (54% of trial population) were available for gene expression profiling using Almac Xcel microarray. Tumours were classified into CMS groups 1 to 4 using previously published methods. We correlated CMS groups with PFS in the MAX trial. The predictive value of CMS was demonstrated as the interaction between CMS and bevacizumab treatment, assessed by Cox proportional hazards model.
After data quality control, primary tumours from 239 patients (51% of trial population) were suitable for survival analysis. Distribution of CMS groups were CMS1 18%, CMS2 48%, CMS3 12%, CMS4 23%. Hazard ratios (HR)(95% CI) of PFS in C vs CB+CBM arms for CMS 1,2,3 and 4 were 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25) respectively (test for interaction between CMS and treatment, p = 0.03). CMS remained a significant independent predictor of PFS after adjustment for prognostic factors in a multivariate analysis (p = 0.04).
In metastatic CRC, CMS 2 and 3 subtypes preferentially benefit from the addition of bevacizumab to chemotherapy, compared to CMS 1 and 4. Validation of these findings in independent cohorts is required. Once validated, CMS classification could be used to guide patient selection for bevacizumab therapy.
Clinical trial identification
Legal entity responsible for the study
Olivia Newton-John Cancer Research Institute, Australia
Olivia Newton-John Cancer Research Institute, Australia and Australian Gastrointestinal Trials Group (AGITG)
P. Wirapati: Funding: Roche, Bayer and Sanofi for research in predictive biomarker for colorectal cancer. T.J. Price, N. Tebbutt: Advisory boards: Roche All other authors have declared no conflicts of interest.