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

Abstract

Background: The consensus molecular subtypes (CMSs) of colorectal cancer (CRC) capture tumor heterogeneity at the gene-expression level. Currently, a restricted number of molecular features are used to guide treatment for CRC. We summarize the evidence on the clinical value of the CMSs.

Methods: We systematically identified studies in Medline and Embase that evaluated the prognostic and predictive value of CMSs in CRC patients. A random-effect meta-analysis was performed on prognostic data. Predictive data were summarized.

Results: In local disease, CMS4 tumors were associated with worse overall survival (OS) compared with CMS1 (hazard ratio [HR] = 3.28, 95% confidence interval = 1.27 to 8.47) and CMS2 cancers (HR = 2.60, 95% confidence interval = 1.93 to 3.50). In metastatic disease, CMS1 consistently had worse survival than CMS2-4 (OS HR range = 0.33-0.55; progression-free survival HR range = 0.53-0.89). Adjuvant chemotherapy in stage II and III CRC was most beneficial for OS in CMS2 and CMS3 (HR range = 0.16-0.45) and not effective in CMS4 tumors. In metastatic CMS4 cancers, an irinotecan-based regimen improved outcome compared with oxaliplatin (HR range = 0.31-0.72). The addition of bevacizumab seemed beneficial in CMS1, and anti-epidermal growth factor receptor therapy improved outcome for KRAS wild-type CMS2 patients.

Conclusions: The CMS classification holds clear potential for clinical use in predicting both prognosis and response to systemic therapy, which seems to be independent of the classifier used. Prospective studies are warranted to support implementation of the CMS taxonomy in clinical practice.

Figure 1.

Flowchart of study identification and selection process. ^aEight studies were used for both prognostic and predictive analysis.

Figure 2.

Forest plots of pooled and single hazard ratios (HRs) for different survival outcomes per pairwise consensus molecular subtype (CMS) comparison in colorectal cancer. A) CMS4 vs CMS1. B) CMS4 vs CMS2. C) CMS2 vs CMS1. Number of cohorts (n) and total number of included patients (N) per meta-analysis indicated with n/N; because several studies described more cohorts, the number of cohorts n does not reflect the number of studies. adjP indicates significance for the random-effect model (corrected for multiple testing). Heterogeneity depicted as I² index and Cochran’s Q-test P value. All tests were 2-sided. ^aEstimate. adjP = adjusted P value; CI = confidence interval; NA = not applicable.

Figure 3.

Median overall survival in metastatic disease per consensus molecular subtype (CMS). Vertical lines indicate statistically significant comparisons (t test). ^aP less than .001, ^bP = .02, ^cP = .001, ^dP = .009, ^eP = .04 (corrected for multiple testing). Number of cohorts (n) and total number of included patients (N) per meta-analysis indicated with n/N; because several studies described more cohorts, the number of cohorts n does not reflect the number of studies. Heterogeneity depicted as I² index and Cochran’s Q-test P value. All tests were 2-sided.

Figure 4.

Forest plots of hazard ratios (HRs) for the predictive value of the consensus molecular subtypes (CMSs) for adjuvant chemotherapy in colorectal cancer. A) Overall survival for adjuvant chemotherapy vs surgery alone. B) Relapse-free survival for adjuvant chemotherapy vs surgery alone. C) Relapse-free survival for oxaliplatin plus 5-fluorouracil and leucovorin vs 5-fluorouracil plus leucovorin. ^aImmunohistochemistry classification: CMS2 and CMS3 depicted as CMS2. 5-FU = 5-fluorouracil; FOLFOX = 5-fluorouracil, leucovorin, and oxaliplatin; FULV = 5-fluorouracil and leucovorin.

Figure 5.

Forest plots of hazard ratios (HRs) for the predictive value of the consensus molecular subtypes (CMSs) for first-line systemic therapy in metastatic colorectal cancer. A) Progression-free survival for an irinotecan backbone vs control regimen. B) Overall survival for the addition of bevacizumab vs control regimen. C) Overall survival for the addition of bevacizumab vs cetuximab. ^aTotal number of patients, no information on the number of CMS4 patients. ^bKRAS wild-type population. ^c75.2% FOLFOX/24.8% FOLFIRI. ^dImmunohistochemistry classification: CMS2 and CMS3 depicted as CMS2. Bev = bevacizumab; Cap = capecitabine; CAPOX = capecitabine and oxaliplatin; Cet = cetuximab; CM = classification method; FOLFIRI = 5-fluorouracil, leucovorin, and irinotecan; FOLFOX = 5-fluorouracil, leucovorin, and oxaliplatin; mFOLFOX = modified FOLFOX; FOLFOXIRI, 5-fluorouracil, leucovorin, oxaliplatin and irinotecan; IRI = irinotecan; Mit = mitomycin; N = number of patients.