Associations Between Molecular Classifications of Colorectal Cancer and Patient Survival: A Systematic Review

Abstract

Background & aims: Colorectal cancer (CRC) is a heterogeneous disease with different mechanisms of pathogenesis. Classification systems have been proposed based on molecular features of tumors, but none are used in clinical practice. We performed a systematic review of studies on the associations between molecular classifications of CRC and patient survival.

Methods: We searched the PubMed, Embase, Cochrane, and Web of Science databases for combinations of terms related to CRC, molecular markers, subtype classifications, and survival (overall survival, disease-specific survival, disease-free survival). We included only studies that used at least 3 molecular markers to classify tumors and provided an estimate of survival associated with each subtype. Data extraction and quality assessment were performed independently by 2 reviewers.

Results: We identified 6 studies that fulfilled the inclusion criteria. In these studies, molecular subtypes were assigned based on pathways associated with tumor development or findings from gene expression clustering analyses. Most studies proposed classification systems with 5 subtypes, including information on microsatellite instability, mutations in BRAF, and mutations in KRAS. None of the studies included TNM stage in their classification system. Three classification systems used similar definitions. Only 3 studies provided internal or external validation of the proposed classification schemes. Tumors with microsatellite stability and mutations in KRAS or BRAF were associated with decreased survival times, compared with tumors with microsatellite stability and no mutations.

Conclusions: In a systematic review of studies of molecular classifications of CRC and patient survival, we found that most subtypes were not significantly or not differentially associated with survival. None of the systems integrated TNM staging. Further research and validation are needed to develop molecular subtype classification systems for clinical practice.

Keywords: Biomarker; Colon Cancer; Genetics; MSI.