Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.

Keywords: Anti-EGFR; Anti-VEGF; BRAF; Biologics; Colorectal Cancer; DNA Mismatch Repair; Immunotherapy; MSI; Molecular Subtypes; Predictive Markers; Prognostic Markers; RAS; Targeted Therapy.

Figure 1

Categorization of stage III colon cancers into 5 subtypes based on mutations in BRAF^V600E and KRAS (exon 2) and MMR status (top) identifies subtypes with distinct clinicopathological features and prognoses . DFS is shown for individual molecular subtypes in an independent cohort of stage III colon cancer patients used for external validation of the subtype classifier (bottom). (Reprinted with permission from Sinicrope FA, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology 2015;148:88–99.)

Fig. 2

Proposed taxonomy of colorectal cancer reflecting significant biological differences in the gene expression-based consensus molecular subtypes (CMS). Prognostic value of CMS1 (yellow), CMS2 (blue), CMS3 (pink) and CMS4 (green) with Kaplan-Meier survival analysis is shown in the aggregated cohort for overall survival (n = 2,129) [left] and for relapse-free survival (n = 1,785)[right]. (Reprinted with permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Nature Medicine, doi: 10.1038/nm.3967. Epub 2015 Oct 12. Guinney J, et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21:1350–6.)