Current biomarkers in use for making treatment decisions in mCRC include RAS mutations as exclusion criteria for anti-EGFR therapy and Microsatellite Instability as a prognostic factor in stage II mCRC. A highlighted Education Session was held at ASCO 2014 to discuss these and emerging molecular markers with relevance to the treatment of mCRC (Tejpar S. What Is the Current Status of Biomarkers in Use for the Treatment of Patients with Colorectal Cancer? ASCO 2014. Education Session). While KRAS exon 2 mutations occur in about 40% of patients with mCRC, KRAS–wild-type (WT) tumors may still have mutations in KRAS exons 3 and 4 and in NRAS exons 2, 3, and 4. These other RAS mutations are important to assess, as has been shown in the PRIME study in which the efficacy of FOLFOX4 versus FOLFOX4 + panitumumab (Pan) varied based on the specific RAS mutation (mut) status. While FOLFOX4 + Pan was more effective in patients with KRAS-exon 2-WT tumors, it was no better or inferior to FOLFOX4 alone for tumors with KRAS exon 2 mutation, KRAS exon 2 WT/NRAS-mut. Moreover, “it is imperative to recognize biological heterogeneity within colon cancer, both to enable cost-effective targeting and to avoid harm.” This requires subtyping multiple mutations and molecular subtypes in colorectal cancers, which is currently being carried out by the Colorectal Cancer Subtyping Consortium , searching for recurrent signals of biologically distinct subtypes that are enriched for key clinical, molecular, and pathway traits. Thus, as our knowledge about molecular subtypes in colorectal cancer increases, further stratification to clinical trials and therapy will be needed. This may include an integrated analysis of single nucleotide polymorphism arrays, functional RNA screening, next-generation sequencing, and functional validation to result in the discovery of novel therapeutic targets. While “innovative cancer treatments have saved the healthcare system $350 billion since 1990, new pathways for cancer management must have the clear potential to improve the value of therapy for patients. We must find a balance between the need for value in healthcare and an investment in innovation.” Nowhere is this issue more acute than in colorectal cancer.
