Prognostic and Predictive Value of RAS Gene Mutations in Colorectal Cancer: Moving Beyond KRAS Exon 2

The advent of anti-EGFR (epidermal growth factor receptor) therapy resulted in significant progress in the treatment of metastatic colorectal cancer patients. However, many patients do not respond to this therapy or develop acquired resistance within a few months after the start of treatment. Since 2008, anti-EGFR therapy is restricted to KRAS wild-type patients as it has been shown that KRAS exon 2-mutated patients do not respond to this therapy. Still, up to 60 % of KRAS exon 2 wild-type patients show primary resistance to this treatment. Recently, several studies investigating the predictive and prognostic role of RAS mutations other than in KRAS exon 2 demonstrated that patients with these mutations are not responding to therapy. However, the role of these mutations has long been questioned as The National Comprehensive Cancer Network Guidelines in Oncology and the European Medicines Agency indications had already been changed in order to restrict anti-EGFR therapy to all RAS wild-type colorectal cancer patients, while the Food and Drug Administration guidelines remained unchanged. Recently, the Food and Drug Administration guidelines have also been changed, which implies the importance of RAS mutations beyond KRAS exon 2 in colorectal cancer. In this review, we discuss the most important studies regarding the predictive and prognostic role of RAS mutations other than in KRAS exon 2 in order to demonstrate the importance of these RAS mutations in patients with metastatic colorectal cancer treated with anti-EGFR therapy.