Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer

- Panitumumab and cetuximab are effective therapies for metastatic colorectal cancer.
- KRAS exon 2 mutation status has been used to guide anti-EGFR therapy.
- Many patients have tumors with other RAS mutations (KRAS exon 3/4; NRAS exons 2/3/4).
- Recent evidence indicates that these mutations can also guide anti-EGFR therapy.

RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations-including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4-can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.