Approximately 30-50% of colorectal tumors are known to have a mutated (abnormal) KRAS gene, indicating that up to 50% of patients with colorectal cancer (CRC) might respond to anti-epidermal growth factor receptor (EGFR) antibody therapy. However, 40-60% of patients with wild-type KRAS tumors do not respond to such therapy.
In these patients, data suggest that the mutated BRAF gene, which is present in 5-10% of tumors, can affect response to these agents.
Clinical implications of KRAS/BRAF
Patients with mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy; it remains unclear that patients with KRAS wild-type CRC will definitely respond, although these individuals may be able to derive some benefit from anti-EGFR therapy. Patients with metastatic CRC who are being considered for anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to therapy.
It is unclear to what extent the lack of response in KRAS wild-type CRC is due to BRAF mutations, but data suggest that mutated BRAF confers resistance to anti-EGFR therapy given beyond first-line treatment.
Cetuximab and panitumumab have a favorable survival impact in patients with KRAS wild-type CRC; both agents should be initiated only in patients with KRAS wild-type CRC. Cetuximab
is no better than best supportive care alone for mutated KRAS CRC. Cetuximab plus FOLFOX (fluorouracil + leucovorin + oxaliplatin) is more effective in achieving a greater response rate and lower risk of disease progression in KRAS wild-type than mutated KRAS CRC.
Cetuximab plus FOLFIRI (fluorouracil + leucovorin + irinotecan) improves survival and response rate in KRAS wild-type compared with FOLFIRI alone
; however, mutated BRAF was associated with a poor prognosis.
Panitumumab plus FOLFOX4 significantly reduces survival in patients with mutated KRAS.
Additionally, testing for microsatellite instability and mismatch repair lends information for the option to use pembrolizumab, a PD-1 inhibitor. Pembrolizumab gained accelerated approval from the FDA in May 2017 for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. It is also approved for any solid tumor that has tested positive for MSI-H or MMR deficiency in patients who have had prior treatment and have no satisfactory alternative treatment options.
Laboratory testing for KRAS/BRAF
Lab tests include the following:
The therascreen KRAS RGQ (Rotor-Gene Q) PCR (polymerase chain reaction) Kit. Tests for mutations in codons 12 or 13 of the KRAS gene on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis. PCR amplification and DNA sequence analysis or allele-specific PCR for BRAF V600E mutation status on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis.
In June 2017, the FDA approved PRAXIS Extended RAS Panel, next-generation sequencing (NGS) kit.
The kit detects 56 specific RAS mutations ([KRAS [exons 2, 3, and 4] and NRAS [exons 2, 3, and 4]) in DNA extracted from formalin‐fixed, paraffin‐embedded colorectal cancer tissue samples.