Colorectal Cancer and KRAS/BRAF 

One actively investigated approach in the management of advanced and metastatic colorectal cancer (CRC) has been the delivery of agents whose primary purpose is to interfere with the biological activity of the epidermal growth factor receptor (EGFR).

However, it is well-recognized that only a subset of patients whose colorectal tumors have been demonstrated to over express the EGFR receptor on their cell surfaces will actually exhibit a favorable biological and clinical response to anti-EGFR antibody therapy. Both the costs and potential toxicities associated with this management paradigm add to the relevance of efforts to more critically define particular patient populations that would be most likely to respond to treatment with this class of agents, or, conversely, that would be highly unlikely to exhibit clinical benefit.

Randomized trials in patients with metastatic CRC that included anti-EGFR antibody therapy have specifically evaluated the impact of the mutational status of KRAS (wild-type [normal] versus mutated [abnormal]) on patient outcome. Notably, the presence of a KRAS mutation was found to be associated with the absence of biological and clinical activity for the anti-EGFR antibody treatment.^{[1, 2]}

Approximately 30% to 50% of colorectal tumors are known to have a mutated (abnormal) KRAS, indicating that up to 50% of patients with CRC might respond to anti-EGFR antibody therapy. However, 40% to 60% of patients with wild-type KRAS tumors do not respond.^[3] In these patients, data suggest that mutated BRAF, which is present in 5% to 10% of tumors, can affect response to these agents.^{[4, 5, 6]}

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Several phase II/III randomized trials have revealed the favorable impact on survival associated with the administration of one of two currently available anti-EGFR antibodies (cetuximab [Erbitux], panitumumab [Vectibix]) in patients with KRAS wild type.^{[1, 2, 7, 6]}

Analysis of tumor samples obtained from 394 patients with metastatic CRC who were randomly assigned in a phase III trial to receive cetuximab plus best supportive care or best supportive care alone demonstrated improved overall survival (median, 9.5 vs. 4.8 months; P < 0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; P < 0.001) in those in the cetuximab arm who had KRAS wild type.

By contrast, patients with mutated KRAS showed no significant benefit from cetuximab vs. best supportive care alone.^[1] Similarly, in the randomized phase II OPUS trial, a significantly greater response rate (61% v 37%; P = 0.011) and a significantly lower risk of disease progression (hazard ratio = 0.57; P = 0.0163) was seen in patients with KRAS wild type being treated with cetuximab and FOLFOX (fluorouracil + leucovorin + oxaliplatin) vs patients with mutated KRAS receiving the same treatment.^[7]

Finally, data from the phase IIICRYSTAL trial, comparing FOLFIRI (fluorouracil + leucovorin + irinotecan) plus cetuximab vs. FOLFIRI alone, showed patients with KRAS wild type who were treated with cetuximab plus FOLFIRI had significantly improved overall survival (median, 23.5 vs. 20.0 months; P = 0.0093), progression-free survival (median, 9.9 vs. 8.4 months; P = 0.0012), and response rate (57.3% vs. 39.7%; P < 0.001) compared with FOLFIRI alone.^[6]

Using tissue from 427 patients with metastatic CRC enrolled in a phase III trial comparing panitumumab plus best supportive care or best supportive care alone demonstrated significantly greater progression-free survival (median, 12.3 weeks vs. 7.3 weeks; P < 0.0001) in patients with KRAS wild type treated with panitumumab, while no difference was seen in patients with mutated KRAS treated with the same regimen (median, 7.4 weeks vs. 7.3 weeks). Although there was no significant overall survival difference between the groups, multivariate analysis showed that KRAS wild type status independently predicted overall survival in both the panitumumab (hazard ratio, 0.64; P = 0.004) and best supportive care (hazard ratio, 0.68; P = 0.007) arms.^[2]

Importantly, data from the phase III PRIME trial with panitumumab, which compared panitumumab plus FOLFOX4 vs FOLFOX4 alone, showed significantly reduced progression-free survival in patients with mutated KRAS who were randomized to the panitumumab + FOLFOX4 arm (hazard ratio, 1.29; P = 0.02) as well as a shorter overall survival (15.5 months vs. 19.3 months, respectively; P = 0.068).^[8]

A careful read of the data from these and other trials clearly demonstrates that patients with mutated KRAS are unlikely to benefit from anti-EGFR antibody therapy. However, it is not clear that patients with KRAS wild type will definitely respond, only that they have a reasonable opportunity to derive clinical benefit from the therapy. For example, in the panitumumab vs best supportive care trial, there were no responders in the mutated KRAS group randomized to the therapy and only a 17% partial response rate was noted in the KRAS wild type group.^[2]

It is unclear to what extent the lack of response in KRAS wild-type patients is due to BRAF mutations, but current data suggest that mutated BRAF confers resistance to anti-EGFR therapy given beyond first-line treatment. A retrospective analysis of 113 patients who received cetuximab or panitumumab demonstrated that none of the KRAS wild-type patients with BRAF mutations responded to therapy, and that none of the responders had BRAF mutations. In addition, BRAF mutant patients showed prolonged progression-free and overall survival compared with BRAF wild-type patients.^[4] Similarly, a retrospective pooled analysis of the two phase III cetuximab studies demonstrated that the best treatment outcomes were observed in patients with both KRAS wild-type and BRAF wild-type tumors, but there were too few patients with BRAF mutations to determine whether BRAF mutation status alone could predict response to therapy.^[5]

Finally, in the cetuximab plus FOLFIRI study, although mutated BRAF was associated with a poor prognosis, it did not independently predict response to treatment.^[6] Thus, although results from these and other studies are compelling, there are as yet no prospective data that can definitively determine the role of BRAF status in response to EGFR inhibitor therapy.

Based on these observations, it is strongly recommended that patients with metastatic CRC who are being considered for treatment with anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to the administration of therapy and that both cetuximab and panitumumab be initiated only in patients with KRAS wild type. This will ensure that the therapy is not administered to patients who are unlikely to obtain benefit.^{[9, 10]} In fact, NCCN Clinical Practice Guidelines recommend testing for KRAS mutations at the time of diagnosis of stage IV disease so as to better prepare an appropriate management plan in case treatment with an anti-EGFR antibody is later considered.^[9] BRAF mutation status should be determined only after KRAS wild type is detected.^[9]

Testing for mutations in codons 12 or 13 of the KRAS gene can be performed on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis using a variety of methods. BRAF V600E mutation status is determined via PCR amplification and DNA sequence analysis or allele-specific PCR on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis.