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 overexpress 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] Data from retrospective studies suggest that mutated BRAF, which is present in 5% to 10% of tumors, can also affect response to these agents, especially in patients with wild-type KRAS.^{[4, 5]}

Several phase 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, 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, 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 withmutated KRAS receiving the same treatment.^[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 = 0004) and best supportive care (HR, 0.68; P = 0.007) arms.^[2]

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 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. 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 pivotal 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] Although results from these and other retrospective studies are compelling, there are as yet no prospective data that can helpdefine the role of BRAF status in response to EGFRinhibitor 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. This will ensure that the therapy is not administered to patients who are unlikely to obtain benefit. Accordingly, NCCN Clinical Practice Guidelines as well as a Provisional Clinical Opinion from the American Society of Clinical Oncology recommend initiating use of anti-EGFR therapy in patients with KRAS wild type only.^{[7, 8]} However, because the value of testing for BRAF is less clear, NCCN notes that BRAF status testing can be considered in patients with wild-type KRAS, but the guidelines do not outright recommend testing.^[7]

KRAS mutation status is determined via PCR analysis of formalin-fixed, paraffin-embedded block, unstained slides, or fresh snap frozen biopsy tissue for the presence of a mutation in codons 12, 13, or 61 of the KRAS gene on chromosome 12. BRAF V600E mutation status is also determined via PCR analysis of formalin-fixed, paraffin-embedded tissue.

The following companies are currently offering KRAS and BRAF mutation status testing:

Clarient, Inc.

Caris Diagnostics *

DxS

Genzyme Genetics *

LabCorp

Response Genetics

*Only KRAS mutation status testing is currently available.

More information about CRC, KRAS, BRAF, and targeted therapies for CRC can be found in Medscape's Colorectal Cancer Resource Center and the Cancer: Biologic Therapies Resource Center as well as in the eMedicine article on Colon Cancer.