Colorectal Cancer and KRAS ?>

Colorectal Cancer and KRAS

Colorectal Cancer and KRAS

Overview

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.

Clinical Implications of the Genetic Mutation

Several phase 3 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.1,2,3

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.3

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

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.4,5

Testing for the Genetic Mutation

KRAS 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.

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