Pitfalls of KRAS Testing for Treating Patietns with Metastatic Colorectal Cancer

Abstract

Background: KRAS testing is a critical initial step of the treatment for metastatic colorectal cancer patients. However, recent clinical trials have raised the issue of whether patient selection as determined by KRAS testing is appropriate. Method: Here, we reviewed guidelines, literatures and clinical trials to elucidate whether detection threshold of KRAS testing is appropriate. Results: It has been recommended that a detection threshold within 1–10% should be considered for RAS testing in Japan, but there is insufficient evidence for widespread adoption in the guideline. In literatures, retrospective studies have shown that high-sensitivity KRAS testing is more effective in the secondor third-line setting but no study has been conducted in the first-line setting. High-sensitivity KRAS testing in recent clinical trials has revealed undetectable mutant clones in tumors before chemotherapy. These clones have been shown to influence the outcome of second-line treatment, but there is no evidence of their influence in the first-line setting. On the other hands, there are accumulating data showing an additional effect of anti-epidermal growth factor receptor (EGFR) antibodies in patients harboring minor KRAS mutations determined by a low detection threshold of 5–10% in the first-line setting. These findings indicate that high-sensitivity KRAS testing have enabled to select super-responders, but may lead to exclusion of patients who could benefit from drug therapy. Conclusion: In order not to deprive patients of the chance to benefit from anti- EGFR antibodies, the optimal cut-off value for KRAS testing should be determined for selection of patients likely to benefit from treatment in the first-line setting.