De Roock W et al. (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19: 508–515

Although cetuximab is approved for the treatment of irinotecan-resistant metastatic colorectal cancer (CRC), response rates are low and markers predictive of response are urgently required. There is some evidence to indicate that KRAS-mutated CRC does not respond to cetuximab. De Roock et al. conducted a retrospective analysis of patients with metastatic CRC treated with cetuximab to determine whether KRAS mutation status and tumor regression following cetuximab treatment can predict outcome.

Among a series of 113 patients, KRAS mutations were identified in 46 (40.7%) cases. Only patients with tumors that expressed wild-type KRAS responded to cetuximab—an objective response was recorded in 27 of 66 patients with wild-type KRAS tumor status but in none of the 42 patients with KRAS mutations (P = 1.0 × 10−7). Patients with wild-type KRAS tumor status had a significantly longer median overall survival (OS) than patients with KRAS mutations (43 weeks vs 27.3 weeks; P = 0.020). In addition, the magnitude of tumor shrinkage was markedly greater in patients with wild-type KRAS tumors than in patients with KRAS-mutated tumors at all assessed time points. Among the patients with wild-type KRAS tumors, those who showed tumor shrinkage of 10% or more within 6 weeks of treatment initiation had a significantly longer OS than those who did not (74.9 weeks vs 30.6 weeks; P = 1.2 × 10−7); OS in patients with KRAS mutations, on the other hand, was not significantly different between initial responders and nonresponders.

The authors conclude that KRAS mutation status can be used to identify the subgroup of patients with irinotecan-refractory metastatic CRC who are most likely to respond to cetuximab.