<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer

TLDR

Cetuximab, an anti‑EGFR antibody, is effective in metastatic colorectal cancer, but the molecular determinants of response remain unclear and may involve genetic alterations in EGFR‑related signaling pathways. The study screened tumors from 30 cetuximab‑treated metastatic colorectal cancer patients for KRAS, BRAF, and PIK3CA mutations by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. KRAS mutations were present in 43% of tumors and were significantly associated with lack of response and poorer survival, whereas EGFR amplification, found in 10% of cases, correlated with objective response, indicating KRAS status predicts resistance and EGFR copy number predicts benefit. Cancer Res 2006; 66(8): 3992‑5.

Abstract

Abstract The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment. (Cancer Res 2006; 66(8): 3992-5)