KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

BACKGROUND: KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC. METHODS: We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients. RESULTS: Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P = 0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P = 0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P = 0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P = 0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P = 0.047) and worse PFS (HR: 0.45, P = 0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P = 0.0005) and PFS (HR: 0.51, P = 0.006) compared with KRAS and BRAF wild-type patients. CONCLUSION: Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs. British Journal of Cancer (2009) 101, 715-721. doi: 10.1038/sj.bjc.6605177 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research UK