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. 2009 Aug 18;101(4):715-21.
doi: 10.1038/sj.bjc.6605177. Epub 2009 Jul 14.

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

F Loupakis  1 , A Ruzzo, C Cremolini, B Vincenzi, L Salvatore, D Santini, G Masi, I Stasi, E Canestrari, E Rulli, I Floriani, K Bencardino, N Galluccio, V Catalano, G Tonini, M Magnani, G Fontanini, F Basolo, A Falcone, F Graziano
Affiliations

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

F Loupakis et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
(A) Progression-free survival and (B) overall survival curves according to KRAS codons 61 and 146 mutational status in study population. (C) Progression-free survival and (D) overall survival curves according to BRAF codon 600 mutational status in study population.
Figure 2
Figure 2
(A) Progression-free survival and (B) overall survival curves according to KRAS codons 61 and 146 mutational status in BRAF wild-type subgroup.
Figure 3
Figure 3
(A) Progression-free survival and (B) overall survival curves according to BRAF codon 600 mutational status in KRAS codon 61 and 146 wild-type subgroup.
Figure 4
Figure 4
(A) Progression–free survival and (B) overall survival curves of patients with KRAS codon 61 or 146 or BRAF-mutated disease compared to those of patients with wild-type disease.
See this image and copyright information in PMC

Comment in

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