P-0206 - Kras Mutations in Metastatic Colorectal Cancer and the Effect of Bevacizumab

Abstract

Background: Laboratory research of metastatic colorectal cancer subdivided the disease into a number of molecular sub-types mainly based on the status of KRAS gene. Recently different effect of certain monoclonal antibody (cetuximab) was shown with G13D KRAS mutation against previous data of drug resistance in KRAS mutant tumors. The question of different biological behavior of a tumor and treatment effect of bevacizumab was evaluated according to a KRAS sub-types status. Methods: Included were 397 colorectal cancer patients from the Israeli population-based Molecular Epidemiology of Colorectal Cancer study treated for their first metastatic event with irinotecan-based or 5-fluorouracil protocols, with or without bevacizumab, and no surgery. Patients were diagnosed between 1998 and 2010 and were followed up until October 2011; Mutations in KRAS codons 12, and 13 were identified by direct sequencing and SNP assay-by-design. Date of metastases and death and treatment details were extracted from the oncological follow-up records supported by computerized pharmacy records. Results: A total of 267 cases were treated with irinotecan-based chemotherapy, 96 (36%) of whom with combination with bevacizumab. A total of 130 cases were treated with 5-FU treatment, majority (98%) without bevacizumab. Mutation in codon 12 or codon 13 in KRAS was identified in 162 cases (41%), with 16.4%, 10.1% and 7.1% harboring mutations in the codon G12d, codon G12V and codon G13D, respectively. Combination 1st line treatment with IRINOTECAN-based chemotherapy and bevacizumab showed improved OS in cases with KRAS wild type tumors (HR = 0.69; p = 0.048), and KRAS codon 12 or codon 13 mutated tumors (HR = 0.68, p = 0.07). This effect was not different across types of KRAS mutation: G13D (HR = 0.46, p = 0.25), G12V (HR = 0.40; p = 0.049), G12D (HR = 0.76; p = 0.46), KRAS mutations (p for interaction =0.54) Assessment of prognostic effect in 5-FU only treated patients shows that relative to cases without any mutation in the codon 12 or codon 13, G13D (HR = 2.43) and G12D (HR = 1.75) mutations experienced a worse OS, while G12V (HR = 1.28) and all other codon 12 mutations combined (HR = 1.17) did not (p for difference = 0.075). Conclusion: The treatment effect of bevacizumab was not found to have a significant difference between KRAS sub-types of metastatic colorectal cancer. The data supports a prognostic effect of G13D and G12D KRAS mutations.