Global impact of KRAS mutation patterns in FOLFOX treated metastatic colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is one of the most frequent events in oncology. Advances in molecular understanding of the processes of carcinogenesis have shed light on the fundamental mechanisms of tumorigenesis. Currently, knowledge of the molecular basis of its pathogenesis is being used to improve patient care and devise more rational therapeutics. Still, the role played by the mutation patterns of mutated genes in the clinical outcomes that patients on pharmacological treatment receive remains unclear. In this study, we propose to analyze the different clinical outcomes and disease prognosis of patients with stage IV CRC treated with FOLFOX chemotherapy (fluorouracil, leucovorin, oxaliplatin) based on different Kirsten ras (KRAS) mutation patterns.Methods: In this cohort study, 148 patients diagnosed with stage IV CRC and treated with FOLFOX were studied between 2008 and 2013. Mutational status of KRAS was determined. Progression-free survival (PFS) and overall survival (OS) were measured, and all deaths were verified. Survival analysis was performed using Kaplan–Meier analysis, comparison among groups was analyzed using the log-rank test, and multivariate analysis was conducted using Cox proportional-hazards regression.Results: Among a total of 148 patients, 48 (32%) had mutated KRAS, 77% at codon 12 and 23% at codon 13. The PFS was significantly worse in the mutant KRAS patients in comparison to wild type KRAS patients (p < 0.05). The OS did not show significant differences between the two groups. Multivariate analysis showed KRAS mutation as an independent negative prognostic factor for PFS. Among the various subtypes of KRAS mutation, G12D was significantly associated with a poor prognosis in PFS (p = 0.02).Conclusion: In our population, the KRAS mutation had an adverse impact on the prognosis for stage IV CRC patients treated with the FOLFOX regimen.

State of Art of Cancer Pharmacogenomics in Latin American Populations

“…The prevalence of KRAS mutations differs amongst human tumors. Previous studies have shown that the frequency of mutation is around 30–40% in CRC and we reported 32% of mutations [20]. These observations are similar when comparing different ethnic groups [18,21,22].…”

KRAS Alleles: The Devil Is in the Detail

“…In patients with advanced CRC who are treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX), the standard first-line therapy for CRC, KRAS mutation is predictive of inferior response and this overall effect is driven largely by those cancers expressing G12D [35]. Consistent with the observation that patients with G12V mutations do better than those with other codon 12 mutations in terms of overall survival [27], late stage lung cancers expressing G12V appear to respond better to platinum-based chemotherapy than do cancers expressing other KRAS alleles [36].…”

Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and <em>KRAS</em> mutation

“…Specifically, mutations within KRAS lead to the constitutive activation of the EGFR signaling pathway,3 and the cumulative survival rate of patients with wild-type KRAS is significantly higher than that of patients with mutations in this gene. A previous study has showed that the survival rate of patients with the wild-type KRAS gene receiving EGFR antibody therapy was significantly higher than that of patients harboring mutants 4. Moreover, a large phase III clinical study has showed that the codons 12 and 13 of exon 2 of the KRAS gene correlate with blocked EGFR gene monoclonal antibody status with cetuximab and panitumumab and that patients with wild-type KRAS benefit the most from EGFR antibody therapy 5…”