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.
Highlights
Colorectal cancer (CRC) is one of the most frequent causes of cancer death in industrialized countries, and ranks third in prevalence in the United States (Siegel et al, 2013).Kirsten ras (KRAS) mutations in FOLFOX treated metastatic colorectal cancer (mCRC)Its occurrence is increasing in many developed and developing countries; in China, colon cancer represents a very important cause of morbidity and mortality (Yang et al, 2004)
The Kaplan–Meier survival analysis of individual subtypes of KRAS mutation performed in this study showed the following results: the G12D subtype was associated with poor prognosis in Progression-free survival (PFS), other subtypes mutations were not associated with differences in progression-free survival (PFS; Figure 3; Table 5)
Many studies indicate that KRAS and other mutated molecules may be important prognostic factors related to disease freesurvival (Douillard et al, 2013) and overall survival (OS) in CRC (Samowitz et al, 2000)
Summary
Colorectal cancer (CRC) is one of the most frequent causes of cancer death in industrialized countries, and ranks third in prevalence in the United States (Siegel et al, 2013).KRAS mutations in FOLFOX treated mCRCIts occurrence is increasing in many developed and developing countries; in China, colon cancer represents a very important cause of morbidity and mortality (Yang et al, 2004). The molecular basis of the disease’s pathogenesis is an active area of research, both in order to improve patient care, and to develop more rational therapeutics (Kim and Kim, 2014). In this context, generating prognostic factors is a major goal in oncology (Sridharan et al, 2014; Phipps et al, 2015). 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. Conclusion: In our population, the KRAS mutation had an adverse impact on the prognosis for stage IV CRC patients treated with the FOLFOX regimen
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