K-Ras gene mutation status as a prognostic and predictive factor in patients with colorectal cancer undergoing irinotecan- or oxaliplatin-based chemotherapy

Abstract

Background: CRC caused more than 600,000 estimated deaths in 2008. Dysregulated signaling through the RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway due to mutations in K-Ras and B-Raf are common events in CRC. Methods: Incidence of mutations in codons 12 and 13 of K-Ras and exons 11 and 15 of B-Raf were analyzed in amplified PCR products from primary tumors of 273 patients with CRC, and their prognostic and predictive significance was assessed. The prognostic role of clinical and pathological factors was also examined. Results: K-Ras mutations were present in 89 patients (32.6%), of whom 76 (85.4%) had mutations in codon 12 and 10 (11.2%) had mutations in codon 13. B-Raf gene mutations were present in 17 patients (6.9%), of whom 6 (35.3%) had mutations in exon 15. Multivariate analysis revealed a predictive significance for K-Ras mutations with respect to time to progression in patients treated with irinotecan and oxaliplatin as first-line chemotherapy. There was no predictive significance for B-Raf gene mutation status in these patients. The following risk factors were found to affect overall survival (OS) rates: primary tumor location, lymph node involvement grade, carcinoembryonic antigen (CEA) level before treatment, and performance status according to WHO criteria. Conclusions: Based on the results of this study, K-Ras mutation status may be a suitable indicator of patient eligibility and a prognostic indicator for responsiveness to anti-EGFR therapy alone, or in combination with chemotherapy. Also, K-Ras mutation status may predict time to progression in patients treated with irinotecan and oxaliplatin.

Keywords: :

• B-Raf mutation
• K-Ras mutation
• RAS/RAF/mitogen-activated protein kinase
• anti-EGFR therapy
• colorectal cancer
• irinotecan
• oxaliplatin

Disclosure of Potential Conflicts of Interest

The authors declare that they have no competing interests.

Acknowledgments

The authors thank the Proper Medical Writing (infrared group s.c.) for the technical and language assistance in the preparation of this paper.

Contributors: Study concepts, R.S., L.B., R.Ch.; Study design, R.S., L.B., R.Ch.; Data acquisition, M.R., M.S., M.C.; Quality control of data and algorithms, L.Ch., W.K., C.Sz.; Data analysis and interpretation, R.S., L.B., R.Ch.; Statistical analysis, L.B.; Manuscript preparation, R.S., L.B., J.K., M.R., M.S.; Manuscript editing, R.S, R.Ch., J.K.; Manuscript review, J.N., C.Sz.; All authors read and approved the final manuscript.

Sources of support: Support from the Military Institute of The Health Services, Warsaw, Poland, Grant No. WIM-50/2008 and WIM-45/2009.