KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803.

Abstract

PURPOSE:

Alterations in the RAS and RAF pathway relate to epigenetic and epigenomic aberrations, and are important in colorectal carcinogenesis. KRAS mutation in metastatic colorectal cancer predicts resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy (cetuximab or panitumumab). It remains uncertain, however, whether KRAS mutation predicts prognosis or clinical outcome of colon cancer patients independent of anti-EGFR therapy.

METHODS:

We conducted a study of 508 cases identified among 1,264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) in 1999-2001 (CALGB 89803). KRAS mutations were detected in 178 tumors (35%) by pyrosequencing. Kaplan-Meier and Cox proportional hazard models assessed the prognostic significance of KRAS mutation and adjusted for potential confounders including age, sex, tumor location, tumor/node stage, performance status, adjuvant chemotherapy arm, and microsatellite instability status.

RESULTS:

Compared with patients with KRAS-wild-type tumors, patients with KRAS-mutated tumors did not experience any difference in disease-free, recurrence-free, or overall survival. The 5-year disease-free, recurrence-free, and overall survival rates (KRAS-mutated versus KRAS-wild-type patients) were 62% versus 63% (log-rank P = 0.89), 64% versus 66% (P = 0.84), and 75% versus 73% (P = 0.56), respectively. The effect of KRAS mutation on patient survival did not significantly differ according to clinical features, chemotherapy arm, or microsatellite instability status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status.

CONCLUSIONS:

In this large trial of chemotherapy in stage III colon cancer patients, KRAS mutational status was not associated with any significant influence on disease-free or overall survival.

• Authors: Shuji Ogino, Jeffrey A Meyerhardt, Natsumi Irahara, Donna Niedzwiecki, Donna Hollis, Leonard B Saltz, Robert J Mayer, Paul Schaefer, Renaud Whittom, Alexander Hantel, Al B Benson 3rd, Richard M Goldberg, Monica M Bertagnolli, Charles S Fuchs, Cancer and Leukemia Group B, North Central Cancer Treatment Group, Canadian Cancer Society Research Institute, Southwest Oncology Group
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 23 Pg. 7322-9 (Dec 01 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19934290 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Irinotecan
• Oncogene Protein p21(ras)
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology)
• Camptothecin (analogs & derivatives, pharmacology)
• Colonic Neoplasms (drug therapy, genetics, metabolism, surgery)
• Disease-Free Survival
• Female
• Genes, ras
• Humans
• Irinotecan
• Male
• Microsatellite Repeats
• Middle Aged
• Mutation
• Oncogene Protein p21(ras) (genetics)
• Proportional Hazards Models
• Treatment Outcome