KRAS Mutation in Stage III Colon Cancer and Clinical Outcome Following Intergroup Trial CALGB 89803

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. (Clin Cancer Res 2009;15(23):7322–9)

[1]  Sabine Tejpar,et al.  Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[3]  C. Compton,et al.  Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Peter Kraft,et al.  PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  A. Jimeno,et al.  KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  C. Bokemeyer,et al.  Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Shuji Ogino,et al.  A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. , 2008, Journal of the National Cancer Institute.

[8]  John Quackenbush,et al.  Comprehensive Biostatistical Analysis of CpG Island Methylator Phenotype in Colorectal Cancer Using a Large Population-Based Sample , 2008, PloS one.

[9]  M. Ladanyi,et al.  KRAS mutations: an old oncogene becomes a new predictive biomarker. , 2008, The Journal of molecular diagnostics : JMD.

[10]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[11]  P. Laurent-Puig,et al.  Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. , 2008, Cancer research.

[12]  Shuji Ogino,et al.  CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer , 2008, Gut.

[13]  S. Ogino,et al.  PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. , 2008, Neoplasia.

[14]  Daniel J. Freeman,et al.  Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. , 2008, Clinical colorectal cancer.

[15]  S. Hamilton,et al.  Targeted therapy of cancer: new roles for pathologists in colorectal cancer , 2008, Modern Pathology.

[16]  Daniel J. Freeman,et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  E. Van Cutsem,et al.  KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  A. Lièvre,et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Minoru Toyota,et al.  Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer , 2007, Proceedings of the National Academy of Sciences.

[20]  F. Cavalli,et al.  PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients , 2007, British Journal of Cancer.

[21]  C. Ghorra,et al.  Jaundice in a chronic hepatitis B carrier , 2007, Gut.

[22]  R. Goldberg,et al.  Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Manuel Hidalgo,et al.  Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  T. Frebourg,et al.  Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy , 2007, British Journal of Cancer.

[25]  J. Meyerhardt,et al.  Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer , 2007, Gut.

[26]  M. Loda,et al.  CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. , 2006, The Journal of molecular diagnostics : JMD.

[27]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[28]  Shuji Ogino,et al.  Molecular Alterations in Tumors and Response to Combination Chemotherapy with Gefitinib for Advanced Colorectal Cancer , 2005, Clinical Cancer Research.

[29]  M. Loda,et al.  Sensitive sequencing method for KRAS mutation detection by Pyrosequencing. , 2005, The Journal of molecular diagnostics : JMD.

[30]  A. Jubb,et al.  Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. , 2005, Journal of the National Cancer Institute.

[31]  S. Schwartz,et al.  The prevalence of PIK3CA mutations in gastric and colon cancer. , 2005, European journal of cancer.

[32]  R. Hofstra,et al.  Genetic alterations in locally advanced stage II/III colon cancer: a search for prognostic markers. , 2004, Clinical colorectal cancer.

[33]  I. Frayling,et al.  Systematic review of genetic influences on the prognosis of colorectal cancer , 2004, The British journal of surgery.

[34]  B. Iacopetta,et al.  Prognostic Significance of Microsatellite Instability and Ki-ras Mutation Type in Stage II Colorectal Cancer , 2003, Oncology.

[35]  R. Goldbohm,et al.  K-ras oncogene mutations in sporadic colorectal cancer in The Netherlands Cohort Study. , 2003, Carcinogenesis.

[36]  B. Iacopetta,et al.  Ki‐ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer , 2001, The Journal of pathology.

[37]  이석호,et al.  Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study , 2001, British Journal of Cancer.

[38]  M. Leppert,et al.  Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[39]  A. Norman,et al.  Kirsten ras mutations in patients with colorectal cancer: the multicenter "RASCAL" study. , 1998, Journal of the National Cancer Institute.

[40]  J. Nemunaitis,et al.  Irinotecan hydrochloride (CPT-11) resistance identified by K-ras mutation in patients with progressive colon cancer after treatment with 5-fluorouracil (5-FU). , 1997, American journal of clinical oncology.

[41]  S. Finkelstein,et al.  Determination of tumor aggressiveness in colorectal cancer by K-ras-2 analysis. , 1993, Archives of surgery.

[42]  H. Hurwitz,et al.  The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. , 2009, The oncologist.

[43]  S. Ogino,et al.  Molecular classification and correlates in colorectal cancer. , 2008, The Journal of molecular diagnostics : JMD.

[44]  P. Jares,et al.  KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program , 2008, Virchows Archiv.

[45]  C. Hsieh,et al.  Molecular lesions in colorectal cancer: impact on prognosis? , 2003, International Journal of Colorectal Disease.

[46]  Emil Frei,et al.  Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide , 1960 .