Wilson I Gonsalves1, Michelle R Mahoney1, Daniel J Sargent1, Garth D Nelson1, Steven R Alberts1, Frank A Sinicrope1, Richard M Goldberg1, Paul J Limburg1, Stephen N Thibodeau1, Axel Grothey1, Joleen M Hubbard1, Emily Chan1, Suresh Nair1, Jeffrey L Berenberg1, Robert R McWilliams2. 1. Affiliations of authors: Division of Hematology/Division of Medical Oncology (WIG), Division of Biomedical Statistics & Informatics (MRM, GDN), Cancer Center Statistics (DJS), Division of Medical Oncology (SRA, AG, JMH, RRM), Division of Gastroenterology & Hepatology/Division of Medical Oncology (FAS), Division of Gastroenterology & Hepatology (PJL), Molecular Genetics (SNT), Mayo Clinic, Rochester, MN; Department of Internal Medicine, Division of Medical Oncology, Ohio State University, Columbus, OH (RMG); Division of Hematology/Oncology, Vanderbilt University, Nashville, TN (EC); Section of Hematology/Medical Oncology, Lehigh Valley Health Network, Allentown, PA (SN); Cancer Prevention & Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB). 2. Affiliations of authors: Division of Hematology/Division of Medical Oncology (WIG), Division of Biomedical Statistics & Informatics (MRM, GDN), Cancer Center Statistics (DJS), Division of Medical Oncology (SRA, AG, JMH, RRM), Division of Gastroenterology & Hepatology/Division of Medical Oncology (FAS), Division of Gastroenterology & Hepatology (PJL), Molecular Genetics (SNT), Mayo Clinic, Rochester, MN; Department of Internal Medicine, Division of Medical Oncology, Ohio State University, Columbus, OH (RMG); Division of Hematology/Oncology, Vanderbilt University, Nashville, TN (EC); Section of Hematology/Medical Oncology, Lehigh Valley Health Network, Allentown, PA (SN); Cancer Prevention & Control Program, University of Hawaii Cancer Center, Honolulu, HI (JLB). mcwilliams.robert@mayo.edu.
Abstract
BACKGROUND: KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. METHODS: Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. RESULTS: KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF (V600E) mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF (V600E) mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. CONCLUSIONS: Specific patient and tumor characteristics are associated with KRAS and BRAF (V600E) mutations.
BACKGROUND:KRAS and BRAF (V600E) mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them. METHODS: Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF (V600E) mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided. RESULTS:KRAS (35%) and BRAF (V600E) (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF (V600E) mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF (V600E) mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR. CONCLUSIONS: Specific patient and tumor characteristics are associated with KRAS and BRAF (V600E) mutations.
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