KRAS and BRAF V600E mutations were nearly mutually exclusive and associated with specific patient and tumor characteristics, such as age and smoking status, according to an analysis of data from the N0147 phase III trial for stage III colon cancer.
Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair status, Wilson I. Gonsalves, MD, of the Mayo Clinic, and colleagues explained in the Journal of the National Cancer Institute. That information was merged with clinical characteristics collected at the time of randomization, and patient characteristics, including activity level, smoking, alcohol intake, and family history of colorectal cancer, obtained from the 2,326 (93%) of the 3,397 enrolled patients who completed questionnaires.
“Specifically, age of 70 years or older, smoking, high-grade histology, and [defective mismatch repair] status were associated with a lower incidence of mutant KRAS tumors but a higher incidence of BRAF [V600E]-mutated tumors. Both mutations tend to [occur in right-sided tumors] and were nearly mutually exclusive, but BRAF [V600E]-mutated tumors are more common in females, non-Hispanic white patients, those having four or more positive lymph nodes, stage T4 disease, and those with a history of gastrointestinal conditions. Finally, within KRAS mutant tumors, those with a KRAS Gly13Asp mutation tend to be associated with [defective mismatch repair] status and high-grade histology,” the researchers reported.
“The presence of a KRAS mutation is predictive for resistance to anti-[epidermal growth factor receptor (EGFR)] monoclonal antibodies in advanced colon cancer,” the authors noted, although “it has been suggested that patients whose tumors harbor a KRAS Gly13Asp mutation may benefit from anti-EGFR [monoclonal antibody] therapy. BRAF activating mutations, specifically V600E, occur in less than 10% of patients with sporadic colon cancer and are a strong negative prognostic marker; however, their predictive value for efficacy of anti-EGFR [monoclonal antibody] treatment is less certain.”
In the current study, there were 783 tumors (35%) that had KRAS mutations, “of which 191 (24%) were KRAS Gly13Asp, whereas 310 (14%) tumors had a BRAF [V600E] mutation. Of 2,231 tumors analyzed for [mismatch repair] status, 279 (13%) were characterized as [defective mismatch repair],” according to the study report.
“KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations [excluding those with KRAS Gly13Asp mutation] were less likely to have [defective mismatch repair] (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),” the investigators stated. “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.”
The authors noted that further studies are warranted to explain the association between the mutations and the cited epidemiologic and clinicopathologic characteristics. ■
Gonsalves WI, et al: J Natl Cancer Inst 106(7):dju106, 2014.