Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients

Abstract

Background: It is unknown if, after controlling for clinicopathologic variables and treatment, racial disparities in colon cancer outcomes persist. Molecular marker analysis in North American patients comparing Asians with other races has not been reported.

Methods: BRAF (V600E) and KRAS mutations were analyzed in node-positive colon cancer patients (n = 3305) treated with FOLFOX-based chemotherapy in an adjuvant trial (Alliance N0147). Race categories included Asian, black, or white. Cox models were used to estimate disease-free survival (DFS) and time to recurrence (TTR). All statistical tests were two-sided.

Results: BRAF mutation frequency in tumors from whites (13.9%) was twice that of tumors from Asians or blacks. KRAS mutation rates were highest in tumors from blacks (44.1%). KRAS/BRAF wild-type tumors were most common among Asians (66.7%) (P overall < .001). The prognostic impact of race differed by age and N stage (both P interaction < .02). Compared with whites, blacks had shorter DFS among patients younger than age 50 years (hazard ratio [HR] = 2.84, 95% confidence interval [CI] = 1.73 to 4.66) or with N1 disease (HR = 1.54, 95% CI = 1.04 to 2.29), independent of BRAF, KRAS, and other covariates. Findings were consistent using TTR as the outcome. Asians had longer DFS among N2 tumors that was partly mediated by less frequent BRAF mutation.

Conclusions: Colon cancers from Asians have a lower rate of BRAF and KRAS mutations than blacks or whites. We report a novel interaction of race with age and N stage in node-positive disease, indicating that racial disparities in survival persist despite uniform stage and treatment in a phase III trial.

Figure 1.

Study profile of the N0147 (North Central Cancer Treatment Group/Alliance) clinical trial.

Figure 2.

Association of race with BRAF and KRAS mutation status in stage III colon cancer patients. * Reference is BRAF or KRAS mutated. † Reference is wild-type for both BRAF and KRAS. Chi-square or Fisher’s exact test was used. All statistical tests were two-sided.

Figure 3.

Survival by race and age in stage III colon cancer patients treated with FOLFOX-based adjuvant chemotherapy in a phase 3 trial. Disease-free survival (DFS) and/or time to recurrence (TTR) are shown by race among patients younger than age 50 years (A, B) and age 50 years and older (C). DFS is shown by age among white (D), black (E), and Asian (F) patients. Univariate hazard ratios and 95% confidence intervals (likelihood ratio test) are shown. Interaction of race with age (cutpoint at 50 years) was statistically significant (P = .01 for DFS, P = .03 for TTR). All statistical tests were two-sided. DFS = disease-free survival; TTR = time to recurrence.

Figure 4.

Age as a continuous variable in relation to patient survival with and without regard to race. Risk of (A) disease-free survival (DFS) or (B) time to recurrence (TTR) event as nonlinear function of age, with highest risk at young and old extremes; risk of (C) DFS or (D) TTR event as function of age according to race. Interaction of race with age (continuous variable) was statistically significant (P = .002 for DFS, P = .008 for TTR). All statistical tests were two-sided. DFS = disease free survival; TTR = time to recurrence.

Figure 5.

Survival by race and N stage in stage III colon cancer patients treated with FOLFOX-based adjuvant chemotherapy in a phase 3 trial. Disease-free survival (DFS) and/or time to recurrence (TTR) are shown by race among patients with N1 (A, B) and N2 (C) stage. DFS is shown by N stage among white (D), black (E), and Asian (F) patients. Univariate hazard ratios and 95% confidence intervals (likelihood ratio test) are shown. Interaction of race with N stage was statistically significant (P = .005 for DFS, P = .005 for TTR). All statistical tests were two-sided. DFS = disease-free survival; TTR = time to recurrence.