DNA Mutational Profiling in Patients With Colorectal Cancer Treated With Standard of Care Reveals Differences in Outcome and Racial Distribution of Mutations.

Abstract

CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics. Primary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, <i>BRAF</i> V600E, all <i>RAS</i> mutations, arm, sex, and age. The median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated <i>KRAS</i> and <i>APC</i> were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while <i>BRAF</i> V600E was less frequent in Black (5%) than White (14%) patients. The median OS in patients with <i>BRAF</i> non-V600E (2.2% of patients) was 31.9 months (95% CI, 15.1 to not applicable [NA]) similar to that of <i>BRAF</i> wild-type (WT) patients (31.2 months [95% CI, 29.0 to 33.9]). Mutated <i>LRP1B</i> (10.7% of patients) was associated with improved OS compared with WT <i>LRP1B</i> (hazard ratio, 0.57 [95% CI, 0.40 to 0.80]). <i>RNF43</i> (5.6% of patients) interacted with treatment arms as, in the cetuximab arm, patients with mutated <i>RNF43</i> had a median OS of 11.5 (95% CI, 10.8 to NA) months compared with 30.1 (95% CI, 24.9 to 35.3) months in patients with WT <i>RNF43</i>, whereas in the bevacizumab arm, patients with mutated <i>RNF43</i> had a median OS of 25.0 (95% CI, 14.2 to NA) months compared with 31.3 (95% CI, 29.0 to 34.3) months in patients with WT <i>RNF43</i>. These results can provide new tools to predict patient outcome and improve therapeutic decisions and trial participation in patient minorities. The molecular alterations identified in this study may direct biomarker-driven studies.