DNA Mutational Profiling in Patients With Metastatic Colorectal Cancer

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As reported in the Journal of Clinical Oncology by Innocenti et al, analysis of DNA mutational profiling in the phase III CALGB (Alliance)/SWOG 80405 trial of patients with metastatic colorectal cancer treated with bevacizumab or cetuximab with chemotherapy showed differences in outcome associated with somatic mutations, as well as differences in racial distribution of mutations.

Study Details

In the trial, patients with metastatic disease were randomly assigned to receive first-line treatment with bevacizumab or cetuximab, plus chemotherapy. Primary tumor DNA was sequenced using FoundationOne from a total of 548 patients among the total trial population of 2,326.

Key Findings

The median number of mutated genes was 5 (first–fourth quartile = 3–7) overall, including 5 (first–fourth quartile = 3–6) in microsatellite-stable tumors and 12.5 (first–fourth quartile = 4.5–32) in microsatellite instability–high tumors.

KRAS mutations (53% vs 27%) and APC mutations (85% vs 65%) were more common in Black vs White patients, whereas BRAF V600E mutations were more common in White patients (14% vs 5%).

Median overall survival in patients with BRAF non-V600E mutations (2.2% of patients) was 31.9 months (95% confidence interval [CI] = 15.1 months to not reached), with a similar outcome observed in those with wild-type BRAF (median = 31.2 months, 95% CI = 29.0–33.9 months).

Mutated LRP1B (10.7% of patients) was associated with improved overall survival vs wild-type LRP1B (hazard ratio = 0.57, 95% CI = 0.40–0.80). The presence of an RNF43 mutation (5.6% of patients) showed an interaction with treatment group: in the cetuximab group, median overall survival was 11.5 months (95% CI = 10.8 months to not reached)  in patients with mutant RNF43 vs 30.1 months (95% CI = 24.9–35.3 months) in those with wild-type RNF43; in the bevacizumab group, median overall survival was 25.0 months (95% CI = 14.2 months to not reached) in those with mutant RNF43 vs 31.3 months (95% CI = 29.0–34.3 months) in those with wild-type RNF43.

The investigators concluded, “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.”

Heinz-Josef Lenz, MD, of the Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and by Bristol Myers Squibb, Genentech, Pfizer, and Sanofi. For full disclosures of the study authors, visit

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