Atypical, non-V600 BRAF () mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize mutations into class II (intermediate to high levels of kinase activity, independent) and III (low kinase activity level, dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown.

Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided.

BRAF mutations were harbored by 257 patients, including 36 with mutations: 22 class III, 10 class II, four unclassified. For patients with mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with mCRC. In contrast to right-sided predominance of tumors with mutation, 53% of patients with mCRC had left-sided primary tumors. Concurrent mutations were noted in 33% of patients with mCRC, and 67% of patients had microsatellite stable disease. Among patients with wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of mutations and subclonal mutations ( < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients.

Efficacy of anti-EGFR therapy is limited in class II and III mCRC. Detection of mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.