Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

BACKGROUND

Patients with BRAF-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF (BRAF mutations) contribute to anti-EGFR antibody resistance.

METHODS

This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort.

RESULTS

In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF (6.0%), and 7 patients with BRAF mutations (4.7%), respectively. The response rates in RAS, BRAF, and BRAF were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF mutations was 2.4 months, similar to that in RAS or BRAF mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months).

CONCLUSIONS

Although BRAF mutations identified were a rare and unestablished molecular subtype, certain BRAF mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.