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

摘要

Background: Patients with BRAF ~(V600E)-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 ~(V600E)( BRAF ~(non-V600E)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 ~(V600E)(6.0%), and 7 patients with BRAF ~(non-V600E)mutations (4.7%), respectively. The response rates in RAS , BRAF ~(V600E), and BRAF ~(non-V600E)were lower than those in RAS / BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF ~(non-V600E)mutations was 2.4 months, similar to that in RAS or BRAF ~(V600E)mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS / BRAF (5.9 months). Conclusions: Although BRAF ~(non-V600E)mutations identified were a rare and unestablished molecular subtype, certain BRAF ~(non-V600E)mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.