Supplementary Table S1 to S4 and Supplementary Figure S1 to S3 Supplementary Table S1. Classification of BRAF variants identified in this study Supplementary Table S2. Patient characteristics based on BRAF classification Supplementary Table S3. Characteristics of patients treated with anti-EGFR antibody therapy Supplementary TableS4. Response to anti-EGFR antibody therapy based on BRAF classification and the sidedness of the tumor Supplementary Fig. S1. CONSORT diagram. Supplementary Fig. S2. Onco-print showing the alterations identified in 96 specimens from 118 patients analyzed for OS. Supplementary Fig. S3. OS in all patients with BRAFnon-V600 mutation (A) and stratified by RASmutation (B), or stratified by BRAFclassification in patients with RASwild-type tumors (C).
Funding
Grants-in-Aid for Scientific Research
Japan Society for the Promotion of Science
Japan Agency for Medical Research and Development
MSK Cancer Center core grant
ARTICLE ABSTRACT
While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy.
We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).
Forty patients with oncogenic non-V600 BRAF–mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14).
Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment.See related commentary by Fontana and Valeri, p. 6896
