Although between 8% and 12% of patients with metastatic colorectal cancer harbor a BRAF gene mutation, not all non-V600 BRAF alterations respond to EGFR antibody treatment, according to findings from a study by Yaeger et al published in Clinical Cancer Research. The study investigated whether colorectal cancers with non-V600 BRAF mutations are sensitive to EGFR inhibition and found that patients with metastatic colorectal cancer carrying class 3 BRAF mutations are likely to respond to anti-EGFR treatment, while patients with class 2 BRAF mutations are unlikely to respond. The study’s findings highlight the need to develop new targeted approaches for this patient population.

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Study Methodology

In metastatic colorectal cancer harboring BRAF mutations, two-thirds of these mutations are classified as class 1 and one-third are classified as class 2 and 3 alterations. Class 1 comprises BRAF V600 mutations; non-V600 BRAF mutations are divided into two classes: class 2 mutations are RAS-independent, and class 3 mutations have enhanced binding to RAS and the kinase CRAF, resulting in increased RAS-dependent signaling.

To determine whether the different functional classes of non-V600 BRAF mutations affected patients’ responses to anti-EGFR therapy, the researchers conducted a multicenter pooled analysis of data from 40 patients with metastatic colorectal cancer diagnosed between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classed based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3).

Results

Patients with oncogenic non-V600 BRAF-mutant metastatic colorectal cancer 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-mutated metastatic colorectal cancer responded, 14 of 28 patients with class 3 BRAF mutations responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = .02). Specifically, in first- or second-line treatment, one of six (17%) patients with class 2 and seven of nine (78%) patients with class 3 BRAF mutations responded (P = .04).

In third- or later-line treatment, none of the six patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutations responded (P =.14).

“Response to EGFR antibody treatment in metastatic colorectal cancer with class 2 BRAF mutants is rare, while a large proportion of colorectal cancer with class 3 BRAF muta[tions] respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment,” concluded the study authors.

Getting Closer to Realizing Precision Oncology

The findings from this research provide clinical guidance on the application of EGFR antibodies in patients with metastatic colorectal cancer with non-V600 BRAF mutations.

“Through the analysis of colorectal cancer tumors with specific BRAF mutations, we identified a potential new indication for anti-EGFR treatment, highlighting the power of precision oncology,” commented principal study investigator Hiromichi Ebi, MD, PhD, Chief of the Division of Molecular Therapeutics at the Aichi Cancer Center Research Institute in Nagoya, Japan, in a statement.

Dr. Ebi is the corresponding author of this study.

Disclosure: Funding for this study was provided by Grant-in-Aid for Scientific Research, the Japan Society for the Promotion of Science, the Takeda Science Foundation, Japan Agency for Medical Research and Development, Memorial Sloan Kettering Cancer Center, and the National Institutes of Health. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.