Anti-EGFR Therapy Appears Beneficial in Colorectal Cancer With Class-3 BRAF Mutations

By Will Boggs MD

September 23, 2019

NEW YORK (Reuters Health) - Metastatic colorectal cancer with class-3 BRAF mutations is likely to respond to anti-EGFR therapy, whereas cancers with class-2 BRAF mutations are unlikely to respond, suggests an analysis of databases and electronic records.

"A recent phase III clinical trial established the efficacy of combining anti-EGFR antibody with BRAF inhibitor and MEK inhibitor in patients with class-1-BRAF-mutant colorectal cancer," Dr. Hiromichi Ebi of Nagoya University Graduate School of Medicine, in Nagoya, Japan, told Reuters Health by email. "We now added a strategy for the use of anti-EGFR antibody against BRAF-class-3-mutant colorectal cancer."

"Functionally, class-3 BRAF mutants were expected to be sensitive to anti-EGFR antibodies because their activation is dependent on receptor tyrosine kinase signaling," he explained. "In contrast, class-2 mutants signal independently of receptor tyrosine kinase."

Dr. Ebi and colleagues analyzed the responses of patients with metastatic colorectal cancer with non-V600 BRAF alterations to EGFR antibody therapy. The study included 32 class-2-BRAF-mutant tumors, 72 class-3-BRAF-mutant tumors, 13 uncharacterized BRAF mutants, and one mutant with no effect on ERK signaling.

Median overall survival for these patients was 40.2 months. Survival trended shorter in patients with concurrent RAS-tumor mutations (median, 29.0 months versus 44.2 months with RAS wild-type tumors), and, among patients with RAS-wild-type tumors, trended shorter among those with class-2-BRAF mutants (median, 26.0 months) than among those with class-3 BRAF mutants (median, 44.8 months).

While about half of patients had a response to first-line or second-line treatment containing an EGFR antibody, 78% (seven of nine) of patients with class-3-BRAF-mutant cancer responded to treatment, compared with only 17% (one of six) of patients with class-2-BRAF-mutant metastatic colorectal cancer, the researchers report in Clinical Cancer Research, online September 12.

With third-line or later-line anti-EGFR treatment, no patients with class-2-BRAF-mutant cancer responded, compared to 37% (7/19) of patients with class-3-BRAF-mutant metastatic colorectal cancer.

The median duration of response to EGFR antibody therapy tended to be shorter for class-2-BRAF-mutant metastatic colorectal cancer (4.0 months) than for class-3-BRAF-mutant cancer (6.1 months).

"Cancer genomic-profiling tests increasingly identify BRAF non-V600 mutations," Dr. Ebi said. "Based on our findings, colorectal-cancer patients with class-3 BRAF mutations should be considered for anti-EGFR antibody treatment, while the use of anti-EGFR antibody should be avoided for patients with class-2 BRAF mutation."

Dr. Ibrahim H. Sahin of Emory University School of Medicine, in Atlanta, who recently reviewed precision medicine for metastatic colorectal cancer, told Reuters Health by email, "These findings suggest that we should not be lumping all BRAF mutations into the same category and clinical heterogeneity exists among BRAF-mutation colorectal-cancer patients. Patients with class-3 BRAF mutations should be considered for anti-EGFR-directed therapies. Further research is needed for class-2 BRAF mutations."

"Personalize each patient's care, and be aware that different types of BRAF mutations exist among colorectal cancer patients, which may benefit from different therapies," he said.

"It is important to remember that the large bulk of the BRAF mutations in colorectal cancer are V600E and V600K, and they are in class 1," added Dr. Sahin, who was not involved in the study. "So the implication of this study will be only in a limited number of colorectal-cancer patients."

Dr. Michel Ducreux from Gustave Roussy Cancer Campus, in Paris, recently reviewed targeted therapy of BRAF-mutant colorectal cancer. He told Reuters Health by email, "The first step is clearly an adequate characterization of the BRAF mutations, and after that to consider anti-EGFR treatment in class 3 and not in class 2."

"It is not clear if all the platforms that are doing BRAF mutations testing are aware of the classification and able to stratify their results according to this classification," said Dr. Ducreux, who also was not linked to the study.

Dr. Alan P. Venook of the University of California, San Francisco, an expert in colorectal and liver cancers, told Reuters Health by email, "It should not surprise anyone that different mutations have different ramifications for a given cancer. Unfortunately, although this finding may very well be correct, this exemplifies the challenge of interpreting results on smaller and smaller subsets."

He recommends cautious interpretation of these findings. "Subtypes of mutations may be beyond the current capacity of many oncologists, and these results are not definitive," said Dr. Venook, who also was not part of the study.


Clin Cancer Res 2019.