Class 3 BRAF Mutations Demonstrate Higher Response Rate With Anti-EGFR Therapy in CRC

By Michael Vlessides, /alert Contributor
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Metastatic colorectal cancer patients with class 3 BRAF mutations are significantly more likely to respond to anti-EGFR therapy than are their counterparts with class 2 BRAF mutations, according to new research. 

The study concluded that patients harboring a subset of non-V600 mutation in the BRAF gene should be considered for anti-EGFR antibody treatment. 

Mutations. Source: Getty

Reporting in a recent issue of Clinical Cancer Research, a multi-center team of researchers noted that although BRAF mutations in metastatic colorectal cancer are most common at the V600 amino acid, the advent of next-generation sequencing has allowed for increasing clinical identification of non-V600 BRAF mutations. Nevertheless, it is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy, they wrote.

Indeed, although tumors with V600 BRAF mutations are often susceptible to RAF inhibitors, such therapy is not predicted to be successful in tumors with non-V600 BRAF mutations, the investigators said. Nevertheless, previous research with smaller groups of patients has shown that some patients with non-V600 BRAF-mutant metastatic colorectal cancer may respond to anti-EGFR treatment.  

To help clarify the issue, the investigators performed a pooled retrospective analysis of 40 consecutive patients, all of whom had non-V600 BRAF-mutated metastatic colorectal cancer that had been identified between 2010 and 2017. Through biochemical assays, non-V600 BRAF mutations were divided into functional classes according to signaling mechanism and kinase activity, and classified as either activating and RAS-independent (class 2; n=12), or kinase-impaired and RAS-dependent (class 3; n=28). 

No significant differences in patients’ clinical characteristics were observed according to mutation class; the participants all received anti-EGFR antibody treatment. 

The study found that while only one of the 12 patients with BRAF responded to anti-EGFR treatment (8% response rate), 14 of their 28 counterparts with class-3 BRAF did so (50% response rate; p=0.02). 

More specifically, the analysis revealed that when anti-EGFR treatment was used as first- or second-line therapy, only one of six patients with class-2 mutations responded (17%), compared with seven of nine patients (78%) with class-3 BRAF mutations (p=0.04). 

Finally, when anti-EGFR agents were used as third-line therapy or later, none of six patients with class-2 BRAF mutations, while seven of their 19 counterparts (37%) with class-3 mutations did (p=0.14). 

“Cancer genomic profiling is rapidly transforming the clinical management of cancer patients,” study senior author Hiromichi Ebi, MD, PhD, Chief of Molecular Therapeutics at the Aichi Cancer Center Research Institute in Nagoya, Japan said in a statement. “Results from our study indicate that metastatic colorectal cancer patients with certain BRAF mutations should be considered for anti-EGFR  treatment, a new indication for this population of patients.”

Despite the strength of its findings, the investigators noted that the study was limited by its relatively small sample size. Additionally, since most patients were also treated with chemotherapy, the investigators were unable to assess the efficacy of anti-EGFR monotherapy based on the functional class of non-V600 BRAF mutations. 

Such shortcoming did not stop the researchers from expressing enthusiasm at their findings, however. “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,” Ebi noted.  


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