Patients with metastatic colorectal cancer harbouring a subset of non-V600 mutations in the BRAF gene, known as class 3 BRAF mutations, are more likely to respond to anti-EGFR treatment, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
"Cancer genomic profiling is rapidly transforming the clinical management of cancer patients," said Senior author, Dr Hiromichi Ebi, chief of the Division of Molecular Therapeutics at the Aichi Cancer Center Research Institute in Nagoya, Japan. "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."
Alterations to the RAS signalling pathway, which controls key functions such as cellular proliferation and survival, is a known driver of oncogenesis. Mutations to BRAF, a kinase that interacts with RAS, can result in activation or amplification of the RAS signalling pathway. Roughly 10 percent of metastatic colorectal cancer tumours harbour mutations in the BRAF gene, noted Ebi.
BRAF mutations belong to one of three functional classes. 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 signalling.
While tumours with V600 BRAF mutations are often susceptible to RAF inhibitors, this therapeutic strategy is not predicted to be successful in tumours with non-V600 BRAF mutations, explained first author, Dr Rona Yaeger, a medical oncologist at Memorial Sloan Kettering Cancer Center. Prior smaller studies have shown that some patients with non-V600 BRAF-mutant colorectal cancer may respond to anti-EGFR treatment, she noted.
To determine if different functional classes of non-V600 BRAF mutations affected responses to anti-EGFR therapy, Ebi and colleagues retrospectively analysed data from 40 patients with metastatic colorectal cancer whose treatment included an anti-EGFR therapy through an international multi-centre collaboration. Using biochemical assays, the researchers classified the patients' tumours as having one of the two classes of non-V600 BRAF mutations: 12 patients had class 2 BRAF mutations and 28 patients had class 3 BRAF mutations. Patients from both groups had comparable clinical characteristics.
Eight percent of patients with tumours harbouring class 2 BRAF mutations responded to anti-EGFR treatment regimens, compared with 50 percent of those with class 3 BRAF mutations.
The researchers also analysed responses to anti-EGFR regimens based on treatment line. In the first- or second-line setting, 17 percent of patients with tumours harbouring class 2 BRAF mutations responded to treatment, compared with 78 percent of those with class 3 BRAF mutations. In the third-line setting or later, no patients with class 2 BRAF mutations responded to treatment, compared with 37 percent of those with class 3 BRAF mutations.
"Through the analysis of colorectal cancer tumours with specific BRAF mutations, we identified a potential new indication for anti-EGFR treatment, highlighting the power of precision oncology," noted Ebi.
Limitations of the study include the small number of patients with metastatic colorectal cancer harbouring class 2 or class 3 BRAF mutations. Additionally, because most of the patients analysed in this study were also treated with chemotherapy, the researchers could not assess the efficacy of anti-EGFR monotherapy based on the functional class of non-V600 BRAF mutations, Ebi added.