Impact of BRAF Mutations on Metastatic Colorectal Cancer

Transcript: Scott Kopetz, MD, PhD: The patients with a BRAF V600E mutation represent a very distinct subgroup of patients with colorectal cancer. They have a very different molecular profile, meaning other alterations in the tumor, and they actually appear to derive from a different carcinogenesis pathway. Meaning, even at the very earliest polyps, we’re seeing that there are differences in the wiring of the tumor. As a result of that, we recognize that this is a very different clinical biology as well. These are patients who have very poor prognoses, they have a limited response to standard chemotherapy agents, and this is really what’s been driving an interest in trying to effectively target that key oncogene.

The BRAF V600E mutation is a poor prognosis indicator. But when we’re doing NGS [next-generation sequencing] testing, we see alternate BRAF mutations that can occur. And these are what we call non-V600E mutations. They are sometimes called atypical BRAF mutations, although they’re collectively present in 3% to 4% of patients. It’s been interesting in trying to understand this. This is the heterogeneous group of mutations. What we can say is these are not V600E mutations, they behave very differently. There’s been some suggestion that they may even have a better prognosis than a BRAF wild-type patient. But at the very least, certainly we don’t see the degree of poor prognosis that we see with the BRAF V600 mutation.

They also are not as sensitive to BRAF-targeted therapies. They’re really focused and the mechanism of action appears to be very different: they impact how the BRAF dimerizes and its sensitivity and amplification of upstream signaling pathways. There are some emerging data about the differences in these BRAF subgroups. There’s a sense that what we call class 2 non-BRAF V600E mutations are ones that are resistant to EGFR inhibition, whereas the class 3 mutations still derive benefit from EGFR inhibition, although I think it’s fair to say that these data are still scant and this is an emerging field.

Transcript Edited for Clarity