Impact of Coexisting BRAF V600E Mutations on the Tumor Microenvironment in MSI-High or MMR-Deficient Colorectal Cancer

Mohamed Salem, MD, Levine Cancer Institute, Charlotte, NC, discusses findings from a study exploring the impact of a BRAF V600E mutation on immunologic characteristics of the tumor microenvironment and associated genomic alterations in patients with microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient colorectal cancer.

These findings were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Transcript:

Good morning. My name is Mohamed Salem. I'm a GI Oncologist at Levine Cancer Institute in Charlotte, North Carolina, USA. First, it's a pleasure to be here at the World GI Cancer meeting. It's always one of the very interesting meetings that we attend in the GI cancer world. I'm also very excited to discuss our abstract, presented earlier today, about the impact of BRAF mutations and immune microenvironment.

I always start by saying colorectal cancer now is perhaps the wrong name, it's an old name. When we started treating colorectal cancer, we used to think of it as one disease. More and more now, we think colorectal cancer is actually divided into multiple subgroups of patients, mainly driven by the molecular markers. So we'll have MSI-high tumor, we'll have RAS mutant tumor, RAS wild-type, BRAF mutant tumor, BRAF wild-type, HER2-amplified tumor and so on and so forth. That's very important, not just because of prognostic impact, but also because of the therapeutic options we'll have.

One of the very important subgroups of colorectal cancer patients are those who carry the MSI-high status or dMMR status. The reason is because of immunotherapy. However, about 1% to 2% of patients with colorectal cancer carry MSI-high status, but also they carry BRAF V600E mutation. So the question is: What is the impact of the BRAF V600E mutation on the immune microenvironment among those patients who have MSI-high tumor? That's important because now we have checkpoint inhibitors that we can use for MSI-high tumors, and in second line, we also have BRAF targeted therapy plus anti-EGFR therapy for a patient who has BRAF mutation.

So, for those who have coexistent MSI-high tumor and BRAF V600E mutation, what is the basic strategy? We decided to examine the immune microenvironment of colorectal cancer patients who have MSI-high tumor as well as BRAF V600E mutation. This was a retrospective review of more than 400 patients. All of them had MSI-high or dMMR status, and BRAF mutation status was known. All patients' tumors were RAS wild-type and among those, about 336 patients had MSI-high tumor, BRAF wild-type tumor, and about 123 patients had the MSI-high and BRAF V600E mutation. We tried to compare the immune microenvironment between the BRAF mutant and BRAF wild-type MSI-high status.

Overall, it appeared that mutational tumor burden was very much the same in both groups in the BRAF mutant tumor and the BRAF wild-type tumor. Also, the inflammatory status was very similar. CD4 and CD8 were very much the same. However, we saw the BRAF mutant tumor had low stemness, and on the other hand had higher growth and metabolic reprogramming, suggestive of more aggressive biology. But overall, it looks like from our data that both BRAF mutant tumor MSI-high and BRAF wild-type mutant MSI-high tumor carry the same immune microenvironment. The reason that's important is because it suggests that both BRAF mutant MSI-high and BRAF wild-type MSI-high are likely to equally benefit from a checkpoint inhibitor. Which is actually what we saw in the clinical trial KEYNOTE-177, that in the subgroup analysis both groups did benefit the same way from a checkpoint inhibitor.

I think the next question will be how RAS mutations play in this, and this is a topic of other studies that we're already looking into. The next generation of questions will be: Should we combine immunotherapy plus BRAF inhibitors plus anti-EGFR inhibitors for BRAF mutant MSI-high tumors? This is also a subject of ongoing clinical trials now. Again, we're very excited about the data, and it just opens the door for more research and more questions to be answered. Thank you very much.

Source:

Salem M, Kopetz S, El-Refai S, et al. Impact of BRAF-V600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC). Presented at: ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022. Barcelona, Spain. Abstract SO-34.