The Hunt for Predictive Markers in Metastatic Colorectal Cancer - Episode 6

Targeting BRAF in Metastatic CRC


Richard Kim, MD: BRAF mutations in occur in colon cancer about 10% of the time. Most of the BRAF mutations are BRAF V600E mutations. However, one-fifth of those mutations are non- BRAF V600E. If you look at the BRAF V600E mutations in terms of clinical profile, they tend to occur in older females. They tend to be seen in right-sided tumors that are poorly differentiated and are MSI [microsatellite instability]-high. They tend to have a worse prognosis, are more likely to be involved in the lymph nodes, and there is more of a chance of peritoneal involvement. If you look at non- BRAF V600E mutations, there are different features. They tend to be seen in younger patients. They are more likely in males and are often seen in left-sided tumors. In terms of prognosis for non- BRAF V600E mutations, retrospective data shows that they may have a better prognosis than BRAF V600E mutations. However, in terms of the predictive value of EGFR resistance, that area is still unclear. More studies need to be done in that area.

John L. Marshall, MD: We know BRAF status in all metastatic colon cancer patients. You could argue that you might need to know that for every colon cancer patient, but for stage IV metastatic disease, you certainly need to know it. Seven percent, 8 %, 9% of all colon cancers are BRAF mutated with the same mutation—the BRAF V600E mutation—that you see in melanoma. But, it behaves differently in colon cancer patients. We do know that for most patients, it’s a negative predictive and prognostic marker. If you have this mutation, the tumors tend to be meaner. They tend to grow and spread more readily, and tend to be more resistant to chemotherapy. So, I want to know that right from the beginning so that I can make some decisions. An important part of that is we have new data that suggest that certain targeted agents could be combined in BRAF-mutated patients. So you want to know BRAF status not only for its prognostic role but because there are new choices for therapy if you a BRAF mutation.

Richard Kim, MD: A patient who is diagnosed with a BRAF-mutant tumor tends to have a very poor prognosis. We know that those patients do not typically live for more than 2 to 3 years. Therefore, we tend to be more aggressive with those patients. Based on the TRIBE study, we could use FOLFOXIRI [fluorouracil, leucovorin, oxaliplatin, and irinotecan] plus bevacizumab. Data with that regimen shows an overall survival benefit compared to FOLFIRI [fluorouracil, leucovorin, and irinotecan] plus bevacizumab. Therefore, for patients with a BRAF-mutant tumor, I tend to be very aggressive at the beginning, as long as they are able to tolerate the chemotherapy. Once they progress on FOLFOXIRI plus bevacizumab, in second-line setting, I try to get them on a trial that targets the BRAF-mutant tumor. Or, I may possibly try to get some drugs off label, using an anti-EGFR drug, possibly plus an anti-BRAF drug, based on the SWOG study that was presented by Dr Kopetz last year. That’s how I would sort of align myself, in terms of managing patients with BRAF-mutant tumors.

Alan Venook, MD: In general, about 20% of patients with a BRAF-mutant primary colon cancer don’t do poorly. While they all have BRAF V600E mutations, there may be a subset, biologically, who do alright. We usually start with standard therapy. Then, as soon as the patient progresses, we jump to a second-line option. That second-line option uses some combination of a BRAF inhibitor, such as vemurafenib, for example, or a drug like irinotecan and an EGFR antibody.

My group has piloted this. Others have done studies. It’s said that more encouraging combinations are on the way. The BEACON CRC trial looked at a different inhibitor as well as the combination of the EGFR antibody and irinotecan. So we tend to go in that direction. I don’t know that one cocktail is better than the other, but we think you need to do this kind of a nonstandard approach to really help patients in this setting.

Transcript Edited for Clarity