Molecular Testing for Advanced Colorectal Cancer - Episode 8
Transcript:Charles S. Fuchs, MD: At our center, the Dana-Farber Cancer Institute, we start with testing for RAS, and if you’re RAS wild-type, we then do testing for BRAF. We don’t routinely do BRAF testing if you’re RAS-mutant. Why? Because what we realize is they’re virtually, mutually exclusive. Tumors that are RAS-mutated are rarely BRAF-mutated and vice versa. We do it sequentially just to reduce cost, but we do it on everybody; it’s important. We know that patients whose tumors are BRAF-mutated have a significantly worse survival. Moreover, we know that there’s a variety of new drug trials directed at BRAF-mutated patients that seem to have benefit. They’re complex, they’re not as simple as just using a RAF inhibitor. They often require a RAF inhibitor, plus a MEK inhibitor, plus an EGFR antibody. But if you combine those three drugs, we’re seeing really significant responses in patients.
Richard Kim, MD: BRAF testing should be done on all the patients up front. We know that BRAF is not a predictive marker, per se, to an EGFR drug, but we know it’s a prognostic factor. Patients with BRAF mutations tend to do worse than the patients with BRAF wild-type mutations. If you look at the TRIBE study, where they looked at FOLFOXIRI in this setting, patients with a BRAF mutation had an overall survival of only 12 months. Therefore, if you know the patient is BRAF-mutant, we know that overall survival will be much shorter, so you don’t have time to give first-, second-, third-, or fourth-line therapy. Having that data up front will tell me that, overall, this patient will have a much worse prognosis. Therefore, I want to be more aggressive with this patient. In the TRIBE study, when they looked at the subset analysis, actually FOLFOXIRI benefitted patients with BRAF mutations compared to FOLFIRI alone. Those are the patients in whom I would actually use more aggressive therapy, such as FOLFOXIRI up front, knowing that I don’t have a long time to treat the patient.
Daniel G. Haller, MD, FACP, FRCP: Right now, most people don’t look at BRAF results. Sometimes they’re not given out. In our hospital laboratory, the BRAF test is available if you want it; there’s no extra charge. It’s already part of the package. But, they only give you what you ask for. I like to see the BRAF results for two reasons: one is that it is clearly a marker of full prognosis. And when one is talking to a patient about their treatment, if, in their mind, they know enough to read and they’ve read about three-year survivals in metastatic colorectal cancer, that’s a best-case scenario. That’s a case from patients selected for clinical trials, who are eligible for clinical trials, who are all KRAS wild-type, and very few BRAF-mutants.
If you look at pure BRAF-mutant populations, it’s not a predictive marker. Those patients do benefit from EGFR inhibitors, but to a much less degree, both relatively and absolutely. And overall, the median survival, even with all the available drugs we have in the United States, is just in excess of a year. I think it’s a responsibility of the physician to do two things. Talk about cost of therapy with patients. Don’t pretend the drugs are not expensive or what the cost is that they might be paying for it. And don’t lead them down the wrong pathway in terms of the tumor they actually have, what is reported in literature. I think there are many ways the doctor can introduce that without being overly morbid or coercive.
There’s currently a phase II trial; Scott Kopetz is doing this at MD Anderson. It’s being done through the Cooperative Groups. And what this looks at is based on laboratory data that shows that a combinatorial approach of adding an EGFR agent, cetuximab, to vemurafenib, a BRAF inhibitor, may restore the effectiveness or allow the effectiveness of the BRAF inhibitor by blocking some of these salvage pathways that occur in colorectal tumors that don’t seem to occur in melanoma.
Transcript Edited for Clarity