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Perspectives in the Treatment of Colon Cancer with Leonard Saltz, MD

Perspectives in the Treatment of Colon Cancer with Leonard Saltz, MD

AJMC®: What defines targeted therapies in cancer treatment?
Saltz: I can make a coherent argument in that there is no such thing. I mean let’s look at what we use for metastatic colon cancer. There’s 5-fluorouracil, a drug that is going to turn 60 years old in the next month. Most people would not call that a targeted therapy, which just shows you how meaningless that term is because we know the target—it targets thymidylate synthase. Because we know what it targets, it just represents chemotherapy, all chemotherapy has a target. Irinotecan, another cytotoxic, targets topoisomerase I but we don’t think of that as targeted therapy. Oxaliplatin cross-links DNA also, so I don’t think that’s what anyone has in mind. Now let’s get to the newer drugs. Cetuximab and panitumumab latch onto the EGFR [epidermal growth factor receptor] and the hypothesis had been that that’s the target and people who had more of that target would be more vulnerable and people who didn’t have that target wouldn’t be vulnerable, and that has turned out not to be true. I don’t think cetuximab or panitumumab are any more or less targeted than 5-flurouracil. We just happen to know what they interact with on the cell. And, most people have turned the more modern term of targeted therapy as precision medicine or personalized medicine. Well, we can personalize it a bit in that we look for mutations in the RAS gene in the tumor and if we see them, we see that the EGFR targeting drugs won’t work.
AJMC®: What is the current role of genetic testing in colorectal cancer and which tests are done clinically?
Saltz: There are a few things that need to be considered standards in colorectal cancer. Probably the most important thing is testing the tumor for the presence of microsatellite instability, also referred to as mismatched repair deficiency. This is a critical factor now because although a very small percentage of metastatic colorectal patients will be mismatch repair deficient—it could be as low as 2%, for those people—the PD-1 [programmed death 1] inhibitors are extremely effective. We need to be sure we are not missing the opportunity to help those people. Patients with the far more common mismatched repair proficiency or microsatellite stable disease do not benefit from currently available standard immune checkpoint inhibitors. So, it’s a very small subset, but we need to identify this subset. There is confusion because mismatched repair deficiency is present in about 15% of all diagnosed colorectal cancer, but most of those people have a good prognosis and never get to metastatic disease, so by the time you get to the treatment of metastatic disease, it’s nowhere near 15% and it’s somewhere between 2% and at best 4%. So, that’s one molecular study. The other issues are basically exclusionary markers. We look at KRAS mutations, NRAS mutations and BRAF mutations, all of which are indicators that the EGFR inhibitors, cetuximab and panitumumab, are not going to be effective and be counterproductive. And so, when we see those markers, we take those drugs out of consideration for treatment. BRAF is potentially something that may be targeted in the future with combination of EGFR and BRAF inhibitors, but thus far, there has been modest activity in clinical trials and that combination is not either FDA approved or in the NCCN compendium so it can’t be considered part of standard practice. Those are probably the ends of standard molecular markers at this point. There is interest in whether the very limited population that have expression in HER-2 might be treatable with HER-2 targeted therapies but that too is something investigational and not standard practice, not something that one can prescribe as standard billable for routine practice. It is not FDA approved or recognized in any compendium recognized by Medicare. Other than that, there are questions about whether next-generation sequencing assays looking for actionable mutations is something that we should be doing for patients and I think the answer is that if you are in a research setting and you have access to research trials with specific targeted inhibitors, that’s something worth pursuing. But thus far, that is not something we consider part of standard practice because we don’t have actionable mutations that we have standardly available drugs.
AJMC®: In terms of reimbursement for genetic testing in colorectal cancer, what is the current policy you have seen for broad panel testing, including next-generation sequencing testing versus genetic testing paired with treatments?
Saltz: So, I’m not an expert in this topic but I’ll give you some general comments. I think it’s clear that people don’t need to be constrained to the specific paired approved test for the FDA. For example, any test for KRAS, NRAS and BRAF is acceptable. However, the question of whether a NGS [next-generation sequencing] assay is approvable or not is one that I don’t think has been adequality answered and I think if one is assaying for the standard billable targets, KRAS, NRAS, and BRAF, and uses a NGS assay to do so, that’s probably okay as long as one is billing for the identified standard targets. I don’t think it’s considered a billable standard practice to do broad NGS assay in cancer right now, and I don’t think colorectal cancer is unique one way or the other. 

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