Molecular Profiling in Renal Cell Carcinoma

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Transcript:Robert A. Figlin, MD: Sandy, one of the things that we’re understanding in oncology is, we’re looking for activating mutations anywhere we can find them. Sometimes we look in the tissue, and, most recently, we’re now looking in liquid biopsies. Is there a role for liquid biopsy testing in your practice for kidney cancer? And what would you recommend for the practicing physicians in the community?

Sandy Srinivas, MD: In general, this is a very confusing topic for most community oncologists. We do both the Foundation and the Guardant liquid biopsies, and I think interpreting those reports can be challenging. They are really prognostic at this time. They tell us that a patient might do better or worse, but they’re really not helpful in selecting which drug to give to a given patient. I would advise community physicians that perhaps a referral to an academic center for a molecular tumor board, which is sometimes what I do, is valuable. I take that report and give it to our tumor board, especially to help advise on the next steps for a given patient.

Robert A. Figlin, MD: Do you do that at the time when a patient is progressing or at diagnosis? Or where in the course of a patient’s disease do you think it’s most helpful?

Sandy Srinivas, MD: Well, it’s interesting. We get people coming in with this report, so sometimes it’s not my choice in ordering the test. That’s one way we have to help advise the patient what to do. But if it were my choice, right now in 2017, I probably wouldn’t do it in every patient. I won’t do it for a patient coming in for first-line therapy. But when I run out of options, considering this patient perhaps for a MATCH clinical trial, that’s a setting in which I would use these tests.

Robert A. Figlin, MD: Michael, we talk mostly about clear cell renal cell carcinoma, but there’s a whole other group of patients with non—clear cell histologies. At the 2017 ASCO Annual Meeting, there were some abstracts about the TCGA analysis of non–clear cell histologies. Do you differentiate when you apply this in your practice?

Michael B. Atkins, MD: In my practice, if I’m treating someone off protocol with a VEGF inhibitor, I’m usually not going to be doing genomic testing on them. Most clear cell kidney cancers have VHL loss and are driven by VEGF. Therefore, you’re going to choose a VEGF inhibitor as your first line of therapy, as your standard of care, no matter what. And only if I see an unusual lack of response to a VEGF inhibitor do I start looking for something else that might be driving a clear cell tumor—like the rare tumors that are driven by PI3-kinase, mTOR, and the fibrosclerotic pathway. Here, you might decide on second-line therapy with an mTOR inhibitor.

In addition, one gene that we’ve looked at—and it hasn’t been fully validated prospectively yet—is p53 mutations, which are relatively uncommon in kidney cancer. And, in our view, that’s actually one of the reasons why kidney cancer is susceptible to VEGF inhibitor therapies as a single agent. It’s one of the few cancers where single-agent anti-VEGF therapy is effective, and that’s because when p53 is wild-type, the tumors that get acutely hypoxic when you give them a VEGF inhibitor are not able to survive that hypoxia as well.

We found in some preclinical models, and then some retrospective analyses, that patient specimens of patients who have p53 mutations are less likely to be responsive to the VEGF inhibitors. And, as it turns out, it’s probably more common to have p53 mutations in metastatic disease than in a primary tumor. So, it gives you a reason to potentially biopsy a metastatic lesion, if that’s a factor in the decision making. But for non—clear cell cancers, which we were talking about there, the only thing that is really similar about them to clear cell is that they’re in the kidney. They have different mutations that tend to drive them, at least in their hereditary forms, and they’re not really as responsive to the treatments that we use for clear cell cancer. They’re not that responsive to those treatments, and they’re not any more responsive than, maybe, another tumor in another organ. Unfortunately, we don’t have good therapies for most non–clear cell cancer, so we’re forced to either use those same therapies or put patients on clinical trials.

Transcript Edited for ClarityBrought to you in part by Eisai

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