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Heterogeneity of Kidney Cancer

Panelists: Robert A. Figlin, MD, Cedars-Sinai Medical Center; Thai H. Ho, MD, PhD, Mayo Clinic Arizona; Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center; Michael B. Atkins, MD, Georgetown Lombardi Comprehensive Cancer Center; Sandy Srinivas, MD, Stanford University Medical Center
Published: Friday, Sep 08, 2017



Transcript:

Robert A. Figlin, MD:
Hello. Thank you for joining this OncLive Peer Exchange. The treatment landscape for renal cell carcinoma has changed dramatically over the past few years, and there are many clinical trials under way that are poised to alter the standard of care and extend survival. This OncLive Peer Exchange panel of experts will discuss the evolving treatment landscape in kidney cancer, including important factors to consider in current clinical decision making, evidence supporting the use of available agents, and emerging approaches that are most likely to impact clinical practice.

My name is Dr. Robert Figlin, and I’m the Steven Spielberg Family Chair in Hematology Oncology, professor of medicine and biomedical sciences, and deputy director of the Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center in Los Angeles, California. Joining our distinguished panel to share their perspectives are Dr. Thai Ho, assistant professor in the Division of Hematology and Oncology at Mayo Clinic Arizona, in Phoenix, Arizona; Dr. Sandy Srinivas, professor of medicine and oncology at Stanford University Medical Center, in Palo Alto, California; Dr. Martin Voss, an attending physician in the Department of Genitourinary Oncology at the Sidney Kimmel Center for Prostate and Urologic Cancers, of the Memorial Sloan Kettering Cancer Center, in New York, New York, and a research scholar of the American Cancer Society; and Dr. Michael Atkins, deputy director of the Georgetown Lombardi Comprehensive Cancer Center, and the Scholl professor and vice chair of the Department of Oncology at the Georgetown University Medical Center, in Washington, DC. Thank you again for joining us. Let’s begin.

Thai, let’s start with a better understanding of the evolution and understanding of kidney cancer, especially as we’ve read in journal articles over the last several years about tumor heterogeneity. How does that play into what’s happening in kidney cancer, how you think about the disease, and how you think about its evolving biology?

Thai H. Ho, MD, PhD: It’s an important topic. As our technology for DNA sequencing is improved, we find that our tumors are heterogeneous. That means that you sample one part of the tumor versus another part of the tumor. You’ll actually see differences in what kinds of DNA mutations you have. One common theme, though, is that a lot of these DNA mutations converge on loss-of-function mutations in the epigenetic pathways. These are things that regulate our DNA and chromatin structure. What is challenging, though, is that if you’re looking for some predictive biomarkers, it can influence where you sample a tumor and what kind of mutations you have. For example, if you were to sample a strand of my hair, you may get a black hair or you may get a gray hair. With tumors, we also have the same kind of challenges ahead of us.

Robert A. Figlin, MD: Martin, one of the things that are evolving in our understanding of this heterogeneity is that mutations change over time. Some become more important. We’ve learned that mutations like PBRM1 and BAP1 are mutations that have been defined. I know that you’ve done some work—reported at the 2017 ASCO Annual Meeting—that looked at the COMPARZ trial, which started to help us understand how some mutations may have different meanings as the tumor evolves. Can you shed some light on that?

Martin H. Voss, MD: We’ve known for a long time that functional loss of VHL [von Hippel–Lindau] is a linchpin into the development of metastatic kidney or, specifically, clear cell kidney cancer. And we have since learned, through some of the efforts that have been described, that there are other genes in a similar region of the human genome, also on chromosome 3p, that are commonly, functionally, lost in these diseases. The 2 that you mentioned, PBRM1 and BAP1, are recurrently mutated in clear cell kidney cancer patients. In metastatic disease, we find loss of PBRM1 by deactivating mutations in up to 50% of patients. Loss of BAP1 is less common—we probably see this in about 20% of the patients we treat in the metastatic setting. We’ve started to explore the biologic significance of that. If we have these recurrent mutation events, what is it that may change about a patient’s course and about how they may fare on the therapies that we use?

The COMPARZ trial was, at its time, the largest trial done in kidney cancer that randomized patients in the first-line setting to receive either sunitinib or pazopanib. All were treated with a VEGF-targeted tyrosine kinase inhibitor, and what we’ve done, in an analysis that we recently did on a trial set of over 400 patients treated on that trial, is we did genomic exploration and specifically looked into mutation status for these recurrently mutated genes and how that may track with outcome on first-line TKI therapy—that being, really, the standard of care in this disease.

What we found is that PBRM1 mutations and BAP1 mutations actually have opposite effects in terms of how patients do. If we look at PBRM1, harboring a PBRM1 mutation in the tumor means that a patient is actually more likely to fare better in terms of progression-free survival and overall survival than PBRM1 wild-type status. For BAP1 mutations, we see the exact opposite effect. BAP1-mutant patients tend to fare worse on TKI therapy than patients who do not harbor a BAP1 mutation in their tumor. We’re trying to understand why that is. It may have something to do with how the presence of these mutations and epigenetic pressures that may exert play into tumor angiogenesis and pathway signaling in patients.

Robert A. Figlin, MD: Do you think that they are predictive, prognostic, a combination? How do you assess this?

Martin H. Voss, MD: That’s a very important question. It’s difficult to assess it on this trial, because all patients that we pooled in this analysis were treated with the same type of therapy. But we are learning now, by looking at different data sets, that they are likely prognostic, not predictive, markers. We have looked at PBRM1 and BAP1 in our group on 3 large clinical trial and non-clinical trial data sets, and we see the same signal each time—be it that we look at VEGF-targeted therapy, mTOR-targeted therapy, and, more recently, also immunotherapy. Having PBRM1 mutations in the tumor seems to confer a better outcome than being wild-type.

Transcript Edited for Clarity

Brought to you in part by Eisai

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Transcript:

Robert A. Figlin, MD:
Hello. Thank you for joining this OncLive Peer Exchange. The treatment landscape for renal cell carcinoma has changed dramatically over the past few years, and there are many clinical trials under way that are poised to alter the standard of care and extend survival. This OncLive Peer Exchange panel of experts will discuss the evolving treatment landscape in kidney cancer, including important factors to consider in current clinical decision making, evidence supporting the use of available agents, and emerging approaches that are most likely to impact clinical practice.

My name is Dr. Robert Figlin, and I’m the Steven Spielberg Family Chair in Hematology Oncology, professor of medicine and biomedical sciences, and deputy director of the Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center in Los Angeles, California. Joining our distinguished panel to share their perspectives are Dr. Thai Ho, assistant professor in the Division of Hematology and Oncology at Mayo Clinic Arizona, in Phoenix, Arizona; Dr. Sandy Srinivas, professor of medicine and oncology at Stanford University Medical Center, in Palo Alto, California; Dr. Martin Voss, an attending physician in the Department of Genitourinary Oncology at the Sidney Kimmel Center for Prostate and Urologic Cancers, of the Memorial Sloan Kettering Cancer Center, in New York, New York, and a research scholar of the American Cancer Society; and Dr. Michael Atkins, deputy director of the Georgetown Lombardi Comprehensive Cancer Center, and the Scholl professor and vice chair of the Department of Oncology at the Georgetown University Medical Center, in Washington, DC. Thank you again for joining us. Let’s begin.

Thai, let’s start with a better understanding of the evolution and understanding of kidney cancer, especially as we’ve read in journal articles over the last several years about tumor heterogeneity. How does that play into what’s happening in kidney cancer, how you think about the disease, and how you think about its evolving biology?

Thai H. Ho, MD, PhD: It’s an important topic. As our technology for DNA sequencing is improved, we find that our tumors are heterogeneous. That means that you sample one part of the tumor versus another part of the tumor. You’ll actually see differences in what kinds of DNA mutations you have. One common theme, though, is that a lot of these DNA mutations converge on loss-of-function mutations in the epigenetic pathways. These are things that regulate our DNA and chromatin structure. What is challenging, though, is that if you’re looking for some predictive biomarkers, it can influence where you sample a tumor and what kind of mutations you have. For example, if you were to sample a strand of my hair, you may get a black hair or you may get a gray hair. With tumors, we also have the same kind of challenges ahead of us.

Robert A. Figlin, MD: Martin, one of the things that are evolving in our understanding of this heterogeneity is that mutations change over time. Some become more important. We’ve learned that mutations like PBRM1 and BAP1 are mutations that have been defined. I know that you’ve done some work—reported at the 2017 ASCO Annual Meeting—that looked at the COMPARZ trial, which started to help us understand how some mutations may have different meanings as the tumor evolves. Can you shed some light on that?

Martin H. Voss, MD: We’ve known for a long time that functional loss of VHL [von Hippel–Lindau] is a linchpin into the development of metastatic kidney or, specifically, clear cell kidney cancer. And we have since learned, through some of the efforts that have been described, that there are other genes in a similar region of the human genome, also on chromosome 3p, that are commonly, functionally, lost in these diseases. The 2 that you mentioned, PBRM1 and BAP1, are recurrently mutated in clear cell kidney cancer patients. In metastatic disease, we find loss of PBRM1 by deactivating mutations in up to 50% of patients. Loss of BAP1 is less common—we probably see this in about 20% of the patients we treat in the metastatic setting. We’ve started to explore the biologic significance of that. If we have these recurrent mutation events, what is it that may change about a patient’s course and about how they may fare on the therapies that we use?

The COMPARZ trial was, at its time, the largest trial done in kidney cancer that randomized patients in the first-line setting to receive either sunitinib or pazopanib. All were treated with a VEGF-targeted tyrosine kinase inhibitor, and what we’ve done, in an analysis that we recently did on a trial set of over 400 patients treated on that trial, is we did genomic exploration and specifically looked into mutation status for these recurrently mutated genes and how that may track with outcome on first-line TKI therapy—that being, really, the standard of care in this disease.

What we found is that PBRM1 mutations and BAP1 mutations actually have opposite effects in terms of how patients do. If we look at PBRM1, harboring a PBRM1 mutation in the tumor means that a patient is actually more likely to fare better in terms of progression-free survival and overall survival than PBRM1 wild-type status. For BAP1 mutations, we see the exact opposite effect. BAP1-mutant patients tend to fare worse on TKI therapy than patients who do not harbor a BAP1 mutation in their tumor. We’re trying to understand why that is. It may have something to do with how the presence of these mutations and epigenetic pressures that may exert play into tumor angiogenesis and pathway signaling in patients.

Robert A. Figlin, MD: Do you think that they are predictive, prognostic, a combination? How do you assess this?

Martin H. Voss, MD: That’s a very important question. It’s difficult to assess it on this trial, because all patients that we pooled in this analysis were treated with the same type of therapy. But we are learning now, by looking at different data sets, that they are likely prognostic, not predictive, markers. We have looked at PBRM1 and BAP1 in our group on 3 large clinical trial and non-clinical trial data sets, and we see the same signal each time—be it that we look at VEGF-targeted therapy, mTOR-targeted therapy, and, more recently, also immunotherapy. Having PBRM1 mutations in the tumor seems to confer a better outcome than being wild-type.

Transcript Edited for Clarity

Brought to you in part by Eisai
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