ONCAlert | Upfront Therapy for mRCC

Understanding the Biological Targets of PARP Inhibitors

Targeted Oncology
Published Online:1:00 PM, Mon November 18, 2019

Bradley J. Monk, MD, FACOG, FACS: Welcome to this Targeted Oncology™ presentation entitled, “PARP Inhibition in Ovarian Cancer: BRCA-Mutated and Beyond.” My name is Brad Monk. I’m a gynecologic oncologist from Phoenix, Arizona, and a professor and director at Creighton University and the University of Arizona College of Medicine, both in Phoenix. It’s my pleasure today to be with my good friend and colleague Dr Thomas Herzog. Dr Herzog comes from the University of Cincinnati, where he is a professor of obstetrics and gynecology. He is also the deputy director of the University of Cincinnati Cancer Institute. Welcome, Tom.

Thomas J. Herzog, MD: Thanks, Brad. It’s great to be here.

Bradley J. Monk, MD, FACOG, FACS: Great times, huh?

Thomas J. Herzog, MD: These are great times, indeed. It gives us, as clinicians who treat ovarian cancer, so many more options than what we had a very short time ago, so it’s exciting.

Bradley J. Monk, MD, FACOG, FACS: And it’s hard to keep up, right?

Thomas J. Herzog, MD: It is. It is. ESMO [The European Society for Medical Oncology Congress 2019] had an avalanche of data that I think many of us are still digesting.

Bradley J. Monk, MD, FACOG, FACS: We’re going to take some time here together and have a conversation about PARP inhibitors, and we’re going to try to add order to chaos.

Thomas J. Herzog, MD: Good luck.

Bradley J. Monk, MD, FACOG, FACS: I want to start by describing what PARP is. PARP is an enzyme, poly (ADP-ribose) polymerase, that repairs single-stranded DNA breaks. If we can inhibit that enzyme, an unrepaired single-stranded break becomes a double-stranded break. If you can’t fix that, the cell dies. And double-stranded breaks are repaired by BRCA. If you have PARP inhibition and a BRCA mutation, that’s synthetically lethal and the cell dies. So tell us a little bit about how BRCA repairs double-stranded DNA breaks and what’s involved in that.

Thomas J. Herzog, MD: I think you said it well. PARP is responsible for the single-strand breaks, and if you have an impairment in the BRCA gene, if it’s mutated and there is a deleterious mutation or functional mutation where the patient can’t repair double-strand breaks, what happens is cell apoptosis occurs and you get cell death. But that can be actually a mechanism that we can leverage for a therapeutic, which is the beauty of it.

Bradley J. Monk, MD, FACOG, FACS: And we, you and I—I hope everyone—follow the NCCN [National Comprehensive Cancer Network], the Society of Gynecologic Oncology, and the ASCO [American Society of Clinical Oncology] Guidelines and test all our patients for germline BRCA mutations.

Thomas J. Herzog, MD: Yes, it’s critically important. I think that’s something that gets lost because we’ll be talking a lot about testing during this conversation. I think people ask, do I tumor test? We’ll get into homologous recombination deficiency [HRD] testing. We’ll explain that in a bit. But people get caught up in all this. One of the important things is germline testing, because not only does it have great implications for our patient, but it is also our opportunity to save others in that family with cascade testing.

Bradley J. Monk, MD, FACOG, FACS: It is the cure for ovarian cancer.

Thomas J. Herzog, MD: It is the cure. We can do risk-reduction surgery with closer surveillance. It’s critical.

Bradley J. Monk, MD, FACOG, FACS: And when we say ovarian cancer, we mean fallopian tube, peritoneal, and epithelial ovarian. We test early, right? We test early because the sister may be getting ovarian cancer next week.

Thomas J. Herzog, MD: That’s right, because the sister may be older or what have you. Of course, there are differences between the genes—BRCA1, BRCA2—in terms of average time of onset of cancer. It occurs much later with our BRCA2 population, which has obviously implications in terms of fertility preservation and that type of thing.

Bradley J. Monk, MD, FACOG, FACS: What BRCA does is this: we have 2 chromosomes, and BRCA takes a double-stranded break, lines up the homologous chromosome to the sister chromatid, and repairs that double-strand break. So it’s a homologous recombination. But it’s more than BRCA. Tell us about that.

Thomas J. Herzog, MD: BRCA pathways are critical because they’re a high-fidelity repair lineage. That pathway is very high fidelity. In other words, the repair process is done very well. It’s like when you take your computer to the Apple Store; it’s probably done well. If you take it to some trailer, it may not be of the same quality. That’s what we see. There are also other pathways that are responsible for repair.

Bradley J. Monk, MD, FACOG, FACS: In the same pathway.

Thomas J. Herzog, MD: Exactly, and other genes that are responsible. That’s where we get into these other genes that can give you the signature of homologous recombination deficiency. That’s important to understand. Genes such as RAD51C, BRIP, ATM. There are a number of genes that we know are important. One way of assessing for homologous recombination deficiency is to actually look for mutations in these genes. There are certainly a number of companies out there right now that do that. They have a panel that looks at the top 40 or so genes and sees if there are any mutations in those. However, that may not be all the story with HRD.

Bradley J. Monk, MD, FACOG, FACS: Because the genes are not created equally.

Thomas J. Herzog, MD: Exactly. There are variable penetrants, if you will, in terms of causing the phenotype that we’re looking for. I think it’s important to understand that there are other ways of measuring for this in terms of the scarring that you get on these chromosomes. One way of looking for this scarring is to do a loss of heterozygosity [LOH] interrogation, and that’s certainly done with, for example, the FoundationOne CDx test, and that’s been used in a number of our PARP trials. That’s important to understand. Then there are cutoffs on that scoring system that are used. If we look at taking it beyond just LOH, are there other things that are important? We know that the telomeres are very, very sensitive, so if we look at the Myriad test, it looks at loss of heterozygosity, but it looks at telomeric imbalance as well as large-state transitions.

Those 3 components come up with an LOH score, which is an arbitrary cut point, and we can talk a little about what that means for some of the recent trials. But using that cut point, it’s not that everyone above that cut point has HRD, but your sensitivity is much higher. As you go below that, it doesn’t mean everyone is without HRD, but the prevalence of HRD is much less below the cut point. And there are a couple of different cut points that have been used.

Bradley J. Monk, MD, FACOG, FACS: That’s really helpful because I think 1 of the key messages of our conversation is that PARP inhibitors work in BRCA; you said it. But they also work in cancers that have BRCA-like gene defects, and that can be measured through this HRD test. So that’s a theme.

Thomas J. Herzog, MD: It’s not perfect. I think we want to point that out.

Bradley J. Monk, MD, FACOG, FACS: But it’s better than nothing.

Thomas J. Herzog, MD: There are other companies right now working on more sensitive tests to see if this could be done in an even more accurate way. Because as I said, the cut points are a bit arbitrary, and there are patients we’re missing below them, and some of the patients above do not really have that phenotype.

Bradley J. Monk, MD, FACOG, FACS: Thank you for that. So HRD is a molecular test for BRCA-like genes that predicts PARP sensitivity.

Transcript edited for clarity.

Bradley J. Monk, MD, FACOG, FACS: Welcome to this Targeted Oncology™ presentation entitled, “PARP Inhibition in Ovarian Cancer: BRCA-Mutated and Beyond.” My name is Brad Monk. I’m a gynecologic oncologist from Phoenix, Arizona, and a professor and director at Creighton University and the University of Arizona College of Medicine, both in Phoenix. It’s my pleasure today to be with my good friend and colleague Dr Thomas Herzog. Dr Herzog comes from the University of Cincinnati, where he is a professor of obstetrics and gynecology. He is also the deputy director of the University of Cincinnati Cancer Institute. Welcome, Tom.

Thomas J. Herzog, MD: Thanks, Brad. It’s great to be here.

Bradley J. Monk, MD, FACOG, FACS: Great times, huh?

Thomas J. Herzog, MD: These are great times, indeed. It gives us, as clinicians who treat ovarian cancer, so many more options than what we had a very short time ago, so it’s exciting.

Bradley J. Monk, MD, FACOG, FACS: And it’s hard to keep up, right?

Thomas J. Herzog, MD: It is. It is. ESMO [The European Society for Medical Oncology Congress 2019] had an avalanche of data that I think many of us are still digesting.

Bradley J. Monk, MD, FACOG, FACS: We’re going to take some time here together and have a conversation about PARP inhibitors, and we’re going to try to add order to chaos.

Thomas J. Herzog, MD: Good luck.

Bradley J. Monk, MD, FACOG, FACS: I want to start by describing what PARP is. PARP is an enzyme, poly (ADP-ribose) polymerase, that repairs single-stranded DNA breaks. If we can inhibit that enzyme, an unrepaired single-stranded break becomes a double-stranded break. If you can’t fix that, the cell dies. And double-stranded breaks are repaired by BRCA. If you have PARP inhibition and a BRCA mutation, that’s synthetically lethal and the cell dies. So tell us a little bit about how BRCA repairs double-stranded DNA breaks and what’s involved in that.

Thomas J. Herzog, MD: I think you said it well. PARP is responsible for the single-strand breaks, and if you have an impairment in the BRCA gene, if it’s mutated and there is a deleterious mutation or functional mutation where the patient can’t repair double-strand breaks, what happens is cell apoptosis occurs and you get cell death. But that can be actually a mechanism that we can leverage for a therapeutic, which is the beauty of it.

Bradley J. Monk, MD, FACOG, FACS: And we, you and I—I hope everyone—follow the NCCN [National Comprehensive Cancer Network], the Society of Gynecologic Oncology, and the ASCO [American Society of Clinical Oncology] Guidelines and test all our patients for germline BRCA mutations.

Thomas J. Herzog, MD: Yes, it’s critically important. I think that’s something that gets lost because we’ll be talking a lot about testing during this conversation. I think people ask, do I tumor test? We’ll get into homologous recombination deficiency [HRD] testing. We’ll explain that in a bit. But people get caught up in all this. One of the important things is germline testing, because not only does it have great implications for our patient, but it is also our opportunity to save others in that family with cascade testing.

Bradley J. Monk, MD, FACOG, FACS: It is the cure for ovarian cancer.

Thomas J. Herzog, MD: It is the cure. We can do risk-reduction surgery with closer surveillance. It’s critical.

Bradley J. Monk, MD, FACOG, FACS: And when we say ovarian cancer, we mean fallopian tube, peritoneal, and epithelial ovarian. We test early, right? We test early because the sister may be getting ovarian cancer next week.

Thomas J. Herzog, MD: That’s right, because the sister may be older or what have you. Of course, there are differences between the genes—BRCA1, BRCA2—in terms of average time of onset of cancer. It occurs much later with our BRCA2 population, which has obviously implications in terms of fertility preservation and that type of thing.

Bradley J. Monk, MD, FACOG, FACS: What BRCA does is this: we have 2 chromosomes, and BRCA takes a double-stranded break, lines up the homologous chromosome to the sister chromatid, and repairs that double-strand break. So it’s a homologous recombination. But it’s more than BRCA. Tell us about that.

Thomas J. Herzog, MD: BRCA pathways are critical because they’re a high-fidelity repair lineage. That pathway is very high fidelity. In other words, the repair process is done very well. It’s like when you take your computer to the Apple Store; it’s probably done well. If you take it to some trailer, it may not be of the same quality. That’s what we see. There are also other pathways that are responsible for repair.

Bradley J. Monk, MD, FACOG, FACS: In the same pathway.

Thomas J. Herzog, MD: Exactly, and other genes that are responsible. That’s where we get into these other genes that can give you the signature of homologous recombination deficiency. That’s important to understand. Genes such as RAD51C, BRIP, ATM. There are a number of genes that we know are important. One way of assessing for homologous recombination deficiency is to actually look for mutations in these genes. There are certainly a number of companies out there right now that do that. They have a panel that looks at the top 40 or so genes and sees if there are any mutations in those. However, that may not be all the story with HRD.

Bradley J. Monk, MD, FACOG, FACS: Because the genes are not created equally.

Thomas J. Herzog, MD: Exactly. There are variable penetrants, if you will, in terms of causing the phenotype that we’re looking for. I think it’s important to understand that there are other ways of measuring for this in terms of the scarring that you get on these chromosomes. One way of looking for this scarring is to do a loss of heterozygosity [LOH] interrogation, and that’s certainly done with, for example, the FoundationOne CDx test, and that’s been used in a number of our PARP trials. That’s important to understand. Then there are cutoffs on that scoring system that are used. If we look at taking it beyond just LOH, are there other things that are important? We know that the telomeres are very, very sensitive, so if we look at the Myriad test, it looks at loss of heterozygosity, but it looks at telomeric imbalance as well as large-state transitions.

Those 3 components come up with an LOH score, which is an arbitrary cut point, and we can talk a little about what that means for some of the recent trials. But using that cut point, it’s not that everyone above that cut point has HRD, but your sensitivity is much higher. As you go below that, it doesn’t mean everyone is without HRD, but the prevalence of HRD is much less below the cut point. And there are a couple of different cut points that have been used.

Bradley J. Monk, MD, FACOG, FACS: That’s really helpful because I think 1 of the key messages of our conversation is that PARP inhibitors work in BRCA; you said it. But they also work in cancers that have BRCA-like gene defects, and that can be measured through this HRD test. So that’s a theme.

Thomas J. Herzog, MD: It’s not perfect. I think we want to point that out.

Bradley J. Monk, MD, FACOG, FACS: But it’s better than nothing.

Thomas J. Herzog, MD: There are other companies right now working on more sensitive tests to see if this could be done in an even more accurate way. Because as I said, the cut points are a bit arbitrary, and there are patients we’re missing below them, and some of the patients above do not really have that phenotype.

Bradley J. Monk, MD, FACOG, FACS: Thank you for that. So HRD is a molecular test for BRCA-like genes that predicts PARP sensitivity.

Transcript edited for clarity.
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