RTP On Demand: Current and Future Role of PARP Inhibitors in the Management of Ovarian Cancer (Video Program) - Video 3Somatic versus germline BRCA mutations and correlation with response to PARP inhibitors
4:13 minutes.
TRANSCRIPTION:
DR HERZOG: One thing we know about ovarian cancer, epithelial ovarian cancer specifically, is that it’s a very genetically garbled disease in terms of looking at the genetic mutational load. There are a lot of mutations that are present there. And yet, interestingly, if we look at a lot of the immune drugs and checkpoint inhibitors, they seem to work well in those that have a high mutational load. So far, we’ve seen some promise with these agents, but it has not been a home run by any means in ovarian cancer. So while we have a lot of mutations, they aren’t necessarily antigenic in terms of the immune system. And so there’s a little bit of a disconnect there. Nonetheless, we still see this very high number, copy number, deletions, additions and so forth — translocations. And, as you look at the Cancer Genome Atlas Project, it’s really impressive in terms of the amount of damage that’s done across the genome in ovarian cancer. DR LOVE: And that kind of leads into this issue, I guess, of somatic mutations as opposed to germline. Can you talk a little bit about what we know about somatic mutations and correlations with response to PARP inhibitors or any other novel agents? DR HERZOG: Yes. One of the things that can occur is, of course, you can inherit this mutation from your mother or your father. The other thing that can happen is you can have de novo mutations that occur in the tumor itself. And so somatic mutations are usually picked up with direct testing of the tumor, in which you can have a BRCA mutation that’s present there that would not be present in the rest of the cells in the body, if you will. So if you tested the blood of a patient and picked up the white blood cells and looked at the nuclei in the DNA there, you would not see a BRCA mutation present. So what’s interesting is that you now have another class there. And then the question is, do you see a response in those patients that’s very similar? And the answer’s yes. So I don’t think most thought leaders think there’s much of a difference in terms of the response that we see between the germline and the somatic mutations. DR LOVE: And there have also been attempts — and this paper that we’re going to talk about looked at so-called homologous recombination deficiency. What are you measuring when you look — measure something like that? And is it — when people look at that, are they looking at the same thing? DR HERZOG: No. And that’s one thing that you need to be aware of, is there’s several ways of assessing for homologous recombination deficiency. And I think that’s important. This particular study embraced a test called myChoice. And they actually did a validation set and tested it and came up with a cutoff score of 42. So for those that were above 42, they were considered to have homologous recombination deficiency, those below that score — DR LOVE: Is this RT-PCR or NGS? What kind of test is it? DR HERZOG: I believe it’s next-gen sequencing. DR LOVE: And it’s on the tumor? DR HERZOG: Right. That’s correct. So these patients had at least 4 samples of their tumor sent. And importantly, it was the original tumor that they could get. It was not at recurrence. DR LOVE: And in terms of to get this score, what did they look at, mutations, or how did they come up with this score? DR HERZOG: Well, they’re looking at a series of genes that are expressed or not expressed. They’re looking for telomeric imbalance. And there was one other — I can’t recall what the third thing was. But there’s a series of things. They came up with a scoring system that’s obviously in a black box — it’s proprietary — that we don’t know how that scoring system works. But it predicts the response rate to these compounds, and it’s very interesting. So the higher your score, the more likely you are to respond. |