Genomic Analysis and Assessment of Treatment Patterns To Better Understand Disparities in Advanced Prostate Cancer – Brandon Mahal

July 30, 2021

In this UroToday discussion Charles Ryan and Brandon Mahal, discuss Dr Mahal’s recent update to his study that was published in last year’s New England Journal of Medicine. Dr. Mahal begins this conversation by discussing the background of his recent study, discussing the differences in mutational landscape, of advanced prostate cancer patients, between men with European and African ancestry. Dr. Mahal also discussed his rationale for using ancestry as opposed to using self-identified race to categorize patients. The largest point from Dr. Mahal’s abstract that was discussed was the relative similarity of prostate cancer aggressiveness across African ancestry and European ancestry, even though it has been shown that African American men have a higher risk for mortality from their prostate cancer. The answer that Dr. Mahal, and his team, came up with for why African American men may be seeing a higher mortality risk from their cancer stems from lack of access to genomic profiling. Dr. Mahal acknowledged that a lot more work is needed to get to the bottom of this, however, it is exciting to begin to look at this kind of data.

Biographies:

Brandon Mahal, MD, Assistant Professor of Radiation Oncology, Assistant Director of Community Outreach and Engagement, Department of Radiation Oncology, University of Miami Health System, Coral Gables, FL.

Charles J. Ryan, MD, the B.J. Kennedy Chair in Clinical Medical Oncology and Director of the Division of Hematology, Oncology and Transplantation at the University of Minnesota, Minneapolis, Minnesota, USA.


Read the Full Video Transcript

Charles Ryan: Hello, an ASCO 2021 update. Hi, Chuck Ryan here from the University of Minnesota. Today, joining me is Brandon Mahal from the University of Miami. Dr. Mahal is a Radiation Oncologist at the Sylvester Cancer Center where he is an Assistant Professor. Brandon, good to see you again. Congratulations on a really interesting ASCO abstract that looks at the ancestral characterization of the genomic landscape in prostate cancer and some of the disparities that it presents to us. Tell us a little bit about your findings.

Brandon Mahal: Yeah. Great to see you. And thanks again for having me on. So this study is an update to a recent study that my group and I had published in the New England Journal of Medicine last year, that was from Project GENIE. This cohort, in particular, includes a cohort from Foundation Medicine with over 11,000 patients, roughly five times the size of the prior study, including over 12% of men with African ancestry. And so, what we did in this study is characterized genomic ancestry using a SNP-based approach. And then we evaluated the genomic landscape in men with advanced prostate cancer. And we also had access to a cohort of over 900 patients with clinical genomic data. And we were able to characterize differences in treatment patterns, access to comprehensive genomic profiling, and also clinical trial enrollment.

And so, we did find specific differences in the mutational landscape across ancestry. In particular, we were just comparing men with African ancestry to men with European ancestry, and the most notable findings were the genes that were significantly depleted in African ancestry which were TP53, PTEN, and TMPRSS2-ERG, while genes that were significantly enriched in men with African ancestry were SPOP, CDK12, MYC, and HGF. So, those were the most notable differences. Also, from the clinical genomic database, we found that men of African ancestry on median received two lines of therapy before getting genomic profiling, whereas men of European ancestry, tended to only receive one line of therapy before getting access to comprehensive genomic profiling. And then the final big data point was that 30% of men of European ancestry went on trial where only 11% of men with African ancestry went on trial.

Charles Ryan: And that's from Foundation Medicine, 11,000, almost 12,000 patients. So, this is not from a select group of academic institutions that do a lot of clinical trials, this is a nationwide database?

Brandon Mahal: Exactly. Yup.

Charles Ryan: There are three really important concepts, I think, to unpack from your work. The first is, you said it really quickly, is that European ancestry and African ancestry were identified on an SNP-based approach. It was not based on the self-report of the patient.

Brandon Mahal: Exactly.

Charles Ryan: Tell us a little bit about that.

Brandon Mahal: So the prior study that we completed from Project GENIE, the race was reported, self-identified race, whereas in this study using again, an SNP-based approach from 1000 Genomes Project (1000GP), we were able to identify ancestry, which tends to be more accurate and reliable, especially when comparing across tumor genomics. And it's important to separate that out from the race, which is, again, a social construct, a social-political construct, and really to use ancestry in this setting was important. And it allows us to identify more meaningful and accurate findings with regards to the genomic landscape.

Charles Ryan: I know there are but are there subdivisions within the African ancestry dataset that should be thought of as West African versus East African, South versus North? I mean, I've heard about this, and does your work take this into account?

Brandon Mahal: Absolutely. So, that is very important. This particular study did not take that into account. In addition, it's important to attempt to quantify the relative Africaness or Europeanness in ancestry, because individuals are not a hundred percent one thing or another. And so, that's something that was not taken into account in this study, as well. So, that is of critical importance going forward for future studies.

Charles Ryan: Yeah. Good. So, the second big concept is the differences themselves, as you point out, the TP53 and other factors. What's interesting to me is that, for example, TP53 is pretty universally recognized as an adverse, prognostic factor. And this was observed less frequently in the African group. And SPOP is generally considered to be a more favorable mutation when occurring. So, there's not really, or am I interpreting this incorrectly? It doesn't look like there is a directionality to say, the genomics of the African ancestry is worse or better. It looks like it kind of goes in both directions here a little bit, is that correct?

Brandon Mahal: Exactly. So, with regards to genes that predict prostate cancer or cancer aggressiveness, we did not see a directionality. There were, as you mentioned, genes that were either depleted or enriched on one side or the other between African and European ancestry men. And then also genes that have therapeutic implications, so actionable targets and DNA repair genes, as well, there was no difference. So exactly, that is exactly correct. We didn't see any directionality there.

Charles Ryan: So we in the prostate cancer research community have known our whole careers that African-Americans have a higher mortality risk. There's a number of features associated with adverse outcome. But what you might be helping us to figure out is that it is not based on the genomics of their cancer. And it ties into the third big finding from your paper, your abstract, which is access to genomic testing. What you described is that the African ancestry cohort got their genomic testing later than the Europeans.

Brandon Mahal: Yeah, exactly. So, what we are seeing is we're not seeing a difference in prostate cancer aggressiveness, as you mentioned. And it appears that these different genes and gene alterations may occur at different frequencies and different populations for a number of reasons. A big reason possibly is just receiving the testing at different times and potentially receiving different treatments before the testing, and certainly receiving differences in test drug, across the testing spectrum. And so, these points must certainly have an impact, but other factors as well, differences in access to other care and differences in diseases, for other diseases not related to prostate cancer, must certainly have an impact. And those are things that we need to look at.

Charles Ryan: Right. And then finally, you point out that there is no difference in actionability in terms of PARP inhibitors or immunotherapies or other aspects of things, and that would potentially have some implications moving forward. I guess that would be if... one of the aspects of your work would be that there are access issues, there are differences, but you didn't identify that we are missing an opportunity perhaps to capture actionable mutations earlier. I don't know, your thoughts on that?

Brandon Mahal: Yeah. Overall, that's what this work points to. I do feel that we need prospective efforts that capture patients at the time of diagnosis and track them through treatment lines to determine whether or not there are potential differences along the disease spectrum. But as far as this study shows, and the results are pretty convincing in a very large cohort, it doesn't seem that we are missing opportunities. And so, the opportunity that is being missed, maybe getting that profiling early to identify patients who might be able to go on trials that might benefit them. And if there aren't, if we're not seeing differences in actual gene alterations or DNA repair genes, doing that testing early might make patients suitable for a PARP inhibitor, better able to identify who those patients are earlier and close gaps that way, as well.

Charles Ryan: I think there are a couple of implications there. In general, in prostate cancer, when we identify an effective therapy for a population, for example, enzalutamide or abiraterone, and we look at them in earlier disease states, they produce more benefit. So, earlier generally is better. So, the mere fact that these are being not identified or identified in later stages is a critical one. And then the other feature is that, and this is something that I think of when I'm in my clinic, is knowing about your patient's genomics earlier, even when they're not actionable, does affect how I will treat the patient. So, if I have a patient with a very low burden of disease, but I get the genomics and I find that he has PTEN loss and TP53 alterations, I know this is going to be a more difficult course, and I'm probably, consciously or unconsciously, going to use more aggressive therapies earlier. So there's the actionability with targeted drugs, but then there's the sort of the nuance actionability of knowing more about your patient earlier, I think.

Brandon Mahal: Absolutely. Yeah, absolutely. Absolutely. It could change everything, in terms of the disease course and management.

Charles Ryan: Right. So, congratulations on this work, again. And tell us where you're going next with this.

Brandon Mahal: Thank you. Yeah. So, we're still working very closely with Foundation Medicine, which is committed to these efforts. We are planning to evaluate these findings and prospective cohorts, in particular through our community outreach network. So, that is what we are working on now. We're going to set up shop and get out there into the community, try to increase access to this testing for populations that receive it less often or later, and also use this type of testing to help identify patients who can go on trials and close gaps that way. So, we're jumping right into that, as we speak, we are meeting about it weekly. So, we're continuing this work.

Charles Ryan: That's great. Well, congratulations, again on being a leading voice and a leading emerging voice in this concept, this really important concept in prostate cancer. And also, congratulations on the ancestry work that you've done in your own home, I understand you are a new father.

Brandon Mahal: Yes. Thank you.

Charles Ryan: And that's really exciting.

Brandon Mahal: Thank you.

Charles Ryan: So, Brandon Mahal, from Sylvester Cancer Center, University of Miami. Thank you for joining me.

Brandon Mahal: Thank you. Thank you for having me.
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