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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, Dr. Kosj Yamoah, who is an Associate Member in the Department of Radiation Oncology, as well as being the Director of Radiation Oncology/Health Disparities Research, and the Section Head for GU Radiation Oncology, all at The Moffitt Cancer Center. Thank you so much for being here with me today, Kosj.

Kosj Yamoah: Thank you so much for having me, Alicia. This is great.

Alicia Morgans: Wonderful. So, I wanted to talk with you about a really important presentation that you had, at ASCO 2021.  Thinking about the VANDAAM trial that you presented, which I would love to have you explain to the audience, both in terms of how important this work is in our prostate cancer community, but also what you found and how we can think about using this information in the future.

Kosj Yamoah: Great. When we think about prostate cancer health disparities, particularly there are two main areas of importance, understanding what the effects are and also figuring out what the implementation strategies could be. Because we know that prostate cancer, as it is, is a disease of the aging population, that what causes prostate cancer is often multifactorial. For that reason, when you talk about disparities, it is also going to be multifactorial, right?

So, one of the things that we know is that it has a higher incidence and mortality in men of African origin, in African-American men, and that, if you look at prostate-specific outcomes, you could have identical outcomes, only if you have a timely diagnosis, appropriate staging and adequate or equitable treatment delivered.

That means that all these factors are going to be critical when looking at health disparities in prostate cancer, in the United States and across the world. But, there is emerging data that a subset of men of African origin might harbor some genomic differences or features that are consistent with aggressive disease.

What that means is, if we were to apply the same clinical characteristics as developed by the NCCN guidelines to stage and treat patients, sometimes we could have a suboptimal classification for some groups of patients. Not all, because of genomic diversity and tumor biology.

Over the last couple of years, the field is moving towards personalized medicine, which means that we could actually look at a tumor tissue and determine, based on the biology, what aggressive features are in there. Interestingly, most of these genomic platforms were developed with predominantly men of European ancestry tumor tissues.

And there has been less representation from minority populations, or African-American men, who are known to have higher incidence and mortality from the disease. But, one of the biggest challenges was that, when we even go back and do retrospective analysis, it's not the same. You are looking at logs that have been stored, several decades old, you are trying to figure out what genomics were involved, validating it.

There has always been the issue of, "Can we do a solid, prospective validation of these biomarkers, to understand if they are applicable to men of African origin? And if not, can we develop newer tools that work better, right?"

So, this is how the study was designed, back in 2017, to say, "This is going to be the first prospective validation study of the genomic classifier in African-American men." Of course, during that time of enrollment, other publications came out that were looking at retrospective tissues. Some that I've been involved in and also other collaborators. Recognizing that, in fact, these genomic classifiers are excellent in risk stratifying tumor biology.

The reason why they work well is that they are agnostic to the clinical characteristics. They do not look at a PSA or a Gleason score, or whatever it is. They are looking for [inaudible 00:03:57] registered information or expressing data to develop those signatures. One of such signatures we used was a genomic classifier decipher test.

In a nutshell, we decided that rather than, and this is, I think, an innovative trial design, study design, because, rather than just saying, "Hey, we're going to enroll 250 patients." We actually said, "No, we are going to enroll African-American men and then match non-African-American men, based on clinical characteristics." Based on CAPRA c-indexes, PSA, Gleason score. Not only the Gleason score but their percentage-positive biopsies, so that we can match the tumor burden, as well as the T-stage and so on and so forth.

And these were only limited to low-risk patients that have a higher burden. So, these are low-risks that are going to get treatment. No active surveillance was allowed, and intermediate-risk, right? We limited intermediate risk, because of the follow-up time. We wanted to have a two-year follow-up. We wanted to just limit it to intermediate risk.

These are the patient cohort that all have genomic testing at the time of biopsy. And then, their treatment was based on physician/patient decision-making. Then, we also did a second biopsy test for patients that underwent surgery, because we have their surgical specimens. So, we can now look at biopsy genomic information and surgical specimen genomic information in a subset of patients. Then, we went on to follow them throughout their treatment. So that was the study design.

Alicia Morgans: Yeah, and can you tell me a little bit about what you found? Because I found it incredible that there seem to be, as we would expect, some reclassification of risk for patients which we've seen before, in studies for Decipher. But, as you said, these are mainly studies that are enriched for men of North American descent or European descent. But, when we look at men of African descent, there seems to be a difference in these groups and reclassification in particular. So, what did you find?

Kosj Yamoah: Thank you. I think, particularly, what the first take-home point here was, even before the results, was on the efficiency of accrual. And I think that has been a big, big roadblock for many studies that are looking to accrue more minorities on clinical trials. In these studies, because this was a targeted approach to make sure that we were reaching the right community, that our message was clear, that this is for that community to understand the disease.

We had trained personnel that were trained in cultural competence and how to have clinical studies brought down to specific grade levels to make sure that we get the participation of patient advocates that understand that, and to also reach out to the communities. We had up to 77% accrual success for this study.

I thought that is something that could be discussed and emulated in other studies as well because the efforts that we put in place paid off. I think this could be a way to really turn the tide on low accrual on clinical trials. And with that in mind, what we recognized, and first we recognized, was that, as we set out to do, the patients were extremely well-balanced.

When we looked at things like PSA, there was no difference. The PSA's between the group's biopsy, Gleason scores, NCCN risk stratification, and presented core positives. However, age was still at almost a six-year gap, in terms of age of incidence. So, clearly, we begin to wonder why. Even though we matched on everything we could possibly match, we still recognize there was an age mismatch. Because, somehow, the disease occurs earlier in the prostate gland of men of African origin.

This is something that, was a big take-home from this study, number one. Another take-home point was that this age disparity was exaggerated in the patients that had a higher genomic risk. I want to just take a few minutes to explain that. These patients were divided according to NCCN risk classification; low, favorable, intermediate, and unfavorable intermediate-risk prostate cancer.

And then, we also have that profile lined up with the genomic risk classifier, which also puts them into low genomic risk, intermediate genomic risk and high genomic risk. So you can see the permutations, where we recognize that, when it came to the high genomic risk bracket, there was an age gap, by a median of 61-years-old for African-American men having high genomic risk features, and about 67 in a non-African-American patient's cohort.

The next thing that was very, very intriguing is that, even among so-called low-risk, NCCN low-risk patients that you would by and large even say, "You don't need treatment." This is accurate, but in a subset of those patients, we found out that none of the non-African-American cases had high genomic's patients in there.

However, up to 20% of so-called low NCCN risk, African-American patients had high genomic risk features within their tumors. Then, when we went on to favorably intimidate risk, it went up to about 29% versus 10%. So, overall, we saw that it was accumulated 49% high genomic risk features in low and favorable intermediate-risk prostate cancer patients, that were found in African-American cohorts, but not so much in the non-African-American cohort, in a well-balanced clinically-matched prospective study.

That really brought home the point that, like I mentioned in the initial part of the conversation, it all comes down to adequate and appropriate staging and risk stratification for adequate therapy. Once we achieve that, we are going to get equitable outcomes, but until we are able to do that, whether using personalized care or all those other [inaudible 00:09:51] mechanisms, we will still continue to experience that disparity.

And I think that it is important to recognize that personalized medicine is here to stay. How we use it to address health disparities is something that we need to start to figure out. This study really sets the tone, for some of those types of applications.

Alicia Morgans: I would completely agree. I think what the study also emphasizes is that we can not only use these clinical characteristics, or perhaps things like a Gleason score to make this adequate and accurate risk stratification, that really, we need to think beyond, go into the molecular details of our patients.

Particularly in men of African descent, because these patients are not, even if we match on everything, as you said, there is an age disparity that could mess with the way that... it doesn't literally mess with you, but it might alter the way you are viewing a patient. If you are viewing this patient as a 50-year-old man of African descent, as compared to a 50-year-old Caucasian man, I mean, these are not the same patient, necessarily, when you get down to the molecular details of that patient's tumor.

So, having the Decipher test really emphasizes that and brings that to light, I think is really interesting. Also, as we are talking to and counseling these patients on the front end, as we are still gathering the information, I think it's important for us to know that, even though the man before us is a younger man, he may have a higher-risk tumor. We need to make sure that we couch our discussions in that way, and do the deep dive into investigating what his actual risk is going to be.

Kosj Yamoah: Absolutely. And I think that what probably gets our field a little bit uncertain is that these studies are not to say that you would treat a patient differently based on the color of their skin. No, no, no. Under no certain terms. I think it is worth saying that we are identifying personalized care for patients that might have enriched biology. Because if there are three pathways of developing prostate cancer and an ethnic group uses two of those pathways more than other groups, it's still okay. We just need to know that.

We need to study all pathways, so that we can treat appropriately. That is really the message here. I think once we get that, then it's more about just applying these tools that we already have appropriately and equitably, to achieve equal outcomes. I think that is really the goal and the message here.

Alicia Morgans: Absolutely. This is so much more than skin-deep. This is molecular, right?

Kosj Yamoah: Yes.

Alicia Morgans: We need to get down to the level of the DNA. We need to get down to the level of expression and we need to understand the patient's risk. Aside from everything else.

Kosj Yamoah: Absolutely.

Alicia Morgans: Thank you so much for doing this work. Congratulations, as you said, on enrolling in a trial, despite what we have seen as this historic barrier to enrolling men of African descent. This is clearly something that you and the team have strived to overcome and have done so successfully. The learnings from that, I think, need to be in their own separate paper. But, the learnings, in terms of the molecular testing, and the differences that you have found here, the reclassification from pure clinical characteristics, is going to be very important, I think, as we face these patients in our clinics each day.

And we try, as you said, to give them the correct risk stratification so that we can really target the right treatments. We know the treatments for the risk category, so we have to appropriately risk stratify our patients so we can apply those therapies, those approaches equitably and appropriately when we are actually seeing these men in our clinic.

As we wrap up, would love to hear final thoughts from you before we end.

Kosj Yamoah: I think it's a great time to be a researcher, it's a great time to be a physician-scientist and work in this field, and also, to be a health disparities researcher. I think we are primed to make a difference. I'm glad that we are galvanizing engagement from all disciplines and all specialties because we need everyone. We need advocates, we need a scientist, we need translational basic scientists, as well as clinical trialists. And I don't want to forget our community advocates and our patient advocates, because together, that is the only way we are going to make inroads to this important work.

Thank you, Alicia. Thank you to UroToday. I'm so excited to be featured in this episode. Thank you.

Alicia Morgans: Well, thank you. Thank your collaborators, thank the patients, thank the community advocates. And, really, thank you for doing this work in the first place, Kosj. This is very important. Something we all recognize as a problem, but until we, as a community, take each step forward, we're really not going to make a difference. And you are making a difference in this, right now. So I appreciate your efforts and your advocacy.

Kosj Yamoah: Thank you so much. We will keep in touch.