Landscape of Circulating Tumor DNA Abnormalities in Advanced Prostate Cancer: Distinctions Between African-American and Caucasians - Pedro Barata
March 24, 2021
The second abstract was titled “Family History and Inheritance of Germline DNA Mutations in Men with Prostate Cancer.” and Dr. Barata and colleagues went back and captured the clinical annotation, with a special emphasis on family history, of consecutive men who were germline, or had available germline data in our clinics and they looked into disparities for family history and germline annotation.
Pedro C. Barata, MD, MSc, Assistant Professor of Medicine, Hematology & Medical Oncology, Tulane University, New Orleans, Louisiana
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a good friend and colleague, Dr. Pedro Barata, who is an assistant professor of medicine, and a GU medical oncologist at Tulane, in New Orleans, Louisiana. Thank you so much for being here with us today, Pedro.
Pedro Barata: Hello, Alicia. Thank you for having me.
Alicia Morgans: Wonderful. Well, I just wanted to talk with you a little bit, about two really interesting abstracts that you presented at virtual GU ASCO 2021. Can you tell us a little bit about the first one?
Pedro Barata: Sure. So maybe we'll start with the one that was titled, Landscape of circulating tumor DNA abnormalities in advanced prostate cancer: Distinctions between African-American and Caucasians.
In essence, this work was actually a collaboration among friends and colleagues, and we went back, and we captured all the data regarding patients with metastatic prostate cancer who had available liquid biopsy. We used a commercially available assay called Guardant [Guardant360®]. We basically had a total of 361 patients, mainly Caucasians, 280, and we compared them with 81 African-American.
Our primary objective was really to potentially identify differences that could be due to changes in the genomic landscape, that we can find in African-American and Caucasians, in liquid biopsy. We tried to take it to the next level by using really, a novel approach, which is called Bayesian network machine learning approach, to validate the potential differences we would find there.
As expected, genomic alterations in liquid biopsy are common in patients with metastatic prostate cancer, and they were actually common here as well. The usual suspects were found commonly, including TP53, AR changes, PI3K alterations, but I'm going to highlight one, which is actually CDK12.
If I had to summarize the findings of our work on this retrospective analysis, I would say that very interesting to us, we found a significant difference in the frequency of CDK12 alterations in African-American, compared to Caucasians. So we see that African-American had a higher frequency of those genomic cultural agents that, as we know, belong to the family of recombination gene defects, and compared with Caucasians. What is also interesting is that the machine learning approach that we used here validated those results as well. We felt that those findings were important because as we know, these genomic alterations have potential treatment implications, and so the next steps for this work would be to expand the cohort, and see if these associations remain true in a much larger data set. It's actually what we've been working for the last several weeks on, and hopefully we'll be able to present those results.
But I would say, as a take-home summary is, it seems like the genomic profile of African-American is different than Caucasians with metastatic prostate cancer. And that definitely validates the work on disparities. Because, not all tumors are the same, and there's something about African-Americans that we don't still know completely. I think studies like this will help us to learn a little bit more about what's going on.
Alicia Morgans: I completely agree. I think it's well known that, not just in terms of tumor sequencing, but also certainly in germline sequencing, we simply don't have enough information on African-American, and other minority men with prostate cancer, to really flush out the differences between those tumors and Caucasian men's tumors. But more than that even, to identify targets that may even be novel, or not coming up in some other patient populations.
It's so interesting that the CDK12 alteration came up in this analysis, and it's important, because, just to remind everyone, Arul Chinnaiyan, and the group in Michigan really identified this as a potential marker that may be associated with sensitivity to checkpoint inhibitors, like pembrolizumab.
Now, I think that this still needs to be absolutely studied prospectively, and really investigated, but there may be, in addition to this, of course, other differences between populations that we may be able to target. So really important and really interesting work. And, as you said, I think it's exciting that you're planning to validate this in a larger data set as, as well. So, what is that data set that you're working on now? What can we look forward to?
Pedro Barata: Yeah. We're going to have a few hundreds of patients from several institutions across the country, that are commonly using a liquid biopsy in the metastatic space. In essence, we're going to be able to... Actually, I've seen some of the preliminary analysis, and I can say that it seems that the changes identified early seem to be holding in a larger cohort that, despite the limitations of retrospective analysis, the factor, including patients treated differently and managed differently in different institutions, in a larger number, hopefully can minimize some of those mutations. We look forward to present it in one of the upcoming meetings, and publish around the same time. So that's where we're working right now.
Alicia Morgans: Wonderful. Well, that is fantastic. And thank you for bringing this to our attention. Thank you for ongoing work. And clearly, a continued call to action to us as a field to understand CDK12, its implications, and how we may be able to harness that. We may even be able to help some populations that have experienced quite a disparity over time, so maybe we can do even better for these men. So, fantastic work.
You also presented a second abstract to GU ASCO, what was that?
Pedro Barata: Yeah, I did. The other abstract, talking briefly was titled, Family history and inheritance of germline DNA mutations in men with prostate cancer. So, here in this work, basically what we did is, we went back and captured the clinical annotation, with a special emphasis on family history, of consecutive men who were germline, or had available germline data in our clinics.
So we basically had a good number of patients. Again, we separated, we really looked into disparities again here, for family history and germline annotation. We had 85 African-American included, and 411. So we have close to 500 men here. And what we did was, we looked into pathogenic alterations, versus non-pathogenic, or of US there, and also we looked into family history. And interestingly, what we found in these analyses was that there were no differences that we could identify in the pathogenic genomic alterations between African-American and Caucasians. And there also, no difference in regards to age, and I said, race, and we did include a cohort of non-metastatic, in addition to metastatic. So just as a reminder, we do have, including the guidelines, the discussion with the patient, regarding the role of germline testing for recurrent and advanced disease, and some high risk as well. So we did include non-metastatic/metastatic cohort in here.
But as I was saying, while we didn't find any changes in the pathogenic genomic alterations at the germline level, interestingly enough, the number of variants of unknown significance were significantly higher in the African-American cohort. What does exactly that means, we're not entirely sure, but it was also true that, what we call today variants of unknown significance might become known in the years to come. And so, that was one of the take-home points from this work. We break down every genomic alteration that was found, including DNA repairs, of course, that we know we were expecting the subset of these patients, among other known genomic alterations.
The final take-home message that I think is important to highlight, is the fact that these alterations were associated with a family history of breast cancer and prostate cancer, but no other cancers. So in other words, we didn't find an association with ovarian, pancreatic, and other malignancies. I think what that would suggest was, is that actually, family history can certainly help us to decide moving forward with germline testing. However, I think there's more of the story beyond the family history positive for malignancy. And so I really think that if I had to summarize it in one sentence, I would say that, family history might be complimentary to germline testing, and not necessarily the only clinical information we should be using to decide who gets germline testing, versus who doesn't. I know you work on this as well, and we talk about this quite often. In our clinics, we are constantly tasking for germline. And it's very rare when patient is not, doesn't want to do it, or not interested in doing it. And so it does have family implications, and also has therapeutic implications.
Alicia Morgans: I think that's so important. And just to emphasize, I think the guidelines even state that, or suggest that, we should be doing this testing in the populations you mentioned, so high risk, localized, recurrent, and metastatic, for germline testing, that's actually recommended regardless of family history. But, I've had multiple conversations with our genetic counselor, which we are so fortunate, and we're so fortunate to have her. But she said she really uses it exactly as you said, as something that's complimentary, and also to think about whether she needs to expand her panel of testing for gene alterations. Because there's a prostate cancer, essentially algorithm to test for, but sometimes she'll use a little broader series of alterations, to ensure that she does look for some other mutations that may be associated with other familial cancer syndromes, that may not necessarily be included in the prostate cancer specific syndrome set. I think that this really supports that approach, and that we should still get family histories, and we also should continue germline testing. I love that.
And I also, I commend your comments on VUSs, and that there may be more VUSs in African-American patients, because we actually need more data there to take them from a variant of uncertain significance, or unknown significance, to a variant of known significance, whether it's benign or pathogenic, but we need more information. So again, a call to us as a community, to try to get more germline samples from our minority patients, so we can try to get some of these VUSs ironed out. I'm sure that you and your group are continuing to do that, because you are always pushing the envelope in the area of genetics, germline and somatic, of course.
So thank you so much for the time that you've put into, certainly, the work that you and your team have done. I appreciate the way that you've emphasized team science and collaboration across the field, to really bring this information to the forefront for our patients, and congratulations on all of that. And thank you so much for your time today.
Pedro Barata: Thank you so much, Alicia, and congratulations on your work too. You've been fantastic. And by the way, and also thank you for highlighting some of the interesting work that's been presented at ASCO GU, but all the meetings as well. So kudos to you as well, and thank you.
Alicia Morgans: Thank you.