Genomic Alterations and Self-Reported Agent Orange Exposure in United States Veterans with Metastatic Prostate Cancer - JJ Haijing Zhang

June 26, 2023

Andrea Miyahira interviews JJ Haijing Zhang on her research exploring the genomic alterations in prostate cancer patients exposed to Agent Orange. Agent Orange, an herbicide used by the US military during the Vietnam War, is linked to various health toxicities, including prostate cancer. Dr. Zhang's study aims to identify any specific somatic alterations related to Agent Orange exposure. The research studied 2,673 veterans, 22.8% of whom reported exposure. Findings revealed somatic alterations in genes like androgen receptor were significantly associated with self-reported Agent Orange exposure. The research is ongoing, aiming to further validate these findings and explore links with long-term outcomes. Dr. Zhang warns that while the initial findings are promising, future validation will be essential.


JJ Haijing Zhang, MD, Urologic Oncologist, UCLA Health, Los Angeles, CA

Andrea K. Miyahira, PhD, Director of Global Research & Scientific Communications, The Prostate Cancer Foundation

Read the Full Video Transcript

Andrea Miyahira: Hi everyone. Thank you for joining us today. My name is Dr. Andrea Miyahira, and I'm the Senior Director of Global Research and Scientific Communications at the Prostate Cancer Foundation. Joining me today is Dr. JJ Zhang, a Urologic Oncology Fellow at UCLA.

Dr. Zhang presented a poster at ASCO on genomic alterations in prostate cancer patients who have been exposed to Agent Orange. So thank you, Dr. Zhang for joining me today.

JJ Zhang: Thank you. It's a pleasure to be here today.

Andrea Miyahira: Agent Orange is a herbicide that the US military has used in the Vietnam War as a major warfare tactic, and it is linked to environmental toxicities, and also, to health toxicities. And prior epidemiological studies have found links between Agent Orange exposure in veterans and earlier prostate cancer diagnosis with more advanced stages. Am I correct? And so in this study, what were you guys looking to determine?

JJ Zhang: So as you mentioned, Agent Orange has been postulated to be an environmental risk factor for multiple cancers, specifically for prostate cancer. Our epidemiologic studies have demonstrated that it is associated with earlier disease onset and more severe disease. What we don't know from published literature, is whether there are specific somatic alterations that are associated with self-reported Agent Orange exposure. So that's the question we asked in our research.

The aim of our study is to elucidate whether there are specific somatic alterations that are associated with Agent Orange exposure in the US veteran population.

Andrea Miyahira: Thank you. So what were the cohorts that you were able to study for this?

JJ Zhang: Yes. So in the beginning, we started off with about 4,500 patients, and these are veterans who are diagnosed with metastatic prostate cancer, who have available genomic sequencing data. And this is all done through a panel-based commercially available sequencing platform called FoundationOne CDx. And so, with the 4,500 patients, we wanted to only look at the veterans who had solid tumor sequencing. So after excluding patients with liquid only biopsies, we then also excluded patients who had no known Agent Orange exposure status.

After that, we actually went through and verified the individual military records of the veterans, to make sure that they served in the Vietnam War, or in the Korean Demilitarized Zone, during specific pre-specified years of known Agent Orange utilization. And so ultimately, our final analysis, we analyzed 2,673 patients, and 22.8% of whom did self-report Agent Orange exposure.

Andrea Miyahira: Okay. And what were the major findings? Did you find any genomic alterations in prostate cancer that was linked with Agent Orange exposure?

JJ Zhang: We did. So on univariable analysis, we found that somatic alterations in Tempus to ERG and androgen receptor, or AR and FGFR were associated, or they were more frequent in veterans who self-reported Agent Orange exposure, compared to the non-exposed cohort. However, we did perform a multi-variable analysis, because we wanted to factor in other covariants, including the age of prostate cancer diagnosis, the race, BMI, presence of secondary malignancies, as well as some environmental factors including smoking history, smoking status, and urban or rural environments. So on our multi-variable analysis, we did find that androgen receptor alterations remained significantly associated with self-reported Agent Orange exposure in our group.

Andrea Miyahira: Okay. And AR alterations are typically associated with prior exposure to AR targeted agents. So were there any differences in your cohorts between patients who were? The sample that you used was from a primary tumor versus from a CRPC sample or different, other different, I guess, clinical characteristics?

JJ Zhang: Yeah. That's an excellent question, and we also asked that question. So that is one of our future steps, and we're actually currently working on that. So we're currently working on collecting the data to tell us whether these are CRPC or these are treatment naive CSPC samples, because we do want to analyze these groups separately. We're also working on collecting the data to tell us if these are primary versus metastatic tumor tissue. So because all of this data collection is done manually, it is taking some time, but that's absolutely the next step, and that's our focus right now.

Andrea Miyahira: And are you guys going to look at long-term outcomes, whether there are any links to overall survival, for instance?

JJ Zhang: Absolutely. That is the plan. So right now, the cohort that we have is a very specialized, unique cohort, in that we're only looking at veterans with metastatic prostate cancer who have genomic sequencing data, so they were all sequenced. Right now, we're also working with a much larger cohort of all veterans with prostate cancer, regardless of whether they have sequencing data or not. And that is actually a better cohort to answer clinical questions regarding whether there are overall survival differences in the exposed versus non-exposed groups. And I think that that cohort is better designed to answer the clinical questions.

Andrea Miyahira: Okay, thank you. Do you have any take home messages, or final thoughts for our viewers today?

JJ Zhang: Absolutely. I think the results are promising. The initial results are promising, suggesting that, in multi-variable analysis, alterations in androgen receptor are significantly associated with self-reported Agent Orange exposure. However, we do caution, that because this is an initial exploratory analysis, future validation of this work will be required, and that is something that we are aiming to do in the next year or so.

I also wanted to acknowledge the senior authors, my mentors, Dr. Isla Garraway and Dr. Kara Maxwell, who have been extremely supportive in this research process.

Andrea Miyahira: Okay. Well, thank you so much for joining me and sharing this with us today.

JJ Zhang: Absolutely. Thank you so much.