Raising Awareness of Prostate Cancer in Transgender Women With Farnoosh Nik-Ahd, MD, and Stephen Freedland, MD

Stephen Freedland, MD: Thank you so much for joining us, everyone. I'm Steve Freedland. I'm a Urologist at Cedars-Sinai Medical Center in Los Angeles, as well as at the Durham VA Hospital in Durham, North Carolina. Thank you for joining us on Oncology Data Advisor for Prostate Cancer Awareness Month.

I'm super excited that we have a great special guest here, Dr. Farnoosh Nik-Ahd. Dr. Farnoosh Nik-Ahd is a Resident in Urology at UCSF. She went to medical school at the University of California, Los Angeles (UCLA) and had the misfortune as a medical student to choose to work with me on some projects, so she's forever cursed from that. We have some interesting findings that we're excited to share with you today, so welcome to the program here, Farnoosh.

Farnoosh Nik-Ahd, MD: Thank you so much, Steve, for having me. Thank you everybody for tuning in. This is a really special opportunity for me, because Steve is my phenomenal mentor, despite what he just said. This is a really special experience, so thank you.

Dr. Freedland: We're excited to have you. Today, we're going to be talking about transgender women with prostate cancer, which is something that you don't necessarily think much about. These are people who are assigned male at birth but identify as women, and they have prostates and are at risk of prostate cancer. You've done some really nice work there, but let me kind of go into the background. Where did you get interested in this topic from the first place?

Dr. Nik-Ahd: This all really started way back—well, it feels way back—in medical school. Initially, one of the things that really drew me to research is the potential of impacting an entire population and not just one patient at a time. At that point, it was my fourth year of medical school, and I had decided on urology. I had done some prostate cancer research with you, and I really wanted to keep that momentum going. I was thinking about where to go next with everything.

I had seen some gender affirmation surgeries and helped take care of some of the transgender patients while they were hospitalized. I started thinking, what about transgender patients? Maybe it's not about the disease, but it's about the population that different diseases affect. I started looking into what we already know about transgender patients, and it was actually really mind-boggling how little primary literature existed on this whole population.

At that point, it also became a really nice opportunity to try to decrease some of the disparities that affect transgender patients. They're incredibly marginalized and stigmatized, so it also became about health equity. At that point, the question became, where do we even start and how do we get this going? We're really at the beginning of our understanding of how best to care for transgender patients, specifically in urology. So, it's just this really exciting opportunity.

Dr. Freedland: How do you begin, given this lack of information? Where do you start? What are the questions that you set out on this study to ask and answer?

Dr. Nik-Ahd: Initially, we wanted to look at prostate cancer and transgender women. Once we started thinking about how to design the study, we encountered this unexpected and interesting dilemma of how do you even find transgender patients? In the electronic medical record, there's no code that's specific to transgender patients, which was also a surprise to us. When we started looking through what codes even exist, the codes that do exist are not specific. They use very confusing and antiquated language that we don't really use anymore.

We were interested in looking at transgender women specifically since we wanted to look at prostate cancer. The previous literature that had been done on how to identify transgender patients wasn't specific to transgender women. What we did was we looked at all the individual codes to try to figure out which ones are sensitive and specific for not just transgender patients, but transgender women specifically. That was kind of an unexpected first project that we ended up doing, just focusing on how do you even find transgender women? Once we had that established, then we had kind of a clearer roadmap of all the different things we could do from there.

Dr. Freedland: Where did you go from there?Now we can identify these women, so what are the questions you asked next?

Dr. Nik-Ahd: Honestly, the sky's the limit with the questions you could ask, but what we wanted to focus on initially was prostate cancer. When we started looking at prostate cancer and transgender women, it was again mind-boggling that there were very few case reports. It was about 10 case reports and very few other primary studies that had been done. So, we wanted to do a study to look at prostate cancer diagnosis in transgender women.

We used the Veterans Affairs (VA), which is a wonderful national database that has huge benefits when looking at transgender patients. We were able to look longitudinally. We had a national dataset, so it was a really nice fit for what we wanted to do. We queried the entire VA database looking for patients who had one of the codes we had identified in our prior work that were specific and sensitive for transgender women and also a code for prostate cancer. Then once we had that cohort, which was just over 400 patients, we did a chart review of those patients to confirm the patients were actually transgender and that they had prostate cancer.

Then we looked through the clinician notes, the medication lists, the lab values, pathology reports, everything that we could get our hands on, even data from community clinicians that had been entered into the system, to try to get a comprehensive view of what does prostate cancer look like in this population? What are the trends in diagnosis patterns that we're seeing? A big piece of that was looking at the gender-affirming hormones that they were on in relation to prostate cancer diagnosis, meaning in terms of the timing of the diagnosis. We found that most patients who were on gender-affirming hormones were specifically on estrogen. That was the overwhelming majority.

We decided then to stratify patients by estrogen use. Of the initial cohort of just over 400 patients, we had 155 who were confirmed to be transgender with prostate cancer. Then after we stratified them by their estrogen usage, 116 had never used estrogen, 17 had formerly used estrogen but had stopped prior to prostate cancer diagnosis, and then 22 were actively on estrogen at the time of diagnosis. So, that's how we organized the study.

Dr. Freedland: So, you found 155 women. In prior world literature, it was 10, so it seems pretty big, but help us put this in context. I mean, prostate cancer is a pretty common disease. Transgender is a small subset of the population. If you see 155, is that a lot? Is that little? How would that compare to cisgender men?

Dr. Nik-Ahd: That was actually one of the things that we wanted to understand. Because we're using the VA dataset, we had a really nice comparison with what's been done in cisgender male veterans. If you look at what we found in terms of an estimate of the number of cases per year for transgender women compared to what's been found in cisgender men using the same data set, what we ultimately found was that over the 22-year period we had looked, this correlated with about 14 cases of transgender women being diagnosed with prostate cancer per year compared to 33 cisgender men.

It's certainly lower than what we would expect if it was going to be an equal comparison, but it wasn't as low as what had been suggested by the prior case reports. In fact, it was much higher, and higher than what we had expected as well. It is 60% lower, but it's still not an insignificant number of patients who were affected by this. Especially when you think about how our society has evolved, there's been tremendous progress in recognizing transgender patients. Despite the ongoing stigma they face and significant political barriers that exist and fluctuate with time, it is projected that the number of transgender patients and women who openly identify as transgender is going to continue to increase. We think that as patients continue to openly identify as transgender, we'll see more cases of prostate cancer as well.

Dr. Freedland: Congratulations on a phenomenal study. A first-author JAMA paper as a resident is a great accomplishment, and it's an important contribution to the field and not just for you personally.

Dr. Nik-Ahd: Well, thank you. It definitely would not be possible without our team, without phenomenal mentorship from you and Matt Cooperberg, so thank you. A couple things that I want to highlight—there are a couple of really cool findings from the study. The first one was that to our surprise, the highest proportion of grade group 5 disease and the highest prostate-specific antigen (PSA) density were actually seen in transgender women who were actively on estrogen at diagnosis. That, to us, suggested maybe there's a delayed diagnosis that these women are experiencing. Additionally, we don't really know why we have lower rates of prostate cancer in transgender women, and we speculate that this may be multifactorial.

I think in terms of next steps, we have to figure out why are we seeing these lower rates of prostate cancer in transgender women? There are possible explanations, such as a lack of awareness that these patients have a prostate and that they should still be considered for PSA screening, both on the part of clinicians and patients. Maybe there are suppressive effects of estrogen that are affecting prostate cancer development. One of the big ones that we thought about is that maybe it's actually that the reference ranges that are being used for PSA values are not going to be appropriate for transgender women who were on estrogen, for example.

When you think about what's normal in terms of PSA values, all of those reference ranges are set based on data that we have from cisgender men. But for a transgender woman who's on estrogen or other forms of gender-affirming hormones, we would expect their PSA to be far lower. If a clinician who knows to screen a transgender woman for prostate cancer sees a normal PSA, it may not be a red flag to them, but a PSA that's normal may actually be very concerning for a transgender woman who's on estrogen, where you would expect their PSA to be far lower than what's been established in cisgender men.

Dr. Freedland: Can you just walk us through why being on estrogen would lower your PSA? Can you just walk us through that for background?

Dr. Nik-Ahd: Yes, so we would expect that estrogen, similar to other forms of androgen deprivation, would really push patients towards a nearly castrate environment. We would expect that they would have a PSA value that is very low. The reference range is zero to four. If someone has a PSA value that's maybe a two or three, that might be normal for someone who's not on hormones, but it may actually be very concerning for a transgender woman who is taking estrogen when you take into account the castrating effects,

Dr. Freedland: That's because you need testosterone to make PSA, right?

Dr. Nik-Ahd: Right.

Dr. Freedland: That's very interesting. So, where do you go, given you have some interesting findings? These women who are on the hormones seem to be walking in the door with worse disease. We're not sure what's the right PSA to use. There are a number of directions to go with things, so where are you taking this?

Dr. Nik-Ahd: It's another one where there are so many different things that need to be done. It's a really exciting opportunity. But I think where we start is by testing some of those hypotheses. Why do these patients have lower rates and possibly more aggressive disease? Well, maybe it's the PSA values. So what should the PSA values be? One of the exciting areas that we're currently working on is trying to understand what the baseline PSA values are in transgender women who are on estrogen. Are they different from cisgender men? How different are they? And how do these PSA values change as a function of the type of gender-affirming hormones that someone is on and how long they've been on it? What is the expected PSA velocity for someone who starts hormone therapy?

Other areas are, do transgender women have lower rates of PSA screening? Is that another reason why we're seeing these lower rates? I think those are the two big pieces in terms of what to work on next. But I think a really critical other piece is to also understand the patient experience and to understand what some of the barriers are that transgender women are facing in terms of PSA screening.

Prostate cancer is traditionally thought of as a male cancer. You can only imagine for a transgender woman—who is openly identifying as such and is already at risk of being misgendered anytime they go see a doctor, who already faces tremendous stigma in our society—what does it feel like for them to be diagnosed with prostate cancer and to not necessarily have the support and resources that may exist for cisgender men? I think it's a combination of understanding how we can best care for transgender patients and what that care should look like, with direct input from transgender patients and the clinicians who are intimately involved in their care.

Dr. Freedland: It's a great study, and you've clearly thought through the next steps. I think that's important—we often ask questions, we get answers, and then we're kind of stumped. But like any good researcher, you identify questions, answer them, and that just leads to more questions. I'm excited to see where this all goes.

At the end of the day, for our listeners out there, what's the take-home message that they need to be aware of, either for the patients out there who are listening, but also put the providers who are listening and seeing patients? What do they need to be aware of?

Dr. Nik-Ahd: There are a few key take-home messages. The most important one is just to make sure everyone is aware that transgender women still remain at risk of prostate cancer even after they've undergone gender affirmation surgery and that they should still be considered for PSA screening. The other takeaway is that keeping in mind what we found about the risk of delayed diagnosis in transgender women who are actively on estrogen, it's important to really be cautious in terms of how you interpret PSA values for transgender women who are actively on estrogen. Maybe a normal value is not actually normal and is a reason to have them be referred to a urologist. I think keeping those two things in mind is important. Hopefully, we'll be able to contribute more in the future on what the PSA value specifically should look like. But I think that's a good starting point for both clinicians and patients.

Dr. Freedland: I'm going to push you here a little bit, Farnoosh. It's nice to say, "Be cautious. PSAs may not be what you think they are." We don't have the data yet, but is there some number you can give out there to say, "Hey, at that point, it just doesn't smell right. Get to a urologist, let them figure it out." What is that number? Or is it too early to say yet?

Dr. Nik-Ahd: Well, the one answer is that we really just don't know. But if we were to speculate, looking at prior literature, I think there are two things. One is, if there's a rising PSA, then that's cause for alarm. The other piece is that it is been suggested in the past to use a PSA cutoff of 1.0. But again, that's just purely speculative. We don't know, but we hope to answer this question soon.

Dr. Freedland: A cutoff of 1.0 compared to the traditional 4.0—so, it's speculative, but a lot lower than what we think.

Dr. Nik-Ahd: A lot lower.

Dr. Freedland: On that note, again, it's been a pleasure talking to you, Farnoosh. As always, thank you for taking the time to talk to us today. To our listeners out there, thank you for joining us for this Oncology Data Advisor Prostate Cancer Awareness interview and talk. Hopefully, you learned something. Have a great day.

Dr. Nik-Ahd: Thank you so much. It was a pleasure to be here.

About Dr. Nik-Ahd and Dr. Freedland

DNik-Ahd, MD, is a Urology Resident Physician at the University of California, San Francisco (UCSF). Her research focuses on the risk and incidence of prostate cancer in transgender women andstandards for prostate cancer screening and diagnosis in this population.

Stephen J. Freedland, MD, is Director of the Center for Integrated Research in Cancer and Lifestyle and Associate Director for Education and Training at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. He also is the Warschaw Robertson Law Families Chair in Prostate Cancer and a Professor in the Department of Urology at Cedars-Sinai in Los Angeles. He also holds a Staff Physician appointment at the Durham VA Medical Center in Durham, North Carolina. Dr. Freedland has published over 700 articles and served on numerous American Urological Association and American Society of Clinical Oncology guideline panels for prostate cancer. His research interests include the role of diet, lifestyle, and obesity in cancer, cancer health disparities, and cancer risk stratification.

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Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.