The Risk of Prostate Cancer in Men with Inherited Germline TP53 Variants - Kara Maxwell

March 16, 2022

In this discussion between Kara Maxwell and Alicia Morgans, Dr Maxwell highlights the role of TP53 in cancer and understanding the Li-Fraumeni syndrome. Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome and the work that Drs. Morgans and Maxwell discuss here sought to determine whether gTP53 predisposes to prostate cancer.


Kara N. Maxwell, MD, Ph.D., Assistant Professor of Medicine and Genetics, University of Pennsylvania, Staff Physician, Corporal Michael Crescenz VA Medical Center – Philadelphia

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, Dr. Kara Maxwell, who is a Cancer Geneticist at the University of Pennsylvania. She also does some work in the VA system there. We are so thrilled to have you. Thank you so much, Dr. Maxwell.

Kara Maxwell: Thank you so much for having me, Dr. Morgans.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about some of the work that you and your lab and your collaborators have been doing looking at TP53, and really all of this stems for you from understanding the Li-Fraumeni syndrome, and really that is kind of how you entered into this prostate cancer interest too. Can you tell us a little bit about that and how TP53 plays a role?

Kara Maxwell: Yes. As many people probably know, the TP53 gene is the most commonly mutated gene in all human cancers, and so for a very long time, my lab has been interested in TP53 biology because we feel that understanding people who carry inherited mutations with TP53 can probably help give us the insight to even more cancers. And as you know, prostate cancer can often carry TP53 mutations as well. And so this whole study honestly came out of some of my patient encounters and some things I was seeing in the patients that I follow with Li-Fraumeni syndrome.

Patients with Li-Fraumeni syndrome have a really high risk of cancer throughout their lifetimes, upwards of 90%. About half of them develop cancer as young adults by the age of 40, but a number of people are living a lot longer with better screening, better treatments, and so we are really interested in what was going on with people as they got older. And so once I had a couple of patients that had developed prostate cancer, I said, well, this really seems to be something that we should look into a little bit more.

Alicia Morgans: That all makes sense, and really led to quite an interesting European Urology paper. Can you tell us a little bit about how you tackled this question, the study that you and your team did, and what you found?

Kara Maxwell: Yeah, so this is a rare cancer syndrome, and so even though I follow a decent number of individuals with this syndrome at Penn, we really had to tap into our network. We are really lucky to have a consortium of other researchers in Li-Fraumeni syndrome who are interested in this at your institution, at Dana-Farber, and also at the Huntsman Cancer Institute and Memorial Sloan Kettering. So we said, well, why don't we just do the most basic epidemiology study and say, let's get all of the men in our families that we know that have the TP53 mutation in their germ-line, and then just ask the question of how many of those men have prostate cancer or not.

We had to do some preliminary work for this. We had looked in a database that is an international database of patients with Li-Fraumeni syndrome, and the rate of prostate cancer was actually really low, about 3% or even lower in that database, which is much lower than the 14% general population prevalence. But then when we looked in this international database, we realized that the average age of the males in this database was actually quite young, almost around 20. So we knew that we wanted to try to get a group of Li-Fraumeni patients that were older.

We pulled our data together, we had about 163, actually 163 men over the age of 18 with Li-Fraumeni syndrome, and then what was striking to us is that as these guys got older and they were in their fifties and above, over half of them actually had developed prostate cancer. What we also noted was that they were developing prostate cancer more like a median age of around 50 to 55, versus in the general population, which as you know is much older.

At that point in time, we were able to connect with researchers at the University of Washington, and I can talk a little bit about their study, but it also allowed us to connect with a really amazing epidemiologist, Roman Gulati, who was able to then compare our Li-Fraumeni cohort to the SEER Database to show that rate of prostate cancer in these Li-Fraumeni men is over 25 fold higher than you would expect in other age categories. So overall, males with Li-Fraumeni syndrome have a ninefold lifetime increased risk for prostate cancer.

Alicia Morgans: I mean, that's so incredible because I remember a time when we really didn't think that folks who had Li-Fraumeni developed prostate cancer.

Kara Maxwell: Right, exactly.

Alicia Morgans: So, how do you interpret this in terms of talking to patients, counseling them on what they need to do? Because this is really kind of a really new finding, I think.

Kara Maxwell: You know, it definitely has been new for my patients to talk about, because it's not only sort of developing cancer, having another thing to deal with and that piece of it, but just the treatment for prostate cancer actually has so many significant implications.

Particularly if we think about androgen deprivation therapy, if we're talking about that age shift in onset, androgen deprivation therapy is difficult for men no matter their matter age, but if you're talking about that age shift into the fifties, even more, difficult for younger men to have to go on that therapy. And so we really think it's important, men with Li-Fraumeni syndrome are already getting a lot of screening, but the type of screening we do doesn't really get a good picture of the prostate. So adding that PSA digital rectal exam in there I think is really critical, so that can direct us to find hopefully these cancers early so these men can avoid ADT.

The other thing is that, as we know, prostate cancer can be treated with radiotherapy or surgery, and we know from many, many years of studies of this syndrome that individuals with germ-line P53 mutations have increased sensitivity to radiation and may develop downstream radiation-induced sarcomas or other cancers. And so knowledge of this then can really help direct that man with prostate cancer to a surgical treatment versus a radiation treatment. That's what we've been discussing with our patients at this point.

Alicia Morgans: I think that's so important. I mean, very, very practical clinical implications. Would you suggest still PSA screening in the 40 to 45 range? Is that the right time to begin?

Kara Maxwell: Yeah, it's always so difficult with these studies. And as we know, as clinicians, we often get very, we practice N of 1 medicine, I like to call it, and so my youngest man that I follow and the youngest man, a couple of men in our cohort actually were in their mid-thirties with prostate eight cancer. And so this has made us question, should it be 40? Should it be 35? Should it be 30?

So I have a discussion with the gentleman in front of me, usually about the exact time, by 40, for sure, I think they should be doing PSAs, but particularly for the patients who end up having a family history of prostate cancer, which we end up finding a lot more once we start pushing. A lot of times when we do family histories, even as geneticists, they might not think about prostate cancer being part of the spectrum. Go back and they're like, "Oh yeah, you know, my dad was only 45 when he had prostate cancer." So in those kinds of situations, starting 10 years younger than that earliest diagnosis is usually what we generally recommend. So by age 40 or 10 years younger than the youngest in the family.

Alicia Morgans: That is really, really helpful. Well, thank you so much for sharing this. I wonder if you have some just final thoughts on what we should take home from your study.

Kara Maxwell: So I did want to touch a little bit about the other half of our study, which was led by Dr. Pritchard at the University of Washington. We were really fortunate to be able to be connected with him, because we looked at this from the standpoint, this question of prostate cancer and TP53 mutations, from the standpoint of the TP53 mutations. Whereas, he was looking at it from the standpoint of prostate cancer patients. So if you take a large group of prostate cancer patients, how many of them are going to have germ-line TP53 mutations?

That was a really interesting finding there as well, in that he found that patients with prostate cancer have a significantly increased rate of TP53 mutations compared to the general sort of population. It's still not that high. It's maybe half a percent of the prostate cancer patients, but then what we were able to do by combining these two data sets was increase the number of Li-Fraumeni or germ-line P53 related prostate cancer patients that we could look at and find that, unfortunately, a lot of the cancers were higher Gleason score diagnosed at a more aggressive stage.

And so I think that what it does then is it brings a couple of different things into focus. One, thinking about the Li-Fraumeni patient and how we should maybe change management. But also hopefully helping to remind individuals seeing prostate cancer patients.  Of course, most of the time they are not going to have a TP53 mutation, but most of the time they are also probably not going to have a BRCA2 mutation, but we do like to make sure we think about that when we're taking a family history, that it should be one of the things to incorporate.  And a lot of young cancer, other prostate cancer, early age, maybe you want to think about doing TP53 mutation testing as well.

One of the reasons that are so important, is that we found in our study that over half of the men with P53 related prostate cancer had a history of young breast cancer, either in their daughters or their sisters, et cetera, and so it's not only important for potentially their treatment but also their family members as well.

So I think as far as a takeaway goes, what I hope that we can bring to the general prostate cancer docs is just a recognition that TP53 is a prostate cancer susceptibility gene. To think about it when you are seeing particularly a very young patient or a patient with a family history, not only of these classic sarcomas, brain tumors, et cetera, but also breast cancer and other early-onset cancers, that this should be something to think about that might be going on in your patient and that it could have treatment implications for them in the selection of radiotherapy versus surgery.

Alicia Morgans: Absolutely. Well, I am so, so appreciative that you've taken the time to share this expertise today, and thank you for getting interested in prostate cancer. I think that your contributions are probably just beginning, and we really appreciate you sharing your expertise with the field.

Kara Maxwell: Thank you so much. I look forward to hopefully being able to talk to you about more work soon.

Alicia Morgans: Sounds good. Thank you.

Kara Maxwell: Thank you.