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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, a good friend and colleague Dr. Lorelei Mucci, who is the Director of the Cancer Epidemiology and Cancer Prevention Program within the Department of Epidemiology at the Harvard T.H. Chan School of Public Health, where she is also a Professor of Epidemiology. In addition, she is the leader of the Cancer Epidemiology Program at the Dana Farber Harvard Cancer Center. Thank you so much for being here with me today, Dr. Mucci.

Lorelei Mucci: Oh, thanks so much Dr. Morgans. I'm delighted to be here.

Alicia Morgans: Well, I'm always delighted to talk to you. Today we are going to talk with you about exercise and lifestyle in cancer care, and how that specifically affects our patients with prostate cancer. But let's take a step back and first talk about the importance of lifestyle and exercise nutrition in cancer in general. Can you tell us a little bit about that?

Lorelei Mucci: Yeah, there are a lot of commonalities in factors that lower the risk of cancer overall that is similar to lowering the risk of cardiovascular disease. So these are things that are part of a healthy lifestyle, engaging in regular physical activity, not smoking, or quitting smoking if someone is smoking, maintaining a healthy weight. Then we're really learning a lot about the specific types of dietary patterns that really are associated with a lower risk of cancer overall. Well, many of these factors also are associated with a lower risk, not prostate cancer overall, but specifically more aggressive forms of prostate cancer or cancers that ultimately will become fatal. So things like, again, not smoking, maintaining a healthy weight, regular exercising, and then a number of healthy dietary patterns as well.

Alicia Morgans: Well, I really would love to dig into this because I know that you have done a lot of work in understanding how these factors intersect, as you said, specifically with higher-risk prostate cancers, and you've done it in various settings. I'd love it if you could share some of the insights that you've learned most recently.

Lorelei Mucci: Well, one of them, I think really exciting and most consistent findings across many different studies is the role that exercise plays. That is both for exercise preventing that more aggressive cancer from forming, and then also among men who have prostate cancer, improving not only cancer survival but also survivorship thinking about things, aspects of quality of life. So we've done some work in a large cohort of men based at the Harvard School of Public Health, it's called the Health Professionals Follow-up Study. What we showed there were that men who engaged in vigorous forms of exercise, such as brisk walking or running, had about a 25% lower risk of lethal forms of prostate cancer. Then, in addition, we looked at a specific molecular subtype of prostate cancer, a subtype known as the TMPRSS2-ERG fusion. It seemed that exercise specifically lowered the risk of that type of cancer. And that is a very interesting cancer because it seems it may be more sensitive, not only to androgens but also to growth factors and metabolic factors. So it kind of biologically makes sense as well. But I think also a very exciting area of research.

Alicia Morgans: I could not agree more. I really want to emphasize your work in this health professional study because it's fascinating just the way that the data is acquired and the way that data on lifestyle and other factors, including prostate cancer and the treatments administered and the outcomes... it can all be linked back to genetics and to biology in certain patients at least where you've collected the samples. Can you tell us a little bit about that cohort? Just because I think it's so fascinating and important as we think about this work.

Lorelei Mucci: Yeah. It's a really amazing cohort study that was started back in 1986. There were 50,000 men who were enrolled. They were all health professionals. So they were veterinarians, dentists, optometrists. We selected them because they felt [inaudible 00:04:22] they'll provide really reliable information about their health. In addition, they would be likely to sustain in a long study. So we send them questionnaires every two years to have them tell us about their health. We follow them for cancer incidents, mortality. Then in addition to all of the sort of lifestyle, diet, and medication information we collect, we also have a really unique bio-repository, a blood-based repository, and then also a tissue repository. So out of the 50,000 men, we have DNA and blood samples for about 18,000. Then we have actually prostate tissue specimens for almost 3,000 of the men who've been diagnosed with prostate cancer.

Alicia Morgans: So from my perspective, this is an extremely powerful real-world type of study. So I am sure that as folks see this, they will be eager to reach out to you to see if they can collaborate on specific questions. I'd love for you to share other insights that you've learned from this study or from others that might inform listeners as they are thinking about lifestyle specifically as it relates to prostate cancer.

Lorelei Mucci: Yeah, well, we're actually always delighted to collaborate. And in fact, one of the really new pieces of data is through a collaboration with Stacy Loeb, who is a urologist in New York, and she's been very interested in plant-based diets and prostate cancer. So we have very exciting data looking at men in the health professionals follow-up study who were more or less likely to eat a diet that was very rich in healthy plants, everything from vegetables, fruits, legumes, et cetera. We found that the men who adhered to the most plant-based diet... So they had the highest plant-based diet index in their life had a much lower risk of again, that lethal form of prostate cancer. In addition, it seemed that really the benefit was for the men who started a little bit early in life, so before the age of 60. So that is one really exciting new piece of data.

We've also been looking at dietary patterns that may induce inflammation or high levels of insulin. Those dietary patterns seem to be associated with an increased risk of more aggressive forms of prostate cancer. So I think there's a lot of interesting ways to translate that information. We have some ongoing projects now where we are looking specifically at prostate cancer patients, again, can you lower the risk of fatal prostate cancer and improve survival through either a plant-based diet? Or avoiding diets that are high in insulin or high in inflammation?

Alicia Morgans: So, Dr. Mucci as you're thinking about this work and some of the challenges because every study that we do of course has limitations. How do you think about the issue of causality versus just association? How in a perfect world would we answer some of these questions in terms of really defining causality?

Lorelei Mucci: That's such an important question. I think one of the exciting opportunities we have for example, through the Prostate Cancer Foundation, are opportunities to collaborate together with people of very different disciplines. So one example of a study like that was together with David [Lavey 00:08:00], who is a PCF Young Investigator, Myles Brown, and [Massimo Loda 00:08:03], where they had an animal model where they looked at the impact of a high-fat diet in a prostate cancer mouse model. They found, in fact, in specific mic models, that the high-fat diet seems to fuel the growth of prostate cancer. They actually identified biological markers that we were then able to look at in our epidemiology study and show that the saturated fat in particular... which we had previously shown to be associated with more aggressive prostate cancer also was associated with these same biological markers.

Then on the flip side, of course, what you want to do ultimately is try to conduct a clinical trial. The problem is with a clinical trial of course, with cancer like prostate cancer is you often would have to wait say 10 to 15 years to really see enough endpoints. So I think what we can do as epidemiologists is to partner with clinicians and basic scientists.  They have this sort of opportunity for bidirectional translation of findings to kind of test epidemiology findings in both clinical studies, and or experimental models and vice versa for example, for basic scientists to collaborate with us, to look at how animal findings might translate in the human population.

Alicia Morgans: Well, I love that, taking the findings back to the bench, back to the mouse models, and then taking findings from those mouse models and from those studies back into your cohorts. I just think as you said, this bidirectional approach is fascinating. So where do you go from here? Where do work and lifestyle, and lifestyle intervention go in prostate cancer?

Lorelei Mucci: I think a lot of the work that's been done so far, specifically in prostate cancer patients has been done on men, primarily who have more localized disease at the time of diagnosis. Where I'd like to see work being done is shifting to the more advanced settings. So in addition to really exciting developments in new therapeutics, I think there are a lot of unanswered questions. For example, how does the fact that somebody might be taking aspirin, or what is something like their body weight, how might that interact with these therapies? And can you reduce potentially some of the side effects by engaging in a healthy lifestyle? So I think that is one exciting area.

Another exciting area is work that we've done in, actually, one of our postdocs was just announced a PCF Young Investigator to extend this work, which is looking at... We know that prostate cancer has a strong inherited genetic component. So about 57% of the variability in the incidence of prostate cancer is due to inherited genetic factors. So an important question is can men at high genetic risk offset that risk, through a healthy lifestyle, diet, aspirins, statins, et cetera. So I think that is a big area that we are going to be exploring, and I hope others will be exploring as well. We were actually on email today talking about the work that you've been doing, looking at cognitive function in prostate cancer patients. It really is a big issue in quality of life.

Well in non-cancer patients, there's some really exciting evidence that would suggest things like regular physical activity or even antioxidants from the diet may improve cognitive function. So I think there are some really interesting questions that we could ask together in the advanced prostate cancer setting. Given the fact that men may be more susceptible to cognitive decline because of newer androgen deprivation therapies. Can you offset or improve cognitive function through a healthy lifestyle? So I think I'm looking forward to working with you on some of those projects as well.

Alicia Morgans: I would absolutely love to work on those and really do look forward to us making all of those impacts, and finding out how effective we can be by using these teachable moments and helping patients make a change on their own, not necessarily with a pill that they take or with an injection that we give. So, thank you so much for all of your efforts, and all of your research in this area. I sincerely look forward to seeing where things take us in the future. Thank you for your time today.

Lorelei Mucci: Thank you so much. It's been a pleasure.