Charles Ryan: Hello from PCF 2019. I'm delighted to be joined by two epidemiologists: Elizabeth Platz to my far left is a Professor and Deputy Chair in the Department of Epidemiology at Johns Hopkins University, and Lorelei Mucci is an Associate Professor of Epidemiology and Director of the Cancer Epidemiology and Cancer Prevention Program in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health. Thank you for joining me.

Lorelei Mucci: Thank you for having us.

Elizabeth Platz: Yeah, this is great.

Charles Ryan: There's a lot of great things going on right now with the interface of epidemiology and clinical prostate cancer really and our understanding of the disease and the numerous drivers of its lethality and relapse and even incidents. So we've been talking about some of the highlights, some of the work that you're doing around various different factors. And I wanted to highlight two of those. So we talked a little bit about vitamin D and its impact on prostate cancer outcomes and also statins. So these are really common things that our viewers are probably, maybe many of them are taking both. And so tell us, Lorelei, your work on vitamin D and sort of the status of what we think about its relationship to prostate cancer.

Lorelei Mucci: Yeah, thank you so much. First, we could even maybe take a step back and think as epidemiologists, we have two parallel questions we like to look at. One is, can we prevent prostate cancer and particularly advanced or lethal forms of prostate cancer from happening altogether? And then men, once they've been diagnosed with cancer, can we prevent progression and the development of death from prostate cancer? So as an epidemiologist, some of the studies that we're doing together are focused on those two parallel but separate types of studies.

Charles Ryan: Okay.

Lorelei Mucci: Really for many years... And I think Ed Giovannucci, who's a colleague of both of ours at the Harvard School of Public Health, has had really among the first to set out the hypothesis about vitamin D and prostate cancer. And he had done some initial case-control studies where you had blood levels of vitamin D many years before cancer occurred. And the data seems to suggest that men who had low levels of vitamin D had a higher risk of more clinically significant prostate cancer.

Charles Ryan: And this has been something that was shown originally from a geographic perspective, right?

Elizabeth Platz: Exactly.

Charles Ryan: And it's felt to be one of the associations between the Scandinavian incidence of prostate cancer due to low sunlight. Is that still the prevailing wisdom on the fact that vitamin D and sunlight interact, or are there other factors that drive vitamin D levels?

Lorelei Mucci: Yeah, I don't know if you want to talk about this, but specifically there's two main sources of vitamin D. One is there are some foods that we can get vitamin D from. For example, fatty fish can be a good source of vitamin D. But for the majority of us, we produce vitamin D when we're exposed to the sun. And so actually the other sort of ecologic reason we've thought about vitamin D and prostate cancer is the fact that black men have a much higher rate of prostate cancer death and because of darker skin cannot produce vitamin D from the sun the same as, high levels-

Elizabeth Platz: To the same extent, yeah. Exactly.

Charles Ryan: There are a number of other health issues associated with low vitamin D, right, beyond prostate cancer, even other cancers, correct?

Lorelei Mucci: Yes, there are. So it's linked to a number of outcomes including immune function, cardiovascular outcomes. So vitamin D, rickets-

Elizabeth Platz: Yeah, of course.

Lorelei Mucci: The best known conditions. But yeah, low vitamin D seems to be linked to many different chronic diseases.

Charles Ryan: And is the incidence relationship to prostate cancer one related to chronic longterm low vitamin D throughout adulthood corresponding with a higher incidence of the disease and even a higher mortality? Is that correct?

Lorelei Mucci: Yes. That's correct.

Charles Ryan: Okay. And so, for a primary care physician or a patient or a non-patient of a man who's out there thinking about prostate cancer and they have their vitamin D checked, do we have definitive evidence at all that correcting low vitamin D is actually associated with a reduction in the risk of prostate cancer? How do we take that information and use it in the real world?

Lorelei Mucci: Right. I think that is a great question. I would say we do not have that direct evidence. For example, there has not been a prospective trial to see whether you could prevent prostate cancer from occurring and I'm not frankly not sure we're going to do that study, given how long it would take to follow men. There is interesting data on colorectal cancer, however, where that's another cancer for which low vitamin D seems to be associated with a higher risk of colorectal cancer. And there they have done supplemental studies.

Charles Ryan: And shown that they can reduce?

Elizabeth Platz: And the evidence is consistent. Yeah.

Lorelei Mucci: Yes.

Elizabeth Platz: Yeah, it's consistent.

Lorelei Mucci: Actually... I'm sorry. Yeah.

Elizabeth Platz: Yeah.

Lorelei Mucci: I was just thinking there actually has been a trial that just was reported out on vitamin D and primary prevention called the VITAL study. It was actually a study not specific for prostate cancer, but looking at all cancer types as well as cardiovascular outcomes. So men and women were randomized either to vitamin D tablet alone, Omega 3 tablet alone, both or neither. And actually from that trial and it just reported out the men of African descent had a lower prostate cancer mortality in that study.

Charles Ryan: Interesting.

Lorelei Mucci: So very, very interesting.

Charles Ryan: So for prostate cancer patients who are diagnosed with this disease and they're facing the disease now and they're listening, should they get their vitamin D checked? Should they take vitamin D?

Elizabeth Platz: Yeah, it's a good question. So I think our view together would be it's important to know whether a person has low vitamin D or not for good health in general, right. At this time, I don't think we're there say that a man should take vitamin D supplementation just to prevent prostate cancer, prostate cancer death. We're not actually there yet. But again, vitamin D is important for good health in general. And so there's, there's a national movement to make sure people do know whether or not they have low vitamin D. People living in the North in the US, for example, tend to have low levels.

Charles Ryan: Right. So I'm in Minnesota now.

Elizabeth Platz: That's right. For example. Right. For example, yes.

Charles Ryan: Actually, I was joking about the fact that now that I'm in the Scandinavia, I need to check more vitamin D.

Elizabeth Platz: So whenever we can come up with strategies that are good for health in general, they're worth pursuing.

Charles Ryan: Yeah, right.

Elizabeth Platz: Because then you get more bang for your public health dollars, right? That's right.

Charles Ryan: That leads us to a new conversation about statin drugs.

Elizabeth Platz: Statin drugs. Yes, yes. So several years ago, I guess it's more than 10 years ago, we became very interested in whether statin drugs were inversely associated with the development of prostate cancer, especially lethal disease. And so we did the first prospective cohort study of that association. And indeed men who took a statin drug, especially for a longer duration, had a lower risk of developing lethal prostate cancer and dying of prostate cancer. So we were very excited about those results. And then we asked, "Well, what's the mechanism?" So we pursued the most obvious one. So people take a statin drug to lower their cholesterol. So we started looking at levels of cholesterol in men. And again, it's that design that you mentioned before where you start with men who don't have the diagnosis. You have a blood specimen for those men. You measure the vitamin D in the prediagnostic blood.

Lorelei Mucci: Or cholesterol.

Elizabeth Platz: Oh, I'm on vitamin D. Yes, cholesterol. Thank you. In that blood. But we do it in a really tricky way. We only measure it for men who later got prostate cancer and a sample of men who did not. And so sure enough, men who had low cholesterol, which is really normal cholesterol because most American men don't actually have low cholesterol, normal cholesterol was inversely associated with high grade prostate cancer compared to men who had borderline and high cholesterol levels. And we saw that in actually several studies. We saw in the health professionals. We also saw it in the prostate cancer prevention trial. So we were very excited about it. Then I had students pursue that question, saw the same thing for cholesterol and another cohort called the CLUE study.

Charles Ryan: So this is independent, sorry, independent of statin use.

Elizabeth Platz: Correct.

Charles Ryan: Men with normal cholesterol had a higher likelihood of having higher-grade.

Elizabeth Platz: No, the opposite.

Charles Ryan: Lower grade of having.

Elizabeth Platz: So right. Because it aligns with the statin data. So men who had low cholesterol, which is really normal cholesterol, had had a lower risk of having high-grade prostate cancer.

Charles Ryan: It may not be the statins. It may be the cholesterol.

Elizabeth Platz: It could be, but it turns out that statins do much more, right? So they're also anti-inflammatory. So at this moment, we actually don't know what the mechanism is, but it may not matter if we don't know the mechanism. And so then the question is, we saw it in health professionals, we saw that inverse association with lethal disease and fatal disease. Does anyone else see it? Well, turns out now many studies have seen the same association, especially for long duration of use.

Charles Ryan: So for me, the statin mechanism is a little bit easier than the vitamin D to understand because statins regulate cholesterol metabolism, steroid metabolism. Androgens are steroids.

Elizabeth Platz: It's probably not effects on testosterone in circulation for example. So yes, cholesterol is the building block of all steroid hormones, including testosterone, but the amount of cholesterol present even after lowering cholesterol or still using a statin, it still is there in vast excess. So it's probably not due to lowering circulating testosterone levels. However, we cannot rule out local effects. So local production.

Charles Ryan: Yeah. And the question that comes up always in these studies is how do you know that the statin use is really not just a mirror of greater general attention to health?

Elizabeth Platz: That's a good question.

Charles Ryan: They exercise or they eat better anyway.

Elizabeth Platz: Or it's the opposite, right? So who takes a statin? So men who have elevated cholesterol or who are diabetic. And so what we did is we took into account all the other medications that the men were using because of course a man who takes a statin also tends to take aspirin every day or every other day, at least back when we did this work, as well as other drugs related to hypertension and so on. So we took into account those other medications. We also took into account lifestyle factors, obesity, physical inactivity. And these results persisted.

Now, this is epidemiologic research, which means it's observational. We cannot prove causation. We did not randomize a man to take a statin or not, which brings us to, should we do such a trial. You might ask us, right? And so the problem with that is so many men are already on a statin. It would not be ethical to ask them to come off of a statin so that we could randomize them to a statin or placebo. So it probably won't happen. So is there evidence from existing trials, right, where statins were used for other reasons, for example, cardiovascular reasons, right? Well, it turns out those trials did not collect prostate cancer mortality data as a primary outcome because they were cardiovascular trials. So we cannot even answer the question in existing completed trials for other indications.

Charles Ryan: I see. So one of the unique common features of both vitamin D and the statins is that they both sort of are associated or lead to something you can take.

Lorelei Mucci: Yes.

Elizabeth Platz: Right, right.

Charles Ryan: And you highlighted obesity and diabetes, which come up a lot as potential risk factors. And I've always wondered what are the links between those two metabolic entities, Lorelei, and prostate cancers? Is it well established that these are risk factors for prostate cancer?

Lorelei Mucci: So it's actually very interesting because the associations that people have seen epidemiologically diverged for those two factors. So I would say the evidence now is quite good that excess body weight, either total obesity or more central obesity, is associated with a higher risk of advanced prostate cancer. And then for patients having excess body weight is associated with worse outcomes. So I think that evidence is quite good. For diabetes, however, and it'd be interesting to hear Elizabeth's thoughts on this, we're actually working on an analysis right now, updated within the same cohort study that we've worked in, the Health Professionals Follow-Up study, that men who've had diabetes for many years actually have a lower incidence of prostate cancer.

Charles Ryan: Interesting.

Lorelei Mucci: Compared to men who've never had diabetes. And that is really, it's a big conundrum I would say.

Elizabeth Platz: It is.

Lorelei Mucci: What that is.

Elizabeth Platz: And it's not just in the health professionals.

Lorelei Mucci: That's right.

Elizabeth Platz: The vast majority of studies, prospective cohort studies that have investigated that association, have observed an inverse association with incidence. Now, what has changed actually just in the last few years is diabetes now appears to be positively associated with mortality, prostate cancer mortality. So for a long time, even death from prostate cancer was inversely associated. So we're not sure what's changed. So obviously other patterns have changed in the population. For example, our population is much heavier now. And so it could be differences in the link between diabetes and obesity compared with years ago.

Lorelei Mucci: Yeah. I think the other part of this project that we're working on now has looked at the types of treatments you take for diabetes. There's been interest in whether something like metformin, but interestingly in our data, although the numbers were on the smaller side, we didn't necessarily see a strong association between metformin and prostate cancer risk, although other studies have seen that.

Charles Ryan: I get asked a lot about metformin by my patients.

Lorelei Mucci: Yes.

Elizabeth Platz: Right, right. And actually there's a study in Finland where they used registry data. Obviously in Finland they've got a really great system where each person has a population identification number, and then they have a cancer registry, and they also have medical registries, and they have pharmaceutical registries for reimbursement. So they were able to link all those data. And what they found was that it didn't matter what type of diabetes medication.

Charles Ryan: Interesting.

Elizabeth Platz: Yeah. All was inverse.

Charles Ryan: A lot to learn. I've learned a lot just talking to you now. So there's a lot of excitement about trying to interface a lot of this with our oncology care and how to think about whether we should be recommending these types of treatments. And it's always a pleasure to learn about what's going on epidemiologically in this disease because I can translate some of that into the clinic. And then also I hope, vice versa, take some questions out of the clinic for further study. So I want to thank you both.

Lorelei Mucci: Thank you so much.

Elizabeth Platz: Thank you.

Charles Ryan: Not only for spending a few minutes with me here today, but for your work and your leadership in this field, in our field of treating prostate cancer.

Lorelei Mucci: Thank you.

Charles Ryan:  Thank you for joining me today.

Lorelei Mucci: Thank you so much.

Elizabeth Platz: Thank you.