Melinda Irwin: Can Nutrition and Exercise Improve Cancer Outcomes?

Harlan Krumholz: Welcome to Health & Veritas. I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University, and we’re trying to get closer to the truth about health and healthcare. This week, we’ll be speaking with Professor—and Dean—Belinda Irwin of the Yale School of Public Health. But first, we’d like to—

Harlan Krumholz: A chaired professor, Howie. She’s got a chair.

Howard Forman: That’s the Susan Dwight Bliss Professor. Absolutely.

Harlan Krumholz: There we go.

Howard Forman: …of public health. But first, we like to check in on current health news. You and I have talked about Evusheld, which is the cocktail of monoclonal antibodies that have been prescribed for those who are immunocompromised to prevent COVID and its most serious outcomes, and probably the most definitive, current paper came out last week that gives us a lot more info on its effectiveness. And it is pretty impressive. It’s comparable to the earlier studies about the vaccines. It’s only six months of data after the initial injection, but it really does seem to be as effective as our vaccines. It was tested during the time of Delta, Beta, and Alpha.

They only test this in unvaccinated, high-risk individuals. There were many questions, but the overall outcomes, including the adverse events, were really very favorable. But one additional fact stood out to me in reading the paper is that four of the participants—two in the placebo group, two in the Evusheld group—died of illicit drug overdoses. So, this is almost 1% of the population in a clinical trial. People who voluntarily participated in a clinical trial died of drug overdoses in a six month period of follow-up.

We have spent some time talking about the opioid epidemic and the vast deaths that have ensued. This is a highly unusual population in some ways, but this data point was shocking to me. It ties in with President Biden’s announcement last week of his comprehensive plan to address the opioid epidemic and addiction. We could go into all the elements of that, but I don’t think we’re doing as much for this as we’ve done for the COVID pandemic. But, we are losing a hundred thousand people a year to opioid overdoses, and I really do hope that our interventions start to bear fruit.

Harlan Krumholz: Well, look, if anybody has any questions about how closely you read articles, you’re proving to us that you actually read every word, because that information’s tucked into the article. It’s not the main finding by any means, and as you said, it was equally distributed in the two groups. So, it’s not... Anyone who’s just casually listening, this wasn’t a complication or an issue related to the intervention, but Howie’s making the point that it occurred unexpectedly commonly. This isn’t just opioid use but actually deaths from opioid use. That’s just disturbing.

Look, there’s a lot of areas of health in this country that deserve our attention, that fall into, I would say, public health, epidemiology, or thinking about the way that our society’s structured and the kind of policies that we do to regulate the medications and to enforce our laws.

At Yale, we have a lot of people working on this issue of substance abuse, and it continues. It continues to be a major cause of death, particularly in younger people, disproportionately than anything that you might expect. But, if you put that together, you roll in violence, accidents, deaths from handguns, overlapping with both intentional and unintentional, the suicides.

We have lots of targets for us that could markedly improve health that we ought to be working on just as much as we are traditional cardiovascular disease and cancer and stroke. These deserve our attention too, and I’m a cardiologist. Believe me. I’m all in on preventing cardiovascular disease, but these other drugs that in a way end up being marginalized or stigmatized, as opposed to mainstreamed. We’ve got to understand them as a blight on society, a major cause of adverse health outcomes, and something that we in the healthcare system need to be able to focus on just as we do anything else.

Howard Forman: As you point out, I will say, to the credit of our colleagues here, this is a continued focus of research, but it is just such tragic loss of life and so many years of productive years of life or loss to this. So, I just was struck by it. I don’t know why it hit me so hard. The idea that you could lose 1% of a clinical trial to something like a illicit drug overdose as they describe it was just shocking.

Harlan Krumholz: Yeah, horrible. Just horrible.

Howard Forman: All right. So, it’s great to introduce Professor Melinda Irwin, the Susan Dwight Bliss Professor of Epidemiology and Associate Dean of Research at the Yale School of Public Health, Associate Director at the Yale Cancer Center, and Deputy Director in the Yale Center for Clinical Investigation. She’s a leader in the field of cancer research, focusing on both cancer prevention and control through lifestyle factors. She currently leads two cancer training programs and has mentored over a hundred trainees at Yale.

Dean Irwin did her graduate work at University of North Carolina Chapel Hill, the University of Washington, and earned her PhD from the University of South Carolina.

I know we’re going to get to hear more about the important work you’ve done in cancer epidemiology, and particularly the intersection of exercise, modifiable lifestyle factors, and outcomes in patients with cancer, but I wanted to start off by asking you about your journey. You went to college in Virginia, did two graduate degrees in the Carolinas, and earned your MPH after your PhD. Can you tell us a little bit about how this happened and how it informs your current work?

Melinda Irwin: Sure. Happy to. So, yeah. So, like many public health students, we often have a little bit of a journey to then end up in public health, right? But also similar to many public health students, I always thought I would go to medical school.

So, growing up, I was an athlete. I actually was a gymnast. I had a whole career in that. I was a D1 [NCAA Division I] gymnast at William and Mary. And so, I was always into sports. I thought I’d be an orthopedist, but then my mom was diagnosed with breast cancer in the early ’80s, in her young 40s, and then died of breast cancer when I was 18.

So, I was just beginning college, and I was interested at that time in the intersection between sports or athletics or physical activity and cancer prevention. There was nothing. There was really nothing in the literature from my naive, young perspective at that time.

So, I just went through college, did all the pre-med classes and whatnot, but then I went to Chapel Hill after college, not sure of... thinking I’d still go to medical school. I went to Chapel Hill and got a master’s in Exercise Physiology. At that time in the orientation of the program, I met an epidemiologist, Barb Ainsworth, who had trained at Minnesota and was sort of a leader at that time in assessing physical activity levels, the behavior, and the challenges behind it, much like with diet or any lifestyle behavior and the intricacies around that. So I sort of focused my master’s on measuring these behaviors, and then she left for South Carolina to head up the CDC Prevention Research Center down there.

So, I followed her down to South Carolina, continued my.... Really, my focus during my PhD was on assessment of these behaviors, but then in 1994, Leslie Bernstein published one of the first papers connecting physical activity with breast cancer risk. So, that took me out to, ah, out west. She was at University of Southern California, and I did my postdoc training at Fred Hutchinson Cancer Research Center with Anne McTiernan and worked on this large NCI-funded trial among women diagnosed with breast cancer, a large prospective cohort.

That really launched my career, starting with some prospective observational findings of these lifestyle behaviors and cancer outcomes. And then, that brought me to Yale to really look at interventions and clinical trials, because there wasn’t any back in the early 2000s. I’ve been fortunate to be able to do that for 20 years now, really looking at how modifiable behaviors might impact cancer outcomes. So, that might have been a long-winded answer to your short question.

Howard Forman: No, that’s what I wanted to hear, and I’m sorry about, losing your mother at that age is an incredibly impactful thing.

Harlan Krumholz: Yeah, I’m really sorry.

Melinda Irwin: Well, I think... In the ’80s versus now, I think some of us might take for granted the major advances in cancer prevention and outcomes. We’ve had a 30% decline in cancer mortality rates from the peak in the 1990s. A 30% decline—that’s huge, right? Much of that is because of a modifiable behavior. Tobacco, tobacco control, which explained probably 50% of that 30% reduction, and of course, major advances in treatment, immunotherapy, and more targeted treatments.

But, sort of the concern we have is over these past 30 years, while cancer mortality has declined, obesity rates have increased. And so, you overlap those two, and what’s going to happen over the next decade? I hope we continue to see a decline in mortality rates, but we have to get a better handle on the role of our food environment, our built environment, because we are more sedentary than ever before, because of the advances we have with technology and whatnot.

Harlan Krumholz: One of the great treats for us doing this podcast when we talk to our colleagues is to really get a chance to actually review the kind of things that they’ve done, and Melinda, I’ve been amazed at just the kind of productivity and the impact of the work that you have and am so interested in it.

People who are listening may know that there’s a lot of focus on lifestyle and—a little less so but some—on social determinants in the prevention of cancer, but you’ve been focused on what it means once you’re diagnosed with cancer. A lot of people might be thinking, “Well, isn’t it that there’s this mutation, and you get cancer, and then it’s sort of your biology would take over at that point?” But I think one of the great things about the work that you’re doing is to suggest that there are things under people’s control outside of the quality of their healthcare that may be able to help them to survive better and longer.

Anyway, I just wondered how you came on that, and what do you think when you’re talking to people about your work that helps convince people that they really should take charge and that there are things under their control that can affect their survival?

Melinda Irwin: Yeah. There’s multiple pathways or mechanisms where lifestyle behaviors can be effective in not just cancer outcomes, but as you know, with cardiovascular disease, diabetes, and whatnot.

When we take cancer, the diagnosis in and of itself can, for some, it can kind of make them look a little bit at their routine, their daily routine, what their priorities are and whatnot, but it also requires us as a organization, a hospital, or an environment.... What can we do to help our patients, right?

And so, the area of my research might look at how, the treatments that the patients receive, how do we reduce the toxicity, right? So, we want to make sure they have the adjuvant treatments available to them, but that we minimize the adverse side effects that in turn might make them not adhere to their chemotherapy or their aromatase inhibitors.

In fact, observational research has shown that with breast cancer chemotherapy, only about 50% of patients adhere to the prescribed amount of chemotherapy recommended for them. So, 50% are not receiving the dose that is recommended, because of the toxicity. So how can our interventions or these modifiable behaviors lower the toxicity to improve their adherence? So, that’s one sort of pathway, but another pathway is direct, is just by eating healthy, following the dietary guidelines, and the physical activity guidelines have a direct impact on prognosis on survival. We don’t yet know that.

So, there’s a lot of large trials right now going on with disease-free survival as the end point, because it could be that at diagnosis, changing your behaviors, changing your body weight, changing your diet, changing extras might not actually have an impact on survival. I hope so. I hope those trials, which are very methodologically strong in their design... I hope they do show, but if they are not, if it’s a null finding, we know there’s evidence that these behaviors can improve the side effects. We are showing that it can improve adherence to treatments and just the overall quality of life and also cardiovascular disease outcomes as well.

So, that’s what I like about the research I do. There’s multiple sort of pathways. The trials that we do with patients, we collect participant satisfaction surveys at the end. What they say is profound with how thinking about having a counselor talking with them weekly has helped them to change their behaviors in a way that was accessible to them, because it’s not all on the patient. It’s the community we live in. It’s not easy to eat healthy and to exercise. We don’t live in an environment that cultivates that.

Harlan Krumholz: Well, you might want to just share what I thought was a kind of promising finding in that study you published around weight loss in breast cancer survivors and its impact on breast tissue markers. I know that’s just a prelude to a study that’s actually going to see whether or not people actually live longer, but I thought that was interesting and promising.

Melinda Irwin: Yeah. So, some of the biological findings we’ve found in a short duration, so within six months, and with not like running a marathon, but walking, brisk walking of say 30 minutes a day and really preventing weight gain. Not significant weight loss, but really more the message of preventing weight gain and reducing sedentary behavior. One of our findings is a 30% decrease in C-reactive protein, which as you guys know is a marker of chronic inflammation. We measure. We take a fasting blood draw from the study participants at baseline. We randomize them to intervention or to usual care. We do another fasting blood draw at six months. And so, the change in these blood biomarkers is directly a result of the intervention.

So, in another study, these participants were so willing. We were able to get breast biopsies to get breast tissue from them at baseline and then six months later. We showed changes in the immune pathways and inflammatory pathways suggesting that eating healthy and exercise had direct effects on these pathways where we have targeted therapies, drugs that are not necessarily standard of care yet, like Metformin, in cancer, but pretty important findings. And yet, lifestyle interventions, at a… somewhat modest change of our lifestyle behaviors can elicit a similar response in these immune and inflammatory and metabolic pathways.

Harlan Krumholz: It just makes me think that, also, we have these medications, the GLP-1 agonists, these pills that can reduce cardiovascular risk and reduce weight. It just opens up a wide range of things that we might prescribe in terms of behavior and in terms of pills. Sorry, Howie. I’m excited to hear all the stuff Melinda’s doing.

Howard Forman: It was pretty much along the same lines. For our listeners to know, Metformin is a drug typically used for diabetes, right? As Harlan said, the intersection of diabetes treatment with cancer epidemiology is not an intuitive one. For our listeners, a lot of people think of epidemiology as the study of infectious disease, but it’s really the study of diseases.

Can you tell us more about sort of the opportunity set that exists in oncology for studying diseases and learning about the intersection between what to the common person is just about cells dividing in a uncontrolled manner, but also interacting with a human biology that we don’t fully understand?

Melinda Irwin: Well, if we think about the role of population sciences or public health and cancer outcomes, there’s no better example. Not cancer-specific, but when you look at COVID-19, all the laboratory-based findings in the clinical trials led to these three FDA-approved vaccines, right? But then, what was the next critically important step? It was getting those vaccines into people, right? If that never happened, those discoveries, while critically important, we wouldn’t have been where we are today, and we still have a way to go with more increasing vaccination rates and whatnot.

But, that’s the same thing in cancer. So, similar to the research and work that Harlan does, we have outcomes research, which is really kind of taking these clinical findings and putting them into a real-world setting. How do we test the effectiveness of whether it’s a drug or a lifestyle behavior or a therapy, but in a real-world setting under real-world conditions?

And so, that’s what I love about cancer prevention and survivorship research. We use the same methodology. It’s very strong study designs. What’s challenging about behavioral research is when we call participants to recruit them into our trials. They want the intervention, and you can’t blind them to it. If they don’t get the intervention, they might drop out. And so, you have to be a little bit savvy in how you keep them in the trial and not adopt the behavior if they’re in the control group, but I think there’s a lot we can do in cancer research that is beyond the laboratory and even beyond the clinic that has such impact.

I’m constantly reminding my basic and clinical scientists we have to translate from not just the bench to the bedside, but to the community, and really bring these interventions, these therapies to those who need them most in the community.

Howard Forman: I’ll just say one of the more recent studies that you participated in with our other colleagues pointed out that even when you adjust for socioeconomic factors, cancer care in under-resourced communities, even when you adjust for income and other factors, is reduced. They have reduced access and reduced outcome or worse outcomes. So, are you involved in any community-based interventions targeting social determinants of health or structural racism, either/or, or both?

Melinda Irwin: Yeah. So, the Yale Cancer Center has supported a lot of research in this area. So, working with Marcella Nunez-Smith and Cary Gross and others, we have a project. It’s actually sort of three projects together to develop a large program project looking at just that, structural and social determinants of health and cancer outcomes.

And so, the team, really led by Cary and Marcella, looking at when... not just at diagnosis, but anytime that you’re coming in to, say, a cancer hospital and you have screening. Better screening for these social determinants of health, and not just the screening but then the referral. And so, when we look at where we, as a system, falling short, it’s number one, the screening of these social determinants of health and then the referral.

When we analyze what are the biggest issues and the challenges... food security, transportation, and housing, and that’s not unique to cancer, right? And so, if we can better understand these structural and social determinants or barriers to access into better health outcomes, focusing on those areas, the food security, the transportation and housing issues, I think we can have a huge impact on health outcomes.

We’re doing research on that now building up to put in a larger grant application to the NIH on this topic. Hopefully, a lot more to come in this space focused in the New Haven area but also across the state of Connecticut.

We have a nice platform here in Connecticut with our Smilow Cancer Hospital, where we have 14 additional care centers across the state delivering the same care you’d get here at Smilow in the care center in one of those 14 across the state. So, it allows us to do research and care from more of an implementation science angle or perspective, which is exciting.

Harlan Krumholz: Where are you thinking we are in terms of understanding exactly what we should be prescribing from lifestyle to people once they’re diagnosed with cancer? And by the way, there’s also stress. I’m sure the more that we can address the stress of the moment and helping them to cope must be part of this. So, how are you thinking about where the science is going to go and how the platforms of being able to do research better and faster are going to evolve?

Melinda Irwin: Yeah, so the research over the past 30 years, the observational research, the large prospect of court studies, it’s interesting, because the physical activity recommendation has changed over the years. I’m talking in general for the healthy adult, let’s say.

In the ’90s, well, prior to the ’90s, it was more about vigorous intensity exercise 30 minutes a week, going to the gym, and that kind of exercise. And then, in the ’90s, there was the Surgeon General’s Report and the CDC and American College of Sports Medicine put out: “No, modern intensity exercise about 150 minutes per week is sufficient,” and that was based on these large cohorts. So, it was all about modern intensity activity. And then, in the last decade, the recommendation now, the primary recommendation is to reduce sedentary time. So, it’s not even vigorous or moderate or certain duration or that. It’s reducing sedentary activity.

And why is that? Because when we look at the graph, we see going from nothing to something is your biggest reduction in risk for cardiovascular disease, for cancer, all cause mortality. So, going from nothing to just something, even if it’s not that two and a half hours per week recommended amount of modern intensity, you see a lot of benefit.

So, that kind of makes it hard in regards to what would we prescribe. Well, number one, something is better than nothing, right? And so, that’s where the apps on our phone... The heart app, if you look at it, how many steps you’re getting a day and making that a challenge is probably recommendation number one. Letting people know what is a good amount of steps per day? Someone might think a thousand steps a day is [enough]. Unfortunately, it’s closer to like 10,000 steps a day. About 2000 steps is a mile.

So, I think starting there... It’s a really easy message to tell patients, and then gear it up based on where they’re at. Meet the patient where they’re at. But, I do think we need to do something, because right now is... let’s say, a patient newly diagnosed with cancer. You come in, and you appropriately meet with the surgeon and the oncologist, but we don’t routinely meet with the physical therapist or the dietician. We have an amazing survivorship clinic here at Smilow led by Tara Sanft, but often the physician has to refer them. We’re not good at that referral process. So, there’s a lot of work to be done in getting these little bits of information out there.

Harlan Krumholz: Sometimes I just think that if we said to people, “We have an additional medication that could produce this size benefit. Would you be interested in it?” Almost everyone would say yes. When we present it as exercise, lifestyle change...

Melinda Irwin: Yep.

Harlan Krumholz: It’s not... It doesn’t ring the same bell, but also for the docs, if you told the docs, would you be interested in prescribing a highly effective medication with very few side effects, most would be on board. But yet, when it comes to lifestyle referrals, we’re not as good about that. I think you’re making a great point. We need to—

Melinda Irwin: It’s interesting. Why are we not good? It’s not as easy as just writing a prescription and going to the pharmacy, but it shouldn’t be as hard, right? Medicare reimburses for obesity counseling, weight management counseling, for Medicare recipients, but do you know what percent actually get that counseling? 2%.

Harlan Krumholz: Oh my gosh.

Melinda Irwin: So, even if we build these incentives, these resources, these programs, we have to figure out what are really the barriers or whatnot.

Howard Forman: I want to make sure that we don’t ignore the other part of your career, which is really mentorship, education, and leading programs at our school and nationally. How do you fit it all in, first of all, and what is your key to success in generativity, in creating leaders in healthcare that’ll pursue these challenges?

Melinda Irwin: Well, not nearly as busy as you both. So, I have a little bit more time probably than you guys. I think what’s been a nice shift we’re seeing that’s not unique to Yale. It’s everywhere.... is that the outreach and the training and the mentoring that we want to do starts early. It’s not just our graduate students nor our college students. It’s high school, and it’s middle school. And like you, we get emails from high school students.

I try to respond literally as best I can to every email I get, because I remember being a high school student. I have high school-aged boys right now, and you’re brave enough to send that email out and craft the email. So, giving them that response might ignite something in them to pursue that field.

So, you have to kind of start there, but then with the students that we have, they have.... They’re the next generation, right? They’re the ones that are going to come up with these innovative treatments, therapies, interventions, approaches, and I think we do an amazing job here at Yale in focusing on the approaches and having really strong designs and educating them in that as well as the content area, right?

Nowadays, you have to be so transdisciplinary in your training and in your research. I think we are doing a good job at that and can continue to. The two training programs I have, that’s probably what I like most about it. It’s not one discipline. It’s taking faculty and students from all these different areas and coming up with ideas together is how to move a field forward.

Harlan Krumholz: I agree. We want to be respectful of your time. I’ll just say one thing is that we do know on the Yale campus you’re a person who really invests in the students, and actually, you’re a great role model for how much you care and how much you’ve helped others. It’s just great to see. So I just want to thank you so much for taking the time to be with us, and like I said, for me, it’s a joy both to talk to you, but also get a chance in preparation to be able to see the kind of work you’ve been doing lately and over your career. Anyway, it’s been really nice to talk to you.

Melinda Irwin: Well, thank you both for disseminating this information from all your guests and just getting more of the... We can’t just be publishing in journals. We got to get the information out there in many different ways. So, thank you for what you guys are doing, too.

Harlan Krumholz: Well, thanks, but it’s all Howie. It’s all Howie.

Howard Forman: Take care. Thanks very much.

Melinda Irwin: All right. Have a great rest of the day. See you later.

Howard Forman: So, Harlan, what’s either inspiring you or catching your attention this week, because there’s an awful lot going on?

Harlan Krumholz: Well, there’s an awful lota going on. That’s for sure. Look, as avid Twitter users, you and I, I don’t think that... It couldn’t escape our attention this week that Elon Musk put together a 40-plus-billion-dollar offer and appears to be on his way towards taking Twitter private and had gotten the financing and pulled this thing off. And, wow. Just, wow.

Let me just say one quick thing about this, because the thing that impressed me most is the speed with which he accomplished this. By the way, he broke almost every rule of what you’re supposed to do when you’re thinking about acquiring a company. He went public from the very beginning. He talked about his involvement, his interest. He was going to go on the board, then wasn’t going to go on the board.

But look, whatever you think of Musk, he’s a can-do guy. This person gets things done. From being able to give internet coverage to the Ukraine, to what he’s doing with launching these rockets, to, of course, Tesla. Everybody was talking about electric cars. He made it happen.

I think we all ought to take at least a little bit of inspiration from the notion that people can come up with ideas and actually with will, skill, and by strategic partnerships make things happen at a pace that are unusual in the world today.

But, with regard to what it’s going to mean for Twitter, for free speech, whether it’ll open the door to more problems on social media... I actually have no idea, but I can tell you in a lot of areas where he’s been involved, he’s produced good products. It’s got a pretty good track record. Can’t say I agree with him on a lot of things, on everything, but in terms of his record, I’m kind of impressed with the stuff that he gets done.

Howard Forman: I am, too. I’ve been a critic of him on a number of levels and also an admirer of the things he’s done, but I will say this. I think it will be fascinating to see how he tackles the issue of free speech and trying to create a better public square, because there’s no perfect public square out there. Twitter is not a true public square either as a private entity, but it is easier said than done to create freedoms for people and to allow people to want to engage in that area. I really do... I’m rooting for him, quite honestly. I want him to succeed. I enjoy Twitter. I think it’s made me a better communicator, even though there are times that I probably act badly myself, but I’m rooting for him.

Harlan Krumholz: I’ve never seen you act badly.

Howard Forman: It’ll make it better.

Harlan Krumholz: Ironically enough, this guy is a super engineer. He solves problems, but this may be his most difficult problem, because it’s about human behavior. It’s one thing to solve the battery or to solve how do you drill in the ground in The Boring Company, or how do you get somebody on Mars? These are engineering technical problems. They may seem so difficult, but the most difficult thing is the human mind and really being able to manage human behavior and social media. I’m really curious to see how he’s able to do.

Howard Forman: Fingers crossed.

Harlan Krumholz: Definitely, and good luck to him. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So, how did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m @ H-M-K-Y-A-L-E. That’s H-M-K Yale.

Howard Forman: And I’m @TheHowie. [00:33:09] That’s at T-H-E-H-O-W-I-E.

Harlan Krumholz: Health & Veritas is produced with the Yale School of Management. Thanks to our researcher, Sherrie Wang, and to our producer, Miranda Shafer. Talk to you soon, Howie.

Howard Forman: Thanks very much, Harlan. Talk to you soon.