Jun 29, 2021
Dr. Hayes interviews Dr. Pamela Goodwin on her work in metabolism and cancer.
Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes’ research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.
SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement
SPEAKER 2: Welcome to JCO's Cancer Stories, The Art of Oncology brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all of this shows, including this one, podcast.asco.org.
Today my guest on this podcast is Pam Goodwin. Dr. Goodwin was instrumental in the consideration of metabolism, exercise, and diet for prevention and/or treatment of breast, and for that matter, other cancers. Dr. Goodwin received her undergraduate medical degree from the University of Ottawa, and then she did a residency in internal medicine at the University of Toronto, where she also did a year residency in pathology, which I was unaware of.
She went on to train in oncology at Princess Margaret Hospital in Toronto, and she spent a year as a research fellow with, in my opinion, the legendary Dr. Norman Boyd. She's on a clinical appointment at Mount Sinai Hospital in Toronto, where she directed the breast program for 15 years. And she's remained on faculty for the University of Toronto since 1986, where she is now the Marvelle Koffler Chair in breast research and a professor in the departments of medicine and clinical epidemiology.
She's won many, many awards for her contributions to science, but perhaps most germane to this discussion-- and I was unaware-- she was named a star in nutrition and cancer by the United States National Cancer Institute a few years ago. She's authored over 200 peer reviewed papers. And she serves as the current editor in chief of the Journal of the National Cancer Institute Cancer Spectrum, and she's also deputy director of JNCI. By the way, she receives research funding in collaborations with Epic Science but has no other declarations of conflicts. Dr. Goodwin, welcome to our program today.
PAM GOODWIN: Thank you. It's a pleasure to be here.
SPEAKER 2: So let's start with a [INAUDIBLE] question that I ask almost everybody in this series. And that is, tell us a little about yourself and why oncology. Was there a light bulb that went on, or you knew you were going to be an oncologists from the time you were in kindergarten?
PAM GOODWIN: Well, I was born in Ottawa. And when I was a young girl at five years old, we moved into the country. And it was just outside of Ottawa, but it's now called Kanata. But at the time, it was a very rural area. And I started my education in a one-room schoolhouse. By the time I was halfway through my schooling, they put a division down the middle of the room and it became a two-room schoolhouse.
But from the very beginning, I remember in grade 1 sitting at the back of my row-- each grade had a row-- and I would listen to the lesson from my row. And the teacher would move to the next row, and I would listen to that lesson, and then I would listen to the next lesson. I always wanted to learn more. I became interested in oncology for a reason that many oncologists have. My mother had cancer and died when I was still in school.
And-- jeez, still emotional. And it really made me realize that-- at the time, cancer was almost uniformly fatal. It made me realize that there was a lot of work to be done in the area of cancer. So I very early on decided that I was going to do medicine and that I was going to do oncology, and I never looked back.
SPEAKER 2: So neither of your parents was a physician?
PAM GOODWIN: No, no. My mother actually worked in the finance department on Parliament Hill for the government of Canada. And my father, in the 1950s, worked on computers for the Department of National Defense. So no medical people there at all.
SPEAKER 2: Well, at least it sounds like there was some science behind you. And when you went into oncology then, were you just dedicated to breast cancer because of the history you just gave us, or was there somebody who talked you into being a breast cancer person?
PAM GOODWIN: I think Norman Boyd had one of the biggest influences me. My mother didn't have breast cancer, she had myeloma. But Norman, at the time, was at Princess Margaret Hospital and was very interested in diet and breast cancer risk. And I was very interested in the role of the patient in cancer from the very beginning.
I thought I might end up doing research in quality of life, because that was an emerging field at the time. But I became very interested in the host factors in obesity, metabolism. And I chose to focus on how these factors impacted the clinical course of cancer for the most part, and I focused on breast cancer. At the time, it was way, way out there to work in this area. And one of my biggest challenges as a new investigator and a new staff person was to be sure that people didn't think I was a little bit of a quack by working in this area.
SPEAKER 2: Actually, I have two follow up questions for that, and I'll get to that in just a moment. But can you tell us a little more about Dr. Boyd. I mentioned him earlier as being legendary, but a lot of our listeners may not know who he is and what he's done.
PAM GOODWIN: So Norman Boyd was a medical oncologist at Princess Margaret Hospital who became a clinician scientist over the years. He was very interested in the role of dietary fat in breast cancer and actually conducted a randomized trial of dietary fat reduction, which, unfortunately, didn't show a beneficial effect on breast cancer. But he was one of the grandfathers of the mammographic density breast cancer risk association. And he did a very large amount of work confirming that association, quantifying that association, and identifying how it made independent contributions to breast cancer risk over and above family history, for example.
SPEAKER 2: I want to say, I have-- obviously, I think you can tell-- enormous respect for Dr. Boyd. He's truly a giant. However, he's caused more trouble in the United States than he knows, because every woman has a mammogram. If she has dense breasts, she gets a little piece of paper saying, speak to your doctor about this. And then we say, I don't know what to do about that.
PAM GOODWIN: That's right. That's right. That happens in Canada sometimes too.
SPEAKER 2: So you've talked about Dr. Boyd being a stimulus. And you sort of hinted on this. Were there obstacles? I can imagine mentors at the time at Princess Margaret or other places saying, are you crazy? This will go nowhere. You're wasting your career.
PAM GOODWIN: Well, I think a lot of people thought that it was a little bit crazy. I think a lot of people thought that it was possibly these people were being under dosed with chemotherapy, that the obesity cancer link wasn't a true biologic association. And that's one of the reasons that I have practiced at a general hospital my whole life.
At a general hospital, we have a very strong diabetes and endocrinology department. And they fully understood that these factors could be important. They had seen the impact of diabetes on a host of organs-- end organ disease in the kidney, for example-- and they were very open to this type of research.
And I was actually recruited to Mount Sinai Hospital by a guy called Lou Siminovitch, who was a molecular biologist. He had just set up a new research institute at Mount Sinai Hospital. And even though he was not an MD, he wasn't a clinician, he would look at all of my grants and ask the most important question, find the fatal flaw that needed to be fixed before it went in. And Lou continued to support me throughout my career. He died just a couple of weeks ago just shy of his 101st birthday.
SPEAKER 2: Oh my. That's great. So you mentioned your grants. Was it hard to get funded early on when you started this?
PAM GOODWIN: With some organizations, yes it was. But I think because I always presented this as a biologic association and my focus, at least early on, was to try to identify what was the biologic link between obesity and breast cancer, I think my grants were somewhat better received. I think I always had hypotheses relating to the biomarkers and not just to the prognostic association.
Now it wasn't always easy, because my first study was a prospective study of obesity and breast cancer. And towards the middle of the 1990s, we confirmed the association and we looked at biomarkers. We collected fasting blood during the study. We looked at biomarkers focusing on insulin, because there was some emerging evidence that insulin might be associated with cancer. And we actually showed that insulin was strongly associated with obesity and was a stronger predictor of breast cancer recurrence and death than obesity.
So as a young staff person-- I think I was an associate professor at the time-- I wrote that up and I sent it to The New England Journal of Medicine, thinking that I really had a great finding there. And New England gave me three reviews. Two of them were glowing. They were fantastic, really nothing to change. And the third one said, I see nothing wrong with this paper, I simply don't believe the results. And New England rejected it.
SPEAKER 2: It's always the third reviewer.
PAM GOODWIN: That's right. But it took another three years to get it published in JCO. And it's now my most highly cited paper, so go figure.
SPEAKER 2: That's interesting. So you talked a bit about the biology. Again for our listeners, my impression is not just that obese people get cancer, but that there is an underlying biology that connects them. Can you go through what your work to show that, and others for that matter.
PAM GOODWIN: Yeah, so it's a really complicated association. And the biology of obesity is complicated. There is an alteration or a change in adipose tissue in individuals that are obese, and that's associated with a change in physiology. And both of those factors can then impact the development and prognosis or clinical course of breast cancer.
We focused more on the physiology. We've looked at insulin, which I think is now accepted as a growth factor in breast cancer. Most breast cancers express insulin receptors on their surface and insulin that is circulating signals with those receptors to turn on the PI3 kinase pathway. Hyperglycemia, which is associated with obesity, may also change cellular metabolism. And there's a lot of people that have been focusing on inflammation in the adipose tissue.
Andy Dannenberg's group in New York has probably been the main people in this area. We've recently looked at that, and we've actually found-- Martin Chang, a pathologist who worked with me at Sinai, and he's now in Vermont, he recently found that the type cellular response to obesity that occurs in adipose tissue may actually determine the physiologic response to obesity and whether obesity impacts breast cancer outcomes.
So in other words, if there are CD68 positive macrophages in adipose tissue, you're going to have insulin resistance and you're going to have poor breast cancer outcomes. But for another woman who has the same BMI, if she has an absence of those CD68 positive macrophages in the adipose tissue, she will not have insulin resistance and she will not have worse breast cancer outcomes. So we're trying to focus there on what is the link between the adipose tissue response and the physiologic response and what drives that.
SPEAKER 2: I think almost everybody listening to this podcast knows that over the last 15 or 20 years, we've really broken breast cancer into a number of different kinds of cancers. In fact, I really believe that they all happen to be different cancers that happen to start in one anatomic site-- the breast-- as opposed to being all breast cancers. Have you seen differences in the emergence or potential treatment of different subtypes related to obesity or obesity management?
PAM GOODWIN: So in some of our earlier work, we actually found that obesity was "perhaps" a little bit more prognostically important in ER negative breast cancer. And I put the word perhaps in quotation marks there. I think more recent work has not shown that, and that obesity contributes across the spectrum of breast cancer. To the extent that obesity impacts are related to estrogen, then you're going to see a greater impact in hormone receptor positive breast cancer. But the association is really seen across the spectrum of breast cancers.
SPEAKER 2: So another question that raises-- and others have addressed this-- do you think it's obesity or specific types of diets that are the culprit?
PAM GOODWIN: I think it's obesity. I think diet contributes to body size, and I think the composition of the diet may play a role in the response to obesity. But I think that if you are normal weight and have non-obese physiology, the dietary composition doesn't matter quite as much.
I think right now when people are looking at diet, they're no longer looking at the fat content of the diet. They're looking at whether it's a healthy diet, whether there are legumes and nuts and healthy oils, but they're also looking at the glycemic index of the diet. I think all of that contributes, but my read is that obesity is the primary driver of this association.
SPEAKER 2: And do you think that once you have obesity, it's too late, losing doesn't help. In other words, this is something that's imprinted early on, because I do want to get into treatment too, but especially for prevention.
PAM GOODWIN: So that's an unknown. Steve Hursting's group has actually done an experiment where they had mice that were either fed a normal diet and weren't obese, or were fed an obesogenic diet and became obese. And the ones that became obese, a group of them, half of them were put back on the normal diet and they became non-obese. And then they injected all three groups with cancer cells.
And what they found was that the currently obese and the formerly obese mice had tumor growth that was the same and was much greater than the mice that were never obese. And they also found patterns of DNA methylation and gene expression in the mammary fat pad that was similar in the formerly obese and the currently obese mice and different from the never obese mice.
That suggests that, perhaps, there may be some carryover after weight loss. But I think we need to be very, very careful. The tumor cells were injected almost immediately after the weight loss. And these were mice, they weren't people. People, I think, are a little bit more complex than mice.
SPEAKER 2: I mean, this raises-- actually, I have to say that this entire series for me has been, what if I was in a cab with these people who have been experts and pioneers in a field and I can just ask ask them any questions I want to. These are questions I've been wanting to ask you for 20 years, but we never had the opportunity.
So the other thing is it's a little bit like early pregnancy. We know there is something about early pregnancy that imprints a cancer reduction compared to late pregnancy. And as you know the Russos have worked on this for years and years. And I've wondered if that's the case with obesity, but now I'm going to [INAUDIBLE] myself instead of you. It's just something I've thought about for a long time.
PAM GOODWIN: We're not going to know until we get the results of some studies. The BWEL study led by Jennifer Ligibel looks at weight loss after breast cancer diagnosis. It's fully accrued. It's a randomized trial. It will give us some definitive information.
But our group did a small randomized trial called the LISA study, which were reported out about a year ago. And in that study, we actually showed that there was a reduced risk of breast cancer recurrence in women that were randomized to the dietary-- the weight loss intervention arm. The hazard ratio was 0.71. We'd hypothesized a hazard ratio of 0.76. So it looked good, but we did not complete accrual on that study. So we didn't have the power to conclude that the effect that we saw was actually significant.
But I actually think that those results are-- I think they're going to lead us in the direction that we hope to see in the BWEL study. In other words, I think that the effect of obesity will not be fully baked in and that there may be some ability to reverse it. We know that losing even 10% of weight will reduce insulin, for example, by 20% to 30%. We know we can see major changes in physiology when we see weight loss.
SPEAKER 2: So in your work with [INAUDIBLE], so go back to biology, and you had an opportunity then to look at things like methylation patterns before and after weight loss in cancer cells, or what's getting turned on. You talked about the CILs in macrophage infiltration, but are there things going on in the cancer cells themselves-- or the normal cells for that matter-- that make them more or less susceptible to going on to become nasty cancers?
PAM GOODWIN: So that's a little bit beyond my focus. In the BWEL study, blood is being collected repeatedly. So we'll at least be able to look at those changes in lymphocytes, for example. When you're looking at the adjuvant setting, there's no tumor to rebiopsy. And I'm not convinced that the obesity link is the same in the metastatic setting as it is in the adjuvant setting. Once you get into the metastatic setting, the presence of tumor itself may alter metabolism and may impact a lot of the factors that we're looking look at.
SPEAKER 2: I'd like to ask you to look forward a little bit now too, because especially in your early work with epidemiology and a focus on lifestyle changes and weight loss, do you think that's going to be where the magic bone will be, or will it be a drug that people can take? I know you've worked quite closely with the Metformin. And imagine you looked in a crystal ball here, I know it's cloudy, but maybe you can give us some insight.
PAM GOODWIN: Well, we've looked at Metformin initially because it was an insulin lowering drug. And then Grahame Hardie identified the AMP kinase mechanism of action, and now there's a host of direct antitumor effects that have been reported with Metformin. I think that Metformin in many ways is an anti-obesity physiology drug. It improves much of the physiology associated with obesity.
As you know, we've done work showing that it lowers insulin in non-diabetic patients who have breast cancer. We've also done a neoadjuvant window of opportunity study, where patients were given Metformin for the two weeks between diagnosis and definitive surgery. And we showed that Metformin actually lowered T67 and increased apoptosis in the cancer cell. So that was the time when we could look at the cancer cells before and after drug administration. So I think we may see some direct-- or we may see some tumor effects.
As you know, we have the large MA-32 adjuvant trial-- 3,600 patients-- which is about to be analyzed. It will likely be analyzed in the next two to three months, and we'll have a definitive answer as to whether Metformin will improve breast cancer outcomes. And because we're looking at contralateral breast cancers, we can also look at whether it impacts the development of breast cancer.
SPEAKER 2: At night, do you look up at the ceiling and worry about things like everolimus and alpelisib that actually block the insulin pathway, and then we see hyperglycemia? I don't know if you've treated many people with alpelisib, but hyperglycemia is one of the major consequences of that. Could we actually be in a vicious cycle with using these drugs, or am I reaching too far?
PAM GOODWIN: No, I worry about it. I do. It's the same with the IGF1 receptor blockers. I think that sometimes we don't look at the impact of a drug that we believe targets the tumor on the patient's physiology, and the patient's physiology may then actually impede the ability of the drug to treat the breast cancer.
If we look at the use of, for example, aromatase inhibitors in premenopausal women, they raise the estrogen levels and the tumor may progress more quickly. We have an example of that. And I think whenever we're doing anything, we need to look beyond the drug itself to the impact-- the drug and the tumor to the impact it has on the patients.
I mean, one of the really interesting things that I've seen recently is that some of the PD-L1 inhibitors, when you look at them used to treat cancers other than breast cancer-- I don't think we have this information yet in breast cancer-- being obese actually predicts a better response. So there's something about the synergy between the PD-L1 inhibitor and the obese physiology that makes the PD-L1 inhibitor work better. And some people think it's leptin that is playing a role, but I don't think that's been definitively established.
SPEAKER 2: I was not aware of that. Actually, when I was at the Dana-Farber, Chuck Scher, who discovered PD, Platelet-Derived, growth factor, was an endocrinologist. He's a PhD, but he's an endocrinologist by training. And he used to tell me the cancer is just endocrinology gone wild, so you need to understand endocrinology if you're going to be an oncologist. And I'm learning that in spades now 40 years later.
PAM GOODWIN: Well, when it comes to breast cancer, yeah, that might be true. Only--
SPEAKER 2: Well, especially in breast cancer, I think. Let's get away from breast cancer for just a moment. I'm towards the end here. And what do you think the role for obesity and diet in other cancers? Do you see such a strong association? And do you have optimism that the kinds of things you're doing in breast cancer will spill over to the others?
PAM GOODWIN: So I think obesity is important for cancer in general. I think obesity is associated with increased risk of most types of cancer. And I think it's even more important in cancers like endometrial cancer than it is in breast cancer. I think that what we're learning about obesity and breast cancer will be applicable to multiple other types of cancers.
One of the big things we need to think about, though, is that we're in the midst of an obesity epidemic. And at some point, this becomes a societal issue. Obesity is a bad thing for cancer. It's a bad thing for many other illnesses too. And it's probably contributing to a shortened life expectancy for obese individuals.
And we need, as a society, at least in the developed world, to start thinking about what we are going to do to try to reduce obesity, to try to get people to eat healthy and to eat proper portion sizes, and to become physically active or to be more physically active. I put that in a very blunt way, but I think these issues extend far beyond breast cancer, far beyond cancer, and really into our general health and well being.
SPEAKER 2: Yes, I agree. I've been fond of saying that I think obesity is the smoking of the next generation. I think we're going to pay the piper for this.
PAM GOODWIN: I think you're absolutely right. And I think we have a generation that's coming up that maybe has never known proper portion size and knows, at a theoretical level, about healthy eating but doesn't understand how to put it into place and follow a healthy diet and be physically active. And because the obesity epidemic is really just the last generation or generation and a half, we should be able to turn it around. This is not something that's baked into our genes. This is something that we, as a society more so than as individuals, [INAUDIBLE].
SPEAKER 2: Well, and I think when we finally do recognize that and understand how to treat the obesity, people will remember that you were at the forefront-- I don't want to age you-- but 30 or 35 years ago when the whole field got started. So thank you for your courage in going that way. Many of us took the path of least resistance. I don't think you did.
Anyway, so thanks for taking time to speak with us today, very much appreciated. And thanks for all you do for the field, and most importantly for our patients. I'm fond of saying that to almost all of our speakers. Without the people who have been on this series, we wouldn't be where we are today. So I'm very appreciative of it. Have a good day. Buh-bye.
PAM GOODWIN: You too. Buh-bye.
SPEAKER 2: Until next time, thank you for listening to this JCO's Cancer Stories, The Art of Oncology podcast. If you enjoyed what you heard today, don't forget to give us a rating or review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode. JCO's Cancer Stories, The Art of Oncology podcast is just one of ASCO's many podcasts. You can find all the shows at podcast.asco.org.