When we think of treating or preventing illness, the role diet plays in keeping your immune system healthy often comes to mind. But how many of us would think of fiber as essential to healthy immune system function?
That’s where Dr. Laura Esserman and her research on immune-driven breast cancers come into play. She’s focused on examining the effects of a fiber-rich diet on the gut microbiome and biomarkers of immunity in women with newly diagnosed breast cancer. Her prior research looked at how immune cells in tumors influence tumor response to immune drugs, and she believes the gut microbiome plays a key role in this complex system. Her work serves as a reminder that, much like the gut microbiome–the plethora of bacteria in our digestive system–patients should also be treated with personalized care.
A BCRF investigator since 1998, Dr. Esserman is an internationally recognized breast surgeon, breast oncology specialist, and personalized medicine visionary. She has led the I-SPY series of trials since 2002 in collaboration from the NCI, FDA, and more than 20 cancer research centers and major pharma and biotech companies. The trial approach has become an international model from translational research because of its design, which shaves several years and tens of millions of dollars off of the drug development process. Dr. Esserman was included as one of TIME Magazine’s 100 Most Influential People of 2016 and received the 2018 Giant of Cancer Care in Cancer Diagnostics award. She has published over 300 articles in peer-reviewed journals.
Chris Riback: Dr. Esserman, thank you for joining. I appreciate your time.
Dr. Laura Esserman: Oh, thank you for having me.
Chris Riback: So I think you might be the exact right person to ask if this life statement that we’ve all heard is actually factual. Is it true that we are what we eat?
Dr. Laura Esserman: Well, I think we are not exactly what we eat, but we create an entire environment based on what we eat. I think what’s so fascinating about our bodies is that we did not realize until maybe 10 or 15 years ago that, especially our whole notions of what is sterile and how to keep things clean or what are you eating? Well, it turns out that what you eat influences the immense number of colonies in the ecosystem in your gut, and your gut is probably the second most important immunological organ in the body. So what you eat is broken down by various bacteria and enzymes in your gut. So it’s a cascade of everyone is what they eat. So you are what you eat, the first bacteria that break it down eat that, and then another colony grows to eat that, etc. So you start the chain by what you eat, and that chain and those bacteria that grow there actually do truly influence your immune system. We don’t understand it anywhere near as well as we should, but I think one thing is clear is that fiber is the key—not probiotics, but eating fiber. I think avoiding antibiotics when you can and eating fiber sets up that ecosystem, or that chain of bacteria that are healthier for you in so many ways, and I think really protect your immune system.
Chris Riback: So tell me, please, why you say that, and maybe what are fibers, just to oversimplify, what are fibers and what are probiotics?
Dr. Laura Esserman: So fiber is that stuff in food, like in spaghetti squash, or avocado has a lot of fiber, raspberries have a lot of fiber. Fortunately, popcorn has a lot of fiber. You can look up the amount of fiber that people get and around the world, people have different amounts of fiber. In the US, 90 percent of people get less than 20 grams a day of fiber in their diet, where probably we should try and aim for 30 to 40 grams of fiber in our diet. One of the colleagues I’ve been working with, and in fact, one of my BCRF projects this year, is to try and figure out how much time it would take to change the microbiome in the gut before surgery.
Can we change it with two weeks of a high-fiber diet? That fiber, again, starts that chain of bacteria that give you the kinds of ecosystem that is actually really healthy for you and stimulates the immune system and the gut and is very protective. A group at MD Anderson has shown this, that in melanoma, for sure, they tested fiber against the probiotics. Probiotics are the things you can buy in the drugstore, that’s in the yogurt or the various things you can reconstitute all the good bacteria in your gut, that’s how they’re advertised. We have no idea what’s really in them. And it turns out they’re not helpful, in fact they’re harmful. You have to be suspicious of that kind of thing.
And as it turns out, in every study where we’ve tried to study vitamins and food, the most important way to get the right kind of vitamins is through food. People say eat the rainbow—that’s try and have a rich plant-based diet. Even if you do eat meat, or you do eat other things, just making sure that you have enough fiber is so important. And I can’t tell you that I know this for sure, but I think that one of the reasons why we have had such a hard time exactly figuring out what the food relationship is to cancer is that there’s an intermediary, and that intermediary are all these bacteria, the ecosystem of bacteria and the gut. I’m collaborating with a professor at UC Irvine who I met at the AACR Rally for Medical Research in Washington. We were in the same group.
Chris Riback: Of course, why wouldn’t two California researchers find out about each other in Washington D.C.? Makes perfect sense.
Dr. Laura Esserman: She does the coolest thing. She teaches this class, this undergraduate class. They learn how to sequence their stool so they can figure out what’s in there, and so they do their own sequencing. And then she doesn’t make them stop eating pizza and the various things they would do as college students, but then she gives them this fiber-rich diet. So you can order these things from, so there’s companies like Thistle and others that will send you these high-fiber diets, and in two weeks their microbiome changes, and they re-sequenced it again. So they learn how to sequence, they learn what the science is, and they get to do the experiment on themselves. I think it’s super cool.
But I said, okay, two weeks might be enough. Just think about it, we give everybody two grams of Capsol at their operation. What are we sterilizing? It’s just so interesting that so many things that we do come from an era where we knew so much less. It’s often we’re stuck applying old principles to new data, when in fact we really have to throw some of that stuff out because our notions often are wrong about what we knew before. We started screening before we knew that breast cancer was many diseases, so it can’t make any sense to screen everybody the same. Everybody has different risk.
It’s hard for us to let go of what we knew from 40 years ago, but I don’t think it should be that hard to let go of it. And the same thing about ductal carcinoma in situ, we always thought, “Oh, it can’t be reversed, this is what you have to do, here are the principles.” But in fact there’s new data to suggest we should be doing things quite differently. How do you let go of old things when you have new information?
Chris Riback: That is a challenge for cancer research. That’s a pretty broad challenge I certainly could apply in many aspects of my life. You’re suggesting potentially, hey, could we assign/suggest a fiber-rich diet two weeks before, I think you said before surgery, to try to alter the gut microbiome situation? And you had said previous to that, I think, that the gut is the second most important immune organ outside the lymph in the body. So I’m hearing that and I’m thinking, well, wait a minute, is this preventative? Should I be going highest fiber possible yesterday? Yes, is the answer?
Dr. Laura Esserman: Yes. I think absolutely. It’s interesting just trying to look around the world and what people eat, and we used to think it was flaxseed or some of these other things, but I think it’s probably related to fiber. And there’s enough data to say that that’s a healthy thing to do. I’m sure everyone can find things in the list of high-fiber foods that they like, whether it’s beans or lentils or chia seeds for their yogurt or…
Chris Riback: Or raspberries.
Dr. Laura Esserman: Raspberries. I ate a box of raspberries, that is eight grams of fiber.
Chris Riback: Outstanding.
Dr. Laura Esserman: So there you go. So I’m a quarter of the way there, almost.
Chris Riback: I was just going to say, I was doing the math, you’re a quarter of the way to 30, for sure.
Dr. Laura Esserman: And then you find the things that you like, find fun recipes. This is one of these things where this may not be the panacea, but it absolutely can help you, and it’s good for you. They have to drink a lot of water if you eat a lot of fiber, because that’s important too. And the other thing that I like about it is it’s not expensive. Beans are probably one of the cheapest things that you can buy and make and learn how to make well, same thing with lentils. And it’s something that is, from an equity standpoint, it’s something that everybody can do and everybody can afford.
Chris Riback: I have had the privilege of talking to BCRF researchers like you—and BCRF-connected researchers like you—and many of these discussions have been with researcher scientists around the world and exactly what you just described. There are unique, regional, local challenges. Many of them around information, obviously access to care, but a lot around preventative measures. And for you to identify something as simple as increased fiber through beans, or lentils, very accessible. That’s really, really powerful.
Dr. Laura Esserman: You can do everything right and still get cancer, it’s not like a panacea. It’s always important to say these are things that you can do to help yourself, and it’s good for your health no matter what. It’s also good for reducing heart disease and everything else, but it doesn’t completely protect you from any of these things. And there are other factors, whether you’re inheriting a gene, or other things that can be the triggers for cancer that you can’t control. And it’s always important, I think, for listeners to understand there are things you can do to be a better driver, for example, these are those kinds of things, but it doesn’t protect you from the drunk driver that crosses the median strip and hits you broadside, that kind of thing.
Chris Riback: Thank you. Yes, thank you for emphasizing that. Short of choosing different parents, which of course none of us would want to do, but we have to-
Dr. Laura Esserman: Can’t do it. It’s a little late, right?
Chris Riback: It’s a little late for that. We have the genes that we’re given. Tell me about your current research. Which of the aspects that you have been talking about right now are you most active in? I’ve read about a program of yours where participants will receive 10 meals per week and recipes and it’s related to fiber. Is that your most current research? Is that the one we should be talking about? What’s the status?
Dr. Laura Esserman: So that’s one of them. I’m also trying to figure out how feasible is it to try and add in a fiber regimen to one of the neoadjuvant therapies. So this is in preparation. So there are three big trials, sort of four trials, that I’m running. And actually, BCRF has had a hand in all of them, as it turns out.
Chris Riback: Wow, that’s fantastic.
Dr. Laura Esserman: So always when I’m starting things up, BCRF has really made it possible for me to get over the hump of where I’m starting to get it rolling on its own. So the I-SPY trial is one of the longest-running trials that I’ve had, and this is taking people at a higher risk, early-stage cancer, stage II and III cancers, and we initially had it mostly for fast-growing tumors. And now we have an endocrine arm that we’re trying to figure out how to optimize endocrine therapy. Again, tailoring treatment to biology and giving the treatments upfront so that we can really understand how they work. There are some cancers that are where immune manipulation is really important, these are immune-driven cancers. These are where it may be super important to complement whatever treatment you’re giving with a diet that helps you optimize that immune response.
That’s what I’m trying to figure out. How feasible is it? How would we do that? There’s some data in melanoma to suggest it can make a big difference. And we actually, in I-SPY, saw one of our agents that was given orally interfered with the PD-1 inhibitors and you’re like, “Oh my God. This is the smoking gun. We have to pay attention to this. These are things that we weren’t paying attention to, and so how would you do that and how would you make that feasible?” And that’s one of the things that’s so amazing about BCRF is they’re like, “Oh, we can make what can seem like a crazy idea not so crazy.” And then if it works, now you’ve got the data to move it forward.
Now what I’m trying to, okay, well what if we thought it’s absolutely essential to have this high-fiber diet? Okay, how would I actually make that practical? How would I do that and how would I do it in a way that’s consistent, that I can put it into a trial, where people wouldn’t melt down saying, “Well, you can’t do that,” so where you’re doing it very consistently? We are actually, in I-SPY, testing the microbiome of patients before and after. We’re starting, we have a pilot for that also. And so we’re trying to understand, how big is the problem? How big is the variation? It’s a very complicated system.
But I-SPY in particular as a bigger entity, what we’re trying to do is start with novel agents. Now there’s so many exciting antibody-drug conjugates, bispecific antibodies, all these things, we always test them in the metastatic setting first, but I don’t know that’s where they have their best impact. Why not start them first? And if you get a complete response, if the tumor goes away, then you can stop. And if it doesn’t go away, then you go on to the best treatment for your particular subtype. And over the years, BCRF has helped us figure out, Dr. van ’t Veer and myself, what are the different subtypes? How can we re-understand or re-imagine the subtypes? So that’s a super exciting trial and that’s open at about 45 sites around the country now.
And then, based on this also, the other thing that’s so interesting is that most of the people in the I-SPY trial do not have screen-detected cancers. And so what do I mean by that? They’re either too young, they’re in their thirties because the average age for these bad cancers is 46, so a lot of people are young, so they’re out of screening age. And some of the cancers grow so fast that they can grow between screens. And some people aren’t screening. So are we doing as good a job as we can with screening? Are we identifying the people who are at risk for fast-growing versus slow-growing tumors? Are we thinking about it? Are we getting ourselves on a path to continuously learn and improve? We aren’t. So I started this, initially funded by PCORI, but when we needed more funding, BCRF actually supported us, they’re supporting us in this transition until we wait for our program project to get funded, which I’m always assuming we’re going to get funding.
Chris Riback: That’s a good attitude to have.
Dr. Laura Esserman: It’s always assumed, to live the expected life. It doesn’t always work. But the idea is to screen people according to what they’re at risk for. If you’re at risk for a fast-growing tumor, screening every two years isn’t going to work. Probably screening every one year isn’t going to work, if you really have high risk. We know that from the BRCA1 cases. The other thing that we’ve learned from doing this population-based genetic screening, 60 percent of the people who have a mutation that increases your risk for cancer do not have a first-degree family relative with cancer.
So family history is usually the way we decide who should get genetic testing. I reject that. This is a low-hanging fruit. Find the people at the highest risk. And so we are now lowering the screening age to 30. Just get that genetic risk and then you can find out who’s got the mutations, and a third of people who have these mutations get cancers in their thirties, or more. So we’re missing that whole thing. So again, trying to change the screening paradigm, and it can be actually much more cost-effective to do more for the people at very high risk and then less for the people who don’t need it, because then there’s a lot of harms that can be done. And then those harms include DCIS. This is a really tricky thing. It’s stage zero, or in situ. I don’t think we should call it cancer because that frightens people, and that’s why a quarter of people wind up getting bilateral mastectomy when they have DCIS. For some people that might be reasonable, but for most people that’s way overkill.
And I think we’ve always assumed that this was irreversible and that you’re on a path to getting cancer. But we have shown that a number of these, especially the hormone-driven cancers, will go away, or there’s not a focal or surgical thing. It’s just a risk factor. So I think about DCIS as prevention. And so you can see how this whole ecosystem, the big trial, leads you to rethink screening, leads you to think about, okay, what are the bad things that come from screening, is all these cases of DCIS that you find. And for years I’ve been working, that BCRF funded me to really think about, there’s about 20 percent of DCIS that are high risk, that are hormone negative or immune-driven, and they really do have a focal lesion. Sometimes they have these big lesions, and how do you get a five-centimeter or eight-centimeter mass that’s DCIS?
Maybe those aren’t the worst DCIS, maybe they’re the best, because somehow you’re keeping them from being an invasive cancer. And it turns out it probably is the immune system that’s helping. And what’s cool about that is that we have figured out immunologically how to stimulate it in just these last few years. This, again, has been a long-standing BCRF investment, to stimulate the immune system of these high-risk DCIS, and half of them, we’ve made them disappear in a month or two. And no one would ever have thought that was possible. Everyone says all those people have to go to the RNI [a form of radiotherapy], so I think it’s like being observant and saying, “What doesn’t make sense here?” How do you apply the principles we know today, not the principles we knew before? Because you have all this new information and you’re applying old standards.
And the thing that’s so cool about BCRF is it allows you to explore—and not everything turns out the way you want, but if you keep at it—it’s that consistent ability to follow new leads and say, “Oh no, this is possible,” that really changes the whole paradigm. I’m just launching a national trial and active surveillance for DCIS, and I’m expanding my vaccine trial, and if that works, hopefully we’ll get to move that program forward. We’ll see.
Chris Riback: What is it about you, do you believe, that allows you to recognize or investigate or be curious about such a wide web of instances, or points on the spectrum, of cancer care? What is it about you that has you thinking in that way when perhaps other people don’t? And it struck me that you might’ve just answered it. Is your superpower being observant?
Dr. Laura Esserman: Maybe. Maybe so. But I think also that I think to question. My superpower is to question constantly, and to ask, Can we do better? And I can look around. And I think my superpower is also to say, “Are we doing all we can for women who are either at risk for or who have breast cancer?” And the answer is no. Our treatments today are not so great. I have yet to have someone say to me, “Oh, wow, that sounds fantastic. I love that. I want to do that.” When they say that, okay, then my job is done. I have the ability to be honest about how well we’re doing. And I don’t look at it as a feeling, I look at it as an opportunity, an exciting opportunity to rethink how we should do things, constantly.
In college, I was a history of science major. And I think you get that really big perspective, which I think has been very influential for me, and I’ve had a lot of training in policy and in basic science, and that’s allowed me to be it. And then I have training in business management, I went to business school, so I’m a multidisciplinary person in my training. And so it’s allowed me to be a system integrator. And if you look back at the history of science, there’s so many things that we used to do that are ridiculous. Look, the guy who invented pithing, the frontal lobotomy, got a Nobel Prize. But you often admire things that are out of fashion, and it’s about what captures people’s imagination.
So I think having that bigger picture, and we used to say that old theories don’t die, the people that espouse them do, and so you like to aspire to not be that, and not be stuck in your ways. And I used to get in trouble when I was an intern in surgery, and I was always going, like, “Well, why are we doing that? Why are we keeping someone in an NPO [nothing by mouth]? Why can’t they have clear liquids when their stomach’s making a gallon or a liter of fluid a day? What’s the problem here?”
Chris Riback: You were history of science, so that’s a noble career and a profession to understand and write about and think about the history of science. Were you always going to go into science and that was just your path to get into it? Or did something happen and you transitioned from thinking to acting?
Dr. Laura Esserman: Well, I was always interested in science. And I had been working in a basic science lab even when I was in high school, all through high school. So always very interested in science and thought about being a basic scientist. But I love people and I love their stories. I find, for me, this compliment of clinical medicine and research, you can’t always change biology, but you can always make the transition and everybody’s journey better by caring a lot, and that’s the art of medicine, and just being there for somebody. But when you’re frustrated about what’s not working, that’s what your research is for. And I am interested in a lot of things that I think require bigger scale, that can’t be done with just one person. The I-SPY trial requires this huge organization that you’re running the experiment in a big way.
But I love taking what I hear and translating that into better trials, more patient-centered, more patient-focused. Where are the problems? Where are the levers? How do we use imaging as a catalyst to change? Because it’s like the difference—I’ve used MRI imaging, I was very lucky when I first came to UCSF I met Nola Hilton, who was writing the sequences for what became breast MRI She was actually getting her PhD at Stanford, but she came up to UCSF because there was no MRI machine down there, and it was up here. And she came to me and said, “How would you like to use this?” And I said, “Oh, I want to look at women who have stage II and III breast cancer and see if they all look the same.”
And at the time, we were treating every woman the same. And I’m looking, I’m like, “Wow, all these cancers look completely different.” I’m like, “Okay, well, let’s treat them first and see if they respond the same.” And guess what? They don’t. And so that gives you that opportunity that’s like, Why are you taking out the biomarker? I’m impatient, and I always, I know my father’s favorite sayings, but I always had in my office is the person who says it can’t be done will soon be passed by the person doing it.
Chris Riback: Great phrase.
Dr. Laura Esserman: I love that. And I am like, “Well, why can’t we do it this way?” And then you start talking to people, and Dr. Larry Norton actually helped me get it set up, and the corporate groups, when he was in charge there, but then they didn’t want to go at the pace I wanted to go and I was frustrated by how slow things were. I’ve studied a lot of other industries, that’s your history of science, and that’s what I took out of business school was also that medicine is a business like others, and you can either learn from other industries or not, and who’s it for? Your patients don’t have 10 years for you to get your act together. They need something faster.
There has to be an engine to drive change. And I was frustrated by the way trials were run. I was frustrated by every time you want to do a new idea, you have to start a new trial. I thought that was so inefficient and wasteful and I’m like, “Okay, there’s a better way to do that.”
So that’s how we started the platform trials and now that’s the way I do everything. And we have a not-for-profit, Quantum Leap Healthcare Collaborative, that is really working on fine-tuning the engine so we can do things fast, we can get things through a central IRB [investigational review board] in three weeks. You don’t want your time wasted over things that are immaterial. And people say, “Well, you can’t do that.” Well, that’s an invitation for me to do it. I like a puzzle. And I’m like, “Okay, I don’t accept that. That’s just a waste of everybody’s time.” It’s like I want to change the way we think about new drugs, which is if you take two drugs that are similar, but one’s less toxic, it doesn’t really matter, they have to do what they call a non-inferiority trial. Well, why is that? If it’s less toxic, why isn’t that superior? So now that means you have to come up with a new end point, which is efficacy and toxicity. And people say, “Well, we don’t do that.” I’m like, “Well, so?”
Chris Riback: Yes.
Dr. Laura Esserman: But it’s not like it’s easy, and it’s not like you have to gaze and say, “Oh yes, great, let’s do it.” They’re skeptical. But then the onus is on you to model it and figure it out and drive all these things. And it’s about assembling all bright young people to keep working on it and I want people to be hungry to move things forward and not satisfied with the pace of change. One of my colleagues, David Dilts, used to say, “People say, well, we have to be careful because we’re in medicine because people can die,” and he said, “Well, guess what? When planes fly, if things go wrong, planes fall out of the sky and people die. You aren’t the only industry where people’s lives are on the lines. Car industry, everything.” So it’s like you need to get out of this mindset that you can’t change. And that’s what research is all about, finding new ways. But then also, there’s this big gap between the ideas that you’re working on and how you get them to practice, and I see it as all one big continuum.
Chris Riback: It is evident that you do, and it’s also evident that you channeled that mantra of your father’s, and I am certain that the people who say it cannot be done are in your rearview mirror, you’ve passed them a number of times. Your patients don’t have 10 years to wait. You’re clearly motivated by speed.
Dr. Laura Esserman: I’ll tell you a very cool BCRF story.
Chris Riback: Yes, please.
Dr. Laura Esserman: Not this year, but last year, Jenny Chang came to me and said that she had this nitric oxide synthase inhibitor. And she said, “Oh, Lisa Carey told me to come and talk to you about it, that maybe you could put it in I-SPY,” and it was for triple-negative patients, that particular type of patient that didn’t respond. And I said, “Oh, we have the subtype,” and I said, “Oh, we’ll do that.” And I said, “Just get it back and we’ll get someone to start a company here, and I know lots of people in the industry anyway.” So that’s all happening and we’re going to put it into I-SPY.
The great thing was that I had a patient who, at UCSF, in I-SPY, had gotten one of the novel agents, one of the TROP-2 antibody drug conjugates. That didn’t work. Then pembro taxol carbo. That didn’t work. And then AC, it worked a little bit, but then it stopped working. And she had these big nodes in this, but she was forty-something, and I was just like, “Okay, I know the drug. We should really try and get that drug.” And we were in the transition and I couldn’t, we were trying to find a way to get it out of Houston Methodist, where Jenny Chang is, because it wasn’t in the company yet, and trying to get it from UCSF but couldn’t because they weren’t a pharmacy recognized by Houston Methodist. And I got compassionate use from the FDA to try it, and I finally, finally found a compounding pharmacy, our pharmacist here found it, it was everyone working on it. We were just about to give up and they were able to do it, and I gave it to her, and her tumor melted away. She had just a little bit left. That’s so cool.
Chris Riback: It’s unbelievable.
Dr. Laura Esserman: You hear something, you know it, you figure it out, you put it in, and it was because we were at the BCRF meeting that all of this is happening. You really live for those moments where “I can actually make a difference here.”
Chris Riback: Dr. Esserman, thank you. Thank you for your time. Thank you for the way that you think. It’s evident in talking to you that you’re the manifestation of that old Apple ad, think different. And thank you for the work that you do every day.
Dr. Laura Esserman: Well, thank you. And I think people think I’m unrealistic, but I think you have to be unrealistic. You have to aspire. But a man’s reach should exceed his grasp, or what’s the heaven for? Whatever that poem my mother used to read to me. So it’s like you aspire to be better, aspire to bigger, believe that it can be done, help lead people to that, and then it will get done.
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