Microbiome and Risk for Cancer Outcomes
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From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science, and clinical practice. Here's your host,

Welcome to listeners from around the world, and thank you for tuning in to this JAMA Clinical Review Podcast. I am your host, Mary McDermott, Deputy Editor of JAMA, and I'm here today with Dr. Jennifer Wargo, who is the R. Lee Clark Professor of Surgical Oncology and Genomic Medicine at MD Anderson Cancer Center.

Dr. Wargo is author of a JAMA translational science review on the topic of the microbiome and cancer. Welcome, Dr. Wargo. Thank you, Dr. McDermott. It's an honor to be here.

Let's get started. Can you tell our listeners what is the microbiome and how is it related to cancer? Thank you, Dr. McDermott, for that great question. So people often ask me, you know, what exactly is the microbiome? So it's really interesting. In our bodies, we actually have trillions of microbes. They actually outnumber our normal cells.

And you can imagine that a lot of these microbes actually sit in our gut and they can actually have a profound impact on our physiology, on normal physiology, and also on disease. And so the microbiome really accounts for all the bacteria, the viruses, and other microbes along with their genomes and their influence on our body. So what would characterize a healthy microbiome that is associated with lower risk of cancer?

In general, when we think about, at least in the gut microbiome, we think of a highly diverse or highly rich microbiome as being a healthy microbiome and one that actually has a high abundance of what we would consider to be favorable microbes.

And the diversity aspect is important because why is a diverse microbiome good? It means you have a lot of bugs and you also have different microbes within the gut. And the reason having a more diverse microbiome is good is because you have functional redundancy with regard to the favorable effects of these gut microbes on shaping our immune system and on other metabolic functions.

In addition to this, having the right microbes in your gut really matters quite a bit because they are microbes that ferment fiber, right? And can actually break down fiber and produce metabolites which are favorable and help our immune system function well. Whereas microbiome that isn't quite as good may have a high abundance of some of the gram-negative microbes that actually can produce systemic inflammation and can actually blunt an immune response.

So is it possible to change one's microbiome from less to more favorable? In a related question, you talked about the importance of having a diverse microbiome. Does that mean a more diverse diet is better for a more diverse microbiome, or how do you attain that?

So one aspect of how can we influence or what things influence our microbiome that is really striking is that the use of broad-spectrum antibiotics can actually reduce the diversity in the microbiome. An extreme example is, of course,

C. diff colitis, where you get an abundance of one particular microbe that's deleterious, but there are other examples as well. For instance, in patients who have cancer who are going on to treatment with immunotherapy, if they are treated with broad-spectrum antibiotics before they get treated with immunotherapy, they actually have much worse outcomes, including worse response rates to treatment and worse survival. And so that's really striking. So that's one aspect is the use of

broad-spectrum antibiotics can actually negatively impact the microbiome. But what can we do to positively impact the microbiome? And so there's a couple of things that you can do to favorably impact the microbiome. One is in patients with cancer who actually have what we would consider to be an unfavorable microbiome, who have been treated with a lot of antibiotics and who maybe haven't had a good response to treatment.

You can use things like fecal transplant, believe it or not, which they also use for C. diff colitis. And patients with cancer have actually been treated with fecal transplant or a fecal microbiota transplant or FMT. And it's actually been shown to reverse resistance to treatment with immunotherapy. Now, mind you, this is just in clinical trials. This is not approved. Nonetheless, I think really promising strategy.

But short of that, I think dietary changes can actually favorably impact the microbiome. And our group actually showed a few years ago that if patients with cancer who were going on to treatment with immunotherapy reported taking a high-fiber diet, they actually were much more likely to respond to treatment with immunotherapy.

For the gut microbiome, are there other things that alter it or is it mainly foods? And like, for example, does physical activity alter it? Do we know? And does smoking cessation alter it?

Definitely. So just about everything can alter the gut microbiome, including medications. Proton pump inhibitors can actually negatively impact the gut microbiome. That's been shown. But things like sleep, exercise, all of these things have an impact on the gut microbes. And if you think about these gut microbes, not only are they producing metabolites, which then go through the portal circulation and through the systemic circulation and influence our either healthy physiology or the development of

trajectory of disease, but they can also educate our immune cells and make us more likely or less likely to respond to things like vaccines or to cancer treatment. You already mentioned how antibiotics can adversely affect response to cancer treatment. Could you give us another example or two of how the microbiome affects the development and progression of cancer?

There are several examples in how these microbes can actually influence the development and progression of cancer. Certainly, there's examples like H. pylori or Helicobacter pylori, which is with gastric cancer, and that's really a striking example where it can actually be treated.

And you can prevent or cure cancer, right? There are other examples as well in, say, colon cancer where Fusobacterium nucleatum is a particular microbe which has been associated with worse outcomes. And what they've actually found, investigators have actually found that you can find these bacteria actually within the tumors of patients with colon cancer.

And these bacteria can actually exist within the cancer cells and travel to distant sites of spread and actually facilitate metastasis and poor response to treatment with things like chemotherapy.

And you mentioned earlier the possibility of fecal transplant as a method in which the microbiome can be used to treat cancer. I just wondered if you could give us another example or two of how altering the microbiome or engaging the microbiome can be used to treat cancer more effectively.

Another aspect in which the gut microbiome has been shown to shape response to treatment for cancer is actually in CAR-T therapy. They're chimeric antigen receptor transduced T lymphocytes treatment for patients with hematologic malignancies.

And what investigators have shown is that if patients are treated with broad-spectrum antibiotics before they go on to CAR-T treatment for hematologic malignancies, they actually have worse outcomes, including worse response rates to CAR-T and also a higher rate of adverse events, which is really interesting.

Furthermore, what they actually find is that if you look at the microbes that are associated with a favorable outcome, better responses and lower rates of toxicity, you actually find that these are some of the same microbes that we see that are associated with a better response to treatment with immune checkpoint blockade, like Ruminococcus, Fecali bacteria, some of these fiber-fermenting microbes.

Is consideration of the GI microbiome currently part of cancer care, or do you use it in your cancer treatments?

That's really a great question. And so can we actually use the gut microbiome as a biomarker for cancer treatment response? Currently, it's only being used in the research setting. We use it widely in the research setting in our patients, not only in patients on clinical trial, but also in patients getting standard of care therapy at MD Anderson. But again, it's still in the research setting. However, I think there's an opportunity for us to use this and to develop

tests that we can actually use like PD-L1 is used when looking at tumors? Could we actually use profiling of the gut microbiome, targeted sequencing to actually really try and gain insight into a patient's gut health, if you will, and see do they have a good microbiome or a relatively poor microbiome, or is it somewhere in between? And then it's actionable. Those results could be actionable, but I think we're still a little bit away from that.

What is some of the emerging evidence regarding the microbiome in cancer that you're most excited about?

So some of the emerging data about the microbiome in cancer that I'm really most excited about are two things. One is with regard to the gut microbiome, how can we target it better? And then another is with regard to the tumor tissue microbiome. So I'll start with the gut microbiome. So we talked about how we might be able to target the gut microbiome to actually improve outcomes to treatment for patients with cancer. And certainly an extreme way to do that is with FMT or a fecal microbiota transplant.

But the issues with that are it's difficult to choose what donor to use. Do we use a healthy donor? Do we use a patient with cancer who's been cured? And furthermore, it's not really scalable. And so can we actually develop a

synthetic communities of microbes that could be used, given to patients to actually improve outcomes to therapy. And there are actually companies that are working on this where we've actually been able to derive what microbes might make up an optimal community and actually been able to engineer these synthetic communities that could be used to treat patients. So stay tuned for those. Those hopefully will be in clinical trials within the next year or two.

So that's with regard to the gut microbiome. But also, I think there's a lot of interest with regard to the tumor microbiome. And certainly, what people have seen is that within tumors of patients with cancer, you can actually identify bacteria and other microbes that can actually not only contribute to cancer development, but can also either promote resistance to cancer treatment. And we showed this a few years ago, where we showed that if patients

actually have these microbes within their tumors, patients with pancreatic cancer, that microbes can actually break down chemotherapy into its inactive form. And so I think as we look closer at these tumors, can we actually identify what microbes are there and strategies to target these?

So we know that human behavior like diet and exercise can affect our own gut microbiome, which may affect our susceptibility to cancer. But what about the microbiome of the cancer itself, which you've indicated is also a determinant of prognosis, potentially? Can the patient's behavior with their diet, with their activity, also affect the microbiome within that cancer?

So one thing that can actually impact what microbes exist within the tumors could actually be related to the leakiness of the gut. And how is that influenced? It actually can be influenced by diet, exercise, and other factors. If a patient has a poor diet, poor sleep, if they're actually taking medications that can disrupt the integrity of the gut and the mucus layer of the gut,

you could actually get translocation of bacteria into those tumors, which could actually impact their response to cancer treatment.

And also, I know you said earlier that it's a little too soon to really directly incorporate the knowledge about the microbiome into patient cancer care. But I'm just wondering, based on your work and what you know, like, do you tell your patients, well, you should eat this diet or you should be sure to exercise because I really think that's going to affect the outcome of your cancer? If so, like, what do you specifically say to them?

Right. All our patients who come in who have been diagnosed with cancer, they really want to know, what can I do for myself to help my cancer treatment? And one really important aspect is diet. So if you think about what are our diets like these days in the Western world, it's not that great, right? So, you know, a lot of people are eating processed foods. Not many people are eating enough fiber. And so we actually asked our patients that and we found that

less than 30% of patients were getting adequate dietary fiber. But if they actually had sufficient dietary fiber, they were actually five times more likely to respond to treatment with immunotherapy. And this is for patients with metastatic melanoma. So really candidly, when I see patients in the office, they come in and see me for treatment of melanoma, I advocate that they try to eat a high fiber diet, especially when they're going on to immunotherapy, because really it's something that they can

do themselves. It's really advocating a healthy diet anyway, but it takes intention to get up to 50 grams per day, which is generally what we recommend. And most people get well under 15 grams per day. But I think that's something that we can really advocate for our patients.

So can we actually educate our patients to get more dietary fiber? Can we work together with policy to create healthier diets? How about school lunches? Could this work in cancer prevention? I think that's another interesting area where we should be really kind of setting our sights. Can we actually reduce the incidence of cancer by promoting a healthier diet? And if you think about it, people are developing cancer at younger ages. What's driving that? Could it be

broad use of antibiotics, it could be. Could it really in part be poor diet? And absolutely, I think it's contributing. Do you find yourself taking a different approach to antibiotic therapy for your patients with cancer based on what you know?

We struggle with this, but I think it's important to consider. Antibiotics are important, right? Patients with cancer develop infections. They need to be treated. But can we be more thoughtful about how we treat those patients, right? And oftentimes, patients with cancer, especially who are going on to treatment with immunotherapy,

They get inflammation as well. They get side effects. And if they come in, say, with a fever, do we automatically reach for broad-spectrum antibiotics or should we use a more targeted approach? One of our infectious disease experts says use bullets, not bombs. So I think there's an opportunity here for antibiotic stewardship with regard to patients with cancer going on to treatment with immunotherapy. I can tell you I've had patients come into my office who have been traumatized.

treated with broad-spectrum antibiotics and had progressed on immunotherapy, and they asked me, did it contribute? And it's challenging, right? It may have because we know the data now. So I think it's really important to consider, sure, patients do need antibiotics sometimes, but sometimes we really need to be more thoughtful and use a more targeted approach. Do you recommend that people, whether or not they have cancer, get their microbiome tested?

Currently, there are some companies that will test your gut microbiome, do 16S sequencing and some of these other techniques. The issue right now is what company do you use and what do you do with that data? So I think we're not to the point where we're doing this broadly, nor is there really an organized effort. And so I think what patients need to do is to discuss with their care providers about the importance of the gut microbiome, to ask them if there's

any testing that they could offer right there where they are, if they're in a community setting or if they're in a university setting, but also to ask about other aspects that impact the microbiome. You know, be their own advocate, ask about diet, ask about antibiotics. And then I think there is an opportunity for us to work together to develop these targeted sequencing approaches to actually apply this to the microbiome, to test it more broadly.

Is there anything else you'd like to add that we didn't cover today?

So one more thing that I'd like to add is the issue of probiotics, because people often ask, well, gosh, given all this information on the gut microbiome and the importance of it, maybe I should run out and buy an over-the-counter probiotic. And so we actually studied this in our patients, and we asked our patients if they took probiotics, patients with melanoma who were going on to treatment with immunotherapy. And we found about a third of patients reported taking over-the-counter probiotics.

And interestingly, if they reported taking over-the-counter probiotics, they did numerically worse. Although it wasn't significant, it wasn't powered to look at this, but we were intrigued. And so we actually took this back to a mouse model where we actually gave mice kind of a perfect microbiome from a complete responder and then treated them with

one of two probiotics we bought off the shelf versus sterile water as control, we found that if they got either of the probiotics, they actually did worse after we treated them with cancer immunotherapy for melanoma. You know, so that's interesting, right? So it suggests that maybe over-the-counter probiotics may not be good for patients with cancer, but there is some other data that suggests that certain probiotics may be helpful. But I think we really need more information. We generally advocate that our patients...

don't take over-the-counter probiotics, that they eat a healthy diet, high in fiber, and that they get adequate sleep and rest and try to reduce stress levels, and they increase their exercise, because all these things matter. Thank you so much for this really informative review in JAMA and also the podcast.

I've been speaking today with Dr. Jennifer Wargo about her JAMA Translational Science Review on the topic of the microbiome in cancer. You can find a link to the article in this episode's description. This episode was produced by Shelley Steffens at the JAMA Network. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thank you for listening.

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