Exploring the Microbiome in Young-Onset Colorectal Cancer

Young-onset colorectal cancer is becoming more common, and the microbiome could be playing a role in the increase of cases. Alok Khorana, MD, Director of the Gastrointestinal Malignancies Program at Cleveland Clinic Cancer Institute, joins the Cancer Advances Podcast to discuss this issue. Listen as Dr. Khorana highlights his research on the link between changes in the microbiome and the development and progression of colorectal cancer in younger patients. He also discusses the ongoing metabolomic analysis and investigations.

Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale. Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Alok Khorana, Director of the Gastrointestinal Malignancies Program here at Cleveland Clinic Cancer Institute.

He was previously a guest on this podcast to talk about a review of GI trials at ASCO and the impact of clinical trials. He's here today to talk to us about changes in the microbiome with patients with young-onset colorectal cancer. Welcome back.

Alok Khorana, MD: Thank you. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. So remind us again a little bit of what you do here at Cleveland Clinic.

Alok Khorana, MD: Sure. So like you, I'm a medical oncologist. I take care of people with GI malignancies specifically, and I have a special interest in colorectal cancer and pancreas and biliary cancers.

Dale Shepard, MD, PhD:

Excellent. We're going to talk about young-onset colorectal cancer. We're going to end up getting into some work you've done about microbiome changes. Let's start off simple, young-onset colorectal cancer, what is that?

Alok Khorana, MD:

This is a real growing problem. It's actually a public health problem in the sense that it's affecting more and more younger people with colorectal cancer. And it stands in contrast to what we viewed as a major victory in the battle against cancer, which is that overall incidence of cancer has gone down and overall mortality from colorectal cancer has gone down.

But recently, about four or five years ago when people started to separate the curves by age, it turned out that the rates of colorectal cancer were going down pretty sharply for people over age 50, both incidence and mortality. But if you separated out people under age 50, you are seeing the opposite trend, which is that rates were going up. And that first came out in these epidemiologic papers in the mid 2010s, and every paper since then has confirmed it.

And now we are in 2024 and they just announced that colorectal cancer is now the leading cause of death in people between 18 and 50. And so this is a major change in this disease. I don't want to overstate this. The rates are still very low compared to the older population. 80, 90% of colorectal cancer still occurs in older people, but it's the sharp increase in incidence which is worrisome.

Dale Shepard, MD, PhD:

And I guess when we talk about young, how young are we talking? Because the guidelines recently changed in many cases to screening at 45 instead of 50. But how young are we talking here? We're talking younger.

Alok Khorana, MD: So the definition of young-onset or early-onset colorectal cancer is age less than 50. Majority of these are occurring in people in their 40s. But you see some GI cancer patients, you see this, we are seeing people in their mid-20s, 30s, mid-30s. We've actually created a whole center devoted to young-onset colorectal cancer specifically to study this phenomenon and treat patients more appropriately based on their age.

Dale Shepard, MD, PhD: Makes sense. We're going to talk about changes in the microbiome. Give us a little bit of a background about what exactly we're looking for and we'll talk more specifically about the study, but why the microbiome? What's the rationale to think about that?

Alok Khorana, MD: We've heard about the microbiome now for quite a while. And in general, the term microbiome refers to all of the different microorganisms that live in our body. What we think of as our body is actually our body plus a few trillion other microorganisms. Actually there's no real boundary between us and these microorganisms. Initially the thought was they're only in certain organs in the body.

They're obviously on the skin. The skin has millions of microorganisms. And they're obviously in the gut, so the gut microbiome's pretty well-known. But more recent data suggests that they're also inside many organs that we used to think of as sterile. And therefore, many cancers that come from these organs that we used to think of sterile also contain microorganisms in them.

And so this whole sub-branch of microbiomics has developed, which is called tumor microbiome. So this is separate than the gut microbiome. We've heard about gut microbiome influencing depression and exercise and physical activity and obesity and so on, and cancer. But what we are investigating in this current project is actually the tumor microbiome.

So what are the microorganisms that live inside colorectal cancer? And then separately, how are they different in younger people with colorectal cancer and older people with colorectal cancer?

Dale Shepard, MD, PhD: All right. That's an important designation because I think a lot of people still when they think microbiome are instantly thinking gut microbiome. So important distinction there. So what exactly were we looking at here in this trial? What'd you guys do?

Alok Khorana, MD: So we wanted to investigate why we are seeing this rise in young-onset colorectal cancer. It's still an unexplained rise, I would say. There's a lot of different theories behind why this is happening. Maybe people who are now getting colorectal cancer when they were children, they're more exposed to antibiotics and antibiotics would've changed the gut microbiome. Maybe there was more exposure to other environmental factors. Certainly obesity rates have gone up very substantially in the last few decades.

But all of these different environmental risk factors, sugar sweetened beverages, high intake of red meat, less exercise, obesity, all of these different environmental factors seem to interact through the microbiome. And if you're postulating, again big if, but if you're postulating that young-onset colorectal cancer behaves differently than the average or usual colorectal cancer, that it might mean that the microbiome of the tumors in younger people is different than the tumor microbiome of older people.

And that really had never been investigated in the past. So we have a good handle on the tumor microbiome of colorectal cancer, but 90% of people on those studies were all older people. Is it the same in younger people? Nobody really knew. So what we wanted to find was, hey, can we distinguish the microbiome in younger people versus older people? Is it the same? Is it any different? And what does that mean for why these younger people are getting colorectal cancer and what does it mean for future in terms of prevention, early detection, even potentially treatment?

Dale Shepard, MD, PhD: And so how many people did you end up looking at in each group?

Alok Khorana, MD: So we are fortunate to have access to a large biorepository here at the Cleveland Clinic. We had close to 140 patients that were of the usually, so more than age 60 actually, and then 136 patients with younger-onset colorectal cancer. And all of these samples were frozen. This is really important because most samples are preserved as paraffin-embedded blocks. And when you embed in paraffin, there's concern that there could be contamination because that's not always handled in a sterile way.

But when it's frozen, you reduce the risk for contamination. There are now techniques to study it in paraffin-embedded blocks as well, but we were fortunate to have access to frozen specimens. We did 16 as our RNA sequencing in those samples, both the younger patients and the older patients, and we're able to identify a bunch of different types of microorganisms in both.

Dale Shepard, MD, PhD: And so essentially the microorganisms, again, just so everyone understands the process, microorganisms were based on genomic analysis, not cultures or things like that.

Alok Khorana, MD: Right, yeah. These are samples that have been preserved for a long period of time. Right. We didn't grow the microorganisms like you would for antibiotic sensitivity or something like that. So it was looking at the genomics of these tumors, taking out the human DNA, and focusing just on the known microbial DNA, and then using that, or excuse me, the genetic material and then using that genetic material and running various different analytic programs to identify what microorganisms that genetic material belongs to.

Dale Shepard, MD, PhD: And then I guess after looking for differences, what did you find?

Alok Khorana, MD: So not a huge surprise, but we did find that the microbial profiles of the younger-onset colorectal cancer, so again, this is the tumor microbiome, not the gut microbiome, but the tumor microbiome of the younger people was different than the tumor microbiome of the older patients. We expected that. That was our hypothesis going in, but it's still important to establish because like I said, nobody's ever studied younger-onset specimens for the tumor microbiome.

And we found some really interesting things, like we saw some types of microorganisms were more common in the younger-onset patients, specifically akkermansia and bacteroids. And then there are other types of bacteria, bacillus, staph, listeria, enterococcus, fusobacterium that were more common in the older-onset patients. And then there were a bunch that overlapped, so they were present in both tumor microbiomes.

Dale Shepard, MD, PhD: And do we know anything specific about why those couple of bacteria might be more common in young people or whether they're more likely to be a cause of developing an earlier cancer? Is there anything mechanistically we know about those bacteria?

Alok Khorana, MD: It is pretty fascinating because it's been postulated, and again, this is a relatively controversial area. There's been some setbacks in the microbiome field because... Not in colorectal cancer, but in these... Remember I mentioned there were some organs that were previously considered sterile and some labs have identified tumor microbiomes in the breast, for instance, or in the pancreas.

And then other labs have analyzed that data and said, "Oh, you're overestimating how many of these microorganisms actually exist. Their biomass is really small. And you're considering that there's a microbiome that's not really there." They've gone back and forth. The original investigators re-reanalyzed the data and they said, "No, we stand by what we said."

So it's a controversial field. And that's how science progresses, right? I mean, you find something, somebody else contests it, and then you either approve it or you don't.

Dale Shepard, MD, PhD: That's why they call it research.

Alok Khorana, MD: Right, that's why they call it research. Yeah, exactly. Colorectal though, everybody's fairly convinced because it's part of the gut and everybody knows there's a gut microbiome. So there's no way you can have a sterile tumor in the gut because, of course, it's going to be colonized by these bacteria. The more important question, so there's not a controversy about whether there's a tumor microbiome in colorectal cancer, but what we are still trying to understand is are these microorganisms helpful in any way in the transformation of a normal gut to a cancerous gut?

And studies have shown that akkermansia, which is one of the bacteria that we found in younger patients, is a mucin-degrading bacterium. And so it promotes mucus thickness and helps maintain gut barrier integrity. And that's important in preventing cancer formation from occurring. And some companies have jumped the bandwagon and they're actually offering akkermansia supplements and so on. What we found was we saw more akkermansia in the younger population. But that's correlation, right?

It's not causality. So we don't know is it contributing to the cancer? Is it helping prevent the cancer from growing? Would giving akkermansia be helpful or would it be harmful? We just don't know those answers. We did see some correlations with survival also, and that's consistent with akkermansia and other the usual onset colorectal cancer as well. And there are studies that have shown that more akkermansia is beneficial if you're getting immune checkpoint inhibitors in colorectal cancer.

There's a lot of angles to this. There's angles about what are these bacteria doing in terms of cancer developing in the first phase. If you have the cancer, are they promoting its growth or are they inhibiting its growth? If you're getting treated for the cancer, are they helping the treatment or are they hindering the treatment? So there's almost an infinite number of questions. And like any good research question, you find an answer and then you have five more questions that follow.

So I think we are on the cusp of discovering more about these interactions. Just a decade ago, we didn't even know any of this existed. Five years ago, we had no idea that it was even important for cancer development. And now we have all these studies that clearly show its importance. And I think we are a few years away from using some of these as targets for treatment improvement and so on.

But this is first step, and the first step is just to understand what bacteria exist in these populations and then move from there.

Dale Shepard, MD, PhD: Is there a good correlation between, and of course, maybe more so because it's colon and it's in the colon, but is there a good correlation between what you find in the tumor and what you find in the gut microbiome?

Alok Khorana, MD: We adjusted for that. We didn't want a bunch of bacteria that would just be there because it's the gut. So when I mentioned, I should have been more clear, when we took the tumor specimens, we also took matched non-tumor specimens from the same patient. So that was the control sample. So we did adjust for that.

Dale Shepard, MD, PhD: Gotcha. I was just wondering. You mentioned things like people offering supplements and bacterial supplements and things, but if you changed the gut microbiome but you're not affecting the tumor microbiome, are you making any difference?

Alok Khorana, MD: We don't know. And that's my concern about people love, "Can I have a pill for something?" So we don't know that yet. And all these pills that are being offered, I have concerns about them because we don't really know. The same bacteria can work in different ways. It can depend on the dose. It can depend on the timing of the cancer. It can depend on the treatment. I think these need to be proven in studies before we jump on the bandwagon.

Dale Shepard, MD, PhD: On the backside, if you have a particular antibiotic that gets rid of that bacteria, you don't really know if that's going to help.

Alok Khorana, MD: Yeah, exactly. I think that's a concern in translating too early into clinical practice. Having said that, I think it's clear that many of these environmental risk factors do have an interplay with the gut microbiome. And one of the things we've done as societies evolved over the past several decades has been moving away from traditional foods.

But if you look at traditional foods in different cultures, they always contain probiotics, fermented foods, whether it's sauerkraut in German food or kimchi in Korean food or Dahi, which is a type of yogurt and Indian food. Every traditional food contains some type of probiotic or fermented material.

Dale Shepard, MD, PhD: So interesting findings, but a little early to have any ability to prevent or treat or anything like that. I guess just from how we are searching for anything that's a clue to why this is going on, are there environmental factors or anything that we think stimulate more of these bacteria that we find in young-onset? Or is it again, sort of an unknown?

Alok Khorana, MD: There's definitely a lot of linkage between specific environmental factors and then specific bacteria, some of which our team are promoting. And there's actually just a paper that came out in Nature, for instance, where you have these two bacteria that everybody has in their gums. But in people who have cancer, one of them is more prominent in the cancer, but not in people who don't have cancer in the gut, colorectal cancer.

So there's no question we are finding every day there's new papers that are finding linkages between specific environmental factors to specific bacteria and then those bacteria being specifically linked to real specific steps in the pathogenesis of colorectal cancer. I think that data is real. And we've known for years that diet and physical activity, too much sugar sweetened beverages, too much red meat, all of those are associated with an increased risk of colorectal cancer.

And I think what the microbiome, both gut and tumor microbiome, research is showing is that that's the linkage between diet and between external risk factors and the development of cancer.

Dale Shepard, MD, PhD: Certainly, like you say, an important problem and looks like some good steps moving forward. I guess while we have you for a couple of minutes here, any updates on other types of research that’s going on through the young-onset colorectal cancer clinic and program we’ve gotten set up?

Alok Khorana, MD: Yeah, we are doing a lot more, actually. So this is, as I mentioned, is one of our first steps in the identification of why this is happening in younger patients. We also recently completed a metabolomics analysis. So same principle, taking younger patients, taking older patients, both with colorectal cancer, and saying, are there metabolic differences between...

And when I say metabolic, we are talking about cancer metabolism. As those of us who've gone through training, the Krebs cycle is probably the most hated, probably just as hated as medical school loans or something, aspect of early medical school training. You try to forget it as soon as you're done with step one. But it turns out that a lot of the citric acid cycle, these are important.

There are really important metabolic derangements in cancer cells, and we've kind of put them aside because we are so focused on oncogenes. So the last 20, 30, 40 years has all been about human genomics, tumor genomics, oncogenes, tumor suppressor genes. But a lot of those tumor suppressor genes, oncogenes, the expression can be modulated by the metabolic aspects of tumor cells.

And so we are doing essentially what we did here, which is the microbiome profile, we are doing metabolomic profile, and that paper also just actually came out. And we are seeing some real differences again between young-onset and older-onset. The younger-onset patients have different metabolic phenotype and potentially that could be harnessed for these specific drugs now for inhibiting portions of the metabolic pathway.

There's arginine synthase inhibitors, for instance, if arginine is upregulated, other things like that. In cholangiocarcinoma, we are using IDH inhibitors and those are a type of metabolic pathway inhibitors. So I think there's a lot more that could be harnessed there. It's a little bit harder because metabolisms occurs in normal cells just as much as it does in malignant cells.

So you want to find drugs that target specifically the derangement of cancer metabolism without upsetting normal cell metabolism. So that's made it a little bit harder. But that's definitely another aspect that we are investigating. And then clinically, we are looking at, hey, how are the symptoms different? How do patients present differently? We are finding that younger patients are having to go to three, four, five doctors before they get diagnosed, whereas older patients, they go to one or two doctors and they get diagnosed.

And so I think there needs to be more awareness of young-onset colorectal cancer. There's a lot of presumption. Oh, it must be irritable bowel syndrome, or it must be inflammatory bowel disease or hemorrhoids. You make a lot of presumptions. And so they have to go and talk to several different specialists before a diagnosis is made.

We are trying to increase awareness and education amongst the physician and healthcare provider community to make sure that younger people presenting with symptoms, it's not always cancer, I don't want to overstate it, but at least have it in the differential.

Dale Shepard, MD, PhD: Yeah, but it's important to rule out bad things. Like you say, it's rare, but it's important to catch. I mean, it's the case, as you remember, I had 20-year-old who is in college and goes in widely metastatic colon cancer. I mean, I'm sure the ER doc, that wasn't the first thing they thought of.

Alok Khorana, MD: Yep, yep, exactly.

Dale Shepard, MD, PhD: Yeah, it's an important problem. Well, it sounds like with the Young-Onset Cancer Center and all the programs you guys have set up and the research, you guys are making good headway toward some solutions, some answers, and appreciate you.

Alok Khorana, MD: Yeah, thanks for having me. Yeah, no, it's a bad problem and we want this to go away, but it is scientifically very interesting and we are trying to figure out why this is happening, so hopefully we can have a public health impact in the future.

Dale Shepard, MD, PhD: Well, I'm going to look forward to talking to you again real soon on the podcast with some answers.

Alok Khorana, MD: Sounds good. Thanks, Dale.

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