Metabolomic Differences: Young Onset (yoCRC) vs. Average Onset (aoCRC) Colorectal Cancer

Podcast 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. Suneel Kamath, a GI medical oncologist here at Cleveland Clinic. He has been a guest on this podcast in the past to discuss Cleveland Clinic's Center for young onset colorectal cancer, funding disparities affecting cancer with high mortality, and the Cleveland Clinic Esophageal Cancer Center. Those episodes are still available for you to listen to. He's here today to talk to us about metabolomic differences between young onset colorectal cancer and average onset colorectal cancer. So welcome back.

Suneel Kamath, MD: Thanks for having me again.

Dale Shepard, MD, PhD: So, you're a four-time guest here, but give us a little reminder about what you do here at the clinic.

Suneel Kamath, MD: Of course. Yeah, it's great to be here. Wow, four times. Amazing. Yeah, so I'm a GI medical oncologist here at Cleveland Clinic. I have a number of research interests in terms of funding disparities that affect GI cancers and others with very high mortality rates.

But another area that I've really developed along with many of our team members is focusing on the rise of young onset GI cancers and in particular colorectal cancer because we're just seeing so much of that in clinics. People that are teenagers in their twenties and thirties in the primes of their lives being affected by this often in advanced stages. And so due to that, we said we really need to start doing more research to investigate this. That's what led to the center we have now and a lot of the research that we're going to talk about.

Dale Shepard, MD, PhD: So just to sort of define terms, a lot of people might be listening in that might not be familiar with specifically the area, young onset colorectal cancer. What does that entail? What kind of group? And then we're going to talk about metabolomics. What exactly is that?

Suneel Kamath, MD: Yes, excellent question. Yeah, so the definition honestly is a bit of a moving target depending on who you ask and which studies you look at. We would define it as being a diagnosis at age less than 50. Mostly we came up with that because during the time we've seen this rise in colorectal cancer incidents, it's been from the eighties through now. And predominantly the screening age during that time period was age 50. Unfortunately, in response to this rise in young onset colorectal cancer we're now recommending people start getting screened at age 45, but most of the era that we're studying the age was 50. And so that's what we've been using as our cutoff.

Dale Shepard, MD, PhD: Excellent. And then I guess just to flesh that out a little bit more, the guidelines have changed in many cases, 45 is the recommendation. You pick up a few more people, but we've both seen way too many people in clinic that are coming in twenties, thirties, metastatic disease. So, tell us a little bit about that shift to 45 helps, but how big of a problem is this? The increase in young onset, is it continuing to increase compared to the regular average onset? What's the size of the impact of this?

Suneel Kamath, MD: Yeah, it's a difficult area because the reason that they chose 45 is that fortunately the majority of this increase that we're seeing in young onset colorectal cancer is in that 45 to 49 age group. Depending on where you look, that's anywhere from 30 to 50 percent of that increase. And so certainly we're capturing quite a few people that way.

But you're absolutely right, there's a significant spike even in the twenties and thirties as well. And I think what we're trying to do is identify their certain populations, whether that's by race or other factors, obesity, other comorbidities, things like that, that might help us to home in on which people specifically are at the greatest risk.

Because the rate of rise is somewhere around one and a half to 2 percent per year, and that's been happening over a long period of time, 20, 30 years. But the problem is the original incidence is still quite low. So even if you're talking about a tripling or quadrupling of this, it's still not that many cases per thousand or per 10,000. And so, it's difficult to really recommend that we screen everybody starting in their twenties and thirties. But I think there are probably certain groups within that that we really do need to focus on.

Dale Shepard, MD, PhD: And that's kind of the key, and we'll talk about some of the things you're looking at. But of course, everyone quickly points the finger at things like today's youth, they're more sedentary, they spend time sitting around gaming or their diet is worse and things like that. There hasn't really been anything clearly established in that arena. Is that right?

Suneel Kamath, MD: That's true. We know that a lot of the same risk factors that lead to colorectal cancer later in life, things like obesity and red meat consumption, eating too much processed foods and alcohol to a small degree as well, all of these factors still influence young onset colorectal cancer, but we really don't have any explanation for why suddenly those same exposures are now causing this cancer two and three decades earlier than it used to.

Dale Shepard, MD, PhD: And then when we think about traditionally, a lot of the screening guidelines have been based on having a family history, and that hasn't really borne out to be as significant in young onset as well. Is that true? It's equivalent to an average onset.

Suneel Kamath, MD: Yeah. That has also been really strange but has been proven over and over in many studies that there really isn't a sudden increase in rates of family history. And most of these are not genetic. We do test all patients that are diagnosed at an early age, and really only about 25 to 30 percent end up having a hereditary syndrome that's reported in the literature. I feel like actually in my practice it's even less than that. I mean, it's almost always we send them, it gets tested and it's negative. So it is purely a random bad luck event essentially and really remains something that we don't understand exactly why it's happening.

Dale Shepard, MD, PhD: Which kind of leads us to the work you're doing metabolomics. What is metabolomics? How's this fit into maybe how we come up with the answer of why this is happening and maybe even targets for treatment?

Suneel Kamath, MD: So, metabolomics is kind of an interesting field. Really what it looks at is the breakdown products of our normal cell metabolism essentially. So that includes with our DNA, the nucleotides from that, how we process proteins, how we process carbohydrates, fats, really all of those breakdown products.

And the idea really for studying it or the concept is that we think that we know that the genome is there and how we modify that, the epigenetics of it, our exposures or exposum if you will. And there are a lot of studies really on the genetics and various sequencing of tumors and all that, which there have been some findings related to that, but not a lot really, not a lot of explanations for why people are developing this younger.

So, we all think it's some sort of exposure. And so, what metabolomics can really do is by measuring these breakdown products of normal cell metabolism, we're not only getting at sort of what that person's mechanisms are in their cells, but also what they are exposed to. It's sort of the confluence of both, because both what you take in and also the way you process what you take in will be represented in a metabolomics study.

Dale Shepard, MD, PhD: So as a more pragmatic clinical trials guy, you have two groups, and you give one something and you don't the other. This seems really complex. How do you even know where to start? There are so many different exposures, so many different pathways. How do you approach this?

Suneel Kamath, MD: Yeah, so the way we did it, because this is pretty new in this space really, we started with a very untargeted, very broad panel, really measuring a large number of the most key elements of all of these nucleotide metabolism, amino acid metabolism, carbohydrate metabolism and lipid metabolism.

And you just sort of see what sorts of things ended up being different between the groups. And oftentimes depending on what's found, that can suggest really, if you imagine if you saw there was a big difference in fatty acids that we're seeing, that's probably going to be dietary exposure in some way. Similar to carbohydrates as well, a lot of times these are exposures that come from diet for the most part. Whereas maybe like with the DNA related thing that might be more chemical exposures and things like that. So, you sort of have to do a little bit of detective work once you get the data back, what do these pathways fit with and what sorts of habits or behaviors might correlate with those?

Dale Shepard, MD, PhD: So, part of it I suppose is if a particular pathway looks altered, an increased level of something and we'll talk about a couple of things here in a second, that could be an exposure, but it also could be a metabolic defect in a cell. Is that right?

Suneel Kamath, MD: Exactly. Yeah. So that's the thing. It could be due to what that person was taking in as an exposure, but you're absolutely right, it could also be something that is different intrinsically to them. Their own genetics led to their cells processing that metabolite at a different level.

Dale Shepard, MD, PhD: So, what kind of information have we learned so far?

Suneel Kamath, MD: So, what we found with this study was really interesting. We found the biggest one was that citrate, which is an incredibly important both breakdown product and carbohydrate part of our TCA cycle, one of the most important energy cycles in our bodies, we found that the levels of that were significantly higher in the average onset population compared to the young onset. And then conversely, we found that many things in amino acid metabolism, so arginine biosynthesis and a few others were more elevated in the young onset population versus the average onset.

Dale Shepard, MD, PhD: And then in order to study this, you looked at about how many people in each group.

Suneel Kamath, MD: Each group, so the total we had about 215 patients, I think. About 150 of those were average onset and about 70 or so were younger. So yeah, it was a relatively kind of small group to start with, but definitely a good signal to carry forward.

Dale Shepard, MD, PhD: And then where does this go from here? Are you sort of investigating maybe the hows and whys of citrate and arginine and am I going to have to learn the citric acid cycle again?

Suneel Kamath, MD: Yes. I have spent so much time back in textbooks and looking at figures with arrows going all over the place. It's been very confusing. But I think the way to take this forward really is this was a very untargeted, very broad panel. And so, I think now that we've identified these few pathways, there are more targeted metabolomic assays that we can pursue.

So, we are going to do that as one of our next steps to basically look at delving into all of them, because the broad shotgun approach, we've used so far looks at some of the elements of these pathways, but not all. And so, I think if we can really delve into every step of that biosynthesis pathway and others, we can actually home in a little bit more on what specifically is the range there. And then also, I think this is a decent size sample, but I think we definitely need to validate this externally in a larger dataset to really confirm are these findings real or not?

Dale Shepard, MD, PhD: And then as part of the Cleveland Clinic's kind of approach to trying to come up with the answers, there are also, I guess for lack of a better way to put it, other omic studies going on looking at microbiome and probiome that sort of thing. Is that correct?

Suneel Kamath, MD: That's right, yes. So, we are also combining this with microbiome analysis, and we call that metagenomics, which is basically just metabolome plus microbiome essentially. So yeah, we are looking at that to see if that further classifies and identifies people who are at risk that are younger versus average onset.

And then I think the other big thing we're really trying to work on is just getting more data as far as what people are exposed to. We're developing a good survey instrument, a good biorepository to really capture every person that comes in with young onset colorectal cancer. And not only do we have specimens, but also making sure we have a good history as far as what did they do when they were kids and where do they live, and all of these factors that we know influence our health.

Right now, there's really a lack of data about what we're exposed to in this space and also what healthy people are exposed to. Because really what we want to figure out is what's different about the young people developing this versus young people who aren't. A lot of the research so far really is looking at differences between young and average onset colorectal cancer, but that ultimately won't really help us as far as preventing this from happening.

Dale Shepard, MD, PhD: So, it might help in some way in terms of if there might be other treatment strategies or things like that, things to look for screening. But I guess what you're saying is that once you establish a difference, then you have to confirm that it's truly different in other youngsters that aren't getting cancer and whether there's that connection?

Suneel Kamath, MD: Exactly. Yes, because obviously the age itself will affect metabolomics, and we did control for that to some degree in our study. We did have a healthy control population as well, and it did not seem like there were any significant differences with the assay that we used just based on age alone. So, it seems likely what we found is actually due to cancer itself being different in the young versus the old. But that definitely needs to be explored more and really, I think to see what makes one young person go through their whole lives without developing this and another 25 develop colorectal cancer. That's really, I think the million-dollar question.

Dale Shepard, MD, PhD: How much is bioinformatics playing in and computing all of this data? Are we utilizing, I mean, we have the quantum computer now, we have great computing resources. What else is involved in a project of this scope?

Suneel Kamath, MD: Yes, that has been a huge resource for us through LRI because yeah, we get these panels back. They're testing two hundred plus metabolites across all of these patients, and they come into different levels. There are usually multiple runs per metabolite, so you have multiple hits for each one.

So, the files you get back from this are just mind-boggling when you look at it. And so yeah, having the computing power and the knowledge with having postdocs and PhDs and everything that do this, their entire lives are about managing and how to interpret big data. I mean, that's just such a strong resource for us, and that's been huge. We haven't used any of the quantum computing yet, but definitely it seems like a great toy to play with. I would love to get my hands on it.

Dale Shepard, MD, PhD: Yeah, absolutely. Just from a very practical standpoint, just kind of back clinically to young onset versus average onset, you go through, and you read things and sort of anecdotally there's this, oh, young onset colorectal cancer is more aggressive, it's worse. Is there truth to that and could these metabolic changes sort of have an impact on that? I mean, I guess just the first question, is that even true?

Suneel Kamath, MD: Yeah, I don't think that turns out to be true. That was a thought some years ago that there might be something genomically very different about them, and they might have just a more aggressive biology. That doesn't really turn out to be true for the most part. Largely that comes from just the stage differences at diagnosis. When you really factor in, if you do a stage-by-stage comparison, outcomes usually are the same for someone with stage two colorectal cancer at age 30 versus 70, really not much of a difference. But the biggest driver really is that probably two to three times more of the younger patients are diagnosed at later stages.

Dale Shepard, MD, PhD: And it's understandable. A 35-year-old, you're not immediately thinking colon cancer when they come in, they're more likely to sort of ignore symptoms, things like that.

Suneel Kamath, MD: Exactly. Yeah. I mean, it's so hard, and a lot of the patients we see, they say that, "Yeah, I went to the ER twice for symptoms for this. I talked to my primary about it." Most have talked to at least one, often two, three, four different doctors over many months before it's finally discovered.

And it's understandable to some degree, you don't think about this. It's still a relatively rare thing, but I think that's a part of what we're trying to do with the center is just make sure people are aware that that thought that someone can be too young to have cancer is just not true anymore. And it's okay to maybe try a PPI or try some stool softeners for a little bit, but if they're still having blood in their stool, still losing weight, whatnot, something's actually wrong and it's not wrong to pursue that.

Dale Shepard, MD, PhD: I mean, I guess that was one of the things I just want to make sure we got out there was that younger people do in fact get colon cancer. It doesn't necessarily have to be hereditary and just to be mindful.

Suneel Kamath, MD: Definitely most are not that we see that are young. And so yeah, we definitely need to get the word out.

Dale Shepard, MD, PhD: What do you think is the biggest barrier to progress in this area?

Suneel Kamath, MD: I think there's a lot of things, but the biggest one to me, not to keep harping on the same issue over and over, but I always have to come back to funding. I have to think, because this is not a new problem, our focus on it has been new in the last five to 10 years but there's literature going back to the early nineties talking about this. There's SEER data showing this trend, nice graphs, average offsets plummeting as we screen. We're catching adenomas. People aren't getting cancer, but the young are just steadily rising. And I have to think if there was more money and more focus on colorectal cancer as a disease, that wouldn't have gone undetected for this long.

Dale Shepard, MD, PhD: So, you might want to shamelessly refer people to a previous podcast.

Suneel Kamath, MD: That's right. Yeah, shameless, very shameless plug. Absolutely. Yes. But I mean, we've all know that everything ultimately comes down to that. I think we solve things that we put resources and funding into, whether that's in medicine or elsewhere. So, I think that to me it is definitely the biggest thing. And that ultimately leads to a lack of awareness of the problem, and then that kind of feeds on itself. So, I think if we can reverse that cycle, if there is more support in terms of advocacy and then also research into it, it just builds. As more people know, more people want to support the cause. And so, I hope we can kind of turn that cycle around into a more positive one.

Dale Shepard, MD, PhD: Well, this is, as you've noted, an increasingly common problem, young onset colorectal cancer. Doing great work to try to figure out why and what we can do about it. Appreciate your insights and being with us today.

Suneel Kamath, MD: Absolutely. Thanks for having me.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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