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> Welcome to Cancer Newsline, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newslines helps you stay current with the news on cancer research, diagnosis, treatment, and prevention, providing the latest information on reducing your family's cancer risk. I'm your host, Lisa Garvin, and today we'll be talking about one of six new moon shot diseases that have been identified by MD Anderson Cancer Center. This is a colorectal cancer moon shot and the principal investigator is Dr. Scott Kopetz, my guest. He is the Associate Professor of GI Medical Oncology here at MD Anderson. Dr. Kopetz, colorectal cancer seems like a pretty logical choice for a moon shot, but it's pretty preventable, but it sounds like you can do more.
> Correct, it, colon cancer is a tumor where are seeing successes with prevention that with the use of colonoscopy, we can indeed prevent some colon cancers. But one of the things that we've recognized is there's a limit to what we can do with our current prevention strategies. And to really continue to make further advances in this tumor type, we need to deploy novel approaches for early detection and prevention.
> Now, colorectal cancer, we're talking about the colon and the rectum. What are the statistics on colorectal cancers? They're pretty high.
> Correct. There's about 140,000 patients that are diagnosed with colorectal cancer every year in the United States. And when we look worldwide, those numbers certainly increase further. Of those, about 40 to 50,000 patients a year will die from the disease, meaning that even though there have been advances in the screening and prevention there's still a lot of unnecessary deaths.
> And there's also quite a few hereditary markers that we know about. There's FAP. There's HNPCC, so we do have a hereditary basis for this cancer. Can we build on that?
> The hereditary syndromes have really taught us a lot about the biology of colorectal cancer, and there have been continued advances in improving the screening and treatment of these patients. These patients, though, still have a lot of needs in terms of better educating the family members about the hereditary risks and also continuing to improve some of the chemo prevention efforts.
> So one of your goals in this colorectal cancer moon shot is to develop new screening approaches beyond colonoscopy. I read somewhere that colonoscopy really doesn't help people as far as morbidity, people with tumors on the left side. Can you explain?
> Correct. So it's the benefit actually is in the patients with the left-sided colon cancer, but we're not able to reduce the mortality for cancers that develop on the right side. So this idea is that colorectal cancer is not just one disease, but really a group of several different subtypes of the disease. And then we may need to come up with different prevention and screening strategies to address these different types of cancer. The right-sided tumors are very different than cancers that develop on the left side. There's a greater degree of epigenetic regulation, meaning not the genes mutated themselves, but this idea that there are other features of the genome that drive the behavior of the cancer. And we know that they have a very different biology once they develop. They utilize different pathways and they have a very different outcome.
> Are right side tumors less common than left side tumors?
> So the incidence of these are changing, the screening being more effective in the left, so we're seeing reduction in some left-sided cancers more than the right. The incidence changes and we do see that older patients, for example, are more likely to develop right-sided tumors and have other certain clinical features. There's a slight predominance of females over males in the right-sided that we don't necessarily see in the left, for example.
> Well, in developing, of course, colonoscopy has been a success, you know, at least for people with tumors on the correct side. How do you go beyond that? What sort of other screening possibilities are there?
> So one of our efforts as part of the moon shot is really recognizing that while colonoscopy is a foundation of a good prevention strategy for colon cancer, that what we need to do is to really focus on also the type of cancers that we may be missing with colonoscopy. So how can we complement colonoscopy? One of the efforts that we're embarking on is a blood-based effort to really ask, is there a noninvasive, blood-based biomarker that we can identify that can help complement colonoscopy and even potentially be useful in environments and health care systems where colonoscopies are not routinely available?
> And a part of the moon shot, and we're kind of getting into it with, you know, developing screening for different types of colorectal cancers, you're trying to get a better handle on the characterization of the subtypes, correct?
> Correct, so our key understanding is that there's not just a single, monolithic entity of colorectal cancer, but when we look on a molecular basis, we can classify colorectal cancer into four different subtypes of cancer. And these have very different biologies. They have different outcomes. And we think are going to require different treatment approaches as well as potentially even different early detection and prevention strategies.
> How do you go about characterizing all these subtypes?
> So it's really making use of a lot of bioinformatic expertise, and this is something that a real strength of MD Anderson. And it's recognizing that we can describe these cancers on a variety of different levels, but when we really look at the biology, how the genes are expressed, that we see clear patterns that emerge, so it requires large numbers of patients, our initial efforts that were supported through the early pilot funding of the moon shot utilized a cohort of about 4,000 patients that we were able to profile and to help characterize. But this also requires a international collaboration as well, and I think one of the great things about the moon shot is this ability not just to work within the institution, but to leverage this expertise and to bring in international partners so that we really can make a difference in changing the approach that we take to treating these cancers.
> Do you foresee changing in colorectal cancer staging guidelines as a result of this work?
> So the staging for now is still very much based on a classic tumor depth of invasion node involvement, but there have been a lot of interests by the international/national groups that develop staging to really start to incorporate some of this molecular characterization. And so we've been in discussions with them about what that would look like, but I think that's something that's going to take several additional years to mature.
> Another goal of the colorectal cancer moon shot is to expand on some early successes you've had in immunotherapy. Obviously, MD Anderson is ground zero for a lot of immunotherapy research. We've seen some big successes in other cancers. But it seems like we haven't quite seen that yet with colorectal cancer.
> That's right. As part of our initial pilot in the moon shot, we were, have been treating a rare subset of patient that include some of the hereditary patients that we've touched on briefly before, but there is a subgroup of patients that's just a few percent where immunotherapy has worked, has worked really well. But this is indeed just a few percent of patients, and when we look beyond that very unique subgroup, what we see is a very different outcome -- the immunotherapy, the checkpoint inhibitors that we have right now have not been active. So we're really leveraging this success that we have in one subgroup and asking what's different about the others. How can we learn from our success and apply that to our other populations? And we're really doing that in a variety of ways that take advantage of some of the expertise that we have at MD Anderson, and one of that is the integration and multidisciplinary care with our hepatobiliary surgeons where we're able to resect metastatic disease in the liver. And this provides a very unique opportunity to explore the impact of this immunotherapy and also use immunotherapy in patients that are most likely to benefit. So I, some exciting work coming forward out of that group to really take advantage of the knowledge that we have, but also to take advantage of the expertise at the institution.
> And another goal of this moon shot is to find prevention strategies with low toxicity. I wasn't aware other than lifestyle choices whether there were chemo preventions available for colorectal cancers.
> So there are. This is an area when we talk about prevention strategies and chemo prevention strategies, we have to recognize that we're talking about taking a group of patients that may have a risk for developing a cancer, but have not yet developed it, and administering some sort of therapy for an extended duration of time. So our threshold for acceptable toxicities is very different than it would be in a patient, for example, with an established cancer where, that we're treating for a shorter duration. So in this setting, when we even talk about something like aspirin, we recognize that there is toxicity that comes with long-term aspirin use. And when we're talking about preventing a moderate risk patient for colon cancer, those toxicities may overwhelm the benefit. And so there's effort as part of this upcoming year's moon shot to really explore broadly what are some of the potential chemo prevention strategies, recognizing that we have to find that right balance between the efficacy and a very well-tolerated therapy.
> And I understand there was recent news out that actually the incidence of colorectal cancer is rising in people under 35, so that kind of gives this moon shot a little bit more urgency.
> Absolutely. So this gets back to the idea that we're not talking about one type of cancer, and we recognize that there are cancers that are occurring in younger patients, that are occurring at a higher incidence than we have seen before. And this is well before the traditional recommendations for screening for colonoscopies. So while the incidence is overall still very rare, it is a worrisome trend, and the efforts that are ongoing are trying to understand what is different about these cancers. And are there avenues to intervene?
> It sounds like once all is said and done and you've crunched all the genomic data and everything that colorectal cancer might, the incidence might almost disappear, it sounds like.
> Well, certainly that's our ambitious long-term goals for all of these efforts, and I, the hope is indeed that by recognizing we're dealing not just with one cancer, but with several different subtypes of cancer, that we can devise strategies that may be unique for each of these and may be very successful with certain types of interventions in these defined subgroups. So that's certainly our goal and we've tried to put together a comprehensive program that really runs the gamut from screening and prevention strategies to molecular classifications to deploying immunotherapy to address established disease.
> Great. Thank you very much. Very exciting. If you have any questions about anything you've heard today on Cancer Newsline, contact Ask MD Anderson at 1-877-MDA-6789 or online at MDAnderson.org/Ask. Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.
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