The incidence of colorectal cancer among people under 50 is rising. In this ASCO Education podcast episode, medical oncologist Nilofer Azad (Johns Hopkins Medicine) and epidemiologist Caitlin Murphy (UT Southwestern Medical Center) discuss risk factors, screening, and treatment.

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Air Date: 7/28/2021

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

NILO AZAD: Welcome to the ASCO learning podcast episode focusing on early-onset colorectal cancer. My name is Dr. Nilo Azad, and I'm a medical oncologist and Associate Professor of Oncology at Johns Hopkins Medicine. I'm joined today by Caitlin Murphy, an Assistant Professor of Epidemiology at the University of Texas Southwestern Medical Center. We wanted to start today with a patient case, just to give a little bit of context about the kinds of patients that we are dealing with.

A year ago, a patient presented to my clinic who was 32 years old. She was having significant symptoms of rectal obstruction. She was having trouble going to the bathroom. Her bowel movements were difficult. She was having bloody stools, and she had gone to see a gastroenterologist who had done a colonoscopy, biopsied her tumor, and found that she had adenocarcinoma of the rectum.

Now, luckily, at that time, she didn't have any metastatic disease. But her tumor was quite large, 15 centimeters in size, and so we decided to move forward with doing chemotherapy in the neoadjuvant setting. She got aggressive chemotherapy with FOLFOX for three months. And when we did a scan, unfortunately, we found that the tumor had grown.

Now, she still didn't have any disease outside of the rectum but, during that time, we had gotten some molecular testing back which showed that the patient had mismatch repair deficiency or microsatellite insufficiency. So we decided to try something a little outside of the box at that time, where we started treatment with immunotherapy.

She had a dramatic response to immunotherapy. Her tumor shrank. And, six months later, she went to surgery and, though on scan it still looked like she had a large tumor, it turned out that that tumor was only scar and that she'd had a complete response.

She came back to see me, last week, in clinic. She looks fantastic, and she's moving forward with planning for a family with her husband. So, Dr. Murphy, can you tell us a little bit about the trends in early-onset colorectal cancer incidence in the US and globally?

CAITLIN MURPHY: Of course. I'll start, first, by talking about trends in early-onset colorectal cancer in the United States. Incidence rates began increasing here in the early 1990s and have nearly doubled over time, from about eight cases per 100,000 persons in the early 1990s to 16 per 100,000 persons in today. The largest increases have occurred in 40 to 49-year-olds. They account for about 80% of all cases.

And we've also noticed that incidence rates of rectal cancer versus rates of proximal colon or distal colon cancers have been the largest increases in incidence. We've also seen a similar increase in local and distant stage disease.

And, to me, one of the most compelling observations that we've made is that incidence rates have increased successively across generations, or about the year that you were born. There's a very clear and marked increase in incidence rates starting with persons born in and around 1960, or who we sometimes call Generation X. Epidemiologist like to call this a birth cohort effect because essentially we see incidence rates increasing across birth cohorts.

More recently, we've observed that incidence rates have started actually increasing in people in the early 50s, the 50 to 54 age group, and this really does not appear to be driven by early stage disease as we might expect with more screening in that age group. But perhaps the increase in this early 50s age group is driven by the same things happening in people under the age of 50.

Globally, we've seen a similar increase occurring in countries that have colorectal cancer screening and even in countries that don't have colorectal cancer screening. There was a recent analysis of 36 countries, and it found that incidence rates have increased in 19 of those 36 countries. Nine of those countries had stable or declining trends in incidence in older adults.

There really wasn't a clear pattern among those countries in terms of the degree of Westernization or income level that might explain those trends. And, importantly, that birth cohort effect that I mentioned as occurring in the United States, where we see increasing incidence rates starting with Generation X, has also been reported in many other countries, including Canada, Australia, and some East Asian countries.

NILO AZAD: And, Dr. Murphy, what is the current thinking regarding causes of this increased incidence of colorectal cancer that we're seeing in young people?

CAITLIN MURPHY: Generally, there are two schools of thought about what's going on here. The first thought is that this is the same disease that's happening in older adults, but it's just now occurring at a younger age. For example, we've seen a steady rise in factors that we know increase the risk of colorectal cancer in older adults, like obesity and diabetes. And, these factors, we also know are now increasingly occurring at a younger age.

But many of my clinical colleagues like you, Dr. Azad, tell me that most of the patients they diagnosed with early-onset colorectal cancer are otherwise fit and healthy and have no obvious risk factors like those. And so this second school of thought about what might be going on here is that this is really a different disease than what's happening in older adults, driven by as of yet unknown risk factors that have also increased in the population.

NILO AZAD: Yes, I definitely feel like that the cohort of patients that I see in my clinic-- and, of course, at a place like Johns Hopkins, we see a little bit more of a skewed cohort in terms of seeing more younger patients-- that most of them aren't people that I would traditionally look at and say that they've got a risk factor that explains the situation. What are the main risk factors for early-onset colorectal cancer?

CAITLIN MURPHY: There's still a lot of research to be done in understanding what the risk factors for this disease are. And I like to think of the risk factors that we know about as affecting early-onset colorectal cancer as falling into one of four sort of categories.

The first category is having a genetic predisposition, so either having a family history of colorectal cancer or even a family history of an advanced adenoma or having a hereditary syndrome like Lynch syndrome or polyposis. Together, these account for about 40% of all new cases and many of the cases that don't have a traditional phenotype or mutations associated with colorectal cancer. So, for example, many of the patients we see with Lynch syndrome don't necessarily have the typical phenotype that we've expected to be associated with Lynch syndrome over the past however many years.

The second category is what I like to call established risk factors. Or maybe another way to think about this is usual suspects, so already known causes of colorectal cancer in older adults. I mentioned these earlier, obesity, diabetes, but then there's also smoking, physical activity, and sedentary behavior.

Then the third category is what I call early life factors, and the importance of understanding early life factors is really driven by the fact that incidence rates have increased by generations. Remember that first cohort effect I was describing to you earlier. This birth cohort effect tells us that risk factors in very early periods of life or vulnerable periods of growth and development are important. It also tells us that we should rethink some of those usual suspects or established risk factors as occurring very early in life. For example, instead of just thinking about obesity, thinking instead about birth weight or childhood obesity as well as growth trajectories in infancy.

And then, finally, the fourth category is unknown risk factors. So the trends in incidence point to some clues, whether things in the population have increased over time or by generation, that might help us understand what's going on here. Some examples of those unknown risk factors might include environmental chemicals like flame retardants or endocrine disruptors, antimicrobials, or other infectious agents. And there really has been no research on these unknown risk factors but, again, people think that these might be related to early-onset colorectal cancer just because the trends in their prevalence have mirrored the trends in incidence.

NILO AZAD: So, Dr. Murphy, you've really laid out wonderfully both the risk factors that we're seeing in some of these younger patients and then just the changes in incidence and occurrence as well. So how has that affected screening guidelines, going forward, as well?

CAITLIN MURPHY: In 2018, the American Cancer Society recommended lowering the age to initiate average risk colorectal cancer screening from starting at age 50 to age 45. At the time, when this was done, all of the GI societies and the United States Preventive Services Task Force recommended still continuing at age 50. This recommendation from the American Cancer Society was a qualified recommendation, meaning that it's based on simulation modeling and not necessarily empirical evidence driven from randomized trials or other clinical studies.

More recently, just last fall, in 2020, the United States Preventive Services Task Force released a draft recommendation to do the exact same thing, so lowering the screening age for average risk people from 50 to 45. The idea of a draft recommendation simply means that they put the recommendation out there for public comment and then consider some of those comments before either revising that recommendation or making the recommendation official. Like the qualified recommendation, initiating average risk screening at age 45 has a grade B recommendation from the task force, meaning that they have fair compared to strong evidence to support that recommendation. And I expect that we'll be seeing a final one coming this spring or summer.

NILO AZAD: Is there anything unique about colorectal cancer in young patients biologically?

CAITLIN MURPHY: That's a good question and something we still don't know a lot about. I'll just give one example of that. We know from certain studies that early-onset colorectal cancer seems to be enriched for certain molecular subtypes like an immune subtype, although the research in this area is really limited by a small number of studies. And most of the studies have been conducted just as a single center and not at the population level.

NILO AZAD: And how do our patients that are younger do in terms of survival, compared to their older cohorts?

CAITLIN MURPHY: Most studies that have looked at this report no difference in survival between younger and older patients with colorectal cancer. We do know, however, that younger patients are more likely to be treated aggressively with surgery, multimodality chemotherapy, and/or radiation therapy. This really raises an important question. If younger patients have no survival advantage despite more aggressive treatment, this could mean that younger patients have tumors that are more aggressive or that they respond differently to treatment regimens that have been developed for older patients with colorectal cancer or risk disease are over treated.

With that in mind, I want to revisit our patient case, the 32-year-old woman with rectal cancer. Dr. Azad, what should be discussed with a young patient before starting therapy? What kind of testing needs to be done?

NILO AZAD: So when we have young-onset colorectal cancer, just as you mentioned, there are a subset of these patients that have a genetic predisposition to developing colorectal cancer and other tumors as well. And so these patients absolutely need to be assessed for these genetic syndromes. So for my patient, in particular, I mentioned that she had mismatch repair deficiency or microsatellite instability.

That suggests that she had what was called Lynch syndrome. And Lynch syndrome is something that, now, luckily, we actually have therapies for in terms of having immunotherapy. But knowing about that kind of a syndrome is important for this patient for her future planning, for the other tumors that she might develop, and of course for counseling for the rest of her family as well.

And what was actually interesting about this case was that she had traditional mismatch repair testing with immunohistochemistry of her tumor, and that testing came back that she had microsatellite stable disease. So initially we actually didn't think that she had microsatellite instability. But because her family history was such that I was still suspicious that this was true, we sent second testing using a different kind of assay, and that's where it became clear that she had mismatch repair deficiency. So it's really important to maintain a high index of suspicion and recognize that even some of the tests that we send are not perfect and, if you still have a high index of suspicion for reasons like the family history or a patient having a second cancer previously, that you should follow that instinct and make sure that you're doing as deep testing as necessary.

The other issue, of course, with younger-onset colorectal cancer, especially for people as young as my patient was, is the question of fertility. And so because she had rectal cancer and, as part of the paradigm for rectal cancer, these patients will have radiation, she was not going to be able to carry a fetus or embryo to term after completing therapy. So that's something that we need to understand early, have those conversations early, and get a multidisciplinary team involved that usually involves fertility experts as well as gynecologists.

And so, for her, what we ended up doing was doing an egg harvest. And then she had in vitro fertilization performed, and then they were able to store embryos for her and her husband. And now they're actually looking forward to moving forward with surrogacy.

CAITLIN MURPHY: So it sounds like your patient had to navigate a lot at the beginning of her diagnosis, considering fertility options, grappling with a new diagnosis at the age of 32, and then going through all of the workup and diagnostic testing. After that, what kind of treatment options would be appropriate for her?

NILO AZAD: So, at this point, we actually aren't treating early-onset colorectal cancer any differently, in terms of how we actually treat the cancer, compared to people who develop colorectal cancer at a more average age. That said, our patients do have specific needs that we need to incorporate and discuss, both when they're diagnosed and as they start treatment and then later as they complete treatment and for their survivorship.

So, clearly, we talked about the fertility issues. But when you've got a patient who's in their 30s or 40s and they're undergoing chemotherapy that's going to leave them with potentially lifelong neuropathy as one of the long-term side effects, that's really something that we need to discuss with patients, both so that they know about it, but what impact could that have on their professional function.

For example, this week, I saw a 40-year-old woman who is newly diagnosed, and she is actually a concert musician. And so the idea that this may actually result in meaningful disability for her for what her chosen profession is, it's something that we need to discuss with these patients because they likely have 20 or 30 more years of professional life that is ahead of them and makes a huge difference for them, and financially as well.

And, on that front, when you are treating people who are kind of in the prime of their life when it comes to their earning potential, that's also a really big issue that needs to be discussed. Sometimes people, in fact, lose their jobs because of the amount of time that they have to take off for treatment during that time. And so working with social work and making sure that we are addressing these issues and not just focusing on the things that are physical is really important.

I'm a believer that impact on sexuality and body impact is not something that is only for the young. But, clearly, that's something that we need to discuss for all ages of patients when it comes to the kind of therapies that we have, especially with rectal cancer where, a lot of times, patients are left with a temporary or permanent colostomy.

And I also think that there is some real issues around feeling isolated from your peers. It's still very rare to develop colorectal cancer, or any cancer, below the age of 50. And so because of that, even though we are seeing an increase in incidence, a lot of times, this is an area where patients can really have significant mental anguish because they feel so isolated from their peers that aren't having to deal with these issues. So I think all of these are really important features of dealing with early-onset colorectal cancer.

CAITLIN MURPHY: I think you said it exactly right, that these patients are in the prime of their life and not necessarily just navigating cancer treatment-related factors, but also having to deal with family and care-giving responsibilities, their job, their economic situation, and their social situation. If all other disease factors and patient characteristics were similar, though, but the patient that you talked about was older, let's say, aged 55, would you do anything different in terms of her care?

NILO AZAD: So, you know, with that particular patient, we were trying very hard to see if we could find a way that she might not have to have radiation because we knew that radiation was going to take away her fertility. And so when she had that initial progression on chemotherapy, what we did was a little bit out of the box, at that point, using data that existed in the metastatic setting showing that immune checkpoint therapy was very effective in patients with mismatch repair deficiency and treating a patient that didn't have metastatic disease, hoping for an excellent response, which is what we got. Now, fortunately or unfortunately, while she had a fantastic response, because the tumor didn't regressed completely and left her with that scar tissue, she did end up getting radiation because we couldn't be confident that we had gotten a complete response with just the immunotherapy.

But I do think that, with younger onset colorectal cancer, what often happens is that we dance a little outside of the box in terms of trying to do things that would help preserve patients' fertility or preserve some of their overall function that might be a little bit different than what we might do for people 20 or 30 years older. I think that, in the right circumstance, that can be the right thing for our patient. But it is something that you have to do very carefully because, as you mentioned, it may well be that sometimes our younger patients are being treated more aggressively than they need to be just because they come in, and they have less comorbid conditions. And people feel comfortable being more aggressive when they might not need it.

CAITLIN MURPHY: This is a really great conversation. And, as an epidemiologist, I often get lost in the numbers and forget about the real impact that this disease has on patients. And so I really appreciated learning about the patient case.

NILO AZAD: Thank you, Dr. Murphy, for joining us as well. I think that this is such a great way for us to put some of those really objective data together in terms of what we're seeing with more patients that are developing young-onset colorectal cancer; what groups that we're seeing that in, both in terms of ethnic groups and risk factors; and then combine it with some of the key features that are important in terms of patient care, which I would say means that all patients should be getting genetic testing, all patients should be treated aggressively, and that there are many both physical and psychosocial factors that we need to be taking into account when we're treating our young-onset colorectal cancer patient. So thank you so much for your time. I've really enjoyed talking about this with you.

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