SPEAKER 1: All right, everybody. We'll go ahead and get started. Thanks to all those here joining in person, as well as everyone out in Zoomland for Medical Grand Rounds today. We have the pleasure of having Dr. Cynthia Yoshida here with us today. Dr. Yoshida attended med school and residency training at the University of Kansas, in Kansas City. She completed GI Fellowship here with us at UVA, and, as is true for so many, has stuck around in Charlottesville ever since then. 

She's had a wide variety of roles within the Department of Medicine, including associate program director of the GI Fellowship, associate chair of the IM Residency, and director of the Women's GI Clinic. She's a master endoscopist and has won multiple awards for her leadership of women in medicine, as well as her teaching skills. She's been invited to give innumerable talks on her expertise on colon cancer screening and early-onset colorectal cancer, which we're lucky enough to hear more about today. So, without further ado, here's Dr. Cynthia Yoshida. 

[APPLAUSE] 

SPEAKER 2: Thank you, Alex. And thanks for having me today. This is a topic that I'm super passionate about. So glad to actually have you here. Today I hope to really help you to recognize the recent increase in early-onset colon cancer. We'll talk a little bit about the epidemiology, and the trends, and incidence. We see it rising over time. 

We'll examine some risk factors and possible ideologies. Finally, I really want to talk to you a little bit about implications for colorectal cancer screening age. And I really, really want to help you to understand your role in identifying this risk, and potentially preventing early-onset colon cancer in your patients. 

All right, I want to start with a patient. I would have had Matthew here today-- this is Matthew Mewhorter-- but, given COVID, we couldn't get him here today. He presented his story to us at the Digestive Health Town Hall in 2017. He so kindly allowed me to share his story with you today. 

Matthew originally started having rectal bleeding and he didn't think very much of it for a while. But after several months of intermittent rectal bleeding symptoms, he finally told his wife and she said, oh my gosh, you actually have to go see a doctor. And then he went to go see his physician only six months later. I mean, he really hemmed and hawed before he decided to make that appointment. 

When he saw his PCP, his PCP told him that they thought he most likely had hemorrhoids and that maybe it was colitis. So they told him to lay off of dairy for about a couple of weeks, and they set him up with a GI appointment. Got to see his gastroenterologist several months later. This wasn't here. He ended up being seen in clinic and they told him again it was probably most likely hemorrhoids or an anal fissure, and said to him that he should probably have a colonoscopy. 

But Matthew was also having a lot of constipation symptoms as well and they thought, well, maybe it was really just as a result of IBS. So they gave him some data on living with irritable bowel syndrome and they sent him on his way. He had his colonoscopy several weeks later and they found a rectal cancer. Matthew was-- that's where he got introduced to the UVA system. He ended up getting preoperative chemotherapy and radiation therapy. He underwent a low anterior resection by Tracy Hedrick here, had an ostomy. 

That was all in 2014. Matthew was 35 years old and he had a new baby girl. When Matthew was diagnosed with early-onset colon cancer he started this blog. He drew himself as an owl-- it's cancerowl.com-- and I hope you read it because it's really funny. But it's also an incredibly poignant reminder of how hard it is to live with early-onset colon cancer. 

Since 1994 early-onset colon cancer has increased about 51%, according to the National Cancer Institute. We see that about one in ten colon cancer diagnoses and one in five rectal cancer diagnoses are in young individuals under the age of 50, so between 20 and 49 years old. The rates of early-onset colon cancer are increasing slowly, but every year we see increases. It's expected that within a decade, by 2030, we should see a doubling of the colon cancer incidence in this young population and a quadrupling of the rectal cancer incidence in this population. 

This was first noted by Becky Siegel. She is the cancer epidemiologist at the American Cancer Society. She does all the stats for colon cancer, and she was noticing that slowly but surely we were seeing an increase in early-onset colon cancer. She published her findings first in 2009, in The Cancer Journal. 

This is the usual trends that we're used to seeing in older adults with colon cancer. If you look at the graph on the left, you look at the incidence and the mortality of colon cancer in men and women, we see that, since the 1980s, we see a decline in early-onset colon cancer. And then, by the 1990s, it's a really sharp decline. 

In the 1980s, that initial decline was felt to be mostly due to lifestyle changes-- decreases in smoking, better diets, et cetera. But from the mid 1990s, in the gray bar on, you can actually see that there's about a 4 and 1/2% per year decline in colon cancer incidence in both men and women, predominantly due to colon cancer screening, and really due to the utilization of colonoscopy. 

In the graph on the right, you can see-- it's colonoscopy utilization in the blue bars-- and, in 2000, about 20% of all age-eligible adults had colonoscopy. But Medicare started paying for colonoscopy as a colon cancer screening tool in 2001. You can see that every year since that there's been a gradual increase in colon cancer utilization to 2018, where about 60% of age-eligible adults have had a colonoscopy for colon cancer screening. You can see that this increase in colonoscopy utilization inversely correlates to the vast decreasing incidence rate in colorectal cancer. 

Again, I showed you that, on the left side, we see the data in older people, where we've seen a 38% drop in colon cancer since 1995. But the data that Becky Siegel showed was that, beginning in 1995, at the same time, for 20- to 49-year-olds, we actually see that there's been a 55% increase in colorectal cancer. 

This is Becky Siegel's data from her original paper. You can see that the incidence rates of colorectal cancer have increased by about 1 and 1/2% per year. So it's not huge, but it's definitely there in men and women. And you can see that it increases at all age groups. In the top graphs, you can see that the diamonds represent 20- to 29-year-olds, the squares are the 30- to 39-year-olds, and the triangles are 40- to 49-year-olds. 

What we see is that the incidence of colon cancer is higher in men, about twice as high-- early-onset colon cancer is twice as high in men, and that it's predominantly in the 40- to 49-year-old age group. This rise in colorectal cancer is predominantly also driven by a rise in rectal cancer. You can see here that in the triangles at the bottom, that in men and women-- that's rectal location-- that the rise is predominantly there. 

Fast forward another decade-- and you have a decade-- this is 2017-- and you have another decade of data and still this continues. We see that in every age group between 20 to 49 there's an increase both in colon and rectal cancers. This again is predominantly driven by the increase in rectal cancers, which you can also see-- it's hard to see from far away-- but if you look at the y-axis here, in the 20- to 29-year-olds the highest is 1.5, 30 to 39 is 5, and the 40- to 49-year-olds is 20, so the actual rates are increasing mostly in the 40- to 49-year-old age group. 

You might look at the 50- to 54-year-old age group and you might wonder, why is it that we're seeing only flat rates in this age group? Really it's because of the fact that, even despite guidelines for us to start screening at age 50, people are not screening at that age. So we're ending up seeing no change really in colorectal cancer incidence rates in this population. It's only in the older population, who are having screening and continue to do screening, that we actually see the decline in the incidence of colorectal cancer. 

You can see that early-onset colon cancer doubled between 1990 to 2016. Even though the rates of increase are staggering you can see that the actual numbers of early-onset colon cancer are really pretty low. Clearly the vast majority of colon cancer still occurs in people over the age of 60. 

But if you take this young onset group and you break it down to their age, you can see that clearly 3/4 of these patients with early-onset colon cancer are in the 40- to 49-year-old age group, and half of them are in the 45- to 49-year-old age group. Again, to put a plug in here, if we were to start colorectal cancer screening at 45, as per the American Cancer Society guidelines, it's very possible that we could find early cancers in young adults and we could maybe save some lives. 

The onset of early-onset colon cancer is pretty low. The numbers are low, but you can see that the numbers of cases are really pretty staggering. 49 young people die every day of early-onset colon cancer and-- I'm sorry, are diagnosed with early-onset colon cancer every day, and 10 deaths per day. This Twitter feed, Never Too Young, that was out in March-- Colorectal Cancer Awareness Month this year-- is tragic. "I'm a 36-year-old stage IV colon cancer survivor from Houston." "I'm a 42-year-old stage III colon cancer survivor from New York." "I'm a 34-year-old stage IV colon cancer survivor from New Hampshire. I was diagnosed at 14 weeks pregnant." "March is Colon Cancer Awareness Month. Help us to spread the story that young onset colon cancer is on the rise." 

This decline in older age colon cancer and the rise in early-onset colon cancer is shifting the population of colon cancer younger. In 2000, we actually saw the median age of diagnosis of colon cancer was 72. Now our median age of diagnosis is 66 and the median age of diagnosis of rectal cancer is 63. And next year we're going to get a new set of data and it's believed that the median age of diagnosis of rectal cancer may be somewhere in the 50s. So although you guys are young and you think this is an old age, this is pretty dang young for people like me. 

Are there racial differences in early-onset colon cancer? The answer is yes. This comes from a 2019 editorial in Gastroenterology. You can see that early-onset colon cancer is highest in Blacks-- it's the solid blue bar-- but it's rising fastest in non-Hispanic whites. This is the same also for rectal cancer. In Blacks the incidence of rectal cancer is in the solid red line, and in non-Hispanic whites it's increasing in the dotted red line, to the point now that rectal cancer incidence in non-Hispanic whites in young people is higher than it is in Blacks. 

I think these geographic differences are also really fascinating. If you look, early-onset colon cancer is lowest in the Western states in yellow and it's highest here, in the Mississippi Delta and Appalachia-- kind of around where we are-- with the highest rates being in Kentucky, West Virginia, Alabama, and Mississippi. You can see those rates here. This Mississippi Delta, Appalachia region is characterized by very high rates of poverty and low access to health care and it's a wonder whether or not-- what is the cause of it? Why could it be there? And it's thought that maybe that these differences geographically might be due to differences in health care, and lifestyle factors, and maybe even environmental exposures. 

The Mississippi Delta, Appalachia is the place where early-onset colon cancer is the highest. But where is it rising the fastest? This data by Becky Siegel, that was published last year, you can see that the incidence of early-onset colon cancer is rising in 40 of 47 states. If you look at the highest average annual percent change it's happening highest in Western states-- you can see in the dark gray here-- with the largest rises happening in Idaho, and in Washington, and Colorado. You can see in Washington state the rate has almost doubled in this time frame and it's mostly confined to an increase in non-Hispanic whites. 

This may make some of you wonder why is it increasing so much in the Western population? We think of these Western states as being younger people who might have better lifestyles. They tend to be more active and have better diets, maybe less smoking of cigarettes, but why is it happening that we're seeing this increase here? 

We're also seeing increases all over Europe. In 20 European countries we see increases in early-onset colon cancer as well. And in Europe we see that increase predominantly in the very young, and more so in colon cancer. Worldwide we actually see increases in 42 different countries. This is published by Becky Siegel, again, last year, and you can see that the lowest rates are in Chennai, India, with the highest rates being in Korea. 

Some people thought that maybe the increased incidence of colon cancer was really due to the fact that young people were having more colonoscopy. I showed you that data early on that colonoscopy numbers-- the numbers of colonoscopies that we're doing-- is actually increasing. Some thought, well, maybe these young people are just coming to colonoscopy with their symptoms and maybe that's why we're seeing more cases. It's kind of like the whole idea of thinking that we're seeing more COVID cases because there's more testing. What we can show is that's not true. 

This study they looked at colonoscopy utilization between 2000 and 2015 in 40- to 49-year-olds, and then they looked at trends in colorectal cancer in that same time period for 40 to 49-year-olds. What we can see is there is actually no correlation between colonoscopy utilization and colon cancer incidence in this young population. So it's not because we're doing more colonoscopy that we're having an increase in colorectal cancer in young people. There really is an increase in this disease. 

All right, deep breath. This is the slide that I want you to really remember from my entire talk, OK? This is the birth cohort effect. What this shows you is that there is an increasing rate of colorectal cancer across birth cohorts. So it's not just because you're young that you get an increased risk of colon cancer. It's something to do with the year of your birth that increases your risk of colon cancer. 

Compared with adults born in 1950, those adults born in 1990 have a 2 and 1/2 times increased risk of colon cancer, and an over 4 times increased risk of rectal cancer in their lifetime. That means all of you in the audience, all you residents and fellows, you have a much higher risk of colon cancer and rectal cancer because of the year you were born than I do-- I was born after the 50s, by the way-- and you are going to carry that higher risk of colon cancer with you throughout your lifetime. That's impressive. This increase in relative risk began with the baby boomers, you can see, and it's increasing, with the highest in the Gen Xers, born between '65 and 1980. 

When we look at early-onset colon cancer patients-- you can see in the red bars here are the 20- to 49-year-olds-- most patients that present with early-onset colon cancer present with [INAUDIBLE] stage and advanced disease. But 3/4 of them will present with stage III or stage IV disease, and 1/4 of them will have metastatic disease at the time that they are diagnosed. 

Why is there a delay in diagnosis? This comes from a 2018 survey from the Colorectal Cancer Alliance, and they looked at 1,195 patients and survivors, from 38 different countries, and they surveyed them with regard to their colon cancer. They found that-- you can see-- colon cancer patients who were young presented with a myriad of different symptoms. Blood in their stool, diarrhea, gas pain, but you can even see weight loss here. And the majority of them presented with over three symptoms. 

The thing about it is that the 50% felt that their symptoms were ignored. You can see 2/3 of them, like Matthew, felt that they saw two doctors before they were diagnosed. And 82% were initially misdiagnosed, and I think it's because of the fact that physicians tend to think of common things in this young patient population, right? We think about anal fissures. We think about hemorrhoids. We think about colitis. I want you to start thinking about early-onset colon cancer when you see these patients in your clinic. I want you to consider this in your diagnosis, because it's out there and it's definitely increasing. 

It wasn't only about the physicians that had a problem, it really was about the patients as well. In this survey you found that 63% waited 3 to 12 months before they actually saw their doctor. And patients themselves didn't even realize that some of the symptoms that they had-- rectal bleeding-- were potentially signs of colon cancer in this young population. This is the part that I think is incredibly tragic, that the median time to diagnosis to rectal cancer in this young population was 217 days, and that was compared to people over the age of 50. Their time to diagnosis was only 30 days. So again, it takes a long time for these patients to actually present. 

We have learned an incredible amount about colon cancer over the last 50 years. In the 1980s, we identified a number of molecular alterations and genetic changes, so now we know about KRAS and BRAF, proto-oncogenes. In the late 1980s, we discovered this concept of multistep carcinogenesis, the adenoma-carcinoma sequence. Most colon cancers begin as small as colon polyps, adenomas, that, over time, they grow, they have genetic changes that happen, and, in about a decade, they can turn into colon cancer. 

In the '90s we discovered microsatellite instability, and also this CpG island methylator phenotype, and this led to the discovery of the serrated pathway. This is different. These are these flat, serrated polyps that happen in the right side of the colon and lead to more right-sided colon cancers. You can see here, by putting these all together, we've been able to create different subtypes for colon cancer. And this nice paper by Phipps, et al., in Gastroenterology this year, they looked at over 5,000 colon cancers from a number of different sites, and showed that if you had, for instance, the KRAS mutated-- the type III subtype-- that's a typical type of adenoma-carcinoma that we see. The type V is the Lynch type, which is mostly microsatellite instability. 

What this really reminds me to tell you is that not all colon cancers are the same. They can be very different, with very different genetics. This is what we know about colon cancer tumors in young adults. That they are poorly differentiated. That they have signet ring histology. They definitely, on presentation, have lymphovascular and perineural invasion. And thus it makes them more aggressive tumors with a worse prognosis. 

When we look at them genetically we find that more of them have microsatellite instability and fewer BRAF mutations. This is very different than colon cancer in older adults. In colon cancer in older adults you tend to see more hypermethylation, but that's not true in younger adults. In younger adults there's less methylation of the DNA, and we actually see that this is associated with shorter survival. So it begs the question, is early-onset colon cancer a different disease with a different mechanism of pathogenesis versus colon cancer in older adults? 

You've seen this slide before. We know that all of these factors contribute to risk in colon cancer in general. But I don't think we understand very much about the pathogenesis of early-onset colon cancer. Let's delve into some potential risk factors. Let's look at diet. 

This is a nice study that came about. It was e-published two weeks ago and it's going to be published in Gut very soon. It looked at over 80 meta-analyses and tried to look at medications, vitamin supplements, and dietary factors to figure out what were the things that increase the risk of colon cancer the most. In dietary factors, there were really only two in all of these patients, all of these studies, and all these meta analysis. It was meat and it was alcohol use. 

You can see that meat and processed meat intake modestly increase one's risk of developing colorectal cancer. It is definitely a dose-response effect, so the more meat, or processed meat, you eat the higher your risk of developing colon cancer, and it is more for the colon than in the rectum. Interestingly, eating poultry may actually be a decreased risk. You can see about a 20% decrease if you eat turkey or chicken, but it's not a dose effect, so don't go out there and eat more Chick-fil-A. And it's more here in rectal cancer. 

But I think the thing that we don't remember very much is the fact that alcohol is probably one of the biggest factors that's associated with the risk of colon cancer. And many of us don't talk about alcohol to our patients when we think about colon cancer risks. You can see here that alcohol in general has a major dose-response effect. That if people take in four servings of alcohol per day you can increase your risk of colon cancer by 50%. 

And you may think, wow, who really takes in four servings of alcohol per day? But today our cans of alcohol are getting bigger, our beer are getting bigger, our glasses of wine are getting bigger. It's not uncommon to actually find that several of our patients are reaching this kind of limit. When we see alcohol risks in colon cancer it's mostly in men and mostly in rectal cancer versus colon cancer. I think it's kind of interesting, don't you? How is it that something that we're eating can affect only one side of our colon? 

This is a really nice study that was published in Gastroenterology in April of this year, and it looks at how people who eat high sulfur diets can actually have an increase in colon cancer in the left side of the colon in men. Remember that high sulfur diets are things like processed meats, low calorie sodas, and diets that are decreased in vegetables and legumes. 

We know that our gut contains these sulfur-metabolizing microbes and they convert these high sulfur diets into hydrogen sulfide, and hydrogen sulfide is carcinogenic. How? Because it leads to epithelial DNA damage, it promotes inflammation and cytokine production, and it disrupts the mucus layer. Remember, that mucus layer over the lining of the colon is very protective and it has those disulfide bonds that are broken down by this hydrogen sulfide. When the mucus layer's broken down it exposes the epithelium to luminal bacteria. 

This nice study was done in health care providers, so it's mostly a study of men, but they showed in these men who ate this high sulfur diets, processed meat and low calorie foods, that there was an increased risk of distal colon and rectal cancers. There's a lot of data today to show that the right side of the colon and the left side of the colon may be very different organs. At UVA here, Graham Casey is doing some incredible work where he takes biopsies from the right side of the colon and the left side of the colon and he makes three dimensional organoids, which are like little mini colons, and then he exposes them to alcohol and shows that there's DNA changes. 

There's also a lot of data Li Li told me, that in taking biopsies from the right side of the colon and the left side of the colon, in Blacks versus whites, we actually see that the Blacks have an older right side of the colon, where they have more right colon cancers, and whites have more older left side of the colon, where whites have more left-sided colon cancers. It's truly intriguing that the left side of the colon and the right side of the colon may be very different organs. 

What do we know about risk factors for early-onset colon cancer? This is the largest study to date. It was published by Samir Gupta in August of this year. It's a veteran study, so it's mostly men of 18- to 49-year-olds who are undergoing colonoscopy. You can see the colonoscopy controls that they had, they had 67,000 controls, and they compared this with National Cancer Registry early-onset colon cancer cases, of which they had 651 cases. 

The population was median age of 43. Again, veterans, so mostly male. And 72% were overweight or obese. They were skewed more to being obese. They were also skewed more to more tobacco use, and skewed more to less aspirin use. What do we see in the results? We see that age and male sex were the predominant major risk factors for early-onset colon cancer. 

Similar to all the data that I showed you earlier, the median age of diagnosis in these young people was 46, with 88% being between 40 and 49, and men had a much higher risk of early-onset cancer than women. It's interesting though, you can see that smoking had no effect on colon cancer risk, and actually BMI-- if you were overweight or if you were obese-- you might have had even a protective effect. And aspirin use, as we know from earlier data, also had a protective effect. This is really mostly in men. 

If they looked at this population who were underweight in a post hoc analysis, they actually found that if a person lost 5 kilograms of weight in the five years before their colonoscopy, that was a sign for colon cancer. I want you to remember that. If you have somebody who's young, who's presenting with weight loss, you might think of colon cancer in their differential diagnosis. 

That was for men, in the Gupta study. What about for women? This is a National Nurses Health Study and they looked at women between the ages of 20 to 42 at enrollment, and they have over 85,000 women enrolled in this study. In this cohort they found 114 cases of early-onset colon cancer. 

What they found is women who were obese, with a BMI greater than 30, had twice the risk of early-onset colon cancer. If a woman gained over 40 kilograms-- that's a lot of weight-- but gained over 40 kilograms from the age of 18, they also had double the risk of early-onset colon cancer. In this study, they also showed that physical activity was also super important, that sedentary television viewing time in women over 14 hours per week increased one's risk of colon cancer in young women. 

Because of the fact that these are young people, a lot of people have really-- a lot of investigators have wondered whether or not birth or early childhood events might increase one's risk of colon cancer. There's definitely been more cesarean sections in the last several decades, less breastfeeding, and maybe childhood infections could have a role. All of these are thought to have impact on the gut microbiome. But, to date, none have been shown to directly affect rates of early-onset colon cancer. 

We do know that genetics and epigenetic factors are very important. If you look at the pie graph on the left, this is the usual demographics of patients with colon cancer over the age of 50. You can see that 90% of colon cancer is sporadic and only about 10% are associated with genetic changes. When you get to people under the age of 50, and that's in the middle graph, about 20% have genetic changes. And in the very young, under 35, up to a third have genetic changes that can be found. 

But you can see-- what's important to remind you is, even in young people, the vast majority of colon cancer tends to be sporadic. If we do see genetic changes it's almost always in microsatellite instability and the Lynch syndrome. Important for you to remember. As a result, clinical practice guidelines now recommend that anybody who comes in with early-onset colon cancer, regardless of their family history, gets sent to genetics and has multigene panel testing. 

I showed you that lifestyle changes impact early-onset colon cancer. Things like our processed meat intake, our obesity and sedentary lifestyle. But we're seeing an increase in colon cancer mostly in the West, where those kinds of things really don't happen-- and this whole birth cohort effect happening, where it's really your year of birth that determines your risk-- makes us all wonder whether or not early childhood exposures may be something that increases one's risk of early-onset colon cancer. 

People have looked at childhood antibiotic use. Certainly, in your era growing up, broad-spectrum antibiotic use has been rampant, particularly with the inappropriate use of antibiotics for ear infections and viral upper respiratory tract infections. Antibiotic use tripled in the 1980s, and we now have about 50 million prescriptions that we prescribe for broad-spectrum antibiotics every year. 

There's a lot of cohort and case-based studies that show that frequent antibiotic use increases the risk of advanced adenomas and colon cancer in all age groups. It's really thought to be affecting the gut microbiome, but to date there's no studies that we know of-- that I know of-- on childhood antibiotic use and the risk of early-onset colon cancer. 

What about prenatal chemical exposures? This is kind of scary. There are 80,000 chemicals in commercial use, and in this little tiny study, looking at 10 babies born in 2004 in United States hospitals, they found 287 different chemicals in umbilical cord blood. You can see, these were crazy things like food packaging, plastics, Teflon, a lot of flame retardants, pesticides. And of these 287, 180 were known carcinogens in humans and animals. 

These are things a lot of people in the colon cancer world are looking at as possible risk factors for colon cancer. We'll just go over a couple of them. DDT was banned in 1972 as a possible carcinogen. Glyphosate, which is Roundup, which was recently found to be a carcinogen as well. But even though DDT was banned in 1972, we still see amounts of DDT in our soil, and thus it's also present in things like our grain, our granola bars, our breakfast cereal. We can still find DDT. 

In 1973, Congress passed the flammable products act, but it basically said that all pajamas in children and all bedding had to be made from flame retardant material. This brominated, chlorinated tris has been shown to be a carcinogen. It's carcinogenic to firefighters, if exposed, and, in Europe, many European countries don't allow children to have pajamas with this substance, because it is known to be carcinogenic. Think how many of you wore those pajamas for many years growing up. 

This triclosan is present in-- its ubiquitous-- it's present in so many of our toothpastes and many of our soaps, and it causes colitis and tumor formation in rats and mice. To date, evidence is limited on the role of environmental toxins in early-onset colon cancer, but something for you to think about as you expose yourself to all these chemicals. 

Let's look at the treatment of early-onset colon cancer. We'll pivot a little. What we know is that, because of this increase in early-onset colon cancer, a number of cancer centers are actually starting early-onset colon cancer clinics, and these are very specific to young people. They have the typical medical and radiation oncologists, the surgeons, the gastroenterologists, the oncologists, but for young people it's very important that there's also this big cadre of genetic counselors as well. There's also a fertility specialist, which we don't see in older adult cancer clinics usually, because many of these young people are at the age where they want to have more children, so it's important for them to think about sperm banking, and maybe even ovary retrieval, before they're about to start therapy. 

We also know that young people with colon cancer are incredibly mindful about their diets. They really want to think about dietary changes during their therapies, so dietitians have been a big role in these clinics, as well as social workers. Remember that many of these young people have young children, and they're losing their jobs, and so they're losing their livelihoods, and a lot of psychological support, because it's very difficult for these young people to deal with early-onset colon cancer. 

Our GI society, the AGA, just came out with updated best practice advice for patients with early-onset colon cancer. This came out a few weeks ago. This recommends that anybody with early-onset colon cancer have fertility preservation before cancer-directed therapy. It reminds us to obtain a family history, not only of colon cancer, but other cancers in first and second degree relatives. Remember that I showed you that many of these patients with early-onset colon cancer could have Lynch syndrome, so you want to ask particularly about a risk of endometrial cancer. 

We want to get all these people to genetic evaluation, regardless of family history, and counsel patients on the benefits of genetic testing before surgery, because if somebody, for instance, had familial polyposis you would want them to have a total colectomy rather than a partial colectomy. You want to do genetic testing and use that result to inform some of the chemotherapeutic decisions that we make. 

And if somebody is found to have one of these hereditary colon cancer syndromes, like Lynch syndromes, you want to make sure that you're also testing these young patients with colon cancer for other cancers that might be associated. So Lynch syndrome, you want to do transvaginal ultrasounds in young women, because you want to make sure that they're not going to get endometrial cancer. And you want to do upper endoscopy to make sure that they're not going to get ambulatory carcinoma or duodenal cancers. 

What impact should this have on colorectal cancer screening? In 2009, the American College of Gastroenterology recommended that all African-Americans be screened for colon cancer at the age of 45. The reason for this was because we saw that the incidence of colon cancer in Blacks was so much higher, and when Blacks presented with colon cancer they presented at a much later stage of diagnosis. 

You can see over the last decade the data shows that African-Americans have had the largest mortality decline of any racial group, and the only decline in colon cancer in people under the age of 50. Nobody has tied these two things together, this increased screening and these wins here, but it makes you wonder whether or not this decade of increased screening in young people of African-American heritage has had some impact in these wins. 

Many of you also know that the American Cancer Society, in 2018, led by our very own Andy Wolf, issued a recommendation that average risk patients should be screened for colon cancer at the age of 45. A recent publication by Uri Ladabaum, in Gastroenterology last year, showed that if you screened people at age 45 it is cost effective. We're still waiting for the United States Preventive Services Task Force recommendations. They should come out sometime either this fall or early next year, and we're hoping that they're also going to decrease the screening rates as well. The reason for that-- the reason why that's important is because USPSTF guidelines are what make insurance companies pay for screening, Medicare and insurance companies. 

So we'll see, and we're hoping that that's going to happen. But I really want you to think about instituting colon cancer screening at 45 because you can potentially make a difference here. This also is a recent publication that was put out in e-publication, ahead of publication, just a couple of weeks ago. It comes from the New Hampshire Colonoscopy Registry, and they looked at 40,000 patients who came in for-- who are average risk-- who came in for screening colonoscopy, and they tried to make an average-risk screening equivalent. 

What it shows is that the prevalence of advanced neoplasia is equal in 45- to 49-year-olds to 50- to 50-year-olds. So it makes sense. These data support the recommendation to begin screening in 40- to 45-year-olds, because we're actually wanting to find advanced cancers, to find early-onset polyps, that might prevent colon cancer. This could affect 20 million Americans-- there's 20 million people in this age group. It's a lot of people and a lot of cost to consider. 

In summary, the increase in early-onset colon cancer is real. One in 10 of all colon cancers are in young people under the age of 50, and it's rising by about 2% every year. In a decade we're going to see that a quarter of all rectal cancers are going to be in adults under the age of 50. And if you ask your radiation oncology colleagues, we're already seeing this massive increase in rectal cancers in our own population. 

This is primarily left-sided cancers. It's rectal cancers. It's highest in the 40- to 49-year-old group. Early-onset colon cancer is higher in men but it's rising in women. It's highest in Blacks but it's rising in non-Hispanic whites at a very fast rate. It's highest in Appalachia, in our area, but it's rising fastest in the West. It's at an advanced stage of diagnosis with poor outcomes. And you can have an impact. How? 

These are opportunities that I really want you to think about. I want you to think about keeping early-onset colon cancer in your radar. If you have a patient who presents with rectal bleeding, abdominal pain, or even weight loss in the last several years, I want you to think about early-onset colon cancer in your differential diagnosis. I want to remind you that a rectal exam is part of your physical exam. Remember that the vast majority of these colorectal cancers are happening in the rectum. 

By doing a rectal exam in clinic, in these patients who present, you may be able to diagnose their rectal cancer right there in clinic and get them to treatment right away. I want you to remember to adhere to recommended screenings. Remember I showed you that graph of 50- to 54-year-olds. We're not seeing a decline in colon cancer there because we're not doing screenings in that population. Make sure you're screening people and think about screening people at the age of 45, because you could have an impact. And it is cost effective. Make sure you're obtaining a family history of colon cancer but also advanced polyps. Having any polyps is not really a risk factor, but having advanced polyps is definitely a risk factor. 

And why? Because you can have an impact on the next generation. If your patient comes in and had an advanced polyp when they had their colonoscopy by me, it means that their children and their siblings should have a colonoscopy every five years, beginning at age 40. That's the current guidelines. 

Encourage healthy lifestyle. We should all be doing that. But I also want you to educate your clinician peers and the public, your young children, and young people about this risk of early-onset colon cancer. This shouldn't be a taboo for us to talk about colon cancer screening in young people, or to talk about the fact that rectal bleeding could be a cause of early-onset colon cancer. 

No talk about early-onset colon cancer can be complete without talking about Chadwick Boseman. Chadwick Boseman was diagnosed with colon cancer at age 39. It was the same year that he first made his debut as Black Panther in Captain America, Civil War. He privately fought his colon cancer for four years. And he died of colon cancer at age 43. It's just tragic to think about, young people like this dying of early-onset colon cancer. 

We can make a difference. You can all make a difference in stopping this disease. And I hope that my talk can help you to do that. Thanks very much. Happy to answer any questions. 

SPEAKER 1: Thank you so much Dr. Yoshida. If there's anyone in the room with questions, please feel free to come up to the microphone and ask. And also, if anyone on Zoom has any questions, you can send them to me in the chat. 

AUDIENCE: In the younger population, at age 45 to 50, if most of it is left-sided and most of it's rectal, is a flex sig just as good as a colonoscopy then in that age group? 

SPEAKER 2: Yeah. A flex sig is definitely something you can do pretty fast and get that done early on. I still tell you that most young people are not going to go for a flexible sigmoidoscopy unsedated and you still have to do some sort of prep. The vast majority of people are getting colonoscopies but, you're right, you might be able to diagnose this with just a flexible sigmoidoscopy as well. 

AUDIENCE: Thank you for the talk. It seems that screening earlier is controversial among gastroenterologists. I hear podcast and-- is cost going to be a problem, like scoping too many-- are there any other concerns in the community by screening too early? Obviously I feel like you are pro it with your talk. 

SPEAKER 2: Cost is going to be a big issue, right? 

AUDIENCE: Right. 

SPEAKER 2: The US Preventative Services Task Force and, in fact, the American Cancer Society, when they make their recommendations they're doing it based on modeling. They're modeling a big population and so they have to make these-- there's ramifications from the standpoint of cost to the insurance companies, cost to the government with Medicare, Medicaid-- so you're right. When they're looking at things they're doing population studies and they're looking at what's best for the entire population. It may be that the USPSTF comes out and says 50 is the better thing. 

My point, and why I'm pro for this, is because one life saved-- one young life saved-- is really important. And I'll tell you too many of us in GI have done too many young people with colon cancer-- have done colonoscopies on young people with colon cancer. So yeah, we're pro this. But again, you have to think about those bigger picture items and that it's population health versus individual savings. 

AUDIENCE: OK. Thank you. 

SPEAKER 1: We have a few questions for you in the chat. First, has there been any recent modeling on combinations of screening strategies, like FIT testing from 45 to 50 and then colonoscopy? SPEAKER 2: Yeah. You know what? I just saw in my feed today that if you actually do-- this is interesting. This is not screening, but if you do a FIT test on people with symptoms it's actually a good negative predictor of not having cancer. That's something for you guys to think about. 

So say the USPSTF decides that they're going to come back with 50 as a screening age, can you still make recommendations? I mean, what was the big problem that we had in this African-American population in 2009? You know, here this big GI society is saying we should screened by 45, but nobody was paying for it, right? So that's hard. Yes you can make a difference. I think here at UVA we think only about colonoscopy as a screening. You know the vast majority of people don't have colonoscopy as screening. 

We should be thinking about FIT testing. FIT testing is inexpensive. It is a good test. So if a patient can't get a colonoscopy paid for, or if they don't choose to have colonoscopy paid for, between the ages of 45 to 49, yeah, definitely. You could get a FIT test for under $50. And if somebody is willing to be screened and pay for that, it's a cheap test, and it is a screening test. So yeah, definitely do that. 

And I think that if you're talking to your patients, we always tell them to call their insurance companies. A number of patients will be referred by their physicians to have a colonoscopy at 47, and we tell them to call their insurance companies to see if they're covered. You'd be surprised that a large number of insurance companies are now-- because of these recommendations-- are now starting to cover colonoscopy at 45. But think about FIT testing. I want to think about FIT testing just in general, and even Cologuard testing, because we do too many colonoscopies here at UVA. 

You should think about-- you know, colonoscopy may be a great test, and it may be the test that most people want to have done, but there are definitely populations of people who don't want to have a colonoscopy. Those are opportunities that we're missing. Those are people who are not getting screened because they're not willing to take your one recommendation of having a colonoscopy. When somebody comes to clinic, offer them a choice. We'll talk about that. I think those are important things to remind you of. 

SPEAKER 1: There's a similar question asking about the role of Cologuard, but then also if there is a potential role for virtual colonoscopy? 

SPEAKER 2: Cologuard is a test where it actually looks at DNA. It has 10 different DNA changes, as well as fecal blood. It looks for human hemoglobin. Cologuard is a good test for young people. I'll tell you why. It's not so good to test for older people, because in older people we tend to see more hypermethylation of the DNA. That's a normal-- our normal DNA gets hypermethylated-- but that's what they're looking for in Cologuard. In older people that you do Cologuard tests on, there's a higher rate of false positives. Not so in younger people. 

Cologuard may be a better test for younger people, but Cologuard's not cheap. I mean, it runs between $500 and $600. And again, it has to be covered by insurance. So if your insurance company is not going to cover screening-- it's not going to cover colonoscopy-- it's not going to cover Cologuard either. 

Virtual colonoscopy I have a bigger issue with, because I think there is, particularly in young people-- remember that a lot of young colon cancer start with a serrated pathway, right? They have more microsatellite instability. These are flat polyps. The data that we have for CT colonography is for the adenoma-carcinoma pathway, the KRAS, BRAF, mutated ones. So we see big honking polyps, right? Or things on stalks. We don't have a lot of data for sessile serrated polyps in CT colonoscopy, and I worry that somebody would have that test and maybe not be able to find these flat polyps. 

SPEAKER 1: There's also a question asking if you have any thoughts on specific microbiota that increase either early or late risk, specifically wondering about the workups in these [INAUDIBLE] looking at toxigenic Bacteroides fragilis. 

SPEAKER 2: You know, I'm not an expert in this at all but there are a number of investigators that are looking at specific different aspects of the microbiome, just like I told you the data that's helping with the left and the right colon. There's a lot of fascinating stuff happening out there and I think we're going to learn more. I don't think we have a lot of say that it's definitely a specific bacterial population that increases one's risk. They looked at these sulphur-metabolizing microbes in this one population. I think people are studying different bacteria throughout. 

SPEAKER 1: The last question I have for you is just wondering about any specific recommendations for young candidates being screened for transplant, like in kidney transplant. 

SPEAKER 2: Good question. It's interesting that there are no data to prove that even transplant patients have an increased risk of colon cancer. And this is very, very controversial. So a lot of the transplant doctors want their patients to have colon cancer screening every five years but-- because they're on immunosuppressive agents-- but if you look at even rheumatologic patients on biologics or immunosuppressive agents, not a lot of very clear-cut data that increases one's risk of colon cancer. 

And there's not guidelines to show that those people should be screened earlier. I don't know that data, whether or not young people who are coming for a kidney transplant should get a colonoscopy screening. I don't think that there's a lot of information known as to whether or not once they get on immunosuppression after, if that's going to increase the risk of colon and/or any cancers. 

I'm going to put one last plug-in and that is that, in your lifetime, maybe not my medical lifetime, but in your medical lifetime, we are going to see that colon cancer screening is going to change. Right now there are companies that are doing incredible things with liquid biopsies, so pretty soon colon cancer screening is going to be about going to your office and having a blood test drawn and getting amplification of DNA. And we're going to see that happening. We're in studies that are happening right now. There are companies that are doing that. 

Colon cancer screening is not going to be about taking a stool sample anymore and sending it off to a lab. There will be easier ways and we will be able to do more screening on our patient population, and hopefully see an even further decline in colon cancer as we go on. 

SPEAKER 1: That is really fascinating. And just to follow up, the esteemed Dr. Andy Wolf, as you mentioned, was just chiming in and saying that our UVA insurer, ETNA, does cover colorectal cancer screening at age 45. A follow-up on your discussion. 

SPEAKER 2: So all your employees that you take care of, make sure they get screened at 45. Thank you, Andy. 

SPEAKER 1: Thank you so much for coming to join us Dr. Yoshida. 

[APPLAUSE]