Archie Bleyer, MD

TWO STUDIES published this year examining the incidence of colorectal cancer in adolescents and young adults (AYAs) show an undeniable and sobering trend: Colorectal cancer rates are increasing in this age group, and younger people are dying of the cancer at slightly higher rates than in previous decades.^1,2 The studies, both led by researchers at the American Cancer Society, found that although the vast majority of colorectal cancers—nearly 90%—are still diagnosed in adults aged 50 and older, once age is taken into account, those born in 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer compared with people born around 1950, when the risk for the cancer was at its lowest. 

What’s more, despite a decline in the risk of death from colon and rectal cancers in the adult population overall, an analysis of colorectal mortality among people aged 20 to 54 from 1970 to 2014 found that death rates had increased slightly to 4.3 deaths per 100,000 people in 2014, compared with 3.9 deaths per 100,000 people in 2004. And the increase in mortality was confined to white individuals, increasing by 1.4% annually, from 3.6 in 2004 to 4.1 in 2014. For other race/ethnicities, mortality rates decreased: 0.4% annually from 8.1 in 1970 to 6.1 in 2014 for black individuals, and 1.1% annually between 1970 and 2006 for persons of other races, and the percentage did not significantly change in subsequent years. 

Brandon Hayes-Lattin, MD, FACP

Although obesity, a sedentary lifestyle, a diet high in red or processed meats, and genetics have all been linked to the development of colorectal cancer in the general population, it is unclear what may be driving the increasing rates of the disease in younger adults. An intriguing new clue may be found in a study published earlier this year by Archie Bleyer, MD, and his colleagues showing that most of the colorectal cancers in AYAs are found in the rectosigmoid junction of the descending colon, which was also associated with a worse prognosis.³ Their results, and the findings from an earlier study,⁴ are leading Dr. Bleyer to theorize that the cause may be from an infectious disease such as human papillomavirus (HPV). However, he cautions that more research needs to be done to confirm evidence of a link between HPV infection and colorectal cancer in young adults. 

The ASCO Post talked with Dr. Bleyer, Clinical Research Professor at the Knight Cancer Institute of the Oregon Health & Science University in Portland, about the possible link between HPV and colorectal cancer; how the biology of common cancers in AYAs is different and more deadly than these cancers in younger or older patients; and how a greater understanding of the biology of this cancer in AYAs is impacting treatment and survival outcome. 

Why Do Young Adults Develop Colorectal Cancer? 

What is accounting for the steady rise in colorectal cancer in young adults? 

We don’t know. Based on the evidence that colleagues at McMaster University and I have generated, I have a concern it has something to do with HPV infection. We found that nearly all of the increase in colorectal cancer in young adults occurred in the distal colon, beyond the splenic flexure; and the closer to the anus, the greater the increase. 

In our analysis, females have had a greater increase in colorectal cancer than males. We also know that HPV is a cause of the increasing incidence of rectal cancer in American AYAs. In addition, from studies in Europe, South America, and Asia, persons infected with HPV had a higher incidence of colorectal cancer in general. I know of only three studies attempting to detect HPV in colorectal cancer specimens, in France, Denmark, and the Caribbean, and they had contradictory results. 

And if the increase is due to the HPV-related virus, we can prevent infection with the HPV vaccine. Thus, we should make a stronger and more urgent effort to ensure all adolescents and young adults are vaccinated. 

“Colonoscopy screening is not risk-free, so we should not immediately recommend that screening start at age 20 or 25, when the disease seems to be occurring….”

— Archie Bleyer, MD

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According to the American Cancer Society study, the increase in colorectal cancer mortality was confined to white individuals. Do you have a theory about why death rates in this disease are increasing for white AYAs? 

No, I don’t. It may be a genetic susceptibility of white individuals to a worse type of colorectal cancer, but we need more research to know for sure. I don’t think the higher mortality is related to HPV infection because it is not more common in white individuals, and, in general, HPV-induced cancer is associated with a better prognosis than other cancers in the same part of the body that are not caused by HPV, so there have to be other reasons. 

Quantifying Risk Factors 

In addition to the possibility of HPV infection, how much of a role does obesity, lack of physical exercise, an unhealthy diet, and alcohol play in the development of colorectal cancer in young adults? 

There are multifactorial underpinnings causing colorectal cancer. I have no doubt there are multiple causes, but how much of the increase is due to obesity, how much potentially to HPV infection, genetic predisposition, diet, and lack of exercise, I cannot estimate. 

Recognizing Biologic Differences in Cancers 

What are researchers learning about the biologic characteristics of cancer, especially colorectal cancer, in AYAs compared with the same types of cancers in younger and older patients, and how do these biologic differences affect treatment and outcome in this age group? 

Frequently, what looks to be the same cancers in younger and older persons are actually biologically different cancers in AYAs, and they act like different cancers. For example, our research suggests that AYAs with colorectal cancer exhibit a more aggressive disease phenotype than adults with the disease. Their cancer has a greater frequency of mucinous histology, signet ring cells, high microsatellite instability, and a higher incidence of mutations in mismatch-repair genes.⁵ 

In other common cancers, such as breast cancer, there is evidence showing differences in cancer type, grade, and aggressiveness compared with the disease in older women. For example, triple-negative and basal-like subtypes are more prevalent and deadly in AYAs. 

We have made the most progress in learning about the biologic and genomic differences in acute lymphoblastic leukemia (ALL) in AYAs. ALL is the most common cancer in children, and we now know that in AYAs, the Philadelphia chromosome–like (Ph-like) gene-expression signature peaks in incidence, and the outcome in AYAs with this subtype is inferior. 

However, now that we know these cancers are not biologically and genomically the same in AYAs, we are approaching treatment strategies differently, and outcomes are improving. 

Please explain more about how the difference in the biology of cancer in AYAs is affecting how oncologists treat these patients. 

Over the past decade, because of the discovery that cancer is often biologically different in this age population, we have been focusing on how to improve survival rates. For example, we are now using drugs targeting Ph-like ALL. Although it is too early to tell whether outcomes are better, because you have to wait 5 to 10 years to see a change in survival statistics, it looks like we are improving survival in this age group significantly. 

We are making progress in understanding the biologic differences in cancers in AYAs, especially in ALL, but we need to work much harder on the other cancers such as colorectal and breast cancers. There is still a gap in the survival gains in AYAs compared with younger and older patients, but we are seeing a greater increase in survival rates than we did a decade ago and definitely better than we saw 20 or 30 years ago. But it is not where it should be or could be if we had paid more attention to the problem. 

Instituting Preventive Care Strategies 

Colorectal cancer screening is credited with reducing the incidence of colorectal cancer in older people. Should young adults also be screened for the disease? 

We first have to learn what the cause is of the rise in colorectal cancer in younger people and then determine who is at greatest risk before we can say with certainty that we should lower the screening age. Colonoscopy screening is not risk-free, so we should not immediately recommend that screening start at age 20 or 25, when the disease seems to be occurring, because there are so many concerns about the risks and costs involved of universal screening of all young adults. We probably should be screening more people in this age group, but it would have to be done in a targeted fashion to be effective. 

As previously mentioned, the problem is we do not completely understand the risk factors for developing colorectal cancer in such a young age. There is definitely the supposition that obesity, diet, lack of physical activity, and genetics are factors, and I am worried about the potential risk caused by HPV infection. If it turns out that they are, in fact, risk factors involved in the development of colorectal cancer in AYAs, we could then selectively target individuals for early screening. But right now, we just don’t know which factors are most important and whether race and ethnicity also play a role. Again, we need more research. 

Investigating the Possibility of HPV-Related Colorectal Cancer 

Is there increased interest among scientists in researching the possibility of HPV-related colorectal cancer in AYAs? 

I hope there is. We have raised this issue at national cancer meetings and are trying to raise awareness of the issue, but the theoretic link is new, and it is just starting to gain attention. I hope more researchers will start investigating this possibility. We should also investigate whether the HPV vaccine is having an impact in reducing the incidence of distal colorectal cancer. 

At the very least, we should step up our efforts to ensure that all adolescents and young adults who have not received the HPV vaccine do so, because we do know it can prevent many other cancers, including cervical, head and neck, and anal. ■

DISCLOSURE: Dr. Bleyer reported no conflicts of interest. 

REFERENCES 

1. Siegel RL, Fedewa SA, Anderson WF, et al: Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst 109(8):djw322, 2017. 

2. Siegel RL, Miller KD, Jemal A: Colorectal cancer mortality rates in adults aged 20 to 54 years in the United States, 1970- 2014. JAMA 318:572-574, 2017. 

3. Levine OH, Zbuk KM, Bleyer A: Topographical incidence and survival analysis of gastrointestinal tract cancer in adolescent and young adults compared with older adults in the United States. J Clin Oncol 35(suppl):545, 2017. 

4. Damin DC, Ziegelmann PK, Damin AP: Human papillomavirus infection and colorectal cancer risk: A meta-analysis. Colorectal Dis 15:e420-e428, 2013. 

5. Smith AW, Seibel NL, Lewis DR, et al: Next steps for adolescent and young adult oncology workshop: An update on progress and recommendations for the future. Cancer 122:988-999, 2016.