Although research so far has failed to uncover the root causes of the development of young-onset colorectal cancer, what is certain is that although colorectal cancer rates are declining in older adults, they are on a steady rise in people younger than age 50, especially those between the ages of 18 and 40.1 According to the National Cancer Institute, about 18,000 people younger than 50 were diagnosed with colorectal cancer in 2020. Over the next decade, colorectal cancer incidence among those younger than 50 is expected to nearly double and is on track to becoming the leading cause of cancer-related death in this age group.2
These trends are a particularly troubling sign for Black and Hispanic young adults, who are more likely to be diagnosed with early-onset colorectal cancer, present with stage IV disease, and have worse overall survival compared with their White counterparts, despite having private health insurance and independent of socioeconomic status.3
Kimmie Ng, MD, MPH
The rising trend in young-onset colorectal cancer—since 1994, the cases of young-onset colorectal cancer have increased by 51%4—prompted the American Cancer Society, the U.S. Preventive Services Task Force, and the National Comprehensive Cancer Network to change their colorectal cancer screening guidelines from age 50 to age 45 for people at average risk. Also disturbing are studies showing that despite their younger age, greater physical fitness, and ability to tolerate more intensive therapy than older patients with advanced colorectal cancer, younger adults do not seem to derive a survival benefit.
A study by Kimmie Ng, MD, MPH, Associate Chief, Division of Gastrointestinal Oncology; Director, Young-Onset Colorectal Cancer Center; Director of Translational Research at Dana-Farber Cancer Institute; Associate Professor of Medicine at Harvard Medical School, and her colleagues investigated the survival differences between young and older patients with metastatic colorectal cancer. They found no statistically significant differences in survival between the two groups. In fact, patients younger than age 35 had the shortest median overall survival of any age group: 22.0 months vs 26.1 months, respectively.4
“The results from our study mirror what other studies have shown. The very youngest patients in their 20s and 30s seem to have more aggressive colorectal cancer that is less responsive to treatment, and the reasons for this are unclear,” said Dr. Ng.
In a wide-ranging interview with The ASCO Post, Dr. Ng talked about the potential risk factors for the development of young-onset colorectal cancer, the role the microbiome may play, and the alarming trend in other usually late-onset cancers (eg, pancreatic cancer) that are now being diagnosed in younger adults.
Understanding the Differences in the Microbiomes of Younger vs Older Patients
In your latest study, you found no survival difference between younger and older patients with metastatic colorectal cancer; and those younger than 35 had the shortest survival of 22.0 months vs 26.1 months for older adults. Why do you think the younger patients did not have a survival advantage?
A lot of oncologists and young patients hope that because they are younger, healthier, have fewer comorbidities, and are more active they will have better outcomes, but that has not been borne out in multiple studies,5 including this one. Another study by researchers at Memorial Sloan Kettering Cancer Center found results that are remarkably consistent with our study.6
Despite receiving more intensive treatment, tolerating higher doses of chemotherapy and having fewer side effects, and being more physically active, none of these advantages conferred an additional survival benefit to these young patients. If anything, the very youngest of these patients, those in their 20s and early 30s, had a significantly shorter median survival compared with the older patients. In fact, this mirrors what we have seen before: the very, very youngest of these patients in their 20s and 30s seem to have extremely aggressive colorectal cancer that is less responsive to treatments.
The reasons for this disparity are unclear. We recently received a grant from the Colorectal Cancer Alliance to investigate whether there are differences in the microbiome of younger patients that may account for why they seem to have more aggressive cancer. We will be looking at and comparing the microbiomes of extremely young patients with those in their 30s vs 40s vs a typically older patient population and investigating the impact of these microbiome differences on antitumor immunity.
Determining Risk Factors for Young-Onset Colorectal Cancer
Two years ago, Dana-Farber/Brigham and Women’s Cancer Center launched the Young-Onset Colorectal Cancer Center to provide young adults with a holistic approach to care, including genomic sequencing on every tumor to identify its specific molecular profile. Have you discovered any similarities in the diet and lifestyle habits, physical fitness, and ethnicity of these patients that might explain why colorectal cancer is rising in this younger population?
We, and other groups as well, have focused a lot on narrowing down the diet and lifestyle factors that may be associated with a higher risk of developing colorectal cancer at a young age. We have published two studies showing that obesity and higher levels of sedentary behavior nearly doubled the risk of developing young-onset colorectal cancer.
We also looked at the consumption of sugar-sweetened beverages, because intake of these beverages has increased dramatically in recent decades and because diets characterized by a higher glycemic index and higher insulin index have been linked to an increased risk of colorectal cancer, regardless of age. We found that among the Nurses’ Health Study II cohort of young, healthy women, those reporting more than two servings a day of sugar-sweetened beverages had a significantly increased risk of developing young-onset colorectal cancer. The risk was triple for those reporting a higher consumption of these beverages during adolescence.7
What this suggests to us is that prolonged exposure to these diet and lifestyle factors probably plays an important role in elevating the subsequent risk of developing this disease as a young adult. For this reason, we have been trying to study early-life factors during adolescence and young adulthood, because we think it is the prolonged exposure of these factors over time that leads to a potentially higher risk of developing colorectal cancer down the road.
We are even seeing that maternal obesity and other in utero events may contribute to a child’s subsequent risk for colorectal cancer in later adult life. Some people hypothesize that one of the mechanisms of that increased risk could be rooted in the microbiome, because clearly there are factors shaping an infant’s microbiome that come from maternal influences.
What we have found that may be potentially protective against the development of young-onset colorectal cancer is the consumption of higher amounts of vitamin D, preferably from dietary sources. In our study, we found that increasing the intake of vitamin D was associated with a 50% lower risk of developing young-onset disease, as well as a lower risk of developing precancerous polyps at a young age, in women in the Nurses’ Health Study II cohort.8
What we hope to do eventually is come up with a risk profile of people who are more likely to develop young-onset colorectal cancer based on diet and lifestyle, family history, and genetics to target them for earlier screening. So, I think this type of risk-adapted precision prevention approach is in the future. We just need to do more work to understand the complete constellation of risk factors to come up with a score that will help identify people for earlier screening.
In your Young-Onset Colorectal Cancer Center, are more younger patients being diagnosed or coming in for treatment with late-stage colorectal cancer?
Yes. Unfortunately, many of our patients have stage III or IV disease when they come to the clinic. Almost all these young patients have delays in diagnosis because they never heard of colorectal cancer or they thought it was strictly an old person’s disease, and they delayed seeing a physician.
The other contributing factor is that they are also commonly misdiagnosed when they initially present with symptoms, likely because clinicians may also not be aware that colorectal cancer can occur in young and otherwise healthy individuals. And, finally, they are not undergoing routine screening because they are too young per guidelines, so by the time they finally are diagnosed, the cancer is advanced.
Delving Deeper Into Tumor Genomics
Are you seeing any evidence in your research of molecular differences in colorectal tumors found in older vs younger patients?
We are still putting together our findings from more than 700 patients in our Young-Onset Colorectal Cancer Center regarding the genomics of their tumors. However, other studies have shown no significant genomic differences between young-onset tumors compared with older-onset tumors when you adjust for factors such as the side of the colon the tumor came from.6 So, I don’t think the differences are going to be found in the genomics of these tumors, although some studies have reported fewer APC mutations in the tumors of the very youngest patients, as well as slightly fewer KRAS mutations in young adults, for example.
What is limiting us in figuring out what the factors are that differentiate young-onset colorectal cancer from older-onset disease is the small sample size of these studies. We need larger studies to be confident about these findings, and we are trying to do that by spearheading the Count Me In Colorectal Cancer Project (https://joincountmein.org/colorectal). This research initiative is generating a large data set of linked patient-reported, genomic, clinical, dietary, and molecular information through a digital social media platform that directly partners with patients.
Since we launched this initiative in September 2021, so far, we have more than 100 patients consented and hope to have 1,000 patients by the end of the first year. Once we have all the tumor and stool samples, we plan to do deep genomic sequencing and microbiome analysis on the biospecimens and correlate that data with dietary and lifestyle information. It’s important to do deeper genomic sequencing on young-onset colorectal cancer tumors, because a lot of the studies published included information from next-generation sequencing panels alone.
Closing the Equity Gap
Young-onset colorectal cancer disproportionately affects Black individuals. A study presented at the 2021 Gastrointestinal Cancers Symposium found that younger patients were more likely to be Black or Hispanic and to be diagnosed with stage IV disease than older patients. Black patients also had the lowest median overall survival; this was true despite income or education status.9 What was the racial makeup of your survival study, and did you find that Black patients had worse outcomes than their White counterparts?
One of the limitations of our study, as is true in many clinical trials, is the small number of non-White patients. When we looked at the racial breakdown of our patients, there were a higher number of Black patients in the young cohort compared with the older cohort, and that is consistent with the findings from the study you mentioned. Black individuals do have a higher risk of colorectal cancer and a higher death rate, and they are diagnosed at an earlier age.
We do think these disparities are most likely the result of a lack of access to care and quality care. In our study, we didn’t find any significant differences in outcomes based on ethnicity or race, possibly because everyone was treated similarly as part of the clinical trial but also because we were underpowered to detect significant differences. So, I think when patients are given equal access to screening and quality care, disparities are mitigated. It’s a question of equity and access that is mainly underlying many of the racial disparities we see in colorectal cancer incidence and mortality.
Sounding the Alarm About Other Young-Onset Gastrointestinal Cancers
A recent study published in JAMA found that pancreatic cancer is also trending among young adults, especially women between the ages of 15 and 34.10 Are you seeing an uptick in pancreatic cancer in younger adults in your clinic?
Yes, we are. We are also seeing an increase in a variety of gastrointestinal cancers beyond just colon and pancreatic. There’s been a rise in gastroesophageal cancers, as well as pancreatic and gallbladder cancers.
The thought is that the increasing rates of obesity in our society may be contributing to why a variety of cancers are occurring more frequently in younger people. That is one hypothesis. However, understanding why pancreatic cancer and other gastrointestinal cancers are developing in younger adults requires the same effort we are putting into understanding young-onset colorectal cancer.
Is the cause genetic, environmental, poor diet, lack of exercise, obesity? Unfortunately, it will take time to get the answers.
DISCLOSURE: Dr. Ng has received institutional research funding from Pharmavite, Evergrande Group, and Janssen; has served on advisory boards for Seagen, BiomX, and Bicara Therapeutics; and has served as a consultant for X-Biotix Therapeutics and Redesign Health.
REFERENCES
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2. Rahib L, Wehner MR, Matrisian LM, et al: Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open 4:e214708, 2021.
3. Kamath SD, Torrejon N, Wei W, et al: Racial disparities negatively impact outcomes in early-onset colorectal cancer independent of socioeconomic status. Cancer Med 10:7542-7550, 2021.
4. Siegel RL, Miller KD, Fedewa SA, et al: Colorectal cancer statistics, 2017. CA Cancer J Clin 67:177-193, 2017.
7. Hur J, Otegbeye E, Joh HK, et al: Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women. Gut 70:2330-2336, 2021.
8. Kim H, Lipsyc-Sharf M, Zong X, et al: Total vitamin D intake and risks of early-onset colorectal cancer and precursors. Gastroenterology 161:1208-1217, 2021.
9. Kamath SD, Torrejon NV, Wei W, et al: Racial disparities negatively impact outcomes for patients with early-onset colorectal cancer independent of income or education status. 2021 Gastrointestinal Cancers Symposium. Abstract 20. Presented January 15, 2021.
10. Gaddam S, Abboud Y, Oh J, et al: Incidence of pancreatic cancer by age and sex in the US, 2000-2018. JAMA 326:2075-2077, 2021.
