Excluding skin cancer, colorectal cancer is the third most prevalent and lethal cancer among both men and women in the United States.¹ Although the risk of developing colorectal cancer increases with age—more than 90% of cases occur in people aged 50 or older²—recent research shows that the incidence of colorectal cancer has been increasing 1% to 3% annually for people younger than age 50 while decreasing in older individuals.³ Since 1994, cases of young-onset colorectal cancer—defined as colorectal cancer diagnosed before the age of 50—have increased by 51%, according to the National Cancer Institute.⁴

The alarming rise in the incidence of colorectal cancer in young adults prompted the American Cancer Society (ACS), in 2018, to change its recommendations for the start of colorectal screening from age 50 to age 45 for individuals at average risk. In addition, research by the ACS has found that people younger than age 55 are 58% more likely to be diagnosed with late-stage disease than older adults, making cure more difficult.⁵

Although the uptick in colorectal cancer incidence in younger adults correlates with the increasing rates of obesity in the United States, it is unclear what role obesity and other common risk factors, including diet, inactivity, and family history, may be playing in the early onset of this disease.

Kimmie Ng, MD, MPH

“My colleagues and I are seeing young patients diagnosed with late-stage colorectal cancer who have none of the typical risk factors we see and worry about with colon cancer, such as a family history, genetic syndrome, poor lifestyle, or even obesity,” said Kimmie Ng, MD, MPH, Co-Director, Colon and Rectal Cancer Center and Director of the Young-Onset Colorectal Cancer Center at Dana-Farber Cancer Institute; Associate Professor of Medicine at Harvard Medical School. “And even if those factors were at play, we need to understand what the underlying biologic mechanisms are so we can try and reverse the steep rise in colorectal cancer that is predicted to continue to happen over the next few decades in younger folks.”

Molecular Characterization of Early-Onset Colorectal Cancer

A RECENT study by Willauer et al evaluating the clinical and molecular features of colorectal tumors in young adults compared with adults aged 50 and older has found that not only are the tumors molecularly distinct from tumors found in older patients, they can even vary among subsets of the young adult population. For example, researchers found unique signaling aberrations among younger patients, aged 18 to 29 years, vs other early-onset patients, aged 30 to 49 years, and among early-onset patients with predisposing conditions, including inflammatory bowel disease or a hereditary syndrome, vs patients without these conditions. In the younger patients, the occurrence of BRAF V600 mutations was significantly lower, and the number of KRAS mutations was numerically but not significantly lower, and the occurrence of combined MAPK pathway mutations were the lowest in the 18- to 29-year-old patients compared with other age groups.⁶

“Right now, we do think that environmental influences are underlying the rise in incidence [of young-onset colorectal cancer].”

— Kimmie Ng, MD, MPH

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To address the unmet medical needs of young adult patients with colorectal cancer as well as to learn more about the clinical and molecular features of early-onset disease and how they compare with those of late-onset colorectal cancer, potentially affecting treatment options and patient outcomes, earlier this year, Dana-Farber/Brigham and Women’s Cancer Center launched the Young-Onset Colorectal Cancer Center. According to Dr. Ng, the newly established center will provide young adult patients with a holistic approach to cancer care that takes into account their unique physical and psychosocial needs, such as fertility and sexual health concerns; a program coordinator to oversee appointment and referral scheduling; a multidisciplinary treatment team to review each case to maximize effective and efficient care; a genetic evaluation; customized colonoscopy screening services for patients who need weekend appointments; and young adult–focused support groups, forums, and programming. In addition, genomic sequencing is performed on every patient’s tumor to identify its specific molecular profile, which is then evaluated by a molecular tumor board for personalized treatment recommendations.

Brandon Hayes-Lattin, MD, FACP

In a wide-ranging interview with The ASCO Post, Dr. Ng discussed the potential causes for the rise in colorectal cancer in young adults; the need for more research to determine mutational differences in early-onset tumors and more effective therapies; and the importance of raising public awareness about young-onset colorectal cancer to detect it early and improve survival outcomes.

Determining Cause and Effect

What are you learning about the causes of the rise in incidence of colorectal cancer in people younger than age 50, especially in young adults in their 20s and 30s?

One of the reasons we wanted to launch the Young-Onset Colorectal Cancer Center was to develop a concentrated effort to take better care clinically of these young patients and also to get as many of them as possible to partner with us in research. This way, we can try to tease out what the underlying factors are in the development of this cancer in such a young population.

Right now, we do think that environmental influences are underlying the rise in incidence. Although there is not a lot of research on the topic, there have been some studies showing that obesity is believed to be a risk factor, and it is interesting that the rise in rates of colorectal cancer in young people parallels the rise in obesity in the general population. Sedentary behavior also appears to be a risk factor. However, most of the young patients my colleagues and I are seeing are not overweight or obese and are physically active, so clearly, these risk factors do not completely explain the worrisome trend.

Learning How the Disease Differs in Younger and Older Patients

What is your research showing about the clinical and molecular features of colorectal cancer in younger adults compared with the disease in older patients?

One of the main research goals of our center is to understand whether these tumors are biologically different from cancers that arise in older people. A few papers have shown some differences in the mutations in the tumors that arise in younger vs older patients, although not enough striking differences to give insight into the mechanisms that may be at play. We do know there are more microsatellite instability–high tumors in young adult patients and those tumors respond to immunotherapy, but otherwise there hasn’t been a magic bullet discovery that clearly distinguishes early-onset from late-onset colorectal cancer, leading to a unique treatment for patients.

This is the main goal of our research: Can we find a unique molecular signature, gene-expression signature, or microbiome signature that would then lead to an effective treatment that would be better than just throwing standard chemotherapy at patients?

“We know from research that young-onset colorectal cancer is diagnosed way too late. Often, patients see multiple physicians before a correct diagnosis is made.”

— Kimmie Ng, MD, MPH

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The other big centerpiece of our research is looking at the gut microbiome in younger patients. We suspect that if the microbiome, which is influenced by everything from diet and lifestyle to exercise and obesity, is different in young adults, it could be altering gene-expression patterns and the immune environment of these tumors. We are going to take a comprehensive look at all of these factors in our studies.

Our research initiative is called the Beyond CRC Project, which stands for Better Understanding of Young-Onset Colorectal Cancer. It aims to assemble a large cohort of young patients to collect their diet and lifestyle data; genetic sequencing information; and tissue, blood, and stool samples. Then we can study with adequate statistical power what might be some of the risk factors leading to cancer in these young people, and whether these tumors are really different from the tumors in older people.

Because young-onset colorectal cancer is still a small number of the overall colorectal cancer population, the Beyond CRC Project will be collaborating with other cancer centers nationwide to conduct these studies, so we can enroll more young patients and get answers more quickly.

Improving Outcomes in Young-Adult Survivors

There are conflicting data on survival outcomes of young adult patients compared with older patients, with some studies showing worse survival in young adults, especially those younger than age 30.⁷ Do you know what may be accounting for poorer survival rates in younger patients? Is it because the cancer is more aggressive in very early–onset disease, or the cancer is discovered at later stages when cure is less possible?

I think both of those factors are contributing to poorer survival, but we don’t yet know for sure. As you mentioned, the studies that have looked at survival in young vs old patients have been conflicting. Some have shown no survival difference, whereas others have shown worse survival for young patients, and still others have shown better survival, so the results are all over the map.

There was one interesting finding, and it mirrors our clinical experience. Because younger patients are so much healthier than older patients and do not have a lot of comorbidities, they tend to receive more aggressive treatment, including more radiation therapy, chemotherapy, and surgery. However, that additional treatment has not necessarily translated into significantly longer survival, so why is that? This leads us to suspect that perhaps these tumors are biologically different and may be more aggressive in younger adults.

Raising Public Awareness About Young-Onset Colorectal Cancer

Please talk about the need for greater awareness among both the public and primary care physicians on the warning signs of colorectal cancer, and the benefit of early detection in young adults.

I have talked about two of our missions for the center: improved clinical care and more research in young adult patients. Our third mission is to raise public awareness and education about colorectal cancer in younger people. We know from research that young-onset colorectal cancer is diagnosed way too late. Often, patients see multiple physicians before a correct diagnosis is made. Many young people are not aware that colon cancer could be the cause of the symptoms they are having, so they wait a long time to see a doctor; this often leads to late-stage diagnosis, which is a tragedy because this cancer is very curable if found early. One thing that will help detect colorectal cancer earlier in younger patients is the change in the American Cancer Society’s recommended age to start screening from 50 to 45.

“It does seem that more and more young people are being diagnosed with cancers that are commonly found in much older patients, and it makes you wonder what the cause could be.”

— Kimmie Ng, MD, MPH

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We are also reaching out to physicians in primary care and gastroenterology, as well as to cancer centers throughout the country, to raise awareness of this increasing burden of colon cancer in young people.

Developing Typically Late-Onset Cancers at Any Age

In your practice, how young are your patients diagnosed with colorectal cancer?

I have a few patients in their 20s, and we are seeing patients as young as age 19 come into the clinic. And we just heard about a 13-year-old with the disease, and there is no genetic syndrome involved, so it’s very frightening.

Are you seeing young people diagnosed with other late-onset cancers?

I have been talking with my colleagues about this issue, and we actually have been seeing many more 30- and 40-year-olds with pancreatic cancer, which is typically seen in the elderly. We have also noticed very young people—many of whom are young women—being diagnosed with gastric cancer. We have some young female patients diagnosed while they were pregnant, which led to a delay in diagnosis and treatment, because a lot of gastrointestinal symptoms women have while pregnant are similar to those associated with gastric cancer.

It does seem that more and more young people are being diagnosed with cancers that are commonly found in much older patients, and it makes you wonder what the cause could be. Is it environmental, poor diet, lack of exercise? We just don’t know right now. ■

DISCLOSURE: Dr. Ng is a consultant/advisor for Genentech/ Roche, Lilly, Tarrex Biopharma, Bayer, and Seattle Genetics; has received institutional research funding from Genentech/ Roche, Pharmavite, Gilead Sciences, Trovagene, and Celgene.

REFERENCES

1. American Cancer Society: Key statistics for colorectal cancer. Available at www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Accessed June 10, 2019.

2. Centers for Disease Control and Prevention: What are the risk factors for colorectal cancer? Available at www.cdc. gov/cancer/colorectal/basic_info/risk_factors.htm. Accessed June 10, 2019.

3. 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.

4. Siegel RL, Miller KD, Fedewa SA, et al: Colorectal cancer statistics, 2017. CA Cancer J Clin 67:177-193, 2017.

5. American Cancer Society: American Cancer Society updates colorectal cancer screening guideline. Available at www.cancer.org/latest-news/american-cancer-society-updates-colorectal-cancer-screening-guideline.html. Accessed June 10, 2019.

6. Willauer AN, Liu Y, Pereira AAL, et al: Clinical and molecular characterization of early-onset colorectal cancer. Cancer 125:2002-2010, 2019.

7. Mauri G, Sartore-Bianchi A, Russo AG, et al: Early-onset colorectal cancer in young individuals. Mol Oncol 13:109-131, 2019.