Soaring Incidence of Young-Onset CRC Raises Screening, Treatment Questions

Colorectal cancer incidence and mortality are at historic lows.

SEER data indicate incidence of new colon and rectum cancers in the United States decreased 3.1% annually over the past decade. Further, mortality rates declined 2.8% yearly from 2003 to 2012.

Despite these favorable statistics, the data reveal alarming trends.

Colon cancer incidence among Americans aged 20 to 34 years is expected to increase 90% by 2030, according to an analysis of SEER data. Incidence of rectosigmoid and rectal cancers is expected to increase 124.2% in that period.

Because few younger individuals undergo colorectal cancer screening, they often to present with more advanced-stage and poorly differentiated disease. Even when they present with colorectal cancer symptoms — such as blood in the stool or abdominal pain — clinicians initially may suspect other causes, such as hemorrhoids or a gastrointestinal disorder.

Genetics appear to account for approximately 20% of colorectal cancers in younger adults; however, isolating the causes of most cases has proven difficult.

“Nobody honestly knows why this is happening,” Christopher Lieu, MD, assistant professor in the division of medical oncology at University of Colorado Denver’s School of Medicine, told Healio Gastroenterology.

Lifestyle factors — such as obesity or lack of physical activity — have been cited as potential contributors, as has the high concentration of red meats and processed foods in the typical Western diet.

Still, the spike in colorectal cancer incidence in otherwise healthy young Americans likely is multifactorial, Lieu said.

“A diet that is high in red meat and processed food will increase your [cancer] risk, but it only slightly increases the risk for colon cancer, so there has to be something else going on,” Lieu said. “It is most likely a combination of diet, environment and genetics. It is not all one or the other.”

Healio Gastroenterology spoke with gastroenterologists and oncologists about the increased incidence of colon and rectal cancers in younger adults, how these patients respond to treatment, whether broader screening parameters are necessary, and how prevention and treatment efforts must evolve to increase the likelihood of positive outcomes among younger patients.

Treatment Outcomes

Young-onset colorectal cancers are relatively rare in the United States. Individuals aged younger than 50 years account for 11% of colon cancers and 18% of rectal cancers.

However, the projected increased incidence has prompted the research community to consider whether current screening and treatment guidelines are appropriate for this demographic.

Prospective data that compare standard colorectal cancer treatments in younger vs. older populations are scarce, but retrospective data show outcomes vary considerably by age.

Although young adults may be more likely to prefer aggressive therapy to extend their lives, research has shown some of these patients do not respond to intense therapy as well as middle-aged patients.

Lieu and colleagues conducted a study within the ARCAD clinical trials program — published in 2015 in Journal of Clinical Oncology — that showed the youngest and oldest patients with colorectal cancers are at increased risk for death and progression compared with middle-aged patients.

The risk for death appeared lowest among patients aged 57 years, and the risk for progression or death appeared lowest among those aged 61 years.

Compared with these middle-aged reference groups, the youngest patients — or those near age 18 years — demonstrated a 19% (95% CI, 7-33) increased risk for death and a 22% (95% CI, 10-35) increased risk for progression or death. The oldest patients, or those aged near 90 years, demonstrated a 42% (95% CI, 31-54) increased risk for death and 15% (95% CI, 7-24) increased risk for progression or death.

These disparities may be a reflection of differing tumor biology or of a greater tumor burden due to lower screening rates in these cohorts, Lieu said.

Data from Kneuertz and colleagues — published in 2015 in JAMA Surgery — showed 61.8% of adults aged 18 to 49 years with colon cancer presented with stage III or stage IV disease.

Younger patients in this cohort appeared more likely to receive systemic chemotherapy compared with older patients whether they had stage I (OR = 2.88; 95% CI, 2.21-3.77), stage II (OR = 3.93; 95% CI, 3.58-4.31), stage III (OR = 2.42; 95% CI, 2.18-2.68) or stage IV disease (OR = 2.74; 95% CI, 2.44-3.07). However, this more intense treatment did not contribute to a significant survival benefit among patients with stage II (RR, 0.9; 95% CI, 0.69-1.17), stage III (RR = 0.89; 95% CI, 0.81-0.97) or stage IV disease (RR = 0.84; 95% CI, 0.79-0.9).

“We know that we are able to treat younger patients and that they are able to receive more therapy,” study researcher George J. Chang, MD, MS, professor in the departments of surgical oncology and health services research and chief of colon and rectal surgery at The University of Texas MD Anderson Cancer Center, told Healio Gastroenterology. “That could mean we are treating the wrong people or that they are not responsive to our current treatments. Our tendency is to treat young patients harder, but it hasn’t been associated with a commensurate improvement in outcome.”

Tumor biology may have the greatest impact on outcomes, C. Richard Boland, MD, chief of gastroenterology and medical director of epigenetics and cancer prevention at Baylor University Medical Center in Dallas, told Healio Gastroenterology.

“These tumors are biologically different,” Boland said. “Seventy-nine percent of the colorectal cancers in young patients are in the rectum or the rectosigmoid. They are mostly distal tumors, and there’s really no explanation yet for why that is.”

LINE-1 hypomethylation could play a role, Boland added.

“This could predispose patients to chromosomal instability, because you are getting hypomethylation near the centromeres and the telomeres, which predisposals the chromosomes to stick to one another and have unbalanced mitoses,” he said. “That’s the way to generate a dangerous tumor with lots of chromosomal rearrangements. When you get rearrangements, you activate oncogenes and you get these really nasty tumors.”

Because young adults with colorectal cancer tend to experience outcomes comparable to elderly patients despite these unfavorable tumor characteristics, it is difficult to say whether the younger cohort is overtreated, Jason A. Zell, DO, MPH, associate professor of medicine and epidemiology and program director of the hematology/oncology fellowship training program in the school of medicine at University of California, Irvine, said in an interview.

“The bottom line is, young adults with colon cancer have more aggressive biologic features that are usually associated with a poor outcome and they do as well or better than the older cohorts,” Zell said. “This area is a little bit muddy. It is very hard for us to say they are overtreated without benefit when there are all of these confounding variables associated with young-onset colon cancer, which gives them more aggressive disease to start with.”

Genetic Biomarkers

Researchers hope to identify genetic biomarkers that may increase the risk for young-onset colorectal cancer.

Data from Mork and colleagues — published this year in Journal of Clinical Oncology — showed the prevalence of hereditary cancer syndromes appeared higher in younger patients with colorectal cancer than the overall population with the disease.

Among 193 patients with colorectal cancer aged younger than 35 years, 67 (34.7%) had an identifiable hereditary cancer syndrome. They included 23 patients with Lynch syndrome, 22 with mutation-negative Lynch syndrome, 16 with familial adenomatous polyposis, two with constitutional mismatch repair deficiency, two with biallelic MUTYH mutations, one with Li-Fraumeni syndrome and one with a monoallelic MUTYH mutation.

“We hope that physicians and other health providers treating patients diagnosed with colorectal cancer under age 35 years are aware of the high prevalence of hereditary cancer syndromes and, therefore, send them for genetic counseling and consideration of genetic testing,” researcher Eduardo Vilar-Sanchez, MD, PhD, assistant professor in the department of clinical cancer prevention at The University of Texas MD Anderson Cancer Center, told Healio Gastroenterology at the time the study was published. “The next step is to continue doing research to determine how genetic testing using gene panels can help improve the diagnosis of genetic syndromes in this young population of patients.”

The identification of biomarkers also may help tailor treatments for this younger population, Andrea Cercek, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center who has focused her research on biomarker identification to create molecular-based therapies for patients with metastatic colorectal cancer, told Healio Gastroenterology.

“We first had to see if there is a distinct biology of these tumors, and we have an idea that there is,” Cercek said. “We have to identify biomarkers that drive these tumors, and then we have to ask if these are new hereditary factors that we didn’t know about or if there are other changes that are causing the cancer. Looking at the at-risk population would be the next step.”

Lieu also seeks to identify biomarkers that may play a role in treatment resistance.

Kopetz, Lieu and colleagues — in a study published in Journal of Clinical Oncology — identified changes during colorectal cancer treatment in plasma cytokines and angiogenic factors that appeared to predict resistance to 5-FU, irinotecan and bevacizumab (Avastin, Genentech). These included increased basic fibroblast growth factor (P = .046), hepatocyte growth factor (P = .046), placental growth factor (P < .001), stromal-derived factor-1 (P = .04) and macrophage chemoattractant protein-3 (P < .001) compared with baseline before the development of progressive disease.

Still, the identification of biomarkers remains in the investigative phase because researchers only recently learned that young patients do not respond as well to standard treatments, Lieu said.

During his fellowship at The University of Texas MD Anderson Cancer Center in 2008, Lieu was told that age was not a confounding factor in the treatment of colorectal cancer. The only differences were derived from anecdotal experiences.

“At the end of the fellowship, we started to ask if there could be a difference between younger and older patients,” Lieu said. “We were seeing more of these younger patients. In some instances they were being diagnosed young, and a couple of months later they would die and we were wondering, ‘What the heck just happened?’”

It was this increased incidence and the unexpected death of otherwise healthy, younger patients that spurred Lieu’s team to examine what might cause treatment resistance.

“I couldn’t provide the rationale to study the genetics or conduct mutational analyses of these younger patients with colorectal cancer until just recently,” Lieu said. “We got the data [to support these studies], and now we’re finally starting to look at the disease genetically.”

The Role of Screening

The identification of biomarkers in this at-risk population could trigger an evolution in the screening paradigm.

Current screening guidelines recommended commencing colonoscopy at age 50 years. Thus, screening individuals in their 20s and 30s would require a massive ideological shift, which could be outweighed by the associated costs and harms of screening.

Still, the lack of screening among younger individuals may directly contribute to the increased proportion of advanced-stage disease in this cohort.

“We are not only seeing more cancers in young people but we’re seeing them at a more advanced stage — and that is probably because we do not screen them,” Chang said. “Young patients also are diagnosed later because colorectal cancer is not on the forefront of their minds. If they see blood in their stool, for example, they are not thinking they should get a colonoscopy. Even their providers may not be thinking colon cancer. It takes longer to get the work-up needed and to make the diagnosis.”

The identification of biomarkers could help researchers isolate a group of younger individuals who may benefit from screening, leading to earlier identification of cancers in this cohort, Cercek said.

Meanwhile, patient and provider education regarding the increased incidence of colorectal cancer in younger patients is key to improving care, Cercek added.

“It is difficult to say that we should overreact to this increased incidence and screen people aged younger than 50 years with colonoscopies,” she said. “Population-wide, that’s probably not the right answer. But, we should increase the awareness among primary care providers and internists that there is an increased incidence of colorectal cancer in younger patients. If a patient has symptoms that the provider might dismiss, like rectal bleeding, they should pursue it further with a colonoscopy as opposed to entertaining other ideologies and having to diagnose the cancer later on.”

Although the time is not right to change screening guidelines, emerging affordable and effective screening approaches other than colonoscopy may be ideal screening methods for these younger patients, Zell said.

Fecal immunochemical testing (FIT) appears as accurate as colonoscopy for colorectal cancer detection, although it is not yet known whether FIT is as effective for prevention of colorectal cancer death, Zell said.

“The data we have so far indicate that it is an excellent test, and it is approved as a screening method for colorectal cancer by the American Cancer Society,” Zell said. “In the past, we’ve had three problems with colonoscopy screening — one, the cost; two, the number of providers is insufficient to screen the entire country; and three, it is a socially unacceptable screening method for many people. As a result, only approximately one-half of patients in the screening age are actually screened.”

Whether FIT, fecal occult blood testing or multitargeted DNA testing would be more accepted and cost-effective in a younger population is unknown, Zell added.

“These are the questions we need to start asking,” he said.

However, starting fecal occult blood testing at age 40 years “may not be the right thing to do,” Cercek said.

“Colonoscopy is the gold standard, but it should be preceded by some symptoms,” she said. “I wouldn’t recommend any other test because, if they were given and there were abnormalities discovered, they would be followed up with a colonoscopy anyway.”

However, the harms of screening may be magnified in this younger population, which still represents a small percentage of colorectal cancer cases, Boland said.

“We’re talking about a problem where, even though there is an increased incidence, it is still really uncommon,” Boland said. “Typically, people develop a test that is 90% specific. That means if you screen 100 people, 10 will have a false-positive test. Screening is not the answer. You cannot screen for a rare disease, and colon cancer is rare in young people.”

Research Priorities

Metabolic causes of colorectal cancer, and providing support to younger patients with the disease, also are high-priority research areas.

Determining the cause of the increased incidence of colorectal cancer in younger adults is a crucial next step, Boland said.

“I don’t think a biomarker is going to help, because the false positives will be too high,” he said. “We have identified most of the high-penetrance colon cancer genes. In younger people, it is either a rare recessive disease, it’s not an autosomal-dominant disease, or it is autosomal dominant with really low penetrance. You have to do some dancing around to come up with a genetic explanation.”

Research should focus on understanding metabolic issues, Boland added.

“If you have extra fat on your body, it’s very metabolically active and it fosters inflammation in your gut and your blood vessels, and that is why these people have more cancers of all types and they have accelerated cardiovascular disease,” he said. “We need to go back to the drawing board ... and figure this out on a very basic level.”

Irrespective of the cause of the disease, more focus is needed on the support younger patients require, Lieu said.

“Regardless of the biology, the needs of young patients are different than those of older patients,” he said. “If you are 75 and retried and you develop colorectal cancer, the impact on your life is not necessarily worse or better, but it is certainly different than if you are a 30-year-old because of the impact on your career, education, family and kids. If you sit in a support group, there will be a bunch of 70-year-olds and one 30-year-old.”

A study by Sanford and colleagues —published in 2014 in Cancer — showed that among 718 patients with colorectal cancer, those who were younger appeared more likely than older patients to experience moderate or severe pain, fatigue, nausea, distress, drowsiness, shortness of breath and rash. They also reported greater interference with general activity, mood, work, relationships and life enjoyment.

“It is important to acknowledge that part of the problem is that the symptoms differ between younger and older adults, and that confuses physicians, patients and family members,” Zell said. “The good news is that 94% of young adults with colon cancer do have symptoms of colon cancer. The higher incidence is in left-sided tumors closer to the rectum, so they should be easier to find than those that are right sided.”

Understanding how these symptoms differ could improve the detection of colorectal cancer in younger patients.

“[The study by Sanford and colleagues provides] important insight into an area that we don’t know much about,” Zell said. “The symptoms of this disease are present but they may not be the classic symptoms — weight loss, constipation and anemia — that we look for in older adults. The more we learn about how younger patients present, the more we can increase early detection.” – by Anthony SanFilippo

• References:
• Bailey CE, et al. JAMA Surg. 2015;doi:10.1001/jamasurg.2014.1756.
• Kneuertz PJ, et al. JAMA Surg. 2015;doi:10.1001/jamasurg.2014.3572.
• Kopetz S, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2009.24.8252.
• Lieu CH, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.9329.
• Meyer JE, et al. Cancer. 2010;doi:10.1002/cncr25432.
• Mork ME, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.61.4503.
• Sanford SD, et al. Cancer. 2014;doi:10.1002/cncr.28297.
• Singh KE, et al. J Adolesc Young Adult Oncol. 2014;doi:10.1089/jayao.2014.0006.

• For more information:
• C. Richard Boland, MD, can be reached at crichardboland@gmail.com.
• Andrea Cercek, MD, can be reached at cerceka@mskcc.org.
• George J. Chang, MD, MS, can be reached at gchang@mdanderson.org.
• Christopher Lieu, MD, can be reached at christopher.lieu@ucdenver.edu.
• Eduardo Vilar-Sanchez, MD, PhD, can be reached at evilar@mdanderson.org.
• Jason A. Zell, DO, MPH, can be reached at jzell@uci.edu.

Disclosure: Boland, Cercek, Chang, Lieu, Vilar-Sanchez and Zell report no relevant financial disclosures.