The New Face of CRC: What to Make of Colorectal Cancer in Patients Younger Than 50?

Some of my most painful clinical encounters have been with young persons with advanced colorectal cancer (CRC) in whom opportunities for early diagnosis or prevention were missed: the young woman with obstructing CRC in late pregnancy after 14 months of symptoms that were not evaluated because of lack of insurance and then reluctance to perform colonoscopy in pregnancy; the young man with liver metastases who had not undergone genetic testing or screening despite a clear history of familial adenomatous polyposis in his estranged father; the young woman with disseminated CRC two years after presenting with bleeding and a non-diagnostic biopsy of a sigmoid mass, whose ongoing symptoms were dismissed because “young people don’t get colon cancer.”

The increasing incidence of CRC in persons younger than age 50 in the U.S. has made headlines in academic circles and in the popular press. What to make of it?

We must appreciate the trends, but also the absolute rates. Recent annual increases in colon cancer incidence and rectal cancer incidence have been, respectively, 2.4 percent and 3.2 percent in 20-29 year-olds, 1 percent and 3.2 percent in 30-39 year-olds, and 1.3 percent and 2.3 percent in 40-49 year-olds.1 In contrast, incidence rates in persons over 50 have decreased by even larger fractions,1 which is attributed at least in part to screening. These percent changes operate on top of very different baseline rates by age, however. The current annual incidence rates per 100,000 persons for colon and rectal cancer, respectively, are approximately one and less than one for 20-29 year-olds, four and three in 30-39 year-olds, and 15 and 10 in 40-49 year-olds.1 For comparison, the respective rates per 100,000 persons in 50-84 year-olds range from approximately 30 to 200, and 20 to 50.1 Thus, the vast majority of CRCs still occur after age 50. However, at the individual level, death from CRC in a young person is particularly devastating.

Why is this happening? Nobody knows. The genetic pool cannot have changed quickly, so we must look at the environment. Obesity or diabetes? There is no firm evidence to confirm this. Anecdotally, many of my young patients with CRC have never been obese. Is it diet, independent of obesity? Increased use of colonoscopy resulting in earlier diagnosis? I don’t think this can explain the trends in adults younger than 40. There may be unique molecular phenotypes in young onset CRC, but this remains to be confirmed, and it is not clear how this may help elucidate etiology.

In light of these concerning trends, it may be tempting to extend our enthusiasm for CRC screening to younger people. However, population-based screening at younger ages is unlikely to be practical or cost-effective at this time. The recent U.S. Multi-Society Taskforce on Colorectal Cancer guidelines conclude that there is insufficient evidence to recommend systematic screening in persons under age 50 without specific risk factors (except in African-Americans, in whom limited evidence supports screening at 45).


Persons with CRC at ages younger than 50 tend to be diagnosed at more advanced stages than older patients.


If earlier universal screening is not currently indicated, can we select subgroups for screening? Genetic assessment and early screening are well established for cancer genetic syndromes, including familial polyposis and Lynch syndrome. However, many families remain undiagnosed and, sadly, within identified families, many people do not receive appropriate management. Inherited cancer gene mutations associated with CRC can now be found in, respectively, 22 percent, 19 percent and 11 percent of 20–29 year-olds, 30–39 yearolds and 40–49 year-olds presenting with CRC.2 The challenges are that most young-onset CRC cases remain unexplained, and that the genetic syndrome is often first diagnosed in the young patient — too late for prevention in that patient, but of potential benefit to relatives.

What about other established indications for early screening? In our cohort of patients younger than 50 with CRC,3 only 30 percent had indications for screening earlier than age 50, including a family history of CRC, a confirmed or suspected cancer genetic syndrome or inflammatory bowel disease. In most young patients with CRC, it seems that “CRC just happens,” and we lack ways to identify these patients for early screening. Of the three patients I opened with, close surveillance (probably leading to prophylactic colectomy) had been indicated only for the young man with familial polyposis.

If widespread screening is not currently viable, what prevention is possible? I believe we should promote a healthy diet (rich in vegetables and fruits, low in fat and meat and total calories, very low in processed foods), exercise, and prevention of obesity and diabetes. This is much easier said than achieved — and we don’t know how much this would affect CRC incidence in young adults.

While CRC prevention may be preferred to early CRC detection, the most important outcome is prevention of CRC death. Because most CRCs in young adults seem to “just happen,” currently our best opportunity is prompt evaluation and early diagnosis. The two young women in my opening suffered because of failures to diagnose them soon after symptom onset.

Persons with CRC at ages younger than 50 tend to be diagnosed at more advanced stages than older patients. Compared with CRC patients 50 or older, we found that patients with CRC under 50 years had significantly longer median symptom duration, time of evaluation and time to diagnosis — pointing to delays by patients as well as clinicians.3 However, younger patients with advanced stage CRC had shorter durations of symptoms and evaluations than those with early stage CRC, suggesting that advanced stage cannot be ascribed simply to delays in diagnosis.

Practically, what can we do now as gastroenterologists? We must identify cancer genetic syndromes in our patients’ families so young family members can be managed appropriately — yet this will not address most cases of young-onset CRC. We must encourage referral of patients with family history of CRC for early screening. We must educate our colleagues in primary care and emergency medicine to consider CRC in young persons with rectal bleeding or new and persistent abdominal and bowel symptoms, and to refer them for endoscopic evaluation — all while recognizing that the rate of CRC in these scenarios is low. Unfortunately, these approaches will not prevent many cases of CRC death in young adults. We will need novel preventive and targeted screening strategies to address the increasing rates of young-onset CRC.

Dr. Ladabaum has done consulting for Medtronic and Quorum. Dr. Ladabaum serves on the scientific advisory board of Universal Dx and Lean Medical.

References
1. Siegel R.L., Fedewa S.A., Anderson W.F. et al, Colorectal Cancer Incidence Patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109.
2. Pearlman R., Frankel W.L., Swanson B. et al, Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017;3:464-471.
3. Chen F.W., Sundaram V., Chew T.A. et al, Advanced-Stage Colorectal Cancer in Persons Younger Than 50 Years Not Associated With Longer Duration of Symptoms or Time to Diagnosis. Clin Gastroenterol Hepatol. 2017;15:728-737.

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