Advances in Understanding Early-Onset Colorectal Cancer

Since the 1990s, the incidence of colorectal cancer in the United States has decreased overall by more than 35%, at a similar rate across all racial groups, largely due to the success of early detection. By contrast, clinically-diagnosed colorectal cancer incidence rates at less than 50 years of age (early-onset colorectal cancer) increased by more than 50% (1). Early-onset colorectal cancer typically exhibits higher pathologic grade and a greater risk of recurrence and metastatic disease (2); although, these differentials may largely be due to diagnostic delay (3), with evidence suggesting that survival is better than for older cases, when stage at diagnosis is considered (4). Initially, increasing trends of early-onset colorectal cancer were largely limited to cancers of the rectum; however, recent data from 2012 to 2016 show 1.8% annual increases for tumors in the proximal and distal colon as well, contributing to the current overall 2.2% annual increase in the U.S. in early-onset colorectal cancer (5).

Racial and ethnic disparities are prominent in early-onset colorectal cancer (6). U.S. blacks overall have a 20% higher incidence of colorectal cancer and experience 40% greater mortality (5). The recent trend of increasing incidence of early-onset colorectal cancer is greater, however, for non-Hispanic whites (2% per year) than for blacks and Asian/Pacific Islanders (0.5% per year, mostly due to rectal cancer). The result of these trends is that early-onset colorectal cancer incidence rates are now equivalent in blacks and non-Hispanic whites, despite the 40% higher incidence rates in young blacks during 1995 to 1996. Furthermore, young American Indians/Alaskan Natives also are experiencing increases in colorectal cancer, similar to non-Hispanic whites.

Beyond the United States, there are at least 8 other high-income countries across North America, Europe, and Oceania where rates of colorectal cancer in young adults are increasing while rates in older adults are stable or declining (7). The pattern of increasing rates internationally for early-onset colorectal cancer has been observed particularly among individuals born during and after the 1960s, suggesting that the differential rates over time may be attributable to changes in risk-factor patterns throughout successive generations. Provocatively, 2011 to 2016 U.S. data now show rising trends for distal colon and rectal cancer at 50 to 64 years of age, consistent with a promotion of the early-onset disease pattern to intermediate ages, as the birth cohorts beginning in the 1960s progress through the life course (5).

The reasons for these alarming epidemiologic patterns for early-onset colorectal cancer worldwide are under intense study, yet major gaps in our knowledge remain. As reported in this issue of Cancer Epidemiology, Biomarkers and Prevention, Arif and colleagues differentiated characteristics and outcomes of early-onset colorectal cancer in patients with the predisposing conditions of inflammatory bowel disease (IBD; 4.1%) or hereditary genetic syndromes (6.8%), in contrast to patients with sporadic disease (89.1%), in a population-based cohort of 2,135 patients with early-onset colorectal cancer in British Columbia. Predisposing conditions were most common in the youngest cases (≤29 years, 34.3%). Compared with sporadic disease, patients with IBD presented more often with synchronous metastatic disease and experienced poorer survival, while patients with genetic syndromes had metastatic disease less often and experienced better survival, particularly among those with the hereditary Lynch syndrome. The study revealed a particularly poor prognosis for early-onset IBD-related tumors, in contrast to the experience previously reported with later-onset IBD-related tumors, which tend to have a clinical course similar to that of sporadic disease (8). In comparison with early-onset colorectal cancer related to predisposing conditions, Arif and colleagues found that sporadic cases occurred more often at older ages, were more likely female, and more often exhibited increased body mass index.

The findings by Arif and colleagues in British Columbia on early-onset colorectal cancer related to high-risk predisposing conditions are largely in agreement with earlier research (9, 10). The strength of the Arif and colleagues study is its comprehensive, population-based inclusion of a large series of more than 2,100 early-onset colorectal cancer cases that were diagnosed province-wide between 1990 and 2016, encompassing the period of overall increase in early-onset colorectal cancer in several high-income countries, including Canada (11). Genetic syndromes (12) and common genetic variants (13) are more strongly associated with early-onset than late-onset colorectal cancer, but temporal trends in these population traits are unlikely to account for the rapid secular changes being observed in the incidence of early-onset colorectal cancer. There is evidence that IBD is increasing worldwide (14); however, the relative proportion of early-onset colorectal cancer linked to IBD remains small and is also unlikely to contribute substantially to the observed increases in early-onset disease. This contribution by Arif and colleagues helps focus our attention on the majority sporadic cases and temporal trends in environmental exposures as a possible explanation for the rise in early-onset colorectal cancer.

Also reported in this issue, Schumacher and colleagues investigated risk factors for early-onset colorectal adenocarcinoma in a nested case-control study among Kaiser Permanente Southern California (KPSC) health plan members (ages 15–49, 2008–2018), using data from the KPSC cancer registry and electronic health records. KPSC is an integrated health care delivery system serving over 4.4 million members broadly representative of the diverse population of southern California. The study included 1,032 early-onset cases and 5-fold matched controls. Subjects with IBD were excluded, and genetic syndromes were not specifically evaluated. The risk of early-onset colorectal adenocarcinoma was significantly associated with obesity (as also found by Arif and colleagues for sporadic compared with predisposition-related cases), but not with diabetes, hypertension, or dyslipidemia. Stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma, but its association with rectal adenocarcinoma was less clear.

Obesity has also been related to early-onset colorectal cancer in meta-analysis (15); some inconsistent results, particularly in case-control studies (16), might be driven by reverse causality resulting from weight loss prior to colorectal-cancer diagnosis. The prevalence of obesity among US adults began to rise dramatically in the 1980s to a degree paralleling the temporal rise by successive birth cohorts in occurrence of early-onset colorectal cancer. Obesity increases have impacted all racial groups in the United States, with evidence that the increase in some obesity measures have recently plateaued among blacks (17). Worldwide increases in obesity are potentially related to increased sedentary behavior, higher consumption of calorie-rich foods and suboptimal diet quality, insufficient sleep, environmental exposure to endocrine disrupting chemicals, as well as multilevel social and environmental factors (17).

Understanding the scope, clinical consequences, and underlying causes of early-onset colorectal cancer is critical for colorectal cancer control. The research presented in this issue on characteristics and outcomes points to the importance of sporadic disease in the rise of early-onset colorectal cancer, while the research presented on risk factors points to the importance of obesity as a potential explanatory factor for this rise. Of course, colorectal cancer is multifactorial, and we already have indication from a first wave of epidemiologic studies that early-onset colorectal cancer could be linked (in addition to obesity) to sedentary lifestyle, poor diet, including elevated consumption of red and processed meat and sugar-sweetened beverages and reduced consumption of vegetables and citrus fruit, as well as to greater alcohol use, smoking, reduced aspirin use, metabolic factors, and diabetes mellitus (16, 18–26).

Perhaps there is a single key-factor that accounts for the rise in early-onset colorectal cancer, and worldwide increases in obesity could be that “smoking gun.” It could also be that parallel changes in several components of the multifactorial risk profile are operative, without any single-causal agent dominating. We also need to consider factors, particularly at an early age, that have yet received little attention in epidemiologic study of early-onset colorectal cancer, such as novel exposure to endocrine disrupters and other recently-introduced environmental chemicals, early exposure to antibiotics and other bioactive drugs, broad environmental influences on the gut microbiome, and the potential role of genetic and epigenetic interrelationships.

Further research, including in international consortia (16, 23) over the life-course and in diverse populations, promises to provide deeper understanding of the causes of early-onset colorectal cancer and the reasons for its recent rise. Improved understanding of these risks will be critical for primary prevention and could improve strategies for early detection (27) of the potentially large pool of preclinical colorectal cancer (and premalignant disease) in people younger than 50 years of age (28, 29).

R.B. Hayes reports grants from NCI during the conduct of the study; and grants from NCI outside the submitted work. No other disclosures were reported.

This work was supported by grants from NCI (to R.B. Hayes).