To evaluate associations between clinicopathologic and demographic characteristics and age groups at colorectal cancer diagnosis within the AYA population, we modeled adjusted multivariable logistic regressions (Table 3). Individuals aged 25–29 years at colorectal cancer diagnosis were 23% more likely to be diagnosed with a right-sided tumor (OR = 1.23, 95% CI 1.01–1.49, P = 0.04) or have signet ring cell carcinoma histopathology (OR = 3.01, 95% CI 1.98–4.56, P < 0.001) compared with 35- to 39-year-old counterparts after adjustment for patient sex, race/ethnicity, AJCC stage, and individual insurance status. Similarly, individuals aged 20–24 years were also 3.69-fold more likely to be diagnosed with colorectal cancer with signet ring cell carcinoma histopathology (OR = 3.69, 95% CI 2.08–6.58, P < 0.001), as well as 55% more likely to be diagnosed with mucinous adenocarcinoma (OR = 1.55, 95% CI 1.02–2.34, P = 0.04) histopathology as compared to individuals aged 35–39 years at diagnosis. Individuals aged 20–24 and 25–29 years at colorectal cancer diagnosis were less likely to be diagnosed with AJCC stage II disease (OR = 0.60, 95% CI 0.37–0.97, P = 0.04, and OR = 0.72, 95% CI 0.52–0.99, P = 0.04, respectively) compared with 35- to 39-year-old counterparts (Table 3).
Our investigation of 5,350 individuals diagnosed with colorectal cancer between ages 15 and 39 years in the United States from 2010 to 2015 identified clinicopathologic and racial/ethnic differences of colorectal cancers by age at disease onset. We observed that among AYAs, primary colorectal cancers diagnosed in younger individuals have a significantly higher propensity for right-sided location and for mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes. Differences in tumor stage was also observed across AYA age groups, particularly for AJCC stage II disease. Furthermore, the proportion of Hispanic individuals diagnosed with colorectal cancer was higher in younger age groups. These findings are novel, as our study is the first to stratify the population of AYAs into more specific age groups to characterize the clinicopathologic and racial/ethnic features of colorectal cancer by age at diagnosis within this population.
Tumor sidedness has recently emerged as a prognostic indicator for patients with colorectal cancer, particularly among those with metastatic disease. Tumors located in the cecum to transverse colon (right side) are associated with faster disease progression, poorer prognosis, and distinct pathways to tumorigenesis in contrast to left-sided tumors (splenic flexure to rectum) (28–30). However, conflicting evidence on the prognostic value of tumor sidedness has been reported among all-comers diagnosed with early-stage cancers of the colon and rectum (31–33). Differences in patient outcomes by tumor sidedness are partly attributed to a continuum of molecular variations associated with anatomical location in the colorectum (34,35), variations in therapeutic efficacy (36,37), and lead time bias for left-sided colorectal cancers (38,39). In the last decade, studies from single institutions have found that colorectal cancer cases diagnosed in individuals younger than 40 years tended to present with left-sided tumors (e.g., distal colon) more often compared with older counterparts (11,40). In 2016, Teng et al. (18) summarized the presentation of colorectal cancers among AYAs as a single group, finding that most individuals presented with distal tumors.
Unique to our study, we focused on age groups specifically within the AYA population to compare clinicopathologic characteristics of colorectal cancer, including tumor sidedness per National Comprehensive Cancer Network clinical guidelines. Consistent with earlier findings, we also observed that most AYAs presented with left-sided tumors using data from the population-based national SEER program. Strikingly, within this population, we identified heterogeneity in histopathologic subtype, clinical stage, and tumor location among AYAs, including increasing trends in right-sided colorectal cancer among cases diagnosed at younger age (25–29 years) compared with older counterparts (aged 35–39 year). Potential explanations for the clinicopathologic heterogeneity observed by age at onset groups among AYAs include differences in the prevalence of Lynch syndrome by age at onset groups, as Pearlman et al. (9) recently demonstrated that among patients diagnosed with young-onset colorectal cancer, the prevalence of Lynch syndrome was higher among patients aged 40–49 years at diagnosis compared with 30- to 39-year-old, and especially 20- to 29-year-old, counterparts. Additional reasons for differences in tumor sidedness and clinicopathologic characteristics among AYAs remain unknown, but could include a combination of genetic predispositions and biological factors (10) such as mutational burden (e.g., KRAS and BRAF), environmental exposures, and race/ethnicity.
Among individuals diagnosed with colorectal cancer younger than 50 years, racial and ethnic disparities in colorectal cancer outcomes are amplified (5). Specifically within the AYA population, we identified racial/ethnic patterns by age of colorectal cancer diagnosis. The proportion of Hispanic AYAs diagnosed with colorectal cancer was strikingly higher among younger age groups. A recent examination of ethnic differences in colorectal cancer incidence and mortality among all-comers at a tertiary university center noted that Hispanics presented with colorectal cancer at a younger age and with more advanced disease compared with NHWs (41). However, similar estimates of mismatch repair (MMR)-deficient tumors have been reported among Latinos and NHWs (42). Stern et al. (43) reported differences in colorectal cancer incidence patterns and tumor characteristics among Latino subpopulations by country of origin, suggesting that genetic ancestral heritage, lifestyle changes, environmental risk factors, and gene-environment interactions may contribute to this ethnic heterogeneity. Parental exposures and epigenetic mechanisms may also play a role for cases in the youngest age groups. Together with the changing landscape of age and race/ethnicity across the United States—where Hispanics are a growing population expected to represent nearly one-third of the population by 2060 (44)—further studies of the clinicopathologic characteristics and cultural, epigenetic, lifestyle, and environmental factors associated with age of colorectal cancer onset by race/ethnicity are warranted.
Although our findings suggest that there are clinicopathologic and racial/ethnic differences in colorectal cancer among AYAs, we acknowledge the limitations of our study. Our analyses were conducted using high-quality data from SEER that allowed for a large number of pathologically verified colorectal cancer cases among AYAs to be identified. SEER does not yet routinely collect data on specific and clinically relevant colorectal cancer molecular characteristics (e.g., somatic mutations and microsatellite instability) or detailed information on familial history of disease. As such, we were unable to separate sporadic vs hereditary cases of colorectal cancer among AYAs in our analyses. As colorectal cancer diagnosis before age 50 years remains one of the primary indications for genetic evaluation (25), the prevalence of genetic mutations associated with hereditary cancer syndromes is higher among patients diagnosed with young-onset colorectal cancer (9). Germline mutations in DNA MMR genes associated with Lynch syndrome, the most common cause of hereditary colorectal cancer (7), predispose to hypermutated cancers with a general predominance for right-sided tumors, mucinous histology, and disease presentation at a younger age (8). With increased use of universal microsatellite instability/MMR screening (45), a larger proportion of colorectal cancers with hereditary etiology may be captured within this study population. We were unable to examine differences in environmental exposures, behavioral factors, and comorbidities by age group and to discern whether these factors contribute to differences in the clinicopathologic and racial/ethnic characteristics of colorectal cancers within the AYA population. We also acknowledge the possibility that differences in racial/ethnic age structures could also contribute to our findings. Thus, our findings raise the possibility that colorectal cancer diversity among AYAs may partially underlie age- and race-related differences in cancer susceptibility and outcomes. However, our study does not present any data about the spectrum of germline genetic mutations nor the prevalence of hereditary syndromes, which contribute to the molecular phenotypes of colorectal cancer.
Notwithstanding these limitations, our findings yield important clinical implications. With advancements in therapies leading to an overall reduction in cancer burden, a better understanding of the molecular complexities of young-onset colorectal cancer by clinicopathologic features remains a prerequisite to the optimization of therapies and to meet the unique clinical care needs of the AYA population (22,46). Equal-access, long-term side effects of overtreatment on AYA fertility and therapies designed for patients older than 50 years present a clinical environment mismatch for AYAs (12,13,47–50). Additional research is needed to guide the development of colorectal cancer screening programs targeting high-risk young individuals. Increasing the representation and participation of AYAs in clinical trials (46,51) is also needed for the advancement of therapies and treatment algorithms designed for young individuals.
In summary, we observed clinicopathologic, particularly in tumor location, histopathologic subtype, clinical stage, and racial/ethnic differences of colorectal cancers among individuals aged 15–39 years at disease diagnosis. Younger age at disease diagnosis was associated with higher proportions of right-sided tumors and mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes within the AYA population. By race/ethnicity, the proportion of Hispanic individuals diagnosed with colorectal cancer significantly increased with younger age groups. Together, these data underscore the need for studies to characterize the molecular phenotype of colorectal cancers, particularly among AYAs, to unravel the underlying colorectal cancer etiologies within this population and reduce the global burden of cancer for AYAs (48).
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