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Colorectal Cancer in the Millennial Generation

Jordan Hill, PharmD BCOP
Clinical Pharmacy Specialist—Solid Tumor Malignancies
West Virginia University Cancer Institute
Morgantown, WV


Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States.1 With a median age at diagnosis of 68 years, colorectal cancer is commonly considered a malignancy of the elderly, with more than half of colorectal cancer diagnoses occurring in adults 65 years and older.2 With increased awareness of the risks of smoking and increased utilization of colorectal cancer screenings, the annual percentage of change in incidence for colorectal cancer has steadily declined by 2.28 from 1998 to 2007 and 3.44 from 2007 to 2013.2 In addition, earlier detection of colorectal cancers and advancements in treatment such as anti-angiogenic drugs, epidermal growth factor receptor blockers, and multikinase inhibitors have led to continued decreased death rates, with rates falling an average of 2.7% each year from 2004 to 2013.2

Conversely, in adults aged 54 years and younger, colon cancer incidence has actually risen. From the mid-1980s for people ages 20–39 years and from the mid-1990s for ages 40–54 years, rates increased 2.4% per year in adults ages 20–29 years, 1.0% in ages 30–39, 1.3% in ages 40–49, and 0.5% in ages 50–54. The increases in rectal cancer incidence are even more dramatic, with increases in incidence of 3.2% for adults ages 20–39 since 1980 and 2.3% for adults ages 40–54 years since the 1990s. When examining age-specific trends by birth cohorts from the 1890s, 1950s, and 1980s, the 1980 birth cohort had double the age-specific risk of colon cancer and triple the risk of rectal cancer compared to the 1950 age cohort. This represents similar age-specific relative risks to those in the 1890s age cohort, indicating that rates of colorectal cancer in the millennial generation are as high as for those born in the late 1800s.3

The increase in colon cancer rates observed in younger patients is primarily driven by an increase in distal or left-sided tumors.3 Recently, primary tumor location has been found to have a role in both prognosis and treatment decisions for colon cancer. Most literature supports an association of primary left-sided tumors with an overall improved prognosis, with the exception of those associated with Lynch syndrome, which are predominantly right-sided and still confer a good prognosis.4-7 Given the increasing trend of mostly distal tumors occurring in younger patients, one could infer an improved prognosis on the basis of primary tumor location alone. Alternatively, some reports show that younger patients are up to 58% more likely to present with distant disease when compared to older patients, most likely due to a delay in a colon cancer workup following recognition of classic signs and symptoms of gastrointestinal malignancy as well as a decreased likelihood of younger adults’ being appropriately insured.8 Taking into account the primary site of the tumor and a generally increased tolerability of cytotoxic chemotherapy, as well as increased rates of more advanced disease at diagnosis, the overall prognosis is likely to be similar for younger adults as compared with older adults. This similar prognosis has been demonstrated in single-center studies as well as in a large population-based retrospective cohort study comparing early-onset colorectal cancer to that in older patients.8-10Conversely, inferior survival has also been shown in some single-center studies.11-12 One argument suggesting a similar overall prognosis is the potential for a higher proportion of early-onset colorectal cancer being attributed to hereditary colorectal cancers and, hence, an overall improved prognosis.

Hereditary colorectal cancers, such as hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, account for only 2%–5% of all colorectal cancers; however, they account for up to 20% of young-onset colorectal cancers.13 In addition to the overall improved prognosis for these cancers compared with that for sporadic colorectal cancer, they are also microsatellite instable. Recent literature indicates that colorectal cancers with high levels of microsatellite instability have high response rates to immunotherapy such as PD-1 blockade; this finding seems to indicate that the prognosis will continue to improve in this small subset of patients.

Even with a higher proportion of young-onset colorectal cancers being attributed to hereditary syndromes compared with colorectal cancers in older patients, the vast majority of these diagnoses are still considered sporadic. This has led to increased discussion supporting alternative contributors to the rise in colorectal cancer rates among young adults. Differences in clinical and molecular features of young-onset colorectal cancer reported in the literature include increased rates of CpG island methylator phenotype, increased frequency of microsatellite and chromosomal stable tumors, and increased LINE-1 hypomethylation. However, for none of these biological mechanisms is substantial data available regarding the significance of their observed differences in age-defined subsets of colorectal cancer.15-17 Recently, a study evaluating the frequency and spectrum of cancer-susceptibility gene mutations in early-onset colorectal cancer found a 16% rate of gene mutations, with 33% of those not meeting genetic testing criteria, which indicates that a substantial amount remains to be learned about the differences in pathogenesis for early-onset colorectal cancer.7

In addition to unique molecular mechanisms found in young-onset colorectal cancer, modifiable risk factors for colorectal cancer are rising at an alarming rate; these include poor dietary habits (e.g., high consumption of processed meat, low consumption of fiber), increased sedentary lifestyles, and higher rates of obesity and diabetes. Over the last 30 years, obesity rates in the United States have doubled among adults and tripled among children. An examination of obesity by birth cohorts has identified an overall increase in cumulative exposure to excess body fat, as more recent birth cohorts are becoming obese in greater numbers and becoming obese at an earlier age.18 Therefore, it is not surprising that the trends in early-onset colorectal cancer parallel those of obesity.

With the vast majority of young-onset colorectal cancers occurring in patients without hereditary syndromes, the examination of family history regardless of age, an increased public awareness of the ever increasing risk in young adults, and an increased awareness of the numerous risks of poor dietary habits and obesity are measures that are now more important than ever. Given their accessibility and vital role in the comprehensive care of patients, pharmacists can be essential agents in the effort to increase awareness and ensure that appropriate screenings occur. After a diagnosis has been made, pharmacists can continue to ensure that patients receive appropriate care by including tumor location, microsatellite instability, and genetic mutational status in treatment considerations. Reversing the current trend in colorectal cancer incidence will ultimately require a significant shift in lifestyle modifications, earlier recognition of signs and symptoms of colorectal cancer by young adults, and a more specialized way to identify appropriate candidates for early screening. It is hoped that an increased awareness of these startling trends will help to reverse the upward trend in modifiable risk factors and that research will continue to aid in the tailored care of those with early-onset colorectal cancer.

References

1. American Cancer Society. Cancer Facts & Figures 2017. Atlanta, GA: American Cancer Society; 2017.

2. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Colon and Rectum Cancer. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed April 2017.

3. Siegal RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974-2013. J Natl Cancer Inst. 2017;109(8). doi: 10.1093/jnci/djw322.

4. Loupakis F, Yang D, Yau L, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3). doi: 10.1093/jnci/dju427.

5. Schrag D, Weng S, Brooks G, Meyerhardt JA, Venook AP. The relationship between primary tumor sidedness and prognosis in colorectal cancer. In: ASCO Meeting Abstracts. 2016;34:3505. Abstract 3505.

6. Warschkow R, Sulz MC, Marti L, et al. Better survival in right-sided versus left-sided stage I–III colon cancer patients. BMC Cancer. 2016;16:554.

7. Pearlman R, Frankel WL, Swanson B, et al; Ohio Colorectal Cancer Prevention Initiative Study Group. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3(4):464-71.

8. Abdelsattar ZM, Wong SI, Regenbogen SE, Jomaa DM, Hardiman KM, Hendren S. Colorectal cancer outcomes and treatment patterns in patients too young for average risk screening. Cancer. 2016;122(6):929-34.

9. Salem ME, Arun M, Dyson G, et al. Characteristics of colorectal cancer in patients younger than 40 years compared to older patients [abstract 371]. J Clin Oncol. 2013;31(suppl 4).

10. Yeo SA, Chew MH, Koh PD, Tang CL. Young colorectal carcinoma patients do not have a poorer prognosis: a comparative review of 2,426 cases. Tech Coloproctol. 2013;17(6):653-61.

11. Khan SA, Morris M, Idrees K, et al. Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg. 2016;51(11):1812-17.

12. Lee J, Kim IH, Kim JS, et al. Different clinical characteristics in sporadic young-age onset colorectal cancer. Medicine. 2016;95(37):e4840.

13. Chang DT, Pai RK, Rybicki LA, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol. 2012;25(8):1128-39.

14. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-20.

15. Ballester V, Rashtak S, Boardman L. Clinical and molecular features of young-onset colorectal cancer. World J Gastroenterol. 2016;22(5):1736-44.

16. Stigliano V, Sanchez-Mete L, Martayan A, Anti M. Early-onset colorectal cancer: a sporadic or inherited disease? World J Gastroenterol. 2014;20(35):12420-30.

17. Kirzin S, Marisa L, Guimbaud R, et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular, and genetics study. PLoS ONE. 2014;9(8):e103159.

18. Lee JM, Pilli S, Gebremariam A, et al. Getting heavier, younger: trajectories of obesity over the life course. Int J Obes (Lond). 2010;34(4):614-23.

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