Recent Updates in Early Onset Colorectal Cancer: What We Know and Where to Go

As the second most common cause of cancer-related deaths globally, colon cancer is amongst the deadliest.¹ An increasing trend in cases of early-onset colorectal cancer (EO-CRC), which is defined as younger than 50 years at the time of diagnosis, has been recognized on a global level over the last 2 decades.² It is now estimated that EO-CRC is responsible for approximately 10% of CRC mortalities and in contrast to trends observed in later onset CRC as a whole.³ Amongst myself and colleagues, these diagnoses are amongst the most startling. A call to action has been declared, with a clear signal of receipt, as oncologists globally explore trends, challenges in diagnosis, and future directions.

Rising Incidence and Etiology

Current data estimate that almost 50 new diagnoses of EO-CRC are being made today with CRC estimated to be the leading cause of cancer death in patients younger than 50 years by 2030.⁴ This is clearly a global phenomenon seen in countries with different lifestyles, diets, exposures, and other environmental factors and without clear urban/rural predilection.⁵ Increasing incidence has been most prominent amongst non-Hispanic White populations, although without clear environmental or biological.⁶

Multiple modifiable risk factors have been posited, including Western dietary patterns (increased red meat and processed sugars, etc.), smoking, and overweight body habitus. In the Nurses’ Health Study II (1991-2015) a western style diet was associated with increased risk of EO-CRC.⁷ Still, a unifying cause of EO-CRC has yet to be found supporting a multifactorial cause including diet and lifestyle.

An emerging area receiving significant interest involves the gut microbiota. Gut microbiota is increasingly recognized as a moderator of obesity, age-related immunity, and inflammation.^8,9 In one of the most robust studies to date, Yang et al explored age-related changes in more than 1,000 samples evaluating both age-related and colorectal adenoma-carcinoma sequences. They discovered several differentiating features: 1) as biological age increases, microbiota richness decreases – potentially implicating high bacterial diversity as a potential etiology and 2) Fusobacterium and Flavonifractor were consistently dominating populations of bacteria in EO-CRC. Additional investigations are ongoing.

Finally, while inherited CRC is higher in EO-CRC, still, a vast majority are still considered sporadic cases and germline variants cannot explain increases.¹⁰

Recognition

One of the most challenging aspects of EO-CRC is the delay in diagnosis. The reasons for this are multifactorial. First, and most obvious, is a lack of awareness by both patients and providers. CRC is most commonly associated with older age. An increase in rates in patients <50 is a relatively new phenomenon and takes time for public consciousness to catch up. A recent survey from the American Association for Cancer Research in 2019 found that a majority of patients were unaware that CRC can occur in patients younger than 50 years, saw more than 2 physicians, and waited more than 6 months to seek medical attention.¹¹ While publicity is increasing it is often only after diagnosis that our young patients become aware of increasing rates of CRC. Similarly, patients’ first interface with the medical system is often with primary care physicians. As oncologists, we see patients with EO-CRC every day; however, this phenomenon is still somewhat rare on a population level and hard to recognize for providers who are not faced with this diagnosis on a daily basis.

Second, until recently, the recommended age at first screening was reserved for patients 50 years of age and older. The United States Preventive Services Task Force updated its recommendations in 2016 to include patients greater than 45, which was followed by the American Cancer Society in 2018.^12,13 There is often a delay to community uptick in guideline updates and studies assessing outcome impacts have yet to be completed.

While therapies for metastatic CRC have improved significantly over the last decade, our most powerful tool is still early recognition. Efforts to increase visibility are increasing, but widespread recognition is still lagging. We are optimistic that strategies such as decreasing the colonoscopy screening age from 50 to 45 will improve outcomes but have had some resistance with uptake. Additionally, there is a bevy of EO-CRC campaign programs such as “Never Too Young.”

Genetics and Molecular Characteristics

Identifying patients at risk of acquiring EO-CRC is of utmost importance. Patients with Lynch syndrome, which represents approximately 5% of CRC, are at the highest risk.¹⁴ Unfortunately, many patients are unaware of the syndrome, increasing the importance of testing all EO-CRC for germline mutations in an MMR gene (MLH1, MSH2, MSH6, PMS2, or EPCAM). Notably, nearly 30% of patients with EO-CRC have a first-degree relative with CRC and represent a high-risk population who can be targeted for screening.¹⁵

Efforts are ongoing to identify differences between early and late-onset CRC. Patients with Lynch syndrome and other hereditary cancer syndromes represent an estimated 35% of EO-CRC, many of which are MSI-H.^16,17 In the most comprehensive study to date, Lieu et all analyzed more than 18,000 patients with CRC with NGS sequencing comparing patients younger than 40, 40 to 49, and 50 years and older.¹⁸ The authors found that a majority of genes analyzed were similar between younger and older cohorts, but did find that TP53 and CTNNB1 mutations were more common in EO-CRC while APC, KRAS, and BRAF were more common in older populations.

At the 2023 ASCO Annual Meeting, there was a dedicated session exploring rising trends, potential incriminating etiologies, and molecular differentiators. First, Deepak Vadehra, MD, explored the molecular basis of EO-CRC using The Cancer Genome Atlas and the Oncology Research Information Exchange Network. They found differences in methylation, immune modulation, metabolism, and oncogenic signaling. Second, Thejus Jayakrishnan, MD, investigated differences in metabolomics between EO-CRC and average-onset CRC. They found differences in pathways of carcinogenic significance suggesting a potential etiology for EO-CRC. Finally, Eric Lander, MD, evaluated genomic differences among patients with EO-CRC, finding they were enriched with TP53 and less commonly mutated with APC. We applaud these authors for contributing to the ongoing data bank needed to fight EO-CRC.

Conclusion

The first step in improving outcomes (and reversing the trend) is recognition followed by widespread dissemination. Our approach must be multifactorial. First, our efforts to educate increased rates of EO-CRC must be robust. Second, we need to continue ongoing epidemiologic and cancer registration studies that explore ongoing trends and potential implicating features. As more data emerge, it is essential that signal studies are followed by prospective studies. Finally, any intervention is only effective when aligned with action.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [published correction appears in CA Cancer J Clin. 2020;70(4):313]. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492
2. Wu CW, Lui RN. Early-onset colorectal cancer: Current insights and future directions. World J Gastrointest Oncol. 2022;14(1):230-241. doi:10.4251/wjgo.v14.i1.230
3. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145-64. doi: 10.3322/caac.21601
4. Lieu C. Early-onset colorectal cancer: rising incidence and opportunities for prevention and treatment. Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. https://meetings.asco.org/abstracts-presentations/217566/video
5. Spaander MCW, Zauber AG, Syngal S, et al. Young-onset colorectal cancer. Nat Rev Dis Primers. 2023;9(1):21. doi:10.1038/s41572-023-00432-7
6. Murphy CC, Wallace K, Sandler RS, Baron JA. Racial disparities in incidence of young-onset colorectal cancer and patient survival. Gastroenterology. 2019;156:958-965. doi:10.1053/j.gastro.2018.11.060
7. Zheng X, Hur J, Nguyen LH, et al. Comprehensive assessment of diet quality and risk of precursors of early-onset colorectal cancer. J Natl Cancer Inst. 2021;113(5):543-552. doi:10.1093/jnci/djaa164
8. Hofseth LJ, Hebert JR, Chanda A, et al. Early-onset colorectal cancer: initial clues and current views [published correction appears in Nat Rev Gastroenterol Hepatol. 2020;17(8):517]. Nat Rev Gastroenterol Hepatol. 2020;17(6):352-364. doi:10.1038/s41575-019-0253-4
9. Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358(6369):1443-1448. doi:10.1126/science.aal5240
10. Sinicrope FA. Increasing incidence of early-onset colorectal cancer. N Engl J Med. 2022;386(16):1547-1558. doi:10.1056/NEJMra2200869
11. Yarden R, Newcomer K. Young-onset colorectal cancer patients are diagnosed with advanced disease after multiple misdiagnoses. Cancer Res. 2019;79(suppl_13):3347. doi:10.1158/1538-7445.AM2019-3347
12. USPSTF recommends expansion of colorectal cancer screening. Lancet Gastroenterol Hepatol. 2021;6(1):1. doi:10.1016/S2468-1253(20)30361-7
13. Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68(4):250-281. doi:10.3322/caac.21457
14. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2017;26(3):404-412. doi:10.1158/1055-9965.EPI-16-0693
15. Stoffel EM, Koeppe E, Everett J, et al. Germline genetic features of young individuals with colorectal cancer. Gastroenterology. 2018;154(4):897-905.e1. doi:10.1053/j.gastro.2017.11.004
16. Mork ME, You YN, Ying J, et al. High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. J Clin Oncol. 2015;33(31):3544-3549. doi:10.1200/JCO.2015.61.4503
17. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69-77. doi:10.1056/NEJM200001133420201
18. Lieu CH, Golemis EA, Serebriiskii IG, et al. Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer. Clin Cancer Res. 2019;25(19):5852-5858. doi:10.1158/1078-0432.CCR-19-0899