Multiple Factors at Play in the Rise of Early-Onset Colorectal Cancer

Jalal S. Baig, MD

My colon cancer patients are getting younger. The diagnoses are happening just as some of these individuals are embarking on their plans for life, while others are in the crucial midst of parenthood. Given this, the tragedy of their cancers feels exponentially greater.

This youthful trend in my clinic is supported by the incidence data. Early-onset colorectal cancer (CRC), which is defined as a diagnosis occurring in patients below 50 years of age, has seen an uptick over recent decades in the United States and other middle- and high-income countries. These cases of early-onset CRC now account for roughly¹ 10% of new diagnoses of this cancer and have contributed to a rise in CRC-related mortality² during the past decade in this younger group. In the next decade, 25% of rectal cancers and 10-12% of colon cancers are expected to be found in those younger than 50.¹

Despite these growing numbers, there remains an awareness deficit with healthcare providers and the younger public on early onset CRC. A dangerous assumption often made here is that any young person presenting with symptoms - hematochezia, abdominal or pelvic pain, bloating or a change in bowel habits - likely has a benign explanation. This makes patients loath to pursue medical care and wrongly reassures health care providers that any serious testing is not warranted.

But swift recognition is important here. Studies have shown that patients with early-onset CRC have more advanced disease at diagnosis (stage 3 or 4) than those with later-onset disease.³ Yet there does not appear to be anything more biologically virulent about early-onset CRC tumors that accounts for the advanced stage disease. Studies comparing younger CRC patients to their older counterparts have shown no survival difference between the two groups when diagnosed with stage II, III⁴ or IV disease.⁵

It is instead far likelier that younger patients have worse outcomes simply because they’re sitting on their symptoms for many months prior to presenting for work-up and diagnosis.

Though no primary risk factor has been identified to account for this worldwide rise of early-onset CRC in the developed world, it is likely to be multifactorial - Western-style diet, smoking, physical inactivity and overweight and obese body types.⁶ Over decades, diet, lifestyle and antibiotic use can affect the gut microbiome, which has a role in the body’s antitumor response. Alterations in this microbiome, coupled with chronic gut inflammation from similar risks, can increase the risk of CRC.

While early-onset CRCs are largely sporadic, hereditary syndromes account for 25% of these cases⁷ and make germline testing necessary at the time of diagnosis to capture patients with Lynch syndrome. The syndrome is attributable to a germline mutation in the mismatch repair (MMR) gene that leads to MMR deficient (dMMR) and microsatellite-instability high (MSI-H). Not only is the detection of Lynch syndrome imperative because of other familial cancers it is associated with, but there is also a significant therapeutic role in metastatic colon cancer for a first-line immune checkpoint inhibitor in dMMR and MSI-H. Current guidelines not only call for universal Lynch syndrome assessment in early-onset patients, but also recommend germline multigene panel testing in this young group to detect these hereditary syndromes for genetic risk counseling and possible treatment implications.

This rise in incidence has pushed the U.S. Preventive Services Task Force to recommend CRC screening to begin at the age of 45 years.⁸ But even this may be a half measure to stem the cases as almost half the early-onset CRC diagnoses occur in individuals younger than 45. More is needed on other fronts.⁹

There will need to be greater awareness and education for both primary care providers and young patients about the existence of early-onset CRC, the importance family history for initiating early screening, concerning symptoms and screening options that may soon include an assessment of circulating tumor DNA in blood plasma for finding early-stage CRC.¹⁰ This will need to include efforts that grapple with access to care, healthcare inequities and screening barriers. Public health strategies must be refreshed and redoubled to address bedeviling CRC risk factors like poor dietary habits, obesity, and sedentary lifestyle. And continued research will be needed to elucidate any early-life exposures that may contribute to disease pathogenesis.

With early-onset CRC still expected to climb and inevitably double by 2030, we may already be behind in the task to alter this trajectory. But any life saved from the singular tragedy of this diagnosis, whether by early detection or screening, is infinitely welcome.

REFERENCES:

1. Zaborowski AM, Abdile A, Adamina M, et al. Characteristics of early-onset vs late-onset colorectal cancer. JAMA Surg. 2021;156(9):865-874. doi:10.1001/jamasurg.2021.2380

2. Bhandari A, Woodhouse, Gupta S, et al. Colorectal cancer is a leading cause of cancer incidence and mortality among adults younger than 50 Years in the USA: A Seer-based analysis with comparison to other young-onset cancers. J Investig Med. 2017 Feb;65(2):311-315. doi: 10.1136/jim-2016-000229.

3. Chen FW, Sundaram V, Chew TA, 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(5):728-737.e3. doi: 10.1016/j.cgh.2016.10.038.

4. Fontana E, Meyer J, Sobrero A, et al. Early-onset colorectal adenocarcinoma in the IDEA Database: Treatment adherence, toxicities, and outcomes with 3 and 6 months of adjuvant fluoropyrimidine and oxaliplatin. J Clin Oncol. 2021;39(36): 4009-4019. doi: 10.1200/JCO.21.02008

5. Cercek A, Chatila WK, Yaeger R, et al. A comprehensive comparison of early-onset and average-onset colorectal cancers. J Natl Cancer Inst. 2021;29;113(12):1683-1692. doi: 10.1093/jnci/djab124.

6. Sinicrope FA. Increasing incidence of early-onset colorectal cancer. N Engl J Med. 2022; 386:1547-1558. doi: 10.1056/NEJMra2200869

7. Stoffel EM, Koeppe E, Everett J, et al. Germline genetic features of young individuals with colorectal cancer. Gastroenterology. 2018 Mar;154(4):897-905.e1. doi: 10.1053/j.gastro.2017.11.004.

8. Colorectal cancer: Screening. U.S. Preventative Services Task Force. Published May 18, 2021. Accsedd May 21, 2023. https://bit.ly/3MQj8PP

9. Anderson JC, and Samadder JN. To screen or not to screen adults 45-49 years of age: that is the question.
Am J Gastroenterol. 2018;113(12):1750-1753. doi: 10.1038/s41395-018-0402-3.

10. Phallen J, Sausen M, Asleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;16;9(403):eaan2415. doi: 10.1126/scitranslmed.aan2415