The Growing Crisis of Colorectal Cancer in Young Adults: What Patients Need to Know

Table of Contents

• Introduction: Why This Matters
• Clinical Features of Early-Onset Colorectal Cancer
• Epidemiology: Tracking the Rising Numbers
• Risk Factors and Potential Causes
• The Gut Microbiome Connection
• Genetic Testing and Hereditary Syndromes
• Screening Recommendations
• What This Means for Patients
• Study Limitations
• Patient Recommendations
• Source Information

Introduction: Why This Matters

Colorectal cancer remains the third most common cancer worldwide and the second leading cause of cancer-related deaths. What's particularly concerning to medical experts is the dramatic increase in early-onset colorectal cancer cases - defined as diagnoses in patients younger than 50 years. This trend has emerged over the past few decades in the United States and other high-income countries, creating what researchers describe as an alarming public health crisis.

Early-onset colorectal cancer now represents approximately 10% of all new colorectal cancer diagnoses. Perhaps more troubling, mortality rates from colorectal cancer have also increased among younger patients during the past decade. This pattern stands in stark contrast to the steady decline in both incidence and mortality rates for later-onset colorectal cancer (diagnosed in patients 50 and older) over the past twenty years.

The concurrent increase in young-onset cases and decrease in older-onset cases has shifted the median age at diagnosis from 72 years in the early 2000s to 66 years currently. Projections suggest that in the next decade, 25% of rectal cancers and 10-12% of colon cancers will be diagnosed in people under 50 years old.

Clinical Features of Early-Onset Colorectal Cancer

Young patients with colorectal cancer often present differently than older patients. Early-onset colorectal cancers are most commonly detected in the rectum, followed by the distal colon. More than 70% of these cancers occur in the left side of the colon at diagnosis. This distribution differs from later-onset cancers, which occur at similar frequencies throughout the colon.

Overall colorectal cancer rates are 30% higher among men than women, but this sex difference is more pronounced for rectal cancer than colon cancer. Early studies suggested higher rates of aggressive tumor types in young patients, including poorly differentiated cancers and those with signet-ring cells, particularly in patients under 40.

However, more recent research from Memorial Sloan Kettering Cancer Center involving 759 patients with early-onset colorectal cancer (seen between 2014-2019) found no significant differences in tumor grade or genomic profiles between young and older patients when excluding cases with known hereditary predispositions.

Patients with early-onset colorectal cancer are more likely to present with advanced disease - stage III or IV cancers - compared to older patients. This pattern has been demonstrated in multiple studies including large population-based cohorts. This advanced presentation raises critical questions about whether these tumors are biologically more aggressive or if diagnosis is simply delayed in younger patients.

The data suggests diagnostic delays play a significant role. Young patients typically experience symptoms for 7-9 months before diagnosis - significantly longer than older patients. In a single-center study of a large cohort, the most common symptoms at presentation were:

• Rectal bleeding (hematochezia) in 38% of patients
• Abdominal or pelvic pain and bloating in 33%
• Changes in bowel habits in 20%

These symptoms particularly align with tumors of the rectum and left colon, which characterize most early-onset cases. Unfortunately, both patients and healthcare providers often attribute these symptoms to benign conditions like hemorrhoids or irritable bowel syndrome, leading to diagnostic delays.

Epidemiology: Tracking the Rising Numbers

In the United States, the age-adjusted incidence of early-onset colorectal cancer increased dramatically from 7.9 to 12.9 cases per 100,000 people between 1988 and 2015 - representing a 63% increase. This steady rise has occurred throughout developed countries, suggesting that similar risk factors and exposures across these geographic areas are major contributors.

The increase has been most marked among non-Hispanic White persons, while incidence rates have remained relatively stable (though elevated) among Black persons. The reasons for this racial disparity remain unclear and require further investigation.

This epidemiological shift is particularly concerning because exposures that lead to early-onset colorectal cancer would need to occur early in life to account for cancers developing before age 50. Researchers are actively investigating what early-life factors might be driving this trend.

Risk Factors and Potential Causes

Although no single predominant risk factor explains the worldwide increase in early-onset colorectal cancer, evidence points to a multifactorial risk profile involving lifestyle and environmental exposures. Putative risk factors identified in case-control studies overlap with established risk factors for later-onset disease but appear to be affecting younger populations differently.

Approximately 50 years ago, significant dietary changes began occurring with increased consumption of:

• Red and processed meats
• Refined grains
• Processed sugars and sugar-sweetened beverages

Modifiable risk factors, ranked from highest to lowest based on relative risk data, include:

1. Western dietary patterns
2. Current smoking (versus never smoking)
3. Consumption of red and processed meats
4. Overweight and obese body habitus

The Nurses' Health Study II (1991-2015) found that a Western-style diet was associated with increased risk of early-onset, high-risk colorectal adenomas (precursor lesions), particularly in the distal colon and rectum. Whole grains appear protective against colorectal cancer, while the protective effect of fruits and vegetables has been relatively weak and inconsistent.

Sugar-sweetened beverage consumption is highest among adolescents and young adults. In the Nurses' Health Study II, women who consumed two or more daily servings of sugar-sweetened beverages in adulthood had double the risk of early-onset colorectal cancer compared to women who consumed less than one serving per week. Even more strikingly, each additional daily serving consumed between ages 13-18 was associated with a 32% increased risk.

Physical activity reduces colorectal cancer risk, while sedentary behavior increases risk of early-onset disease. Obesity prevalence among US adults rose from 30.5% in 1999 to 42.4% in 2017, with severe obesity nearly doubling during this period. Multiple studies have linked adolescent obesity with increased incidence of early-onset colorectal cancer and related mortality.

Metabolic syndrome has increased among young adults and is associated with early-onset colorectal cancer. Type 2 diabetes has also substantially increased among younger adults, and patients with adult-onset type 2 diabetes have a slightly increased risk of colorectal cancer that is stronger for men than women.

The Gut Microbiome Connection

Abundant evidence links the gut microbiome with colorectal cancer development. The microbiome consists of trillions of bacteria and other microorganisms living in our digestive tract that interact with our immune system and can influence anti-tumor responses.

Patients with colorectal cancer typically have reduced bacterial diversity compared to healthy people. Specific bacteria including Firmicutes, Bacteroidetes, enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum appear enriched in colorectal cancer patients.

Diet significantly influences gut microbiome composition. Western-style diets and obesity can lead to gut dysbiosis (microbial imbalance) and chronic intestinal inflammation, which promotes colorectal tumor development. Plant-based diets promote beneficial anti-inflammatory gut microbes, while Western diets promote unfavorable microbes that contribute to inflammation and increased cancer risk.

Analysis from three prospective cohort studies showed that Western-style diets were associated with excess sulfur-metabolizing bacteria in feces. Patients with excess these bacteria had increased colorectal cancer risk after adjusting for other risk factors. This association was particularly strong for distal colon cancers.

Mechanistically, sulfur-metabolizing bacteria produce hydrogen sulfide, which is genotoxic - causing inflammation, DNA damage, and ultimately promoting cancer development. Beyond diet, antibiotics substantially alter the gut microbiome, and prolonged antibiotic use may be a risk factor for early-onset colorectal cancer.

Genetic Testing and Hereditary Syndromes

Nearly 30% of patients with early-onset colorectal cancer have a family history of this cancer in at least one first-degree relative. Population data indicate a 3-5% overall prevalence of hereditary colorectal cancers, with Lynch syndrome being the most common.

Unfortunately, Lynch syndrome remains undiagnosed in most affected patients, leaving them unaware of their high cancer risk. This syndrome results from germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, or EPCAM) that cause deficient DNA mismatch repair (dMMR) and high-frequency microsatellite instability (MSI-H).

Current guidelines recommend universal testing of all newly diagnosed colorectal cancers for MMR and MSI status to detect Lynch syndrome. This testing also has therapeutic importance since patients with dMMR or MSI-H metastatic colorectal cancer may benefit from immune checkpoint inhibitors.

The prevalence of mutations in high-penetrance cancer-susceptibility genes is relatively high among patients under 50. Germline multigene panel testing shows that 16-25% of early-onset colorectal cancer patients have pathogenic germline variants - nearly double the prevalence in unselected colorectal cancer patients.

In a prospective study of 450 early-onset colorectal cancer patients at 51 Ohio hospitals, multigene panel testing (25 genes) identified germline mutations in 16% of patients, with approximately half having Lynch syndrome. Importantly, one-third of patients with mutations didn't meet guideline-based genetic testing criteria for the mutated gene.

At a tertiary care clinic, 315 patients under 50 with colorectal cancer underwent clinical germline sequencing, and 25% had a hereditary colorectal cancer syndrome. The Collaborative Group of the Americas on Inherited Gastrointestinal Cancer recommends germline multigene panel testing for all colorectal cancer patients under 50, and the National Comprehensive Cancer Network recommends genetic risk counseling and evaluation for all early-onset patients.

Screening Recommendations

In response to the rising incidence of early-onset colorectal cancer, the American Cancer Society now recommends starting colorectal cancer screening at age 45 for people at average risk - down from the previous recommendation of age 50. This change reflects the growing recognition that colorectal cancer is increasingly affecting younger populations.

Screening options include colonoscopy, stool-based tests, and other imaging modalities. The appropriate screening method depends on individual risk factors, family history, and patient preference. Patients with family history of colorectal cancer or known genetic syndromes may need to begin screening even earlier and undergo more frequent surveillance.

What This Means for Patients

The rising incidence of colorectal cancer in young adults has significant implications for patients, healthcare providers, and the healthcare system. Younger patients often face unique challenges including:

• Delayed diagnosis due to low suspicion of cancer
• More advanced disease at presentation
• Treatment-related side effects including sexual dysfunction and infertility
• Substantial financial and psychosocial consequences
• Potential genetic implications for family members

There is an urgent need for increased awareness among both younger patients and healthcare providers about the possibility of colorectal cancer in young adults with gastrointestinal symptoms. Physicians should maintain a higher index of suspicion for colorectal cancer in younger patients presenting with rectal bleeding, abdominal pain, or changes in bowel habits.

Study Limitations

While the evidence for increasing early-onset colorectal cancer is compelling, several limitations in the current research deserve mention. Many studies rely on retrospective data, which may be subject to selection biases and incomplete information.

For risk factor studies, reverse causality can complicate interpretations - body weight measured at study entry may not account for disease-related weight loss before cancer diagnosis. Additionally, abdominal fat distribution may be more important than overall body weight in influencing risk, but this is not consistently measured.

Prospective studies examining early-life exposures in relation to cancer risk are limited, though ongoing initiatives like the Nurses' Health Study 3 and the Colon Cancer Family Registry Cohort study are working to address this gap. The Colorectal Cancer Pooling Project in Europe, which will combine data from over 25 prospective cohort studies, should provide additional insights into potential risk factors.

Patient Recommendations

Based on the current evidence, patients can take several steps to address their risk of early-onset colorectal cancer:

1. Know your family history - Understanding your genetic risk is crucial, especially if you have relatives who developed colorectal cancer at young ages
2. Don't ignore symptoms - Rectal bleeding, persistent abdominal pain, changes in bowel habits, or unexplained weight loss warrant medical evaluation regardless of age
3. Adopt a healthy lifestyle - Reduce consumption of processed meats, sugary beverages, and refined grains while increasing physical activity
4. Follow screening guidelines - Begin colorectal cancer screening at age 45 if at average risk, or earlier if you have risk factors
5. Discuss genetic testing - If diagnosed with colorectal cancer under 50, pursue genetic counseling and consideration of multigene panel testing
6. Advocate for yourself - If you have concerning symptoms, persist in seeking appropriate evaluation even if initially dismissed due to age

Source Information

Original Article Title: Increasing Incidence of Early-Onset Colorectal Cancer

Authors: Frank A. Sinicrope, M.D.

Publication: The New England Journal of Medicine, April 21, 2022

DOI: 10.1056/NEJMra2200869

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine. It preserves all significant data, statistics, and findings from the original scientific publication while making the information accessible to educated patients.