Linking To And Excerpting From JAMA’s “Early-Onset Gastrointestinal Cancers: A Review”

Posted on July 11, 2026 by Tom Wade MD

Today, I review, link to, and excerpt from Journal of American Medical Association (JAMA)‘s “Early-Onset Gastrointestinal Cancers: A Review”. [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. JAMA. 2025 Oct 21;334(15):1373-1385. doi: 10.1001/jama.2025.10218.

All that follows is from the above resource.

Abstract

Importance:

Early-onset gastrointestinal (eoGI) cancer is typically defined as GI cancer diagnosed in individuals younger than age 50 years. The incidence of eoGI cancer is rising globally, and eoGI cancers represent the most rapidly increasing early-onset cancer in the U.S.

Observations:

Worldwide, among eoGI cancers reported in 2022, colorectal cancer (CRC) was the most common (54.3%, 184,709 cases), followed by gastric cancer (23.8%, 80,885 cases), esophageal cancer (13.2%, 45,056 cases), and pancreatic cancer (8.6%, 29,402 cases). In the U.S., among eoGI cancers reported in 2022, 20,805 individuals were diagnosed with eoCRC, 2,689 with eo-gastric, 2,657 with eo-pancreatic, and 875 with eo-esophageal cancer. Most eoGI cancers are associated with modifiable risk factors including obesity, poor-quality diet (e.g., sugar-sweetened beverages, ultra-processed foods), sedentary lifestyle, cigarette smoking, and alcohol consumption. Non-modifiable risk factors include family history, hereditary syndromes (e.g., Lynch syndrome), and inflammatory bowel disease for patients with eoCRC. Approximately 15–30% of eoGI cancers have pathogenic germline variants in genes such as DNA mismatch repair genes and BRCA1/2. All patients with eoGI cancers should undergo germline and somatic genetic testing to guide treatment, screen for other cancers (e.g., endometrial cancer in Lynch syndrome), and assess familial risk. Treatment for eoGI cancers are similar to later-onset GI cancers, and may include chemotherapy, surgery, radiation, and therapies such as poly (ADP-ribose) polymerase inhibitors for BRCA-associated pancreatic cancer. Compared with GI cancers diagnosed after age 50, patients with eoGI cancers typically receive more treatments but often have similar or shorter survival. Specialized centers and multidisciplinary teams can support patients with challenges around fertility preservation, parenting with cancer, financial difficulty, and psychosocial distress. Currently, screening is not recommended for most eoGI cancers, although in the U.S., screening for CRC is recommended for average-risk individuals starting at age 45. High-risk individuals (e.g., those with Lynch syndrome, first-degree relative with CRC or advanced colorectal adenoma) should begin CRC screening earlier, at an age determined by the specific risk factor.

Conclusions and Relevance:

eoGI cancers, typically defined as cancer diagnosed in individuals younger than age 50 years, are among the largest subset of early-onset cancers globally. Treatment is similar to later-onset GI cancers and typically involves a combination of chemotherapy, surgery, and radiation, depending on the cancer type and stage. The prognosis of patients with eoGI cancers is similar to or worse than that of later-onset GI cancers, highlighting the need for improved methods of prevention and early detection.

Keywords: early-onset cancer, pancreatic cancer, gastric cancer, esophageal cancer, colorectal cancer, early-onset colorectal cancer, young-onset colorectal cancer, screening, public health

Introduction

Early-onset gastrointestinal (eoGI) cancers are GI cancers diagnosed in adults younger than age 50 years. From 2010–2019, the age-standardized incidence rate of eoGI cancers in the U.S. increased from 11.49 to 13.65 per 100,000 population, corresponding to an annual percent change (APC) of 2.16% (95% CI, 1.66–2.67%; P<.001) and representing the most rapidly rising type of early-onset cancer. The increasing incidence of early-onset colorectal cancer (eoCRC) led the U.S. Preventive Services Task Force (USPSTF) to lower the recommended age for initiating CRC screening from 50 to 45 years for “average-risk” individuals (described below) in 2021. The increase in eoGI cancers follows a birth cohort effect, with generational variation in risk, suggesting a potential association with changes in environmental exposures.

CRC, pancreatic cancer, and esophagogastric cancer are the most common eoGI cancers, but recent reports also suggest a rising incidence of early-onset appendix, small bowel, biliary tract, and neuroendocrine cancers. However, published data on these rarer eoGI cancers are limited to small, single-center retrospective studies, and are therefore not discussed in this review. Although the incidence of GI cancers has also increased among children and adolescents, this review summarizes current evidence on adults aged 18–49 years with eoCRC, eo-pancreatic cancer, and eo-esophagogastric cancer.

Methods

A PubMed search was performed for English-language clinical trials, meta-analyses, systematic reviews, observational studies, narrative reviews, and guidelines on early-onset CRC, pancreatic, and esophagogastric cancers published between January 1, 2014 and March 7, 2025. We prioritized recent, high-quality original research and excluded studies that did not include individuals aged 18–50 years. Of the 1,693 articles retrieved, 118 were included (1 clinical trial, 6 meta-analyses, 2 systematic reviews, 86 observational studies, 7 narrative reviews, and 16 guidelines). We also used 3 publicly available cancer statistics databases: Surveillance, Epidemiology, End Results (SEER) program of the National Cancer Institute, U.S. Cancer Statistics Data Visualizations Tool, and GLOBOCAN 2022 database version 1.1 from the International Agency for Research on Cancer.,

Early-Onset Colorectal Cancer (eoCRC)

Epidemiology

Although CRC incidence among U.S. individuals of all ages has declined by 1.3–4.2% annually since the mid-1990s, the incidence of eoCRC has increased by approximately 2% annually, and currently represents 14% of all CRC cases. The age-adjusted incidence rate (AAIR) and average annual percent changes (AAPC) of eoCRC from SEER are presented in Table 1. Similarly, while CRC-associated mortality in the U.S. has decreased by 1.7% per year, likely due to increased screening and improved treatments, eoCRC-associated death rates increased by 1% per year (2011–2020). In 2022, among U.S. individuals aged 20–49 years, CRC was the leading cause of cancer-related death among men (2,073 deaths) and the second among women (1,604 deaths). Although lowering the CRC screening age to 45 years may improve early detection and prevention of eoCRC, the steepest increase in annual eoCRC rates are among those under age 40 (4.1 to 5.5 per 100,000 [2013–2022], AAPC 3.4% [95% CI 2.4–3.8]).

Table 1.

Annual Incident Cases of Early-Onset Gastrointestinal Cancers in the U.S. by Sex, with Age-Adjusted Incidence Rates per 100,000 Population Shown in Parentheses (For Year 2022) and Average Annual Percentage Change (AAPC, 2018–2022) as Reported in the SEER Registrya,b

Organ Site Annual Incident Cases and Incidence (per 100,000), for 2022, age <50 years, Female AAPC (95% CI), 2018 – 2022, Female Annual Incident Cases and Incidence (per 100,000), for 2022, age <50 years, Male AAPC (95% CI), 2018 – 2022, Male
Colon and Rectum 4,570 (9.8) 5.1 (3.4 – 4.4) 4,972 (10.5) 3.5 (3.1 – 4.2)
Stomach 826 (1.8) 4.0 (3.5 – 4.9) 772 (1.6) 2.6 (0.3 – 5.8)
Pancreas 688 (1.4) 2.8 (1.1 – 4.7) 636 (1.4) 1.0 (0.6 – 1.5)
Liver and Intrahepatic Bile Duct 361 (0.8) 1.4 (1.0 – 2.0) 594 (1.3) −2.8 (−3.3 to −2.4)
Small Intestine 319 (0.7) 3.5 (3.0 – 4.1) 319 (0.7) 2.6 (2.1 – 3.2)
Esophagusc 91 (0.2) 5.7 (−1.5 – 13.7) 305 (0.7) 1.1 (−1.4 to 4.4)
Anus, Anal Canal, and Anorectum 192 (0.4) −0.6 (−1.2 to −0.1) 178 (0.4) −3.4 (−4.7 to −2.5)
Gallbladder 95 (0.2) 0.8 (−0.1 to 1.8) 28 (0.1) −6.3 (−12.8 to 2.1)

Abbreviations: SEER=Surveillance, Epidemiology, End Results

a This table includes individuals <50 years and is not restricted to 20–49 years due to the availability of data. The data represent nationally representative cancer statistics obtained from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. The table is ordered by declining annual incidence per 100,000, Standardized to the 2000 U.S. Standard Population.
b Positive AAPC values denote an increasing trend in incidence over the time period, while negative values represent a decline.
c Combines esophageal adenocarcinoma and squamous cell carcinoma.

eoCRC incidence is also increasing globally since the 1990s, particularly in high-income countries, including Australia, New Zealand, and South Korea. Worldwide, there were 184,709 new eoCRC cases reported in 2022, representing 40% of all eoGI cancers,, with the largest increases in New Zealand (AAPC 3.97%, 95% CI 2.44–5.52, 2007–2017).

Compared to females, U.S. males have a higher incidence of eoCRC (male-to-female incidence rate ratio of 1.20, 95% CI, 1.18–1.22). Rates are increasing in all racial and ethnic groups. From 2013–2022, AAPC in eoCRC incidence was 5.1% for Hispanics (AAIR 5.5 to 8.9 per 100,000), 3.3% for non-Hispanic Whites (AAIR 7.8 to 10.9), and 4.7% for non-Hispanic Blacks (AAIR 8.2 to 10.4). Compared to later-onset CRC, patients with eoCRC are more likely to be Black (15% vs. 11%) or Hispanic (9% vs. 5%) than White (70% vs 80%).

Risk Factors

Modifiable risk factors associated with eoCRC (Table 2) include exposure to carcinogens such as cigarette smoke and alcohol, and certain dietary and lifestyle exposures starting in early life such as processed meat, sugar-sweetened beverages,– obesity, and sedentary behavior. In the Nurses’ Health Study (NHS) II prospective cohort of 29,474 women, individuals in the highest quintile of Western dietary pattern, including intake of processed meat (e.g., canned meat, sausages), red meat, butter, high-fat dairy products (e.g., heavy cream, desserts), eggs, and refined grains (e.g., white bread, white rice), had a significantly increased risk of early-onset high-risk colorectal adenomas, with 300 cases identified in the highest intake group compared to 183 in the lowest (odds ratio, OR, 1.67, 95% CI, 1.18–2.37). Among 95,464 women in the NHS II prospective cohort, consumption of ≥2 servings/day of sugar-sweetened beverages was associated with a higher risk of eoCRC compared with <1 serving/week (16 cases per 138,469 person-years vs 45 cases per 536,446 person-years; relative risk, RR 2.18, 95% CI, 1.10–4.35). Conversely, among 116,429 women in NHS II, higher total vitamin D (dietary and supplemental) intake (≥450 vs <300 IU/day) was associated with a lower risk of eoCRC (27 cases per 406,189 person-years vs 64 cases per 528,107 person-years; hazards ratio, HR, 0.49, 95% CI, 0.26–0.83).

Table 2.

Screening Recommendations and Modifiable Risk Factors for Early-Onset GI Cancers (diagnosis at age <50 years)a,b

Early-Onset Colorectal Cancer Early-Onset Pancreatic Cancer Early-Onset Esophagogastric Cancer
Screening Recommendations While some countries, such as Austria and Italy, start screening at age 40 years, and the U.S. at age 45 years (USPSTF guidelines), most other countries start screening at age 50 years. Recommendations vary by region and risk factors.d Both U.S. (American College of Gastroenterology, American Gastroenterology Assocation) and international guidelines (International Cancer of the Pancreas Screening Consortium) recommend screening only for high-risk individuals (e.g., inherited genetic syndromes, familial pancreatic cancer), with age varying by risk factors (e.g., begin at age 50 years, or 10 years younger than the initial age of familial onset; age 40 years in CKDN2A and PRSS1 gene variant carriers with hereditary pancreatitis; age 35 years with Peutz–Jeghers syndrome) Routine EGD screening for eoEGC is not currently performed in most countries. However, in South Korea, biennial screening for gastric cancer with EGD or upper gastrointestinal series begins at age 40 years. The American College of Gastroenterology recommends a single screening EGD for individuals with chronic GERD symptoms and at least 3 of the following risk factors: male sex, age >50 years, White race, tobacco use, obesity, and family history of Barrett’s esophagus or esophageal adenocarcinoma in a first-degree relative. Taipei Global Consensus guidelines endorse mass screening and eradication of H. pylori in individuals aged 20–40 years in regions with a high incidence or high risk of gastric cancer.
Associated Risk Factors and RR/OR/HR (95% CI) e
Diet Sugar sweetened beverages
RR 2.18 (1.10–4.35), P=0.02;
Sugar sweetened beverage consumption ≥2 servings/day vs. <1 serving/wk		 Not available Beef and canned, smoked, and salted food
OR 2.1 (1.3 – 2.8)
Western pattern diet
OR 1.67 (1.18 – 2.37), P<0.03;
For high-risk adenomas (highest vs. lowest quintile for Western diet score)		 Not available Not available
Obesity (BMI >30 kg/m2) Obesity
OR 1.88
(1.40 – 2.54)		 Obesity
OR 1.85
(1.19 – 2.88)		 Obesity
OR 1.7
(1.5 – 2.0)
Alcohol Alcohol consumption
RR 1.71 (1.62 – 1.80);
Highest defined category in studies compared with never drinkers		 Not available Alcohol consumption
OR 2.0 (1.3 – 2.6)
For alcohol consumption vs. none
Physical activity Sedentary behavior
RR 1.69
(1.07 – 2.67), P=0.03
Television viewing >14 hours/week vs. <7 hours		 Physical activity (protective)
HR 0.25 (0.07 – 0.93)
For active vs. inactive participants per study criteria		 Not available
Smoking Smoking
OR 1.33 (1.17 – 1.52)
Current smoker vs. nonsmoker		 Smoking
HR 1.84 (1.29 – 2.62)
Ever smoker vs. nonsmoker		 Smoking
OR 1.5 (0.6 – 2.3)
Smoker vs nonsmoker
Metabolic dysfunction-associated steatotic liver disease (referred to as nonalcoholic fatty liver disease in study)
(Fatty liver index > 30)		 Non-alcoholic fatty liver disease
HR 1.14 (1.06 – 1.22)		 Non-alcoholic fatty liver disease
HR 1.23 (1.09 – 1.40)		 Non-alcoholic fatty liver disease
HR 1.14 (1.06 – 1.24)
Infection Not available Not available H. pylori
OR 2.3 (1.4 – 3.2)
Others Hyperlipidemia
(high levels of fat – cholesterol and triglycerides in the blood)
RR 1.61 (1.22–2.13)		 Not available Not available
Being breastfed as an infant
OR 1.46 (1.16 – 1.83) for high risk adenomas
Breastfed in infancy vs. non-breast fed		 Not available Not available
Total vitamin D intake including dietary and supplemental intake (protective)
HR 0.49 (0.26 – 0.83)
≥450 IU/day vs. <300 IU/day		 Not available Not available

Abbreviations: OR=odds ratio; RR=relative risk; HR=hazard ratio; BMI=body-mass index; USPSTF= U.S. Preventive Services Task Force; EGD=esophagogastroduodenoscopy; GERD=gastroesophageal Reflux Disease

a Preference was given to high-quality meta-analyses and large prospective cohort studies where available. Definitions of terms are included where available.
b Early-onset defined as age at diagnosis <50 years; later-onset defined as age at diagnosis >50; unless otherwise noted.
c The incidence is without screening for majority of the population since the U.S. screening guidelines for eoGI cancers in average-risk individuals apply only to patients with CRC in the 45–49 age group.
d Individuals without a personal history of CRC, inflammatory bowel disease, hereditary CRC syndromes, other CRC predisposing conditions, or a family history of CRC.
e OR, RR, and HR apply to groups with vs. without exposure to risk factors, unless otherwise specified. Definitions per the referenced studies are included where available. The risk factors are ordered by numerical value (descending) for eoCRC and prioritizing those with the most data across cancers.
Obesity, an established CRC risk factor, may be contributing to increasing eoCRC rates given the rising prevalence of both childhood and adult obesity worldwide., Proposed mechanisms of adiposity-induced carcinogenesis include chronic inflammation and insulin resistance, among others. In a meta-analysis of 12 studies with 242,561 participants aged ≤55 years, the OR for eoCRC was 1.32 (95% CI, 1.19–1.47) among individuals with overweight (BMI 25–29.9 kg/m2) and 1.88 (95% CI, 1.40–2.54) with obesity (BMI >30 kg/m2), vs. those with BMI <25 kg/m2. Moreover, childhood and adolescent obesity (HR 1.53; 95% CI, 1.17–2.0) and maternal obesity (HR 2.51, 95% CI, 1.05–6.02) are also associated with increased eoCRC risk.

 

 

 

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