Reviewed by:
MDChar et al., BJS 2025
https://doi.org/10.1093/bjs/znaf102
This comprehensive review by Char et al. provides a timely and valuable synthesis of the rapidly evolving field of early-onset gastrointestinal (EO GI) cancers.
Early-onset gastrointestinal (EO GI) cancers, defined as cancers diagnosed before the age of 50, have shown a significant and alarming increase worldwide, particularly in colorectal cancer (CRC), oesophagogastric cancer (OGC), and pancreatic cancer (PC). This trend exhibits a birth cohort effect, suggesting environmental and lifestyle factors such as obesity, Western-pattern diet, sedentary behavior, smoking, and alcohol use as potential contributors, although the precise causal mechanisms remain unclear. EO GI cancers disproportionately affect racial and ethnic minorities including Black, Hispanic, Indigenous, and Asian populations, and frequently present with more aggressive clinical and molecular features compared to average-onset (AO) GI cancers.
Germline pathogenic variants (gPVs) are more common in EO GI cancers than in AO GI cancers, with Lynch syndrome genes predominating in EO CRC and homologous recombination gene mutations (e.g., BRCA1/2, ATM) in EO PC. Despite a higher prevalence of these genetic predispositions, most EO GI cancer cases are sporadic and linked to modifiable risk factors. EO GI cancer patients often present at more advanced stages due to delayed diagnosis and experience unique psychosocial challenges, including fertility concerns, financial toxicity, and quality-of-life impairments.
Treatment guidelines for EO GI cancers largely mirror those for AO cancers, though younger patients tend to receive more aggressive therapies without consistent survival benefits. Recent clinical trials have investigated treatment de-escalation strategies, especially for rectal cancer, to mitigate treatment-related toxicities important for younger patients’ quality of life. Survival outcomes vary by cancer type and stage, with racial and socioeconomic disparities influencing prognosis. Screening guidelines have begun to adjust, such as lowering CRC screening age from 50 to 45 in the United States, but adherence remains suboptimal, especially among vulnerable populations.
Rare EO GI malignancies, including appendiceal cancers, neuroendocrine tumors (NETs), and biliary tract cancers, are also increasing in incidence. These often have distinct clinical and molecular features, emphasizing the need for detailed histological characterization in epidemiological studies. Future directions call for multidisciplinary research using multi-omics approaches integrating genomic, epigenomic, metabolomic, microbiome, and lifestyle data to unravel the etiologies of EO GI cancers. Specialized centers focusing on young patient needs—including fertility preservation, psychosocial support, and genetic counseling—are crucial for comprehensive care.
Char et al.'s review aligns well with and builds upon recent key findings:
1. EO-CRC Disparities: Confirms and extends findings like Demb et al. (JAMA Netw Open, 2024) showing significant racial survival disparities in EO-CRC persisting after adjusting for stage and treatment. Nogueira et al. (JCO, 2024) adds that Black EO-CRC patients are less likely to receive guideline-concordant care.
2. Molecular Landscape: Supports Varghese et al. (JNCI, 2021) and Castet et al. (EJC, 2023) on distinct molecular features in EO PC (more gPVs, KRAS WT, targetable fusions). Recent studies (e.g., Jayakrishnan et al., JCO PO 2024) now highlight FGFR2 fusions as enriched and therapeutically relevant in EO biliary cancers.
3. Treatment Intensity & Outcomes: Reinforces observations like Kneuertz et al. (JAMA Surg, 2015) and Cercek et al. (JNCI, 2021) that aggressive treatment in EO-CRC doesn't consistently yield superior survival, especially in the very young (35). The ORCHESTRA trial (Gootjes et al., JCO 2024 - post-review) adds nuance, showing no OS benefit from aggressive local therapy in multi-metastatic CRC, relevant to EO patients often receiving such approaches.
4. Rising Rare Cancers: Corroborates Koh et al. (JAMA Netw Open, 2023) and Abboud et al. (JAMA Oncol, 2025) on dramatic increases in appendiceal NETs and EO GEP-NETs. Bleyer et al. (JNCI, 2025 preprint) specifically attributes much of the rise in "young colon cancer" incidence to reclassified appendiceal NETs.
5. Screening & Early Detection: Echoes the urgent need for improved strategies highlighted by Shaukat & Levin (Nat Rev Gastro Hepatol, 2022). Recent data (Pilonis et al., Gastroenterology 2021; Quintero et al., NEJM 2021) support FIT as a viable alternative to colonoscopy, crucial for improving adherence in younger populations, which the review mentions.
6. Survivorship: Fletcher et al. (JCO OP, 2024) qualitatively detail the unmet needs of EO-CRC patients (isolation, system overwhelm, desire for research participation), strongly supporting the review's call for specialized care models.
Areas Where the Review Could Be Enhanced by Latest Data:
1. Microbiome: Emerging studies (e.g., Wirbel et al., Cell 2024 - B. fragilis enterotoxin) provide more concrete mechanistic links between specific microbes, diet, and CRC pathogenesis, relevant to the "environmental factors" hypothesis for EO-GI cancers.
2. Non-Invasive Screening: Blood-based mt-sDNA tests (e.g., Shield) are gaining traction beyond FIT/stool DNA-FIT, warranting mention in future screening discussions.
3. Refined Risk Stratification: Studies exploring polygenic risk scores combined with environmental factors for EO-CRC risk prediction are emerging.
4. Oligometastatic Disease: While METAPANC is mentioned for PC, data on local ablative strategies in oligometastatic EO GI cancers (beyond CRC liver mets - TransMet trial cited) are evolving rapidly.
Overall Assessment & Conclusion:
Char et al. deliver an exceptionally valuable, comprehensive, and timely review of EO GI cancers. Its major strengths lie in its breadth, consolidation of epidemiological and clinical comparison data across multiple cancer types, emphasis on disparities and unique patient challenges, and clear articulation of future research and care imperatives. While naturally limited by its narrative format in providing deep critical appraisal of every cited study or exploring the most cutting-edge molecular mechanisms in detail, it serves as an outstanding foundational reference and call to action for the field. It accurately reflects the current state of knowledge (as of early 2025) and aligns well with the latest high-impact studies. This review is essential reading for clinicians, researchers, and policymakers focused on understanding and addressing the growing challenge of early-onset gastrointestinal cancers. Future updates will need to incorporate rapid advances in molecular understanding, novel therapeutic strategies leveraging EO-specific biology, and real-world outcomes from evolving screening and survivorship programs.
Dr.
,General Surgeon and Founder of Surgical Pioneering Newsletter and Series#gastrointestinalcancers #early-onsetcancer #gicancerreview #cancerepidemiology #youngadultscancer #gastrointestinaltumor #cancerdiagnosis #cancertreatment #cancergenetics #cancerresearch #oncology #earlydetection #futurecancertherapies #gastrointestinaloncology #cancerprognosis #surgicalPioneering #SurgicalPioneeringPodcast #surgicalinnovation #Dr.RezaLankarani #RezaLankarani #RezaLankaraniMD
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