Critically appraising the existing evidence, this work identifies key knowledge gaps, such as the understudied sporadic EOPC subgroup and the lack of dedicated clinical trials, and proposes future research directions to inform early detection and optimize therapeutic strategies for this unique patient population.
Abstract
The incidence of early‐onset prostate cancer (EOPC) is rising, and by 2045 a 24.5% increase in cases and a 50% rise in mortality are projected. Accumulating evidence indicates that EOPC represents a distinct disease entity, characterized by unique molecular features, risk factor profiles, and clinical behavior that differ from standard‐onset prostate cancer (SOPC). Nevertheless, research in this field remains nascent, and no consensus exists regarding the optimal management of EOPC. We synthesize current evidence on the epidemiology, molecular pathology, clinicopathological characteristics, survival, management, and early detection of EOPC. EOPC exhibits a distinctive molecular landscape, with TMPRSS2–ERG fusions occurring in 63–90% of cases as a hallmark alteration, whereas mutations in PTEN, SPOP, and CHD1 are significantly less frequent. Notably, the prevailing focus on hereditary EOPC has inadvertently led to the neglect of sporadic cases, which dominate clinical practice. Although localized EOPC confers no significant prognostic advantage over SOPC, high‐risk or metastatic early‐onset disease substantially elevates prostate‐cancer‐specific mortality. By critically appraising the existing evidence, we identify key knowledge gaps, such as the understudied sporadic EOPC subgroup and the lack of dedicated clinical trials, and propose future research directions to inform early detection and optimize therapeutic strategies for this unique patient population.
Current evidence on early-onset colorectal cancer epidemiology, biology, clinical presentation, screening, and treatment is summarized, and emerging directions including liquid biopsy, artificial intelligence, and microbiome-based strategies are highlighted.
Ahmed Sohaib, Ashwaq Salami, Wesal Alghwyeen et al.· Integrated Oncology Diagnost...· 0 citations
Esophageal Cancer: Other
Early onset gastric cancer (EOGC), defined as diagnosis before 55 years, represents a growing global health challenge. Although traditionally rare, its incidence is rising and now constitutes the second most common early onset gastrointestinal malignancy after colorectal cancer. EOGC has been hypothesised to reflect distinct biology, yet risk factors, clinicopathological features and survival outcomes remain poorly synthesised. We aimed to evaluate global evidence on EOGC and, where possible, compare findings with late onset gastric cancer to determine whether EOGC represents a distinct clinical entity with implications for earlier diagnosis and targeted prevention strategies.
A systematic review and meta-analysis was conducted according to PRISMA guidelines. PubMed, Embase and Scopus were searched from inception to 20 June 2025. After deduplication, titles, abstracts and full texts were screened for eligibility. Studies were included if they reported EOGC (<55 years) as a distinct cohort and provided extractable data on risk factors, clinicopathological characteristics or overall survival. Comparative late-onset cohorts were included when available. Case reports, reviews, studies without age stratification, mixed-malignancy cohorts and studies lacking sufficient numerical data were excluded. Non-English studies were excluded unless reliable translation was possible. Effect estimates were extracted or calculated, and pooled using random-effects models. Heterogeneity was assessed using I2 statistics. Survival proportions were synthesised where comparable time points could be extracted.
Ninety-one studies comprising 30,067 EOGC patients were included. EOGC showed a significant female predominance globally (53.3% vs 46.7%; p < 0.0001), and women were more likely to have EOGC than late-onset disease (OR 1.50, 95% CI 1.45–1.56). Significant associations were identified for Helicobacter pylori (OR 4.12, 2.37–7.18), family history (OR 4.02, 3.03–5.36), high salt intake (OR 2.06, 1.44–2.94) and obesity (OR 1.81, 1.58–2.07), while smoking and alcohol were not associated. Diffuse-type and signet-ring morphology were prominent (38.9%). EOGC more frequently presented at advanced stage than late-onset cancer (52.5% vs 45.9%; p < 0.0001). Pooled overall survival was 78.0% at 1 year, 51.1% at 3 years and 43.0% at 5 years, with no significant difference compared with late-onset disease (OR 1.08, 0.39–2.97; p = 0.88). Distal gastric cancers predominated across all global regions, but the highest burden of proximal tumours was observed in East and South-East Asia.
EOGC exhibits a distinct clinicopathological and risk-factor profile, characterised by strong associations with H. pylori, family history, high-salt diet and obesity, alongside a high burden of diffuse and signet-ring histology. Despite younger age, advanced-stage presentation is common and long-term survival remains poor, with outcomes comparable to older adults. These findings indicate that youth does not confer prognostic advantage and support the need for targeted prevention, earlier recognition and tailored research efforts focused on gastric cancer in younger populations.
Unaiza Waheed, Abigail Burn, A. Ribbits et al.· Diseases of the esophagus· 0 citations
Pancreatic cancer is one of the most aggressive malignancies worldwide, and the incidence is increasing in patients under the age of 50. We systematically reviewed the clinicopathological features of early-onset pancreatic cancer (EOPC) and late-onset pancreatic cancer (LOPC) to help develop tailored therapeutic strategies and earlier diagnosis for younger patients. A total of 21 studies involving 1,813,719 patients were included, comprising 139,554 patients with EOPC and 1,674,165 with LOPC. EOPC was more commonly associated with tumors in the pancreatic tail, poor or undifferentiated histology, lymph node involvement, and abdominal pain at presentation, whereas LOPC more frequently involved tumors in the pancreatic head. No significant differences were observed between EOPC and LOPC in tumor resectability, surgical resection rates, or the prevalence of jaundice, cachexia, and diabetes mellitus. Overall, EOPC demonstrated a distinct clinicopathological phenotype characterized by more aggressive pathological features and advanced nodal disease, emphasizing the need for age-specific pancreatic cancer management.
M. Alzoubi, Rahaf Al Jibarat, A. O. Saleh et al.· iScience· 0 citations
PURPOSE The incidence of early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before age 50 years, has been rising globally, in contrast to declining rates in older populations. However, despite its distinct clinical features, the genomic characteristics of EOCRC and its biological relationship to average-onset CRC (AOCRC) remain incompletely defined, particularly in the metastatic setting. METHODS We conducted a genomic analysis of patients with metastatic CRC who underwent next-generation sequencing (NGS) as part of routine clinical practice. Using targeted NGS panels (TruSight Oncology 500 and Oncomine Comprehensive Assay), we analyzed the genomic landscape of 1,892 patients, including 376 with EOCRC and 1,516 with AOCRC. Genomic alteration frequencies were compared between age groups, and age-stratified analyses were performed to evaluate associations between patient age and recurrent genomic alterations. RESULTS The overall genomic landscape was largely similar between EOCRC and AOCRC, with comparable frequencies of canonical CRC drivers, including TP53, APC, and KRAS. MYC alterations were significantly more frequent in EOCRC than in AOCRC. By contrast, age-stratified analyses revealed an inverse association between age at diagnosis and alteration rates in specific DNA damage repair–related genes and tumor suppressor genes, including BRCA2, BARD1, FAT1, HIST1H1C, and LRP1B, whereas canonical drivers showed no significant age-dependent trends. CONCLUSION In metastatic disease, EOCRC shares a conserved canonical genomic backbone with AOCRC, indicating that it is not a genomically distinct entity. Nevertheless, limited binary differences involving MYC and broader age-dependent enrichment of specific DNA damage response–related alterations suggest that CRC arising at younger age may reflect distinct age-associated biological vulnerabilities.
J. Shin, Eunbyeol Lee, Yun-Ha Sang et al.· JCO Precision Oncology· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) remains a significant global health burden, projected to become the second leading cause of cancer-related mortality in the Western world by 2030. Due to the lack of effective population-wide screening methods, targeted surveillance of high-risk individuals-those with a lifetime risk exceeding 5-10% based on family history or pathogenic germline variants-represents the most viable strategy for early detection. Current surveillance protocols utilize endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) to identify potentially curable T1N0M0 tumors or high-grade precursor lesions. Clinical evidence demonstrates that these programs significantly improve outcomes, increasing the detection of stage I tumors and raising 5-year overall survival rates from 9% to 50%. This editorial emphasizes that the future effectiveness of PDAC prevention lies in refined risk stratification through universal germline testing, the integration of polygenic and environmental data, and the provision of comprehensive psychosocial support to manage the emotional impact of surveillance.
D. Campa, C. Rizzato, A. Kataki et al.· Revista Espanola de Enfermed...· 0 citations
Abstract Background The rising incidence of young-onset cancers is a global public health concern. From 2010-2019, eoRCC had the third largest increase after breast and colorectal cancers. However, molecular drivers and survival implications for eoRCC remain unclear. This analysis compares somatic, germline, immune, transcriptomic, and clinical features of eoRCC vs. typical-onset RCC (toRCC) using a multi-omic real-world dataset. Methods The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the multimodal de-identified database to identify RCC patients (pts) with xT (DNA) and xR (RNA) sequencing with tumor purity ≥30%. Pts with clear cell RCC (ccRCC; n = 1,842), papillary RCC (pRCC; n = 242), and chromophobe RCC (chRCC; n = 117) were stratified by age at diagnosis as eoRCC (18 to ≤ 46 years) and toRCC (>46 years). Demographic, clinical, somatic, germline genomic features, and transcriptomic profiles were compared. Tumor immune infiltration was inferred from the transcriptomic RNAseq data (quanTIseq). Differential gene expression and pathway enrichment used log2 (TPM+1) normalized RNA-seq data against Hallmark and GOBP gene sets. Results Among pts with ccRCC (eoRCC: n = 211, 11.5%; toRCC: n = 1,631, 88.5%), pts with eoRCC were more often Black/African American (8.7% vs. 3.8%, p = 0.029) and Hispanic/Latino (32% vs. 17%, p < 0.001) compared to pts with toRCC. Germline alterations occurred in 11.3% eoRCC pts and 7.3% in toRCC (q = 0.5), with no age-enriched variants. Early-onset ccRCC had lower somatic alteration rates in PBRM1 (21% vs. 43%, q < 0.001), SETD2 (13% vs. 25%, q < 0.001), and KDM5C (6% vs. 12%, q = 0.025), while VHL alteration rates were identical (76%). Transcriptomic profiling revealed upregulation of hypoxia- and VEGFR-signaling pathways in early-onset ccRCC (q < 0.05). In contrast, immune-related pathways (IFNgamma/IFNalpha, IL6/JAK/STAT) and cell cycle regulators (E2F, mTOR) were downregulated (q < 0.05). Immune cell composition analysis indicated reduced infiltration of M1 macrophages in eoRCC vs. toRCC (p = 0.003). Among pts with pRCC (eoRCC: n = 35, 14.5%; toRCC: n = 207, 85.5%) and chRCC (eoRCC: n = 28, 23.9%; toRCC: n = 89, 76.1%), baseline characteristics were similar, and no significant differences in somatic or germline alterations or immune cell infiltration were observed. However, in the chRCC cohort, the oxidative phosphorylation pathway was upregulated in eoRCC, with concomitant downregulation of the epithelial-mesenchymal transition pathway (q < 0.05). In the pRCC cohort, oxidative phosphorylation was downregulated in eoRCC (q < 0.05). Conclusions Age-stratified analysis showed that among patients with ccRCC, eoRCC has distinct features with more non-white racial/ethnic groups. Early-onset ccRCC is associated with distinct biological phenotypes, exemplified by upregulation of the hypoxia/VEGF pathway and downregulation of immune, inflammatory, and cell cycle pathways. These hypothesis-generating findings highlight potential age- and histology-specific therapeutic targets and the need to explore age-adapted treatment strategies for this unique and growing population.
H. Ebrahimi, S. Haake, M. Weitz et al.· The Oncologist· 0 citations
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