Catching pancreatic cancer early: the promise of affordable biomarkers to regularly screen high-risk individuals

The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, has been increasing globally and regionally over the last 30 years and more, with substantial rises in case numbers and disease burden. According to the most comprehensive data to date which tracks a long-term period ranging from 1990 and 2021, global pancreatic cancer cases more than doubled from approximately 208,000 to over 508,000 annually, with the age-standardized incidence rate (ASIR) increasing modestly from 5.47 to 5.96 per 100,000 population (1,2). Furthermore, mortality rates similarly rose, with deaths increasing from around 212,000 to over 505,000 and the age-standardized mortality rate (ASMR) showing a slight increase from 5.655 to 5.948 per 100,000 (1,2). The longitudinal data collected from an extensive 25-year period from 1992 to 2017 reveal that incidence, prevalence, and mortality of pancreatic cancer increased by approximately 55%, 63%, and 53%, respectively (3). Of note, the near-equivalence of incidence and mortality indicates remarkably high short-term fatality. Furthermore, projections suggest that pancreatic cancer deaths worldwide may nearly double by 2050, reflecting an escalating clinical and societal burden (3). In the US, invaluable 10-year trend data (2009–2018) from the Surveillance, Epidemiology and End Results (SEER) program indicate that the overall age-adjusted pancreatic cancer incidence rate was roughly 13.0 per 100,000 population (4). Incidence rates increased across nearly all racial/ethnic groups for both males and females, except for Black males, whose rates remained stable, and American Indian/Alaska Native females, whose rates slightly decreased (4). The latest SEER data analysis, covering an extensive 21-year period (2000 to 2021), showed that 87% of PDAC cases had occurred in the senior group aged than 55 years (5), highlighting the importance of aging and its related factors for high PDAC incidence. The mortality in senior populations closely mirrors incidence, with PDAC causing substantial cancer-related deaths among elderly adults in the US, especially the 75-84 age group experiences the highest number of deaths because of the advanced stage of the disease in seniors associated with age-related factors such as weak immunity as well as tumor biology and treatment resistance (6,7).

PDAC remains extremely lethal with a current average 5-year overall survival rate around 13% and is often incurable despite technological advancement and countless research efforts over the past six decades. The survival rate of PDAC continues to be the lowest of any major cancer. According to American Cancer Society published in January 2026, the 5-year relative survival rates for PDAC are: 44% for localized PDAC, 17% for regional PDAC which cancer cells have spread to nearby tissues and/or lymph nodes, and 3% for distant PDAC with metastases in the distant organs. With the majority of PDAC cases that were initially diagnosed as advanced diseases, especially in seniors, it signals the necessity of early detection to effectively intervene in PDAC progression and significantly maximize patients’ survival chance. The pancreas is deeply buried inside the body and protected under the rib cage, making it impossible to regularly examine during physical checkups. Early development of PDAC often progresses silently with minimal or absent pain, which contrasts sharply with the severe pain commonly experienced in advanced stages. The silence of pain at the early stage involves complex modulation of nerve-tumor interactions within the microenvironment, alteration of neuronal signaling and prevention of pain transmission despite tumor growth until advanced stage with nerve invasion (8,9). Recent genome-wide and molecular studies suggest that the earliest oncogenic mutations in PDAC can occur approximately 20 years before clinical symptoms arise (10-12). This long latency period implies a substantial window for early detection and intervention before the disease becomes symptomatic and clinically evident.

Early detection of PDAC at its early stage drastically increases patients’ chances of survival as numerous treatment options/strategies can be applied to destroy abnormal pancreatic epithelial cells and tumor cells completely and effectively while still with a partially functional pancreas. This is particularly crucial, especially in the major high-risk population: senior individuals aged older than 55 years as their weaker immune system and other age-related factors such as decreased organ functions restrain cancer treatment options. Similarly, in other high-risk groups including individuals with diabetes and familial pancreatitis, the medicines for these diseases can interact with PDAC cancer drugs which can increase risks or reduce treatment efficacy. From the cancer therapy affordability aspect, cancer treatment costs do create severe personal financial toxicity and enormous economic burdens on society, and treatments for early stage PDAC are significantly cheaper than those for the advanced disease. Furthermore, the financial distress to pay off the required cancer therapy can further attenuate individuals’ immunity leading to unfavorable outcomes for PDAC patients.

The diagnostic landscape for PDAC remains a field of high stakes and narrow windows, where the disease’s typically late presentation and aggressive progression render early detection an elusive, yet vital, goal. However, recent advances move the field toward a multi-modal paradigm that integrates artificial intelligence (AI), advanced imaging, and sophisticated biomarkers. Within this framework, emerging molecular biomarkers offer a critical breakthrough by identifying PDAC at precancerous or early stages, which effectively addresses the diagnostic gap left by conventional tools that often fail to catch the disease while it is still resectable (13,14). These biomarkers include microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and circulating apolipoprotein A2 isoforms present in the peripheral blood or plasma samples. Other biomolecules in body fluids, including exosomes, metabolites, and molecular signatures in urine, saliva, and feces, are increasingly being studied as potential non-invasive diagnostic tools for early PDAC (15). Despite these advances, many of these biomarkers require large-scale, rigorous validation before routine clinical implementation.

In the current study entitled “Validation of two plasma multi-metabolite signatures for patients at risk of or with suspected pancreatic ductal adenocarcinoma (METAPAC): a prospective, multicentre, investigator-masked, enrichment design, phase 4 diagnostic study” by Mahajan et al., it represents a significant leap forward in the quest for early detection of PDAC through metabolomic signatures (16). Mahajan et al. successfully validated two plasma-based metabolic signatures: the comprehensive 12-analyte i-Metabolic and the streamlined m-Metabolic, as robust tools for early diagnosis of PDAC. Most notably, both signatures demonstrated a high specificity over 90% for all tumor stages, significantly outperforming the current clinical standard marker, carbohydrate antigen (CA) 19-9, which often fails to identify resectable disease and produces excessive false positives in benign conditions. For patients with resectable disease, the m-Metabolic signature that is constituted of ceramide (d18:1, C24:0), lysophosphatidylethanolamine (C18:0), phosphatidylethanolamine (C18:0, C22:6) and sphingomyelin (d17:1, C16:0) along with CA19-9 achieved a specificity of 93.6% and 79% accuracy, offering a highly reliable negative predictive value that could effectively reduce the need for unnecessary invasive procedures in high-risk individuals. This streamlined approach is particularly promising for clinical translation by utilizing a single, cost-effective liquid chromatography-tandem mass spectrometry run, and it maintains robust diagnostic performance across various comorbidities while simplifying laboratory implementation.

Despite these impressive results, a critical appraisal illuminates that the study’s enrichment design relied on a cohort with a 20% PDAC prevalence, which requires careful projection to broader “real-world” populations where the annual risk is closer to 1%. Mahajan et al. noted a recruitment bias toward surgical centers and data gaps caused by the coronavirus disease 2019 (COVID-19) pandemic, which may limit the immediate generalizability of these findings to non-surgical or primary care settings. Furthermore, while a proof-of-concept analysis suggested the m-Metabolic signature could identify PDAC in individuals with new-onset diabetes, the exploratory nature of this sub-analysis requires further prospective testing in larger, dedicated cohorts. To address these current gaps, results from larger initiatives such as UK-EDI trial and the US Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer are urgently needed. Upon integration of these metabolites—particularly m-Metabolites along with CA19-9, due to their high specificity and affordability—into routine clinical practice would offer an excellent opportunity to reduce PDAC mortality. Implementing this as part of annual physical examinations for high-risk groups, such as seniors aged 55 and older and patients with diabetes, could significantly improve early detection. It is also crucial to include this regular screening for these seniors as part of standard preventive care services—fully covered by medical insurance—to truly achieve early detection since other alternative screening methods are either too expensive or too invasive (Table 1). Meanwhile, more research studies are needed for investigating efficient treatment options/strategies in aging animal models of PDAC to specifically combat the encountered drug resistance/toxicity commonly in seniors with PDAC. It is also crucial to continue developing other potential screening tools, such as circulating pancreatic epithelial cells (CECs) in the bloodstream. These cells are shed from PDAC precursor lesions, including intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasms (PanINs). Advancing these tools will not only lower early detection costs via market competition but also catch PDAC development immediately after initiation which can drastically reduce required treatment duration and dosage.

Acknowledgments

The author gratefully acknowledges the protected research time and career development support provided by the SC1 Research Enhancement Award. Additional administrative and infrastructural support was graciously provided by the Research Capacity Core of the RCMI program at CAU.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0064/prf

Funding: This work was partially supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Heath under award number SC1GM140907 (to G.Y.L.) and by the National Institute on Minority Health and Health Disparities (NIMHD) through the Research Centers in Minority Institutions (RCMI) Program under award number U54MD007590. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0064/coif). The author has no conflicts of interest to declare.

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