Modifiable risk factors for pancreatic cancers: an editorial commentary

Introduction

Pancreatic cancer incidence is rising globally, and it remains one of the most fatal cancers (1). Thus, identification of modifiable risk factors is an important strategy to curb its development and reduce the overall burden from the cancer. A recent article by Peila and colleagues in Cancer Epidemiology, Biomarkers, & Prevention explored risk factors for pancreatic cancer development in the Women’s Health Initiative (WHI) study (2). We have been invited to provide commentary on this work and discuss future directions for research to better understand risk factors and potential risk-reduction strategies for pancreatic cancer.

Brief epidemiology of pancreatic cancer

The incidence of pancreatic cancer is rising globally across many demographic groups (1). There has been a 14% increase in incidence rates over the past 30 years (1,3). Pancreatic cancer affects approximately 500,000 individuals worldwide annually (1,3). It is one of the deadliest cancers globally in terms of mortality-to-incidence ratios, with nearly 450,000 people succumbing to the disease each year (1,3-5). Overall, about 90% of people with pancreatic cancer will die of the disease within 5 years of diagnosis (4-6). While advancements in cancer detection and treatment have improved survival of other gastrointestinal cancers in the previous two decades, progress in lengthening pancreatic cancer survival has been minimal (4,6). While progress in early detection and treatment is important for improving survival, etiologic research is necessitated for reducing the occurrence and death of this lethal disease.

Overview of risk factors for pancreatic cancers

Tobacco use, type 2 diabetes, chronic pancreatitis, and obesity or excess body fat are known risk factors for pancreatic cancer (5,7). Data from the Global Disease Burden project indicate that approximately 21% of pancreatic cancer deaths are attributable to cigarette smoking, 9% to glucose dysregulation, and 6% to obesity (3). Evidence also suggests a link between moderate-to-heavy alcohol use and pancreatic cancer risk with potential synergistic effects with cigarette smoking (8). The relationship between dietary factors and pancreatic risk is less clear, although data suggests a link between red meat intake and cancer risk (7). These modifiable risk factors are similar to those for other gastrointestinal cancers. For example, cigarette smoking and alcohol use have been identified as major contributors to oral cavity, throat, esophageal, gastric, and liver cancer (9). Additionally, the associations between obesity or increased central adiposity and diets high in processed foods and saturated fats and low in fiber and fruit and vegetable intake have been linked to increased risk of esophageal, gastric, and colorectal cancers (10-12). Specific health behaviors can have independent or synergistic effects on cancer risk, and individuals often exhibit more than one risk-associated behavior. On the other hand, other biologic factors such as age, sex, genetics, and prior infections especially with Helicobacter pylori (H. pylori) may contribute to the development of gastrointestinal cancers, and not all cancers develop in persons with the identified modifiable health behaviors (4,5), making it challenging in untangling intricate etiologic effects of factors.

Peila and colleagues’ study on risk factors for pancreatic cancer among participants in the WHI

A recent study published in Cancer Epidemiology, Biomarkers, & Prevention investigated pancreatic cancer risk factors among women enrolled in the WHI, a well-known cohort with detailed data on postmenopausal women with extensive follow-up (2,13). The study by Peila et al. included 40,205 women enrolled into the observational and clinical trial arms of the WHI study between 1993 and 1998 who self-reported no smoking or alcohol use at enrollment and with follow-up for pancreatic cancers until 2023 (2). The WHI data include socio-demographic (age, race), lifestyle (food frequency, physical activity, sleep), and medical information (weight, height, waist circumference, reproductive history, medications, comorbidities) using a combination of measured and self-reported data (13). The authors found that a body mass index (BMI) ≥35 kg/m², height-adjusted waist circumference ≥88 cm—a measure of abdominal adiposity, self-reported diabetes mellitus, and ≥0.5 servings of red meat per day were associated with an increased risk of pancreatic cancer among the study cohort (2). Additionally, the authors reported that higher quality diets consisting of ≥7 servings of fruit or vegetables and ≥20 g of daily dietary fiber were associated with a lower risk of pancreatic cancer (2).

The study assessed a well-established cohort with granular lifestyle data and included an average of 17 years follow-up to evaluate the associations between possible risk factors and incidence of pancreatic cancer, which strengthens the study (2). However, there were a few notable limitations of the study which affect the interpretation of the results and the generalizability. First, the authors presented data for women who were non-drinkers and non-smokers at enrollment, considering this a unique aspect of the data. However, the exclusion of nearly 75% of the WHI cohort based on alcohol and tobacco use criteria alone limits the generalizability of the results. In the authors’ own discussion of the literature, they noted that for some factors, such as weight or BMI, there was evidence that the associations with pancreatic cancer risk may not be modified by cigarette smoking or alcohol use (2). Thus, the exclusion of women with these behaviors at enrollment may not have been necessary, and it limited the ability to determine whether modification effects by alcohol or tobacco use occurred in the cohort. Second, while the authors presented the characteristics of included and excluded participants, there was no formal assessment of whether participants differed on potential confounding factors and how they may affect the analyses. Further, it was unclear in the analyses if the models appropriately controlled for potential confounders. For example, the analyses did not specify whether each lifestyle factor was tested independently, and if potential moderating, mediating, or intervening effects of each lifestyle factor on the others could be evaluated. Next, there was no information on second-hand smoking or other environmental toxin exposure, which may be related to cancer development (5,14). Likewise, there was no information on family history of pancreatic cancer, genetic risk (pathogenic germline alterations are identified in up to 20% of patients with pancreatic cancer), or past H. pylori infections which are identified risk factors (5,15,16). Thus, any interactive effects of environmental exposures and genetic profiles with the identified modifiable factors could not be evaluated in this study. In addition, lack of information on loss to follow-up and outcome data, and the inability to account for changes in behaviors (e.g., smoking, alcohol drinking) over time are limitations for explaining the study findings.

Nevertheless, the study provides insight into the risk factors for pancreatic cancers among females without a history of alcohol or tobacco use from a large, population-based cohort of postmenopausal women (2). Any implications for cancer prevention are based on the accuracy and reliability of the study findings and what is corroborated by the literature. The risk factors identified by Peila et al. of obesity, central adiposity, and type 2 diabetes mellitus are consistent with those risk factors acknowledged by the American Cancer Society and the Pancreatic Cancer Action Network (7,16). Additionally, the WHI study provided more evidence on the associations between dietary components and risk of pancreatic cancer that have been explored in the literature (5,7,16).

Future research and significance for pancreatic cancer prevention

The risk factors for pancreatic cancer identified by Peila et al. and respected organizations, combined with knowledge on modifiable risk factors for other gastrointestinal cancers, support primary prevention of cancers through healthy lifestyles that promote maintenance of a healthy body composition, glucose regulation, non-smoking or smoking cessation, moderate alcohol consumption, and diets rich in whole grains, lean proteins, and polyunsaturated fats (2,7,10-12,16). This opens the door for further research to investigate the effectiveness of holistic medicine approaches for the prevention of pancreatic cancers (17,18). These may include smoking cessation programs and lifestyle interventions focused on approaches to improve body composition and glucose regulation through dietary changes, physical activity, stress management, and good sleep hygiene (19-21). Such programs have been developed for preventing type 2 diabetes, which shares similar risk factors in common with pancreatic cancer and is a risk factor itself (2,5,17). The U.S. Centers for Disease Control and Prevention (CDC) National Diabetes Prevention Program (NDPP) may be a promising start for addressing modifiable risk factors among those at-risk for pancreatic cancers (22). However, testing these interventions in randomized controlled trials for a relatively rare, although fatal, cancer may be not realistic and feasible. Thus, pragmatic trials, simulation studies, or analyses of existing observational data using rigorous methods may provide evidence (23-25). If the effectiveness of lifestyle interventions for preventing pancreatic cancers is demonstrated by these methods, integration of these holistic approaches into primary care and gastroenterology with referrals to existing programs like the NDPP for high-risk individuals may be the next logical step.

There may also be an opportunity for investigating any potential role of surgical weight management interventions or pharmacologic treatment with glucagon-like peptide-1 agonists (GLP-1s) in reducing the risk of pancreatic cancers and other obesity-associated cancers among those who are at high risk based on BMI, abdominal obesity, or type 2 diabetes mellitus (26,27). Surgical weight loss is associated with decreased cancer-related incidence and mortality, though its preventive mechanisms remain unclear (28,29). Procedures such as gastric bypass, banding, or vertical banded gastroplasty may be potential candidates for evaluation in reducing pancreatic cancer risk (28). While pharmacologic agents may not be the answer, GLP-1s have been approved for those with type 2 diabetes and are under investigation for other indications (27,30). They act by mimicking hormones which regulate blood sugar and suppress appetite, which can lead to substantial weight loss (27). Since type 2 diabetes is both a risk factor for pancreatic cancer and increases risk of mortality among those with pancreatic cancer (5), there may be an opportunity to study real-world pancreatic cancer incidence and mortality patterns in patients who are prescribed GLP-1s for diabetes mellitus versus those who are not taking GLP-1s and are at risk for pancreatic cancer to better understand their potential role in pancreatic cancers.

Regardless of the method, the need to understand when to intervene to prevent cancer has never been more pressing. While Peila et al. rightly highlighted the latency from the initial carcinogenic event and death from metastatic disease (2), the latent period of the disease from the effects of exposures or initiation of health behaviors is largely unknown. Therefore, when to employ an intervention to modify risk factors remains poorly understood, especially in the context of risk factors which may vary over time in response to other health states or external stressors, such as diet and body composition. Nevertheless, the potential benefits of interventions leading to weight loss and improved metabolic efficiencies implemented at any point along the continuum likely extend well beyond pancreatic cancer prevention to other cancers, type 2 diabetes, and cardiovascular diseases (26,31-33).

Conclusions

The current literature, including the recent effort by Peila et al., demonstrates the role of obesity or increased central adiposity, glucose dysregulation, and low-quality diets in the risk of pancreatic cancer (2,10-12,17,34). While the study by Peila et al. is not without methodological limitations as discussed herein, it does have some implications for pancreatic cancer prevention research. A unified effort is needed to study strategies which may reduce the risk of pancreatic cancers by modifying these factors among individuals with one or more high-risk attributes or behaviors. In the case of highly fatal pancreatic cancers, the wise words of Benjamin Franklin that “an ounce of prevention is worth a pound of cure” may be even more prudent.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0005/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0005/coif). Y.L.E. and K.Z. are employed by the Henry M. Jackson Foundation, Inc., a 501(c)(3) nonprofit organization. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclaimer: The contents of this commentary are the sole responsibility of the authors and do not necessarily reflect the views, assertions, opinions, or policies of the Uniformed Services University of the Health Sciences, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of War, or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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