Pancreatic cancer: Recent epidemiological trends and risk determinants

Abstract

Pancreatic cancer is one of the common malignancies worldwide, characterized by late-stage diagnosis, aggressive progression, and persistently high mortality. Despite being the 12^th most diagnosed cancer globally, it ranks as the sixth leading cause of cancer-related death, reflecting its poor prognosis and limited survival gains. Here we form a narrative review synthesizing current global epidemiological data on pancreatic cancer, drawing primarily from GLOBOCAN, Surveillance, Epidemiology, and End Results, and other large population-based studies, with a focus on incidence, mortality, and survival trends. Survival remains dismal, with 5-year survival rates generally below 15%, largely due to delayed diagnosis and limited effective screening strategies. This review comprehensively examines modifiable risk factors, including tobacco use, alcohol consumption, obesity, diabetes, and occupational and environmental exposures. We also provide elaborate evaluation of non-modifiable factors such as age, sex, race, family history, and inherited genetic mutations (e.g., BRCA1/2, PALB2, ATM, and mismatch repair genes). We discuss emerging evidence on metabolic health, gene-environment interactions, and disparities in outcomes. A comprehensive summary of recommendations for pancreatic cancer screening and surveillance in high-risk populations is highlighted. Despite the growing understanding of individual risk factors, there remains a need to further characterize the interplay between the risk factors. With a greater understanding of a patient’s individual risk profile, screening for pancreatic cancer and possibly identifying earlier stages can hopefully lead to improved prevention strategies, guide targeted screening, and optimize resource allocation in addressing the growing global burden of pancreatic cancer.

Key Words: Pancreatic cancer; Pancreas; Epidemiology; Risk factors; Screening; Prevention

Core Tip: Pancreatic cancer is a diagnosis that is often devastating due to high mortality rates. This review covers up-to-date data regarding global incidence and mortality, then further delves into important risk factors for developing pancreatic cancer in detail. Some of the risk factors discussed are modifiable, such as tobacco or alcohol use, while others are not modifiable, like age, race, or genetics. Finally, this review covers current screening and surveillance recommendations.

INTRODUCTION

Pancreatic cancer is one of the deadliest cancers, with challenges of late stage at diagnosis, rapid progression, and high mortality. As of 2022, it is estimated to be the 12^th most common cancer globally[1]. Pancreatic cancer continues to present challenges and imposes a high socioeconomic burden to both patients and healthcare systems worldwide. Despite its relatively lower incidence compared to colorectal cancer, it has been shown to generate the second-largest indirect costs[2]. Therefore, studying the epidemiological features of this neoplasm is crucial to optimizing resource allocation in efforts to combat it.

The pancreas is a glandular organ with two essential functions of the body in the form of endocrine (hormone regulation and glandular secretions) and exocrine (digestive gland secretions)[3,4]. Neoplasms represent the most severe disorders affecting the pancreas, with pancreatic ductal adenocarcinoma accounting for over 90% of all pancreatic cancer cases[5-7]. Due to its aggressive nature, pancreatic cancer ranks as the sixth leading cause of cancer-related mortality globally[1]. It continues to be predominantly a disease of old age, disproportionately affecting males more than females. Additionally, it is more prevalent in high-development-index countries compared to lower ones, likely due to the longer life expectancy in these regions[1].

Most pancreatic cancers arise from microscopic pancreatic intraepithelial neoplasia, typically originating from ductal cells. However, some studies suggest that acinar cells may also serve as a source. Somatic mutations cause alterations to tumor suppressor and oncogenes which leads to precancerous lesions. Continued evolution of these lesions can then lead to high grade dysplasia or pancreatic carcinoma[8]. Moreover, evidence suggests that there is more involvement in the microenvironment and neuronal crosstalk such as neurotransmitter release that drives cell proliferation and migration and further growth[9]. Genetic expression can also be altered at a biochemical level causing disruption in normal cellular regulation processes[10]. These intricate details involving cellular pathways and their involvement in cancer progression are vital in understanding pathophysiology and disease mechanism. Novel research methods continue to arise such as tumor organoid models which can help understand these critical details as well as create a platform for evaluating therapeutic options as well[11].

The disease is notoriously difficult to detect in its early stages due to vague and non-specific symptoms, leading to diagnosis often occurring at advanced stages. Consequently, the survival rate for pancreatic cancer remains low, at approximately 11%-13%[12,13]. Several risk factors contribute to the increasing incidence of pancreatic cancer, including tobacco smoking, alcohol consumption, obesity, and occupational exposure to pesticides and other harmful chemicals. Additionally, advancing age, genetic predisposition, and a family history of pancreatic cancer have been identified as key factors. In this review, we examine recent trends in pancreatic cancer epidemiology and comprehensively analyze the associated risk factors (Table 1).

Table 1 Modifiable and non-modifiable risk factors for pancreatic cancer.

Risk factors for pancreatic cancer
Modifiable risk factors	Tobacco use	Smoking is causally associated with pancreatic cancer, contributing to 20%-30% of cases in the United States and Europe. The risk increases with smoking duration and pack-years and persists for 10 years after cessation. Passive smoking also raises risk
	Alcohol consumption	Heavy alcohol consumption (> 3 drinks/day) is associated with an increased risk, particularly in men and heavy liquor drinkers. However, a clear linear relationship remains debated
	Obesity	Obesity (BMI > 30) increases pancreatic cancer risk by approximately 20%. Abdominal fatness and metabolic obesity phenotypes are also linked to higher risk
	Occupational and environmental exposures	Exposure to hydrocarbons, pesticides, and heavy metals (such as in aluminum smelting, textile industries, and printing industries) may contribute to pancreatic cancer risk
Non-modifiable risk factors	Age	Risk increases significantly with age, particularly in those > 60 years old
	Gender	Higher incidence in men than women, possibly due to sex hormone differences
	Race and ethnicity	Higher incidence in Black populations, lower in Asian and Pacific Islanders, with genetic and environmental factors contributing
	Family history	Having a first-degree relative with pancreatic cancer increases risk 5%-10%. Familial cases tend to develop precursor lesions more frequently
	Genetic factors	Mutations in BRCA1, BRCA2, PALB2, ATM, MLH1, and MSH2 increase risk. Lynch syndrome and Peutz-Jeghers syndrome are also associated
	Diabetes mellitus	Diabetes nearly doubles the risk of pancreatic cancer. Mechanisms include insulin resistance, chronic inflammation, and IGF-1 pathway activation

BMI: Body mass index; IGF-1: Insulin-like growth factor-1.

METHODOLOGY

For epidemiologic data, the public databases of GLOBOCAN, Surveillance, Epidemiology, and End Results (SEER) were accessed and synthesized. Data obtained from GLOBOCAN database was used to create the figures using choropleth mapping software. Data was also obtained from the American Cancer Society. For literature review, electronic databases PubMed, MEDLINE, and Ovid were used to search for articles. The results were narrowed to primarily include peer-reviewed manuscripts written in the English language and that were published within the last 15 years. A variety of search terms were used. Primary search terms such as “pancreatic cancer”, “pancreatic adenocarcinoma” and “pancreas cancer” were combined via advanced search functions with additional search terms that included but were not limited to “risk factors”, “tobacco use”, “alcohol use”, “family history”, “genetics”, “electronic cigarettes”, “obesity”, “diabetes”, “insulin resistance”, “age”, “gender”, “race”, “ethnicity”, “occupation”, “exposures”, “chemicals”.

INCIDENCE

According to GLOBOCAN data from 2022, an estimated 510992 people were diagnosed with pancreatic neoplasm, with a global age-standardized rate (ASR) of 4.7 per 100000[1] (Figure 1A). A relative risk of 1.1 was noted for males (269709 cases) compared to females (241283 cases), with an estimated global cumulative risk at 0.64% compared to 0.44% for females. The ASR for pancreatic cancer was recorded at 3.5 per 100000. Pancreatic neoplasm continues to be a malignancy predominantly affecting older individuals, with 94% of cancer diagnosed after the age of 50 with a median age of 70 at the time of diagnosis.

Figure 1 Incidence and mortality of pancreatic cancer age-standardized rate (world) per 100000 both sexes in 2022 (global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A: Incidence of pancreatic cancer age-standardized rate (world) per 100000 both sexes in 2022 (global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries; B: Mortality of pancreatic cancer age-standardized rate (world) per 100000 both sexes in 2022 (global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. This figure is adapted from Bray et al[1]. ASR: Age-standardized rate.

The highest incidence was noted in Northern America and the European region, at 8.5 and 8 per 100000, respectively, while lower rates were recorded in Africa (2.4 per 100000) and Asia (3.6 per 100000). Notably, pancreatic cancer is more prevalent in countries with a very high Human Development Index (HDI), where the incidence rate is 7.9 per 100000, compared to just 1.4 per 100000 in low-HDI countries. Uruguay had the highest ASR at 8.7, followed by Hungary (8.3), Japan (9.8), and France (9.4). Among men, the highest risk was reported in Armenia, with an ASR of 10.6, while women in Burkina Faso had an ASR of 8.2. Malawi and Pakistan continue to have lower incidences of pancreatic cancer[14]. The disease remains most prevalent in the older population, with an incidence rate of 21.6 per 100000 among individuals over the age of 50.

In the United States of America, the incidence rate was noted to be 66440 in the year 2024, accounting for 3.3% of all newly diagnosed cancers[12]. As seen in the global trend, the incidence rates were higher in males at 15.4 compared to females at 12 per 100000 population. The highest incidence rates were noted in non-Hispanic Blacks at a rate of 17.7 per 100000.

MORTALITY

Despite ranking 12^th for incidence, pancreatic cancer has a high mortality rate and is the 6^th leading cause of cancer-related death. In total, 467409 deaths were attributed to pancreatic cancer[1] (Figure 1B). The cumulative risk was 0.57% in men compared to 0.38% in women, while the ASR was noted at 3.7 per 100000 in men and 2.4 per 100000 in women[12]. Hungary and Uruguay have high ASRs of 7.6 and 7.1 per 100000, respectively. This is followed by Czechia, Latvia, Moldova, Armenia, and France, with rates ranging from 6.5 to 6.7 per 100000. Consistent with incidence trends, mortality rates were significantly higher in very high HDI countries, at 5.1 per 100000, compared to 1.1 per 100000 in low-HDI countries.

In the United States, an estimated 51750 patients succumbed to pancreatic cancer in 2024, accounting for 8.5% of all cancer-related deaths. As expected, mortality rates were higher in men, at 12.9 per 100000, compared to 9.8 per 100000 in women[12]. Among racial groups, non-Hispanic Black males had a disproportionately higher mortality rate of 15.3 per 100000. The median age at death in the United States was 72 years. Mortality rates have remained relatively stable in the United States, increasing only slightly from 10.7 per 100000 in 1975 to 11.1 per 100000 in 2022.

TREND

Pancreatic cancer is projected to become an increasingly significant global health challenge, with both incidence and mortality expected to rise sharply by 2050, according to the Global Cancer Observatory[1]. It is estimated that the incidence of pancreatic cancer in males is predicted to have a 91% increase, accounting for around nearly 500000 new cases, while the female population has a 99% increase by the year 2050. Similarly, following the incidence rates, the mortality of pancreatic cancer is expected to exceed dramatically with a 96% and 104% increase in mortality compared to the year 2022. Over the coming years, with rising urbanization and lifestyle changes, the United Nation regions of eastern Africa and Western Asia are estimated to have a staggering uprise in cases at +135% of today.

Regarding these high HDI and high-income countries, there are numerous considerations to explain these trends. To begin, it is always important to consider technology advancements and greater ability to detect diseases. These highly populous countries in Asia, Europe, and the Americas continue to have higher prevalence of tobacco use despite what seems to be an overall decrease in tobacco use[15,16]. Beyond this, obesity and insulin resistance are a rapidly growing concern worldwide. The following risk factors we discuss, and possibly other unrecognized risk factors all play a role in the evolving global trends regarding incidence of pancreatic cancer. Rising incidence and mortality is concerning as most gastrointestinal related cancers have the opposite trend. Take, colorectal cancer for example. Incidence and mortality have been trending downwards recently[17,18]. As screening guidelines continue to evolve over time, more cases are getting identified earlier. Earlier detection offers sooner treatment action and importantly likely contributes to better ability to research and study the disease process and response to novel therapies. Pancreatic cancer, on the other hand, remains difficult to detect early and, as will be discussed, still has significant limitations regarding screening guidelines.

SURVIVAL

Pancreatic cancer remains a significant global health burden, as its survival prognosis remains exceptionally poor. Due to the lack of clinical symptoms and effective diagnostic screening tools, many individuals are diagnosed at advanced stages of the disease.

The survival rates for endocrine and exocrine pancreatic cancers vary significantly due to differences in healthcare systems, treatment options, and stage at diagnosis among low, middle, and high-income countries. Globally, the 5-year survival rate for pancreatic cancer remains variable, with an estimated rate of 10%-12% in high-income countries[1]. In the United States, pancreatic cancer had a 5-year survival rate of 6% in 2013. Encouragingly, this improved to approximately 12%-13% by 2020, reflecting advancements in early detection and therapeutic interventions[19].

According to the SEER the 5-year relative survival rates for pancreatic cancer by stage were 44% for localized cases, 16.2% for regional cases, 3.1% distant-stage cases[19]. Between 2000 and 2004 the 5-year survival at less than 7%. In the United Kingdom, the estimated 5-year survival rate between 2012 and 2014 was 10%[13]. The 5-year survival rates by stage in England, Wales, and Northern Ireland were 25% for localized cases, 15% for regional cases, and only 1% for distant-stage cases[20].

RISK FACTORS: MODIFIABLE

Tobacco

The International Agency for Research on Cancer has confirmed that smoking is causally associated with pancreatic cancer, with population-attributable fraction (PAF) estimates ranging from 11% to 32% globally[21]. In the United States and Europe, tobacco use is estimated to account for 20%-30% of pancreatic cancer cases[22]. In Asian and African countries, the PAF due to tobacco is variable based on the region and smoking prevalence, with PAFs ranging from 20%-27% in Korea[23], Japan[24], China[25], and 10%-15% in Nigeria[26]. Current tobacco smokers are two times more likely to develop pancreatic cancer compared to non-smokers[27]. Cigarette smoking causes an increase in the risk of pancreatic cancer by 75% compared to non-smokers, and this risk persists for at least 10 years after smoking cessation[28,29].

A pooled study from the Pancreatic Cancer Cohort Consortium determined that the risk of pancreatic cancer increases with the duration of smoking and the number of cigarettes smoked daily. There is a 2-fold risk of pancreatic cancer in current smokers compared to non-smokers. Risk also increased with greater tobacco use and longer duration of smoking. The study also determined that individuals with smoking history exceeding 40-pack-years history or those who smoked more than 30 cigarettes per day had an increased risk of pancreatic cancer[27]. Similarly, the European Prospective Investigation into Cancer and Nutrition study demonstrated that the risk of pancreatic cancer increased for every five cigarettes smoked per day, with a 50% higher risk observed in individuals exposed to passive smoking[30].

A pooled data study found that compared to non-smokers, cigar smokers had an increased risk of pancreatic cancer and were comparable to cigarette smokers. Furthermore, consuming 10 g or more of tobacco per day increased the risk of pancreatic cancer. However, no association was determined for the duration of consumption. Additionally, no association was found between pipe smoking or smokeless tobacco use and pancreatic cancer[31]. A European study exploring risk profiles for different tobacco types and smoking habits found an increased risk of pancreatic cancer in current smokers who used black tobacco compared to blonde tobacco. There was a non-linear dose-response for smoking duration, intensity, cumulative dose, and smoking cessation[26].

A prospective cohort study assessed cigarette smoking and overall survival among persons diagnosed with pancreatic cancer and found a 37% increased risk of death for current smokers compared to nonsmokers. Further reduction in survival was observed for increased pack-years, with 49% higher mortality risk for individuals with a smoking history exceeding 60 pack-years[32].

With the advent of electronic nicotine delivery systems, specifically e-cigarettes, vapes, and tank systems, there is believed to be a lower exposure to carcinogens compared to combustible tobacco[33]. Theoretically, reduced exposure can potentially reduce tobacco-related cancer and deaths. However, another type of electronic nicotine delivery systems, Heat-Not-Burn device [heated tobacco product (HTP)], uses disposable tobacco leaf heated with sticks, plugs, or capsules, aerosolizes HTPs[33]. HTPs contain tobacco, nicotine, and additives such as humectants and flavoring. Moreover, these devices also are implicated in delivering high concentrations of toxic metals including Cd, Ni, Pb, and Cr which have been shown to affect mitochondrial function leading to oxidative stress at a cellular level[34]. The World Health Organization has determined that the toxic chemicals and carcinogens present in HTPs are like those found in cigarette smoke and pose health risks. With this growing societal change towards these delivery systems, there is emerging evidence and dialogue regarding their effects on various organ systems[34,35] as well as their overall associated risk with cancers[34], however, further research is imperative to better definitively understand the associations regarding the development of pancreatic cancer. Additionally, these devices have many more variables the need studied given the wide range of customizability for the user. For example, flavors/add-ons, type of battery, temperatures, among others.

Alcohol

An increased risk of pancreatic cancer has been associated with alcohol consumption. However, evidence for a clear linear relationship remains limited. Discrepancies amongst the current literature may partially exist due to differing cultural relationships with alcohol. Also, some studies have reported inconsistent findings due to underpowered analyses and residual confounding by smoking. For example, one nested case-control study failed to show statistical significance between moderate and high levels of alcohol intake. Of the included studies, some did not control for tobacco use[36]. In 2018, the World Cancer Research Fund and the American Institute for Cancer Research published their Third Expert Report, Diet, Nutrition, Physical Activity and Cancer: A Global Perspective, which examined potential risk factors for pancreatic cancer[37]. The report found limited evidence supporting a direct linear association between alcohol consumption and pancreatic cancer risk. However, a dose-response analysis suggested an increased risk in heavy drinkers that consume more than 3 drinks per day (30 g per day)[37]. Comparable findings were observed in nonsmokers from a prospective study using data from American Cancer Society Cancer Prevention Study[38,39].

The United Kingdom Million Women study found compelling evidence for a positive association that moderate consumption of one drink per day was linked to increased risk of pancreatic cancer in women[40]. Conversely, an analysis of the European Prospective Investigation into Cancer and Nutrition study found alcohol intake was positively associated with pancreatic cancer risk in men with heavy consumption that exceeded 60 g per day. The risk was higher for beer and spirit/Liquor intake than wine[41]. Results from prior pooled analysis, Pancreatic Cancer Cohort Consortium, revealed no significant association between total alcohol intake and pancreatic cancer for 60 g/day. Despite the lack of overall significant association, a statistically significant increase in risk was observed in men consuming 45 g or more of liquor per day[36].

A Japanese population-based cohort study found no significant association between alcohol consumption and pancreatic cancer risk in the overall population. However, a significant association was observed when the analysis was restricted to men with a stable alcohol-drinking habit over five years compared to non or occasional drinkers. Furthermore, a stronger association was noted for those who had never smoked[42]. To better understand the etiology of pancreatic cancer in heavy drinkers, a recent genome-wide interaction study analyzed single-nucleotide polymorphisms in individuals of European ancestry. The study identified several single-nucleotide polymorphisms in a genomic region that may be associated with heavy alcohol consumption and risk of pancreatic cancer. Risk stratification analysis of individuals with specific genetic profiles who engaged in heavy drinking had a higher risk of developing pancreatic cancer compared to individuals without genetic variants[43]. These findings highlight the potential for personalized risk assessment and could aid in developing targeted prevention strategies for individuals with a genetic predisposition to heavy alcohol consumption.

Ultimately, the data indicates that alcohol use increases risk for pancreatic cancer. Moreover, heavy consumption has been shown to further increase risk however there remains variety in what classifies as “heavy consumption” amongst various studies. While amount is the often-considered metric, frequency is also a measure that may be important. Some studies suggest that increased drinking frequency, even if controlling for amount, may lead to higher risk profile[44]. On the other hand, binge drinking is a risk for pancreatitis, which may also play a role in the increased risk. Often, studies relating to alcohol or tobacco use face risk of response bias. Gaps in the research remain regarding differences amongst genders as well as more clarity on the relationship between tobacco use and alcohol consumption. Lastly, it would be important to understand how alcohol cessation alters the risk profile.

Obesity

According to the American Cancer Society, obesity [body mass index (BMI) of 30 or more] increases the likelihood of developing pancreatic cancer by 20%. The 2017 Global Burden of Disease study estimated that 6.2% of pancreatic cancers were attributed to obesity[45]. Several studies have established the risk of pancreatic cancer in obese individuals compared to persons with normal weight[46-50]. A cohort study based on follow-up data from the Health Professionals Follow-up Study and the Nurses’ Health Study reported an increased risk of pancreatic cancer in individuals with a BMI of greater than 30 kg/m² compared with individuals with a BMI of less than 23 kg/m² after controlling for the effects of age, smoking, and diabetes[49]. Similarly, a large-scale study utilizing the Korean National Health Insurance database found an increased risk with a BMI greater than 28 kg/m²[50].

A systemic review and meta-analysis of 23 prospective investigated the association between BMI, abdominal fatness, and risk of pancreatic cancer. The study found a nonlinear relationship between BMI and pancreatic cancer risk. Additionally, a high waist-to-hip ratio was associated with an 11% increased risk per 10 cm increase in waist circumference and a 19% increased risk per 0.1-unit waist-to-hip ratio increment. Furthermore, both men and women classified as overweight (BMI ≥ 25) had an increased risk[48]. While, another study concluded that obesity and overweight experienced during early adulthood were associated with a greater risk and a younger age of disease onset[46]. As with many cancers, losing weight is common and therefore, it is important to recognize the possible biases that can exist in studying these relationships. With pancreatic cancer being diagnosed late, consideration of the patient’s historical weight compared to weight at diagnosis is important to reduce possibility of skewed results[51].

With the steadily increasing prevalence of overweight and obesity globally, an increased incidence of pancreatic cancer is expected. Therefore, identifying and controlling the potential risk factors are necessary to decrease pancreatic cancer. Current pathological mechanisms, including inflammation, oxidative stress, and insulin resistance play a vital role in pancreatic cancer development[52]. Recent studies are investigating metabolic obesity phenotypes to assess the risk of pancreatic cancer independent of obesity. Profiles categorized as metabolically healthy obese (individuals with obesity but without cardiometabolic risk factors) and metabolically unhealthy normal weight (individuals with normal weight but with metabolic syndrome features). To examine the effects of metabolic health and obesity phenotype on pancreatic cancer, a nationwide population-based study utilizing the longitudinal National Health Insurance Service-National Health Screening Cohort database in Korea was conducted. It was determined that regardless of BMI, metabolically unhealthy phenotype demonstrated a significantly increased risk of pancreatic cancer, whereas obese individuals with metabolically healthy phenotype did not[53]. This finding highlights a potential risk factor that is independent of obesity for pancreatic cancer.

Overall, obesity is a key factor that requires continued attention. With the rapid rise in obesity, more resources are being allocated to studying this condition. There is also been more treatment modalities becoming available. Further research regarding duration of obesity, effects of weight loss, and even method of weight loss will be vital in capturing further details about how this can help reduce the risk of pancreatic cancer.

Occupational and environmental exposures

Multiple studies have been performed that demonstrated a link between occupational exposure and high rates of pancreatic cancer. However, this is complicated by a variety of different biases. Recall bias remains a limitation due to exposure data often being self-reported. Additionally, obtaining accurate measurements of the exposure remains a challenge which makes for dose-response assessments difficult. Lastly, controlling for confounding variables can be difficult given high prevalence[54]. It has been estimated that up to 12% of cases of pancreatic cancer are related to occupational exposures[55]. Various compounds have been hypothesized to increase the lifetime risk of pancreatic cancer, including hydrocarbons, pesticides, and heavy metals.

Workers in aluminum smelting, road pavers, coke oven workers, and those in the crude oil industry have been at increased risk of occupational exposure to hydrocarbons[56,57]. Cellular exposure to hydrocarbons has been shown to increase the expression of aryl hydrocarbon receptors, which have been implicated in carcinogenesis across multiple organ systems. These receptors promote cellular migration and proliferation, inhibit apoptosis, and contribute to dysplasia[58]. A 2016 cohort study of 3660 female textile workers in China found that the duration of exposure to textile solvents had a significant uptrend in the hazard ratio (HR) [0-10 years of exposure HR = 0.61, confidence interval (CI): 0.35-1.07; 10-20 years of exposure HR = 0.99, CI: 0.60-1.63; 20+ years of exposure HR = 1.51; CI: 0.99-2.30; P-trend = 0.004] of development of pancreatic cancer[59]. Similarly, a meta-analysis of Spanish workers demonstrated a significantly higher rate of developing pancreatic ductal adenocarcinoma in patients with exposure to chlorinated hydrocarbons [odds ratio (OR) = 4.1, 95%CI: 1.1-15.2, P-trend = 0.04][60].

Pesticide exposure has also been hypothesized to increase the risk of pancreatic cancer. The United States-based Agricultural Health Study, which examined pesticide applicators and their spouses, found that exposure to two specific pesticides - pendimethalin and S-ethyl dipropyl thiocarbamate (EPTC) - was associated with an increased risk of pancreatic cancer[61]. Higher exposure to pendimethalin was found to have a 3.0-fold risk, while exposure to EPTC was found to have a 2.56-fold risk compared to those with no exposure[61]. However, the Queensland Pancreatic Study did not demonstrate any attributable risk of pancreatic cancer in patients with prior exposure to N-nitrosamines or pesticides[62].

Occupational exposure to heavy metals has traditionally been implicated in the development of pancreatic cancer. However, multiple meta-analyses have demonstrated that evidence of higher levels of various heavy metals has not correlated to higher rates of pancreatic cancer[62,63]. A study conducted at the Mayo clinic found that exposure to pesticides, chlorinated hydrocarbons, benzene, and asbestos was associated with higher rates of pancreatic adenocarcinoma. However, no significant association was found between pancreatic cancer and exposure to chromium or nickel[64]. An analysis of Russian printing press workers demonstrated a higher rate of pancreatic cancer among individuals with greater cumulative lead exposure[65]. Additionally, increased concentrations of aromatic hydrocarbons, chlorinated hydrocarbons, pesticides, and formaldehyde were correlated with higher toenail concentrations of various heavy metals, including cadmium, lead, arsenic, and vanadium, in patients with diagnosed exocrine pancreatic cancer[66]. Heavy metal exposure may be a confounding factor in the implication of other occupational exposures in the development of pancreatic cancer. As technology advances, it is possible that being able to more accurately measure exposure data can lead to greater assessments of the dose-response relationship between these exposures. Given the lipophilic nature of some of the hazardous substances, some researchers have been studying adipose tissue deposition or urine concentrations of associated chemical compounds[67].

RISK FACTORS: NON-MODIFIABLE

Age and gender

Increasing age is a known risk factor for many kinds of cancer, and pancreatic cancer is no exception. According to the GLOBOCAN database, the highest risk for the development of pancreatic cancer occurred in patients aged between 60 years old and 80 years old[68]. Multiple observational studies have seen similar results[69,70]. Younger patients at the time of diagnosis tend to have more identifiable risk factors for pancreatic cancer than those diagnosed at an older age. In a combined cohort of the European Genome-Wide Association Study and United States SEER program, the OR of developing pancreatic cancer in patients with at least three of five identified risk factors (diabetes, obesity, cigarette smoking, height, and non-O-blood group) was 9.24 among those greater than 60 years old, 3.00 among those 61-70 years old, and 1.46 in those 71+ years old[71]. Further studies are ongoing to determine whether an age-related increase in pancreatic cancer incidence exists independently of these known risk factors.

Pancreatic cancer is more common in men than women. According to the 2022 GLOBOCAN database, it was noted that the incidence of pancreatic cancer in men was 5.5 per 100000 people, and in women, the incidence was 4.0 per 100000 person-years[1]. Additionally, pancreatic cancer has a higher mortality rate in males than females, with 5.1 deaths per 100000 males and 3.8 deaths per 100000 males[1,6]. Multiple recent studies have demonstrated the effects of sex hormones in increasing or decreasing risk for various cancers. It has been shown that a higher incidence of G-protein coupled estrogen receptors leads to a reduced rate of pancreatic ductal adenocarcinoma. Additionally, direct activation of this pathway can lead to inhibition of pancreatic cell proliferation[72]. Further studies are necessary to explore other potential mechanisms of gender disparities in pancreatic cancer, as many potential pathways remain under investigation.

Race and ethnicity

Generally, the incidence of pancreatic cancer is higher in Black populations[73-75]. The lowest risk of pancreatic cancer has been seen in Asian and Pacific islander populations, with Caucasian populations demonstrating an intermediate risk when compared to the other ethnicities[19]. In one study of the Southeast United States, it was found that the age-adjusted incidence of pancreatic cancer was 14.6 per 100000 in Black populations and 10.8 per 100000 in Caucasians. Similarly, it was found that the age-adjusted mortality of pancreatic cancer was 13.3 per 100000 in Black populations and 9.7 per 100000 in White populations[74].

It has been postulated that most of the racial disparity in pancreatic cancer risk is attributable to modifiable risk factors, such as diet, smoking, alcohol consumption, and vitamin D deficiencies[6]. However, other studies have suggested that the risk cannot be fully explained by these factors alone. Analysis of the Cancer Prevention Study II cohort demonstrated that population attributable risk due to modifiable risk factors such as diabetes, smoking, and obesity was 24.3% in Whites and 21.8% in Blacks[76]. Additionally, different ethnicities respond to treatment of pancreatic cancer with variable mortality. In a single institution analysis, a comparison of response to gemcitabine or fluorouracil-based therapies was compared across different ethnicities, with Asians demonstrating a worse overall survival compared to Whites (HR = 2.62, P = 0.018)[77]. This, combined with observed differences in rates of point mutations in oncogenes between Western and Asian populations, suggests a potential genetic component contributing to the observed differences in pancreatic cancer rates[78].

Family history of pancreatic cancer

Independent of inheritable syndromes, a family history of pancreatic cancer is associated with an increased risk of developing pancreatic cancer. Studies have demonstrated that 5%-10% of patients with pancreatic cancer have a first-degree relative with the disease[6,79-81]. A prospective study demonstrated that the observed-to-expected rate of pancreatic cancer in those with a first degree relative was nine times higher[82]. The histopathology of pancreatic cancer in individuals with a significant family history is similar to that of sporadic cases. In an analysis of the National Familial Pancreas Tumor Registry, there was no statistically significant difference in the histologic subtypes between familial and sporadic pancreatic cancers[83]. Additionally, there was no statistically significant difference in the extent of tumor invasion or tumor size. It has been noted that a family history leads to a higher risk of precursor lesions, including pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm[83]. This suggests that patients with a first-degree relative are more likely to develop precursor lesions that then progress to pancreatic cancer, leading to a rate of detection of pancreatic cancer in patients with a family history.

Genetic factors

Hereditability is an important risk factor for pancreatic cancer as it is estimated that inherited genetic mutations are present in 20%-36% of individuals with the disease[84,85]. Several known genetic mutations and syndromes are associated with increased rates of pancreatic cancer, and many other genetic loci are currently being studied. Some studies have looked into as many as 19 different genetic markers and associated mutations in regards to pancreatic cancer[86]. Genetic research continues to be pivotal as it is likely that there are genetic factors that have yet to be discovered or have yet to show significance. However, the known genetic mutations that are implicated in increasing risk for pancreatic adenocarcinoma are BRCA1, BRCA2, PALB2, ATM, CDKN2A, MLH1, MSH2, MSH6, and EPCAM[87]. As genetic testing becomes more advanced and accessible, heredity will be a vital risk factor to evaluate in pancreatic adenocarcinoma. Identifying these mutations will also be valuable as targeted therapies continue to develop.

BRCA1 and BRCA2 are genes that are widely known for their association with cancer, particularly hereditary breast and ovarian cancer. The Breast Cancer Linkage Consortium estimates that men who carry a BRCA2 mutation to be at a 32% lifetime risk of all cancer by the age of 70, and for women who carry a mutation, that risk increases to 90%[88]. In the case of pancreatic cancer, studies have shown that individuals had a 2.26-fold and 3.5-fold increase in the relative risk for developing pancreatic cancer in BRCA1 mutation carriers and BRCA2 mutation carriers, respectively[88,89]. Mutations in these two genes are among the most common contributors to familial pancreatic cancer, with BRCA2 mutations found in 5%-10% of familial cases and BRCA1 mutations in approximately 1%[90]. Carriers with these mutations have better one-year overall survival rates compared to non-carrier pancreatic cancer patients[91]. It has also been observed that patients with BRCA1/2 mutations tend to present at a younger age compared to those without germline mutations, which may be a factor in the overall survival rates[92]. Highlighting the importance of early identification. A recent systematic review revealed that targeted therapies may be more effective for patients carrying BRCA mutations, although some chemotherapies did not show the same efficacy[93]. Another gene mutation associated with pancreatic cancer is in the ATM gene. Deleterious mutations were identified in 2.6%-4.6% of individuals with a family history of pancreatic cancer[94]. Furthermore, one study found a lifetime risk of 6.3% by age 70 and 9.5% by age 80 for those with an ATM mutation[95].

The prevalence of mutations in the PALB2 were identified in between 1%-3.7% of patients with family history of pancreatic cancer[96-98]. Carriers of mutations in CKDN2A were overall less prevalent among pancreatic cancer patients, as identified by one study that reported a rate of 0.6%. However, this study also cited a significantly increased risk for mutation carriers with smoking history vs non-carriers with a HR of 25.8[99].

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a syndrome caused by germline mutations mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. The Prospective Lynch Syndrome Database has shown that the cumulative risk for developing pancreatic cancer by the age of 75 is 6.2%, 0.5%, and 1.4% for carriers of mutations in MLH1, MSH2, and MSH6, respectively[100]. Another study identified that patients with Lynch syndrome carry an 8.6-fold increase in developing pancreatic cancer by the age of 70 when compared to the general population[101]. Although Lynch syndrome is more commonly associated with colorectal cancer, it is important to note the elevated risk for pancreatic cancer as well. Another GI-related hereditary disease that confers an increased risk for pancreatic cancer is Peutz-Jeghers syndrome caused by genetic mutations in the STK11 gene. One study identified the risk for developing pancreatic cancer to be 26% by the age of 70[102].

Diabetes

Increased insulin resistance and the development of new-onset diabetes are unique hallmarks of pancreatic adenocarcinoma, distinguishing it from other neoplasms. In a 2014 retrospective cohort study of 600 Mayo clinic patients, 68% of those with pancreatic cancer had diabetes mellitus, a prevalence multiple times higher than those with lung, breast, prostate, and colorectal cancers[103]. Interestingly, recent literature has suggested that diabetes mellitus may be a cause, rather than just a consequence, of pancreatic cancer. A 2014 meta-analysis of 88 independent studies (50 cohort and 39 case-control) revealed an overall 1.97-fold risk of pancreatic ductal adenocarcinoma among diabetic patients[104]. Another 2011 meta-analysis of 35 cohort studies came to similar conclusions, where diabetic patients had an almost 2-fold increased risk of pancreatic cancer as compared to the general population. This link was notably independent of BMI, smoking status, and alcohol consumption[105].

Numerous hypotheses exist regarding the biological mechanism and pathophysiology of diabetes attributing to higher cancer risk. It is important to note that diabetes is associated with an increased risk of various cancers, not just pancreatic adenocarcinoma. A 2020 meta-analysis with bias analysis comprising 151 cohorts found that those with type 2 diabetes mellitus have a 15%-25% higher risk of all-site cancer incidence and mortality[106]. After bias analyses for unmeasured confounding, results were particularly suggestive for causal relationships between type 2 diabetes mellitus and liver, pancreatic, and endometrial cancer incidence as well as pancreatic cancer mortality.

One proposed mechanism is insulin resistance, as well as direct molecular effects resulting from hyperinsulinemia. A 2019 in vivo study found that between two groups of LSL-KRAS (widely used pancreatic cancer mouse model), the mouse group altered to have reduced insulin had less burden of preneoplastic pancreatic intraepithelial neoplasia precursor lesions + pancreatic tumor area despite both groups being hyperglycemic[107]. Mechanistically, in vitro studies have shown that insulin both increases glucose use and the proliferation of pancreatic cancer cells[108]. Additionally, elevated levels of insulin lead to upregulation of the bioavailability of insulin-like growth factor-1 (IGF-1) by reducing IGF-binding proteins found in the liver[109]. Both IGF-1 and its receptor IGF-1R are highly expressed by pancreatic cancer cells, and activation of IGF-1R is associated with increased angiogenesis in these cells[110] alongside mitogenic and antiapoptotic effects[111].

Diabetes mellitus contributes to metabolic syndrome, a chronic inflammatory state that dysregulates the complex interplay of our immune and metabolic systems. This constant inflammation can be considered an additional pathway for the development of neoplasms[112]. Mouse models have demonstrated that hyperinsulinemia acts directly on insulin receptors on acinar cells in order to promote trypsin release but also increases the chances of trypsin-induced injury, resulting in increased chances of localized inflammation, increased Kras signaling, and promotion of acinar-to-ductal metaplasia[113]. Patients with metabolic syndrome release pro-inflammatory adipokine leptin and less anti-inflammatory adipokine adiponectin[114]. Obesity in metabolic syndrome also induces infiltration of M1 macrophages within adipose tissues, correlating with increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β[115].

PANCREATIC CANCER SCREENING AND PREVENTION

In 2019, the United States Preventive Services Task Force reaffirmed their previous 2004 recommendation regarding pancreatic cancer screening: Recommending against screening asymptomatic adults a “D” grade recommendation[116]. This recommendation was issued with the context that the vast majority of those diagnosed with pancreatic cancer, 85%-90% of cases, do not have known familial risk or inherited genetic syndromes that predispose them to pancreatic cancer. Out of the remaining positive cases, 5%-10% have familial risk, while 3%-5% can be contributed to the inherent genetic cancer syndromes such as Peutz-Jeghers mentioned above[117-119]. The United States Preventive Services Task Force did not find studies at the time that reported on the sensitivity or specificity of computed tomography (CT) scan, magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) as screening tests for pancreatic cancer, but did assess 13 cohort studies (n = 1317) that reported on the specific yield of screening[120-124]. It was deemed that the applicability of this data to those with normal risk was uncertain and would potentially have a lower positive predictive value and a higher rate of false-positive results[125-129]. The procedure and surgery-related harms to surgery were also reported and taken into consideration[130-132].

Most pancreatic surveillance methods involving high-risk individuals (HRI, those with familial involvement or germline mutations mentioned above) involve imaging with the use of MRI, EUS and CT of the abdomen. The CAPS 3 (American Cancer of the Pancreas Screening Consortium) prospective cohort study found CT detected fewer pancreatic lesions than MRI or EUS, supporting their conclusion that MRI and EUS are currently the best initial tests for detecting early pancreatic neoplasia[133]. It is important to note that these former imaging modalities also lead to avoidance of ionizing radiation for the patient, unlike CT. EUS has also been shown to be better at detecting small pancreatic ductal adenocarcinomas[126]. However, EUS diagnostic yield is highly operator dependent, one of the many reasons that there have been attempts to set minimum standards for trainees when it comes to EUS and endoscopic retrograde cholangiopancreatography[134].

In terms of specific groups and screening guidelines, the International Cancer of the Pancreas Screen Consortium (CAPS) released consensus recommendations for the management of HRIs in a manuscript published in 2019[135]. The consensus involved 91 experts from a variety of fields and countries, including gastroenterologists, surgeons, pathologists, radiologists, geneticists, oncologists, and epidemiologists from eleven countries and four continents. For those with familial risk, it was agreed that surveillance should start no earlier than age 50 years old or 10 years earlier than the youngest relative with pancreatic cancer. Preferred surveillance tests were EUS and MRI/magnetic resonance cholangiopancreatography. It was agreed that if no abnormalities were seen on imaging, or only non-concerning signs such as pancreatic cysts without worrisome features, then a 12-month interval between screens was acceptable. If MRI/magnetic resonance cholangiopancreatography/EUS demonstrated concerning features, then it was deemed necessary to obtain a serum carbohydrate antigen 19-9, a serum biomarker that has been shown to have a sensitivity and specificity of 80%-90% in patients presenting with symptomatic disease[136]. Finally, it was recommended to obtain EUS with fine needle aspiration for solid lesions greater than or equal to 5 mm, cystic lesions with worrisome features, or asymptomatic main pancreatic duct stricture. The panel of experts also set earlier screening timeframe of 40 years old for individuals with the genetic syndromes of familial atypical multiple mole melanoma (FAMMM, CDKNA2 mutation), FAMMM with the p16 Leiden variant, hereditary pancreatitis (PRSS1 mutation), and Peutz-Jeghers (STK11/LKB1 mutations). The panel also reached a consensus regarding glucose testing for these HRI.

Likewise, major society guidelines such as American Society for Gastrointestinal Endoscopy and American Gastroenterological Association discuss similar screening recommendations for HRIs which they also define by assessment of affected relatives and genetic syndromes[137,138]. No formalized guidelines exist for assessing risk based on the aforementioned risk factors, and thus it would be reasonable for clinicians to assess each patient’s individual risk factors and be weary of early identification of symptoms since currently it is not recommended to screen asymptomatic individuals. Furthermore, identification of modifiable risk factors should be promptly addressed, and patients should be counseled accordingly. As previously discussed, initial symptoms can be vague and non-specific and therefore patients who are symptomatic and do have risk factors, whether modifiable or not, can be assessed for laboratory, imaging, or procedural screening if reasonable. Further investigation is needed to assess how combinations of these risk factors synergize and alter overall risk over time.

CONCLUSION

Pancreatic cancer is common worldwide and remains a difficult disease due to the often late recognition, rapid advancement, and significant mortality. GLOBOCAN data shows that men are slightly more at risk than women. Additionally, risk increases significantly with increased age. The same trend is true for mortality. There is disproportionately higher risk and mortality for non-Hispanic Black males as well. There are significant risk factors that are well studied. Modifiable risks such as tobacco use and alcohol use are well described. Regardless of the tobacco delivery device, the risk of cancer is increased. Alcohol consumption carries a dose-response relationship putting heavy consumption at a higher risk. Obesity is also implicated in carrying additional risk likely due to inflammation, oxidative stress, and insulin resistance. Certain occupations can incur more risk as well, often industrial jobs such as metal work, road paving, oil industry, or textile workers. Other jobs that have exposures to chemicals or metals show increased risk too. Non-modifiable risk factors include race and ethnicity, which shows that black populations confer a higher risk. Family history and genetic mutations can predispose individuals as well. Common gene associations include, but are not limited to BRCA1 and BRCA2, ATM mutations, and the mismatch repair gene mutations. Lastly, diabetes confers an elevated risk of many malignancies but notably has a significant association with pancreatic cancer.

Presently, there are no recommended screening guidelines for pancreatic cancer in asymptomatic individuals due to overall low positive predictive value. Typically, surveillance is reserved for HRI and involves imaging modalities such as CT, MRI, or EUS. Continued research efforts would be beneficial to understand the interplay between the aforementioned risk factors. Doing so would give clinicians the opportunity to better assess risk amongst their patients. While screening is an important piece of the puzzle, addressing these risk factors is another key component to improving the global burden of this disease. Tobacco use is declining amongst younger generations, however, despite this, the emergence of alternative nicotine delivery systems has brought about new concerns. Furthermore, alcohol use seems to be on the decline as well. Regarding obesity and diabetes, the introduction and widespread use of glucagon-like peptide-1 and similar medications are proving to be impactful at treating these conditions. As we continue to strengthen our understanding of how these risk factors are associated with pancreatic cancer, additional studies will be necessary to also understand how combating these risk factors changes the landscape as well.