Pathogenesis and Risk Factors of Pancreatic Cancer

#### **Chapter 2**

## Obesity and Pancreatic Cancer: Its Role in Oncogenesis

*Nikitha Vobugari and Kai Sun*

#### **Abstract**

Incidence rates of pancreatic cancer are increasing worldwide. The lack of screening tools, late-stage diagnosis, and resistance to chemo and radiation therapies make pancreatic cancer the fourth leading cancer-related killer. Recently, awareness has increased about obesity as a strong yet modifiable risk factor for pancreatic cancer. The prevalence of pancreatic ductal adenocarcinoma (PDAC) was significantly higher among obese patients with a body mass index of more than 35 who did not undergo bariatric surgery versus their counterparts. Global obesity rates have increased considerably over the past decades, especially since the coronavirus pandemic. There is still a lack of understanding of the mechanisms of obesity-related PDAC. Emerging evidence suggests that chronic inflammation, circulatory lipids, insulin resistance, adipokines and cytokines release, oxidative stress, and changes in the microbiome associated with obesity are linked to its initiation and progression. Obesity also potentiates driver mutations, including Kirsten Rat Sarcoma viral oncogene (Kras) in PDAC. It is also unclear why obese patients have poorer postoperative outcomes than nonobese PDAC patients highlighting the need for better mechanistic understanding. In this chapter, we aim to provide clinicians and researchers with a comprehensive overview of the carcinogenic pathogenesis of obesity in PDAC and its implications for prevention and treatment.

**Keywords:** obesity, pancreatic cancer, pancreas, adenocarcinoma, exocrine pancreatic cancer, pathogenesis

#### **1. Introduction**

In the United States (US), pancreatic cancer (PC) continues to have a poor prognosis due to delayed diagnosis, late-stage disease at the time of diagnosis, and limited treatment options. Since 2000, annual incidence rates have grown at a 0.6–1% in all races, both sexes, and age categories, making it the eighth most common cancer in women and the tenth most common cancer in men [1, 2]. The risk of PC increases with age. The median age of diagnosis is around 70 years old [3]. Recent incidence trends between 2000 and 2014 show a bimodal age distribution, between 20 and 29 years and >80 years [4]. The incidence is higher in males than females, with an incidence risk ratio (IRR) of 1.32; >1 for age groups >35. There may be a link between males and environmental risk factors, such as smoking and alcohol. The incidence (496,000) and deaths (466,000) in 2020 are almost equal [5]. This equal ratio has remained constant since 2010 [6]. PC accounts

for 8% of all cancer-related deaths in the US and is the third leading cause after lung and colorectal cancers [7]. In the US, 5-year survival rates for all stages steadily increased from 0.9% in 1975 to 4.2% in 2011 and 10% between 2010 and 2016. Globally, the 5-year survival rates have not exceeded 10%, except for surgically resected patients; their 5-year survival rates increased from 1.5% to 17.5% [8].

The term obesity encompasses excessive fat accumulation that impairs health [9]. Indirect anthropometric measures include body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and body fat percentage estimated skin foldness; with the BMI being the easiest and most widely used [10]. BMI ≥ 30 is considered obese. It is further classified; class 1: 30–34, class 2 35–39, and class 3 (morbid or severe obesity) ≥ 40 [11]. In the US, the age-adjusted prevalence of obesity among adults over 20 years was 41.9% between 2017 and 2020 [12]. There was a significant rise in obesity prevalence of 30.5% between 1999 and 2000, when the Centers for Disease Control and Prevention (CDC) first recognized obesity as an epidemic [9, 13]. Adult obesity prevalence spiked by 3% between March 2020 to March 2021, the first year of the coronavirus disease 2019 (COVID-19) pandemic, which coincided with higher alcohol and tobacco use, lower rates in exercise activity due to quarantine, and higher average sleep duration [14]. Obesity can foster various detrimental health problems and increase mortality from all causes, including cardiovascular diseases, and cancers. The estimated prevalence of obesity-associated cancers is 684,000 US annually, including 210,000 among men and 470,000 among women, per CDC data. The evidence of obesity-associated cancers is consistent with breast cancer in postmenopausal women, adenocarcinoma of the esophagus, colon, endometrium, gall bladder, gastric, renal cell, pancreas, thyroid, meningioma, and multiple myeloma [15, 16].

#### **1.1 Obesity and pancreatic cancer risk**

Numerous prospective, observational, and epidemiological studies have recognized obesity as an independent and modifiable risk factor for PC [17–20]. The incidence and outcomes of PC are both adversely affected by obesity [21, 22]. According to a systematic review and meta-analysis of 23 prospective studies, both general and abdominal fatness are associated with an increased PC risk with a relative risk (RR) of 1.1 [95% confidence interval (CI), 1.07–1.14], when stratified by gender and geographical location [20]. In a 12-year study by a metabolic syndrome and cancer project, obesity increased the risk of PC by 1.5 in women and no correlation was found in males [23]. In other studies, a stronger association of obesity to PC risk is found in men and further higher in smokers [22]. Confounding risk factors such as smoking and alcohol consumption in males and females may explain the contrasting findings. Higher WHR is associated with an increase in risk in women, while higher BMI is associated with an increase in risk in both men and women [17]. Incidence risk is specifically higher with a BMI ≥ 95th percentile in early adulthood and a gain of ≥10 kg/m2 BMI in early adulthood years [24, 25]. Those with a calorie intake at the highest quartile experienced 70% higher risk than those with the lowest quartile in a case control study [26]. High BMI and underlying genetic profiles may also contribute to the elevated average PC risk among African Americans. A 20% higher risk of PC was found in African Americans than European Americans when adjusted for other risk factors [8].

PC patients with obesity in all age groups, regardless of disease stage and tumor resection status, were associated with reduced overall survival of PC with a hazard ratio 1.26 (95% CI, 0.94–1.69) [22]. The risk of early and elevated PC mortality is

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

significantly elevated by central obesity independent of BMI during early adulthood [21, 27]. People with BMI ≥ 35 have a worse survival rate after surgery for potentially curable PDAC. According to a retrospective study, patients with a BMI >35 are 12 times more likely to have lymph node metastasis, and their chances of recurrence and death double, compared with patients with BMI <35 [28]. Considering all of the above results, it is imperative to understand the underlying pathogenesis and implement obesity-specific prevention interventions for PDAC.

#### **2. Biologic pathogenesis**

The exact biologic interlink between obesity and PC remains unclear. PDAC represents more than 90% of all PC cases [8, 29]. PDAC develops from various precursor lesions, including mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), and pancreatic intraepithelial neoplasms (PanIN). PanINs are categorized into grades 1–3 which sequentially progress into PDAC. Several in vitro and in vivo studies are ongoing to decipher the molecular foundation of obesity-associated PDAC. A number of mechanisms are proposed, including, chronic inflammation, insulin resistance, circulatory lipids, adipokine and cytokine release, hormonal factors such as elevation of insulin-like growth factor 1 (IGF-1) and sex hormones, oxidative stress, changes in intestinal microbiome, food carcinogens, and potentiation by driver mutations. The pathogenesis is further convoluted with accumulating evidence of influence of variants in genes or genetic mutations in cell synthesis, metabolism, binding, and signaling [8, 30–32].

#### **2.1 Obesity and potentiation of Kras activity**

The activating mutations in the protooncogene Kras are the key driver mutation among 90% of the PDACs. It is the earliest genetic event in the pathogenesis noted in PanIN grade 1. In 98% of Kras mutated PDACs, missense mutations occur in glycine (G)12, G13, or glutamine71 (Q61) regions, that lead to the activation of Kras permanently [33]. In pancreatic Cre driver mice models, constitutive overexpression of active Kras G12D was identified as an important step in PanIN development and carcinogenesis [34]. Kras is found in almost all PDACs, but it is insufficient in developing PDAC. In mouse models, despite the expression of mutated Kras, mice did not readily develop into PanINs/PDACs [35]. Additional genetic, epigenetic, and tumor microenvironment alterations were required in the transformation into PDAC. The further accumulation of acquired genetic alterations in tumor suppressor genes, such as CDK2N2A, SMAD4, or TP53 contributed to the inhibition of pancreatic cell death and tumor transformation [36]. The non-genetic factors or alterations caused by other environmental factors including chronic inflammation or obesity in the tumor microenvironment are postulated to be critical steps in early steps of PanIN and progression into PDAC. Several preclinical studies have also convincingly demonstrated the accelerated transformation rates of ductal cells into PanIN among engineered obese mice [32]. In conditional KrasG12D mice model, an elevated risk of PDAC was observed among high-fat high-calorie-fed obese mice compared to normally fed non-obese mice, suggesting a synergistic effect of Kras and obesity [37]. Obesityassociated factors including insulin resistance, inflammation, and gut dysbiosis that are upstream of Kras enhance the downstream signals creating multi-loop effects [38]. Some have postulated the obesity-induced activation of signaling molecules

downstream of Kras, including increased levels of phosphorylated mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinases (ERK) may also be contributory [39]. Kras mutations further trigger the progression from PanIN1 to PanIN2. A positive feedback loop is created, demonstrating obesity and its tumor environment changes to be a major Kras potentiator, paving a path for prospective preventive avenues of this dismal cancer [29].

#### **2.2 Adipokines**

Adipose tissue (AT) is increasingly recognized as a dynamic hormonal and metabolically active organ that produces biologically active peptides known as adipokines. Adipocytes are capable of various internal and external cellular interactions which regulate cellular processes including food intake, insulin sensitivity, inflammation, and immune responses. Leptin and adiponectin are among the first identified and highly expressed adipokines; they are known to have opposing functions on immune cell activation [32, 40]. Other adipokines currently being evaluated include Lipocalin-2 (LCN-2), fibroblast growth factor (FGF)-21, and wingless-type mouse mammary tumor virus integration site family member 5A (Wnt5a).

Leptin is positively correlated to obesity. Higher Levels of leptin are found in women than men irrespective of BMI. Leptin plays a role in appetite control and as a pro-inflammatory modulator of pancreatic tissue. Hyperleptinemia in obesity is thought to be secondary to leptin resistance and therefore, the role of leptin in PDAC development remains controversial [41]. However, in vitro and clinical studies have demonstrated elevated serum leptin levels were higher among PDAC subjects [42]. Further studies are required to confirm its role and significance in clinical settings. Adiponectin is inversely correlated to obesity by its active role in insulin regulation, glucose and fatty acid metabolism, and overall anti-inflammatory properties. The imbalance created by adiponectin and leptin creates a pro-inflammatory pathway [40]. Several preclinical studies were consistent with adiponectin's role in pathogenesis however current evidence of adiponectin levels and PDAC is contradictory. Higher adiponectin levels correlated with lower PDAC in several prospective studies versus others showed higher levels correlated with increased risk [43, 44]. It is unclear if this is due to timing of adipokine level checking or if adipokines in pancreatic tumor environment did not correlate with serum adipokines levels, as opposed to mice studies where adipokines levels showed a positive correlation.

LCN-2 is a small extracellular protein with several biological functions including energy metabolism, inflammation, and innate immunity. Adipocytes secrete LCN-2 during metabolic stress and obesity, where LCN-2 acts as a homeostasis regulator. LCN-2 is implicated in T2DM, chronic pancreatitis, and more recently, in PDAC. Its role in both pro and anti-tumor effects has been reported. Absence of LCN-2 prevented obesity in high-fat-fed mice and decreases rate of pancreatic fibrosis, inflammation, and aberrant cell proliferation, proving its inclination toward antitumor activities. There is a need for more clinical studies to evaluate if LCN-2 could be a potential target in prevention of obesity and early stages of PDAC [45–47]. FGF-21 has recently come into spotlight as a regulator in glucose and lipid metabolism with the potential to treat obesity. Emerging data on its role in PDAC is underway [48]. In the presence of Kras oncogenic mutations in obese mice, FGF-21 levels were found to be significantly reduced and are implicated in the extensive inflammation, PanINs, and PDAC [49]. The intricate intracellular pathway remains unclear at this time. A pro-inflammatory adipokine, Wnt5a works in conjunction with secreted

frizzled-related protein (sfrp)-5 key regulators studied in obesity. Release of Wnt5a from visceral adipose tissue (VAT) and overexpression of Wnt5a has been reported in PDAC microenvironment have shown positive correlation to downstream activity of yes-associated protein (YAP) among Kras independent aggressive squamous subtype of PDAC which operates via YAP-mediated mechanisms [50]. Further pre-clinical studies are needed to confirm such an association.

Other AT-derived cytokines include interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha that is secreted by adipocytes via effect of leptin excess and macrophages in the tumor microenvironment plays a role in obesity accentuated chronic inflammatory process as well [51]. More recently, AT is studied to have effects systemically via soluble mediators released by visceral fat depots and reach pancreatic microenvironment through systemic circulation by extracellular vesicles produced by adipocytes which attach to targets on pancreatic cells [52]. It is unknown if these extracellular vesicles communicate with the precursor PanIN or PDAC cells differently from normal pancreatic cells.

Expansion and hypertrophy of AT in obesity creates an imbalance in inflammatory and anti-inflammatory cytokine release, subsequently lead to progression to PanIN and PDAC, as described in chronic inflammation section. A differential inflammatory process is well studied in visceral AT (intrabdominal fat pads, omental, mesenteric) compared to subcutaneous AT. Adipose hyperplasia is often seen in subcutaneous AT but is associated with low levels of inflammation and balanced insulin sensitivity. In contrast, hypertrophy and hyperplasia in visceral AT predominately cause the elevated pro-inflammatory response which strongly correlates with obesity-induced metabolic dysfunction and PanIN formation compared to subcutaneous AT [32, 53, 54]. The synergistic combination of elevated inflammatory response with systemic deposition of extracellular vesicles in pancreatic microenvironment is a well accepted mechanism in the pathogenesis of PDAC [54, 55]. While the differences between VAT and subcutaneous AT is well established, recent focus has driven toward intrapancreatic fat and "fatty pancreas disease" in PDAC carcinogenesis from metanalysis showing 52% pooled prevalence of intrapancreatic fat among PDAC and premalignant lesions [56]. This creates a platform for combinational effects of VAT expansion and fatty replacement of pancreas. This association remains under investigation and requires attention to guide future screening models incorporating intra-pancreatic fat measurements. A need for adequate tools to differentiate normal versus excess pancreatic fat on imaging remains a challenge.

#### **2.3 Hormonal effects and insulin resistance**

A high BMI and obesity are associated with elevated levels of insulin and C peptide levels, leading to hyperglycemia, insulin resistance, and type 2 diabetes mellitus (T2DM). All have demonstrated a role in the development of PDAC in prospective studies and meta-analysis [31, 57]. Elevated circulating and intrapancreatic insulin levels cause suppression of circulating insulin growth factor binding proteins (IGFBP)-1 and 2 and subsequently lead to higher levels of IGF-1. IGF-1 and insulin bind to IGF receptors (IGF-R) on pancreatic acinar cells and propagate cell proliferation, apoptosis, and angiogenesis [31, 58]. A crosstalk between insulin and IGF-R and G protein-coupled receptor (GPCR) signaling converges on the mechanistic target of rapamycin (mTOR) responsible for cell proliferation. Inhibitory function of metformin on insulin and IGF-R emerged its role in PDAC prevention [59, 60]. This crosstalk also stimulates YAP and transcriptional coactivator with PDZ binding motif

(TAZ) which are critical molecules in PDAC [61]. The individual levels of IGF-1, IGF-2, and IGFBP-3 did not correlate with the risk of PDAC. However, a higher IGF-1/ IGFBP-3 ratio represented increased free IGF-1 which showed a significant positive trend toward elevated risk of PDAC [62]. At this time, this ratio is not routinely used as a screening tool and would need further evidence in prospective studies. In obesity, increased insulin/IGF-1 and gastrointestinal peptides that activate the GPCRs further cause increased cell proliferation. Finally, elevated levels of glucose and advanced glycation end products are known to be tumor-promoting factors and important modulators in metabolic dysfunction and carcinogenesis [63].

Stress adaptiveness of pancreatic cells is another proposed mechanism of tumorigenesis by promoting cell growth and resistance to anti-cancer therapies. Recently, stress granules (SGs) have been described, which are the intracytoplasmic condensations of proteins and mRNA driven by oxidative stress, hypoxia, endoplasmic reticulum stress, and osmotic stress. A specific pathway described where IGF1 binds to IGF-R activates S6 kinase (S6K)-1 subsequently activates serine/ arginine protein kinase (SRPK)-2 and mediates the formation of IGF-1-driven SGs among obesity-induced PDAC carcinogenesis. This pathway of SRPK-2-dependent SGs formation highlights its uniqueness and context-specific to obesity-related pathway in PDAC however needs further validation. In addition, mutant Kras upregulates the capacity of PDAC cells to form SGs, further enhancing resistance to several stimuli and chemotherapeutic agents. However, SGs are considered to cause PDAC proliferation by Kras independent pathways as well and are thought to be one of the mechanisms of PDAC resistance to Kras targeted therapy [58].

Elevated estrogen activity was observed as an initiating factor in carcinogenesis. Leptin plays a role in transcription of aromatase; a key enzyme converts androstenedione and estrone to estrogen. The data on direct activity of these steroids on androgen and estrogen receptors on pancreatic cells remains unclear in the pathogenesis of PDAC but has shown some positive cell proliferation at low levels of estrogen compared to inhibition of cell proliferation with high doses [64]. However, further studies have shown mixed expression of estrogen receptors on PDAC cells and unclear benefits with anti-estrogen therapies and prognosis [64–66].

#### **2.4 Chronic inflammation**

Obesity is a chronic subclinical pro-inflammatory state. In general, overnutrition creates an imbalance between calorie intake and energy expenditure, leading to expansion of AT. AT expansion and imbalance of adipokines leads to reduction of anti-inflammatory immune cells such as CD4+ T helper (Th) 2 cells, IL-C2s, Tregs, eosinophils, type II natural killer (NK) T cells which occur in lean state. On the other end, AT expansion leads to activation of major histocompatibility complex (MHC) II expression and myeloid cells and stimulates CD8+ Th 1 inflammatory pathway sequentially activating interferon (IFN) gamma. This immune activation causes adipocyte apoptosis and histologic changes including formation of crown-shaped clusters of engulfed macrophages which is the signature of AT inflammation [32, 67, 68]. These hypertrophied adipocytes, lymphocytes, and macrophages in the AT increase the circulatory levels of cytokines such as TNF-alpha, IL-6, leptin, and adiponectin which promote inflammation and abnormal cell growth [69]. Chronic inflammation is a key mediator of carcinogenesis noted in several cancers. Alterations in fibro-inflammatory microenvironment triggers abnormal cell proliferation, halt apoptosis, activate angiogenesis, migration, and metastasis [69]. AT can also induce insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, vascular injury which are associated with oxidative stress [30].

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

Inflammatory cytokines and oxidative stress mainly activate the nuclear factor-kappa B (NF-kB) pathway leading to downstream activation of PanIN and PC carcinogenesis [30, 55]. Therefore, obesity-associated inflammation is a stronger risk factor for PC than chronic inflammation alone, due to this augmented interplay. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), a NFkB receptor is a key regulator of pancreatic cell metabolism, cell differentiation, and anti-inflammatory role is currently being evaluated as a potential target in prevention of PDAC [30].

#### **2.5 Gut and pancreatic microbiome**

Alteration of gut microbiota is well studied in obesity-associated metabolic dysfunction and development of T2DM [70]. Obesity-associated altered gut microbiome is implicated in colorectal and hepatocellular carcinoma [71, 72]. Over the recent years, obesity-associated genetic, environmental, and nutritional factors have been implicated in the disequilibrium and crosstalks between intrapancreatic, intratumoral, and gut microbiome and its role in PDAC [55, 73–75]. Akkermansia muciniphila an intestinal symbiotic bacterium that plays a role in maintaining a functioning gut barrier and its abundance is correlated to a lower incidence of obesity and other metabolic diseases. Metformin use in preclinical studies showed reduced levels of Clostridium sensu stricto and elevated levels of Akkermansia bacteria in high-fatfed mice, one of the possible benefits of metformin in PDAC prevention, introduced the possible underlying pathomechanism [76]. These microbiota dysbiosis causes a release of metabolites (short-chain fatty acids or lipopolysaccharides), activation of intestinal GPCRs, enabling gut permeability and translocation of bacteria/ bacterial

#### **Figure 1.**

*Several proposed pathways of PDAC carcinogenesis. Obesity potentiates the Kras pathway via PanIN progression. Kras further reduces pancreatic FGF-21 increasing cancer propagation. High BMI, insulin resistance, and a highfat diet contribute to increased insulin and visceral and intrapancreatic AT inflammation. AT-derived cytokine release and VAT stem cell translocation cause chronic pancreatic inflammation, including potentiation of Kras pathway. Changes in the gut microbiome cause pancreatic microbiome alterations, subsequently activating chronic inflammation via recruiting of M1 macrophages. Chronic fibroinflammatory changes lead to PanIN progression via NFkB pathway. Increased insulin and IGF-1 lead to stress granule formation that contributes to carcinogenesis via mTOR pathway independent of Kras pathway.*

components leading to a systemic pro inflammatory state [77]. Certain lipopolysaccharides (LPS) producing bacteria alter the microbial profile in pancreas by reducing probiotics and butyrate-producing bacteria. LPS acts as a pro-inflammatory protumor trigger by activating NFkB pathway which subsequently activates cytokines including IL-6, TNF, and IL-1. LPS excess could further lead to recruitment of proinflammatory M1-like macrophages, pancreatic fibrosis, chronic inflammation, and PanIN lesions [68, 74]. A positive feedback loop is initiated by amplification of Ras activity by NF-KB which triggers further inflammation and initiates a positive feedback loop found among oncogenic Ras activated mice [74].

#### **2.6 Food carcinogens**

Diet consisting of high grilled and fried meats, preservatives, some grains, and vegetables containing heterocyclic amines, aristolochic acids, polycyclic aromatic hydrocarbons, pyrrolizidine alkaloids, aflatoxins, acrylamide, N-nitroso compounds, and benzopyrenes have been positively associated with both obesity and PDAC in epidemiological studies [78–82]. An increased PC risk has been associated with higher exposure of these diets; however, evidence of temporal relationship and pathogenesis remains unclear. More recently, contradictory findings of deep-fried foods inversely related to risk of PDAC was found in prospective study (**Figure 1**) [83].

#### **3. Implications in prevention**

Epidemiology demonstrates obesity is one of the vital modifiable risk factors of PDAC [17–19]. Measures to combat obesity is therefore of utmost importance in prevention of this lethal cancer with delayed diagnosis, aggressive nature, and poor responses to current treatment options. At the national level, several strategies were implemented after the recognition of obesity as an epidemic. These include environmental changes, increase access to healthy foods, increasing fruit and vegetable intake, dietary approaches to stop hypertension (DASH) diet, encouraging breastfeeding, more physical activity for general health and cardiovascular disease prevention, and further focus on its role in PC prevention.

#### **3.1 Calorie restriction**

Animal models have shown calorie restriction slowed the PC growth and development. In a study using conditional KrasG12D mice, intermittent calorie restriction and chronic calorie restriction have shown a relatively lower percentage of PanIN3 lesions. Calorie restriction and diet modifications have been proven to reduce incidence of breast and endometrial cancers in observational studies. Efforts to combat obesity are increasingly identified. The biggest challenge is short-term weight loss occurs with calorie restriction and a vast majority of people cannot keep up and gain back the lost weight in the long term [55].

#### **3.2 Bariatric surgery**

A significant reduction in risk of PDAC and mortality was found in obese patients who underwent bariatric surgery consistently among several studies. Of note, 73% of patients in bariatric surgery arm were female and 79% were younger than 65 years

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

of age. Relatively small sample size and short follow-up duration studies were unable to detect a significant difference in PC risk. Several mechanisms are proposed in its beneficial role in PDAC. A significant reduction of inflammatory markers (CRP, IL-6) activated T cells ratio and increased anti-inflammatory regulatory T cells in epididymal adipose tissues was noted as early as 3 weeks post-surgery [84]. Bariatric surgery significantly improved insulin resistance and improved intestinal microbiota profile with equal benefits with both Roux-en-Y gastric bypass and vertical banded gastroplasty [85]. Bariatric surgery provides a long term and durable weight loss than calorie restriction. At this time, overall survival rates in PDAC patients who underwent prior bariatric surgery are unclear.

#### **3.3 Antidiabetic treatments**

Metformin is implicated in reduction of PC risk by inhibition of cell growth, proliferation, migration, and cell invasion, however, is still not completely understood [39, 59–61, 86]. Inhibition of crosstalk of GPCR and insulin/IGFR pathway, activation of liver kinase B1 (LKB1), repurposing the adenosine monophosphate-activated protein kinase (AMPK) and ultimately the disruption of downstream mTOR pathway is a well-accepted mechanism [59, 87]. Metformin also downregulates the expression of YAP and TAZ in pancreas acinar cells in addition to reduction of insulin/IGF-1 levels [39, 61]. Mice studies have shown metformin in high-fat-fed mice normalized the obesity-induced gut dysbiosis and maintained higher levels of Akkermansia related to Clostridium sensu stricto microbiota which helps in maintaining a functioning gut barrier [75]. In an epidemiological meta-analysis, metformin reduced the risk to onethird compared to other diabetic treatments [88]. Metformin has shown significant survival benefits in patients among T2DM, early stage and resected PCs in contrast to metastatic stages where the benefits were unclear per a large meta-analysis [89, 90]. It is proposed that in the later stages, amount of metformin is relatively less in the tumor cells to show its fullest benefits owing from the observation that metformin showed increased survival rates among resected advanced-stage PDAC. Overall, current evidence has not proven metformin-associated survival benefits in PDAC. Given its well tolerability, a potential beneficial role in chemoprevention is favored rather than therapeutic setting. Metformin is not currently a part of guideline-based protocols. Randomized controlled trials are required to explore this further. Recent evidence has shown synergistic effects of aspirin and metformin in chemoprevention in PDAC by inhibition of COX and NFKB pathway in addition to mTOR pathway which might essentially benefit obese population [74, 91].

The idea of use of thiozolidiones and PPAR-gamma agonists navigated its way into experimental studies of PDAC prevention, as PPAR-gamma a vital regulator in cell differentiation and inflammation. In vitro studies demonstrated that PPAR-gamma agonists induce apoptosis, ductal differentiation, reduce cell motility, tissue invasion, and arrest in G0/G1 phase by PPAR-gamma dependent and independent mechanisms [92]. PPAR-gamma agonists also alter the total urokinase activity by reducing urokinase plasminogen activator, which is causally involved in PDAC pathogenesis, further studies are required for its use in therapeutic setting [30].

#### **3.4 Anti-inflammatory agents**

Mice studies demonstrated disruption of NFkB-mediated inflammatory pathway by decreasing the expression of NFkB kinase 2 or Cox-2. Interruption of the positive

feedback loop by Cox-2 inhibitors is a potential preventive strategy among Ras-mediated cancers including pancreas, colon, and lung. This paved path for aspirin in PDAC and a synergistic effect with metformin, especially among obese patients [74]. However, an earlier prospective study of extended aspirin use showed statistically increased risk of PDAC among women [93]. Further studies are required for its validation.

#### **3.5 Fibroblast growth factor-21 supplements**

Normal pancreatic acinar cells express high levels of adipokine FGF-21 as described above. Among obese Kras mutated mice, FGF-21 levels were significantly low. In preclinical studies, FGF-21 injections have shown prevention of extensive inflammation, PanINs and PDAC among obese mice [48, 49]. FGF-21 might be used in chemoprevention and treatment of PDAC and requires further preclinical and clinical studies.

#### **3.6 Beta-blockers and statins**

Beta-blockers have come into focus in PDAC chemoprevention by its effects on downregulation of cAMP-dependent endothelin growth factor (EGF) and vaso endothelin (VEGF) production. Statins are being evaluated in PDAC prevention by its effects of inhibition of 3 hydroxy3 methylglutaryl coenzyme A (HMGcoA) reductase effects on degradation of TP53 and reduced Ras activity. However, these agents have not been studied in relation to obesity-associated PDAC [86].

#### **3.7 Screening**

Currently, no screening guidelines exist for PDAC in high-risk obesity. Computed tomography (CT) screening was evaluated in T2DM at the time of diagnosis, however, has not reached evidence of significance. A predefined elevated IGF-1/IGFBP-3 ratio could be used as a screening tool to identify high-risk obesity patients. It is possible to identify prediction models based on epigenomic, transcriptomic, and proteomic approaches for obesity-driven carcinogenesis using appropriate in vitro and in vivo models that may be used for early detection of PDAC in obese high-risk individuals [29].

#### **4. Implications in treatment**

Surgery remains the mainstay for curative intent. However, at presentation, only 15–20% of PDAC are resectable. For locally advanced unresectable and metastatic PDACs, palliative systemic therapy including combinational chemotherapy has shown improvement in disease-related symptoms and prolonged survival. Genetic testing is recommended in all newly diagnosed PDAC patients and molecular testing for mutations in metastatic setting. Currently, we have limited treatment options beyond first line therapies. Treatment choices must be weighed against best supportive care.

#### **4.1 Targeted agents**

At this time, there are limited targeted therapy options in PDAC outside of clinical trials. Currently, targeted options are approved for BReast CAncer gene (BRCA) 1/2 mutations (olaparib), Microsatellite Instability (MSI) high (pembrolizumab),

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

Neurotrophic tyrosine receptor kinase (NTRK) mutations (entrectinib, Larotrectinib), and B-Rapidly Accelerated Fibrosarcoma (BRAF) V600E mutations (Dabrafenib+ Trametinib) [94–98]. Although Kras mutations are major drivers of PDAC, several decades of research has not been able to find a targeted therapy against Kras due to its high affinity for GTP activity and absence of an amenable surface topologic target [33]. As a result, past efforts have mainly focused on indirect strategies to target the downstream signals. Recent success in identifying small molecules that directly bind to RAS, has fueled hope that RAS may be druggable after all. Sotorasib, a KrasG12C inhibitor traps Kras in the inactive GDP-bound conformational state by fitting tightly into a unique phosphate binding pocket and is recently FDA approved. A phase 1/2 trial, CodeBreak100 (NCT03600883), demonstrated that 8/38 (21%) patients had confirmed partial responses and 32/38 (84%) patients had disease control in a median follow-up of 16.8 months. Only 1–2% of PDAC patients have KrasG12C mutations and its inhibitor is clinically meaningful in these cases [99, 100]. Currently, there are ongoing trials for KrasG12D siRNA-targeted therapies (NCT03608631). Understanding pathogenesis of obesity-driven PDAC could potentially recognize further therapeutic targets. Several studies in preclinical settings are ongoing for targeting various steps in the pathogenesis of PDAC. One such example is blocking the downstream step of SG formation. Hyperactivation of IGF-1/PI3K/ mTOR/S6K1 pathway leads to SRPK2-mediated SG formation, a vital step in obesityassociated PDAC. S6K1 inhibition selectively attenuates IGF-1-driven SGs formation and can potentially be a treatment target [58].

#### **4.2 Future perspectives for adjunctive therapies**

Strategies for microbiome modification or other options could potentially control metabolic endotoxemia as an adjunctive treatment of PDAC remains unknown [70].

#### **4.3 Exercise interventions**

Individualized exercise interventions are increasingly identified as effective therapy as an adjunct in PDAC management, improving quality and quantity of life, reducing treatment side effects, enhancing fitness preoperatively, combating cancer-related fatigue, and overall psychological health benefits [101–103]. Aerobic and resistance exercise reduced symptoms of depression and anxiety in all PDAC stages and settings, in line with other common cancers such as breast cancer [103, 104]. Exercise regimens tailored to improve skeletal muscle health preoperatively and in neoadjuvant settings has shown to improve clinical and quality of life outcomes [101, 105]. The feasibility of multimodal cachexia intervention with resistance training, nutritional supplements, and anti-inflammatory agents such as celecoxib was tested in PDAC-related cachexia. These modalities have cleared the safety threshold and compliance goals. Currently, phase II studies are underway to test the efficacy [106, 107]. A systematic review that looked at overall exercise effects did not show any adverse effects related to exercise in PDAC patients. However, limitation includes a smaller sample size and finite data from case reports/studies. Overall results supported safety and feasibility of exercise training in PDAC patients [103]. The underlying mechanism of this benefit remains unclear. Due to the high burden of disease and treatment-related adverse effects, exercise compliance also is a major challenge for PDAC patients. Individualized regular exercise regimens and shorter assessment intervals are required to evaluate the short-term benefits of exercise in a disease which has shorter life expectancy.

#### **5. Conclusion**

Obesity is a major independent and modifiable risk factor of PDAC. The biological link between obesity and PDAC is complex and convoluted. The interplay is driven by genetic, hormonal factors, insulin resistance, adipokines, circulating lipids, and gut microbiome dysbiosis. These findings indicate that there is unlikely to be a single mechanism to explain obesity-associated PDAC. Awareness and deeper knowledge could help implement potential preventive measures (diet modifications, exercise, and bariatric surgeries) and treatment modalities. Prospective trials to evaluate metformin in chemoprevention, screening in high-risk obese populations, risk predictive models, KrasG12D directed therapies, adjunct use of gut microbiota transplantation, and personalized therapies are some future perspectives.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **List of abbreviations**


*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*


#### **Appendices and nomenclature**

None.

#### **Author details**

Nikitha Vobugari and Kai Sun\* Department of Hematology/Oncology, Houston Methodist Hospital, Houston, TX, USA

\*Address all correspondence to: ksun2@houstonmethodist.org

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Ali H, Pamarthy R, Vallabhaneni M, Sarfraz S, Ali H, Rafique H. Pancreatic cancer incidence trends in the United States from 2000-2017: Analysis of Surveillance, Epidemiology and End Results (SEER) database [version 1; peer review: 2 approved]. F1000Research. 2021;**10**:529. DOI: 10.12688/ f1000research.54390.1

[2] Moshayedi N, Escobedo AL, Thomassian S, Osipov A, Hendifar AE. Race, sex, age, and geographic disparities in pancreatic cancer incidence. Journal of Clinical Oncology. 2022;**40**(4\_suppl):520

[3] McWilliams RR, Maisonneuve P, Bamlet WR, Petersen GM, Li D, Risch HA, et al. Risk factors for earlyonset and very-early-onset pancreatic adenocarcinoma: A Pancreatic Cancer Case-Control Consortium (PanC4) Analysis. Pancreas. 2016;**45**(2):311-316

[4] Wu W, He X, Yang L, Wang Q, Bian X, Ye J, et al. Rising trends in pancreatic cancer incidence and mortality in 2000-2014. Clinical Epidemiology. 2018;**10**:789-797

[5] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a Cancer Journal for Clinicians. 2021;**71**(3):209-249

[6] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a Cancer Journal for Clinicians. 2010;**60**(5):277-300

[7] American Cancer Society. Cancer facts & figures. Atlanta American Cancer Society. 2022;**2022**:1-80

[8] Hu JX, Lin YY, Zhao CF, Chen WB, Liu QC, Li QW, et al. Pancreatic cancer: A review of epidemiology, trend, and risk factors. World Journal of Gastroenterology. 2021;**27**(27):4298-4321

[9] Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. Journal of the American Medical Association. 2002;**288**(14):1723-1727

[10] Physical status: The use and interpretation of anthropometry. World Health Organization Technical Report Series. 1995;**854**:1-452. PMID: 8594834

[11] Garrow JS, Webster J. Quetelet's index (W/H2) as a measure of fatness. International Journal of Obesity. 1985;**9**(2):147-153

[12] Stierman B, Afful J, Carroll MD, Chen TC, Davy O, Fink S, et al. National health and nutrition examination survey 2017–March 2020 prepandemic data files-development of files and prevalence estimates for selected health outcomes. National Health Statistics Reports. 2021;**2021**(158). DOI: 10.15620/ cdc:106273

[13] Dietz WH. The response of the US Centers for Disease Control and Prevention to the obesity epidemic. Annual Review of Public Health. 2015;**36**:575-596

[14] Restrepo BJ. Obesity prevalence among U.S. adults during the COVID-19 pandemic. American Journal of Preventive Medicine. 2022;**63**(1):102-106

[15] U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, Based on 2021 Submission Data (1999-2019). U.S. *Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2022 Available from: https:// gis.cdc.gov/Cancer/USCS/#/RiskFactors/

[16] Davoodi SH, Malek-Shahabi T, Malekshahi-Moghadam A, Shahbazi R, Esmaeili S. Obesity as an important risk factor for certain types of cancer. Iranian Journal of Cancer Prevention. 2013;**6**(4):186-194

[17] Arslan AA, Helzlsouer KJ, Kooperberg C, Shu XO, Steplowski E, Bueno-De-Mesquita HB, et al. Anthropometric measures, body mass index, and pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium (PanScan). Archives of Internal Medicine. 2010;**170**(9):791-802

[18] Jiao L, Berrington De Gonzalez A, Hartge P, Pfeiffer RM, Park Y, Freedman DM, et al. Body mass index, effect modifiers, and risk of pancreatic cancer: A pooled study of seven prospective cohorts. Cancer Causes & Control. 2010;**21**(8):1305-1314

[19] Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet. 2008;**371**(9612):569-578

[20] Aune D, Greenwood DC, Chan DSM, Vieira R, Vieira AR, Navarro Rosenblatt DA, et al. Body mass index, abdominal fatness and pancreatic cancer risk: A systematic review and nonlinear dose-response meta-analysis of prospective studies. Annals of Oncology. 2012;**23**(4):843-852

[21] Kasenda B, Bass A, Koeberle D, Pestalozzi B, Borner M, Herrmann R, et al. Survival in overweight patients

with advanced pancreatic carcinoma: A multicentre cohort study. BMC Cancer. 29 Sep 2014;**14**(1):728. DOI: 10.1186/1471-2407-14-728. PMID: 25266049; PMCID: PMC4242603

[22] Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009;**301**(24):2553-2562

[23] Johansen D, Stocks T, Jonsson H, Lindkvist B, Björge T, Concin H, et al. Metabolic factors and the risk of pancreatic cancer: A prospective analysis of almost 580,000 men and women in the metabolic syndrome and cancer project. Cancer Epidemiology, Biomarkers & Prevention. 2010;**19**(9):2307-2317

[24] Genkinger JM, Spiegelman D, Anderson KE, Bernstein L, Van Den Brandt PA, Calle EE, et al. A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk. International Journal of Cancer. 2011;**129**(7):1708-1717

[25] Zohar L, Rottenberg Y, Twig G, Katz L, Leiba A, Derazne E, et al. Adolescent overweight and obesity and the risk for pancreatic cancer among men and women: A nationwide study of 1.79 million Israeli adolescents. Cancer. 2019;**125**(1):118-126

[26] Silverman DT, Swanson CA, Gridley G, Wacholder S, Greenberg RS, Brown LM, et al. Dietary and nutritional factors and pancreatic cancer: A casecontrol study based on direct interviews. Journal of the National Cancer Institute. 1998;**90**(22):1710-1719

[27] Genkinger JM, Kitahara CM, Bernstein L, Berrington de Gonzalez A, Brotzman M, Elena JW, et al. Central adiposity, obesity during early adulthood, and pancreatic cancer

mortality in a pooled analysis of cohort studies. Annals of Oncology. 2015;**26**(11):2257-2266

[28] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. Adults. The New England Journal of Medicine. 2003;**348**(17):1625-1638

[29] Kfoury S, Michl P, Roth L. Modeling obesity-driven pancreatic carcinogenesis—A review of current in vivo and in vitro models of obesity and pancreatic carcinogenesis. Cell. 10 Oct 2022;**11**(19):3170. DOI: 10.3390/ cells11193170. PMID: 36231132; PMCID: PMC9563584

[30] Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World Journal of Gastroenterology. 2016;**22**(8):2441-2459

[31] Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Archives of Physiology and Biochemistry. 2008;**114**(1):63-70

[32] Eibl G, Rozengurt E. Obesity and pancreatic cancer: Insight into mechanisms. Cancers (Basel). 10 Oct 2021;**13**(20):5067. DOI: 10.3390/ cancers13205067. PMID: 34680216; PMCID: PMC8534007

[33] Waters AM, Der CJ. KRAS: The critical driver and therapeutic target for pancreatic cancer. Cold Spring Harbor Perspectives in Medicine. 4 Sep 2018;**8**(9):a031435. DOI: 10.1101/ cshperspect.a031435. PMID: 29229669; PMCID: PMC5995645

[34] Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;**4**(6):437-450

[35] Notta F, Hahn SA, Real FX. A genetic roadmap of pancreatic cancer: Still evolving. Gut. 2017;**66**(12):2170-2178

[36] Iacobuzio-Donahue CA. Genetic evolution of pancreatic cancer: Lessons learnt from the pancreatic cancer genome sequencing project. Gut. 2012;**61**(7):1085-1094

[37] Dawson DW, Hertzer K, Moro A, Donald G, Chang HH, Go VL, et al. High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prevention Research. 2013;**6**(10):1064-1073

[38] Eibl G, Rozengurt E. KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. Seminars in Cancer Biology. 2019;**54**:50-62

[39] Chang HH, Moro A, Chou CEN, Dawson DW, French S, Schmidt AI, et al. Metformin decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity in the conditional KrasG12D Mouse Model. Scientific Reports. 12 Apr 2018;**8**(1):5899. DOI: 10.1038/s41598-018-24337-8. PMID: 29651002; PMCID: PMC5897574

[40] Bracci PM. Obesity and pancreatic cancer: Overview of epidemiologic evidence and biologic mechanisms. Molecular Carcinogenesis. 2012;**51**(1):53-63

[41] Izquierdo AG, Crujeiras AB, Casanueva FF, Carreira MC. Leptin, obesity, and leptin resistance: Where are we 25 years later? Nutrients. 8 Nov 2019;**11**(11):2704. DOI: 10.3390/ nu11112704. PMID: 31717265; PMCID: PMC6893721

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

[42] Friedman J. The long road to leptin. The Journal of Clinical Investigation. 2016;**126**(12):4727-4734

[43] Bao Y, Giovannucci EL, Kraft P, Stampfer MJ, Ogino S, Ma J, et al. A prospective study of plasma adiponectin and pancreatic cancer risk in five US cohorts. Journal of the National Cancer Institute. 2013;**105**(2):95-103

[44] Dranka-Bojarowska D, Lekstan A, Olakowski M, Jablonska B, Lewinski A, Musialski P, et al. The assessment of serum concentration of adiponectin, leptin and serum carbohydrate antigen-19.9 in patients with pancreatic cancer and chronic pancreatitis. Journal of Physiology and Pharmacology. 2015;**66**(5):653-663

[45] Moniaux N, Chakraborty S, Yalniz M, Gonzalez J, Shostrom VK, Standop J, et al. Early diagnosis of pancreatic cancer: Neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia. British Journal of Cancer. 2008;**98**(9):1540-1547

[46] Xu B, Jin DY, Lou WH, Wang DS. Lipocalin-2 is associated with a good prognosis and reversing epithelial-tomesenchymal transition in pancreatic cancer. World Journal of Surgery. 2013;**37**(8):1892-1900

[47] Tong Z, Kunnumakkara AB, Wang H, Matsuo Y, Diagaradjane P, Harikumar KB, et al. Neutrophil gelatinase-associated lipocalin: A novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Research. 2008;**68**(15):6100-6108

[48] Lu W, Li X, Luo Y. FGF21 in obesity and cancer: New insights. Cancer Letters. 2021;**499**:5-13

[49] Luo Y, Yang Y, Liu M, Wang D, Wang F, Bi Y, et al. Oncogenic KRAS reduces expression of FGF21 in

acinar cells to promote pancreatic tumorigenesis in mice on a high-fat diet. Gastroenterology. 2019;**157**(5): 1413-1428.e11

[50] Tu B, Yao J, Ferri-Borgogno S, Zhao J, Chen S, Wang Q, et al. YAP1 oncogene is a context-specific driver for pancreatic ductal adenocarcinoma. JCI. Insight. 2019;**4**(21)

[51] Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature Reviews. Immunology. Feb 2011;**11**(2):85-97. DOI: 10.1038/nri2921. Epub 2011 Jan 21. PMID: 21252989; PMCID: PMC3518031

[52] Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metabolism. 2021;**33**(9):1853-1868.e11

[53] Rebours V, Gaujoux S, D' Assignies G, Sauvanet A, Ruszniewski P, Lévy P, et al. Obesity and fatty pancreatic infiltration are risk factors for pancreatic precancerous lesions (PanIN). Clinical Cancer Research. 2015;**21**(15):3522-3528

[54] Hertzer KM, Xu M, Moro A, Dawson DW, Du L, Li G, et al. Robust early inflammation of the peripancreatic visceral adipose tissue during dietinduced obesity in the KRASG12D model of pancreatic cancer. Pancreas. 2016;**45**(3):458-465

[55] Xu M, Jung X, Hines OJ, Eibl G, Chen Y. Obesity and pancreatic cancer: Overview of epidemiology and potential prevention by weight loss. Pancreas. 2018;**47**(2):158-162

[56] Sreedhar UL, DeSouza SV, Park B, Petrov MS. A systematic review of intra-pancreatic fat deposition and pancreatic carcinogenesis.

Journal of Gastrointestinal Surgery. 2020;**24**(11):2560-2569

[57] Abbruzzese JL, Andersen DK, Borrebaeck CAK, Chari ST, Costello E, Cruz-Monserrate Z, et al. The interface of pancreatic cancer with diabetes, obesity, and inflammation: Research gaps and opportunities: Summary of a national Institute of Diabetes and digestive and kidney diseases workshop. Pancreas. 2018;**47**(5):516-525

[58] Fonteneau G, Redding A, Hoag-Lee H, Sim ES, Heinrich S, Gaida MM, et al. Stress granules determine the development of obesityassociated pancreatic cancer. Cancer Discovery. 2022;**12**(8):1984-2005

[59] Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Research. 2009;**69**(16):6539-6545

[60] Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between insulin/ insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: A novel target for the antidiabetic drug metformin in pancreatic cancer. Clinical Cancer Research. 2010;**16**(9):2505-2511

[61] Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domaincontaining transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World Journal of Gastroenterology. 2019;**25**(15):1797-1816

[62] Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, Stolzenberg-Solomon RZ. Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening

trial. Cancer Epidemiology, Biomarkers & Prevention. 2010;**19**(9):2298-2306

[63] Garay-Sevilla ME, Gomez-Ojeda A, González I, Luévano-Contreras C, Rojas A. Contribution of RAGE axis activation to the association between metabolic syndrome and cancer. Molecular and Cellular Biochemistry. 2021;**476**(3):1555-1573

[64] Polvani S, Tarocchi M, Tempesti S, Galli A. Nuclear receptors and pathogenesis of pancreatic cancer. World Journal of Gastroenterology. 2014;**20**(34):12062-12081

[65] Chan KS, Ho BCS, Shelat VG. A pilot study of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC). Translational Gastroenterology and Hepatology. 5 Jan 2021;**6**:9. DOI: 10.21037/tgh.2020.02.16. PMID: 33409403; PMCID: PMC7724184

[66] Seeliger H, Pozios I, Assmann G, Zhao Y, Müller MH, Knösel T, et al. Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma. BMC Cancer. 29 Oct 2018;**18**(1):1049. DOI: 10.1186/s12885-018-4973-6. PMID: 30373552; PMCID: PMC6206939

[67] Martinez-Santibañez G, Cho KW, Lumeng CN. Imaging white adipose tissue with confocal microscopy. Methods in Enzymology. 2014;**537**:17-30

[68] Teper Y, Eibl G. Pancreatic macrophages: Critical players in obesitypromoted pancreatic cancer. Cancers (Basel). 2020;**12**(7):1-16

[69] Deng T, Lyon CJ, Bergin S, Caligiuri MA, Hsueh WA. Obesity, inflammation, and cancer. Annual Review of Pathology: Mechanisms of Disease. 2016;**11**:421-449

[70] Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, *Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;**57**(6):1470-1481

[71] Chen J, Pitmon E, Wang K. Microbiome, inflammation and colorectal cancer. Seminars in Immunology. 2017;**32**:43-53

[72] Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;**499**(7456):97-101

[73] Thomas RM, Gharaibeh RZ, Gauthier J, Beveridge M, Pope JL, Guijarro MV, et al. Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models. Carcinogenesis. 2018;**39**(8):1068-1078

[74] Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, et al. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. The Journal of Clinical Investigation. 2012;**122**(4):1519-1528

[75] Dong TS, Chang HH, Hauer M, Lagishetty V, Katzka W, Rozengurt E, et al. Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2019;**317**(6):G763-G772

[76] Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: Relationship with gut microbiome richness and ecology. Gut. 2016;**65**(3):426-436

[77] Boutagy NE, McMillan RP, Frisard MI, Hulver MW. Metabolic endotoxemia with obesity: Is it real and is it relevant? Biochimie. 2016;**124**:11-20

[78] Anderson KE, Kadlubar FF, Kulldorff M, Harnack L, Gross M, Lang NP, et al. Dietary intake of heterocyclic amines and benzo(a)pyrene: Associations with pancreatic cancer. Cancer Epidemiology, Biomarkers & Prevention. 2005;**14**(9):2261-2265

[79] Li D, Day RS, Bondy ML, Sinha R, Nguyen NT, Evans DB, et al. Dietary mutagen exposure and risk of pancreatic cancer. Cancer Epidemiology, Biomarkers & Prevention. 2007;**16**(4):655-661

[80] Anderson KE, Sinha R, Kulldorff M, Gross M, Lang NP, Barber C, et al. Meat intake and cooking techniques: Associations with pancreatic cancer. Mutation Research, Fundamental and Molecular Mechanisms of Mutagenesis. 2002;**506-507**:225-231

[81] Stolzenberg-Solomon RZ, Cross AJ, Silverman DT, Schairer C, Thompson FE, Kipnis V, et al. Meat and meat-mutagen intake and pancreatic cancer risk in the NIH-AARP cohort. Cancer Epidemiology, Biomarkers & Prevention. 2007;**16**(12):2664-2675

[82] Kobets T, Smith BPC, Williams GM. Food-borne chemical carcinogens and the evidence for human cancer risk. Food. 2022;**11**(18):88-100

[83] Zhong GC, Zhu Q, Gong JP, Cai D, Hu JJ, Dai X, et al. Fried food consumption and the risk of pancreatic cancer: A large prospective multicenter study. Frontiers in Nutrition. 22 Jul 2022;**9**:889303. DOI: 10.3389/fnut.2022.889303. PMID: 35958255; PMCID: PMC9362838

[84] Schneck AS, Iannelli A, Patouraux S, Rousseau D, Bonnafous S, Bailly-Maitre B, et al. Effects of sleeve gastrectomy in high fat diet-induced obese mice: Respective role of reduced caloric intake, whiteadipose tissue inflammation and changes in adipose tissue and ectopic fat depots. Surgical Endoscopy. 2014;**28**(2):592-602

[85] Tremaroli V, Karlsson F, Werling M, Ståhlman M, Kovatcheva-Datchary P, Olbers T, et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metabolism. 2015;**22**(2):228-238

[86] Miyaki C, Lynch LM. An update on common pharmaceuticals in the prevention of pancreatic cancer. Cureus. 30 May 2022;**14**(5):e25496. DOI: 10.7759/ cureus.25496. PMID: 35800820; PMCID: PMC9246430

[87] Sinnett-Smith J, Kisfalvi K, Kui R, Rozengurt E. Metformin inhibition of mTORC1 activation, DNA synthesis and proliferation in pancreatic cancer cells: Dependence on glucose concentration and role of AMPK. Biochemical and Biophysical Research Communications. 2013;**430**(1):352-357

[88] Wang Z, Lai S t, Xie L, Dong ZJ, Yi MN, Zhu J, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2014;**106**(1):19-26

[89] Li X, Li T, Liu Z, Gou S, Wang C. The effect of metformin on survival of patients with pancreatic cancer: A meta-analysis. Scientific Reports. 19 Jul 2017;**7**(1):5825. DOI: 10.1038/s41598- 017-06207-x. PMID: 28724893; PMCID: PMC5517652

[90] Zhou PT, Li B, Liu FR, Zhang MC, Wang Q, Li YY, et al. Metformin is

associated with survival benefit in pancreatic cancer patients with diabetes: A systematic review and metaanalysis. Oncotarget. 2017;**8**(15):25242-25250

[91] Yue W, Yang CS, DiPaola RS, Tan XL. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prevention Research. 2014;**7**(4):388-397

[92] Hong J, Samudio I, Liu S, Abdelrahim M, Safe S. Peroxisome proliferator-activated receptor γ-dependent activation of p21 in Panc-28 pancreatic cancer cells involves Sp1 and Sp4 proteins. Endocrinology. 2004;**145**(12):5774-5785

[93] Schernhammer ES, Kang JH, Chan AT, Michaud DS, Skinner HG, Giovannucci E, et al. A prospective study of aspirin use and the risk of pancreatic cancer in women. Journal of the National Cancer Institute. 2004;**96**(1):22-28

[94] Salama AKS, Li S, Macrae ER, Park JI, Mitchell EP, Zwiebel JA, et al. Dabrafenib and trametinib in patients with tumors with BRAFV600E mutations: Results of the NCI-MATCH trial subprotocol H. Journal of Clinical Oncology. 2020;**38**(33):3895-3904

[95] Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, de Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/ mismatch repair–deficient cancer: Results from the phase II KEYNOTE-158 study. Journal of Clinical Oncology. 2020;**38**(1):1-10

[96] Hammel P, Vitellius C, Boisteau É, Wisniewski M, Colle E, Hilmi M, et al. Maintenance therapies in metastatic pancreatic cancer: Present and future with a focus

*Obesity and Pancreatic Cancer: Its Role in Oncogenesis DOI: http://dx.doi.org/10.5772/intechopen.110216*

on PARP inhibitors. Therapeutic Advances in Medical Oncology. 9 Jul 2020;**12**:1758835920937949. DOI: 10.1177/1758835920937949. PMID: 32695234; PMCID: PMC7350045

[97] Wang S, Zheng Y, Yang F, Zhu L, Zhu XQ, Wang ZF, et al. The molecular biology of pancreatic adenocarcinoma: Translational challenges and clinical perspectives. Signal Transduction and Targeted Therapy. 5 Jul 2021;**6**(1):249. DOI: 10.1038/s41392-021-00659-4. PMID: 34219130; PMCID: PMC8255319

[98] Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH, et al. Metastatic pancreatic cancer: ASCO guideline update. Journal of Clinical Oncology. 2020;**38**(27):3217-3230

[99] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS G12C inhibition with sotorasib in advanced solid tumors. The New England Journal of Medicine. 2020;**383**(13):1207-1217

[100] Strickler JH, Satake H, Hollebecque A, Sunakawa Y, Tomasini P, Bajor DL, et al. First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: A phase I/II study evaluating efficacy and safety. Journal of Clinical Oncology. 2022;**40**(36\_suppl):360490

[101] Singh F, Newton RU, Galvão DA, Spry N, Baker MK. A systematic review of pre-surgical exercise intervention studies with cancer patients. Surgical Oncology. 2013;**22**(2):92-104

[102] Speck RM, Courneya KS, Mâsse LC, Duval S, Schmitz KH. An update of controlled physical activity trials in cancer survivors: A systematic review and meta-analysis. Journal of Cancer Survivorship. 2010;**4**(2):87-100

[103] Luo H, Galvão DA, Newton RU, Lopez P, Tang C, Fairman CM, et al.

Exercise medicine in the management of pancreatic cancer: A systematic review. Pancreas. 2021;**50**(3):280-292

[104] Cormie P, Spry N, Jasas K, Johansson M, Yusoff IF, Newton RU, et al. Exercise as medicine in the management of pancreatic cancer: A case study. Medicine and Science in Sports and Exercise. 2014;**46**(4):664-670

[105] Parker NH, Gorzelitz J, Ngo-Huang A, Caan BJ, Prakash L, Garg N, et al. The role of home-based exercise in maintaining skeletal muscle during preoperative pancreatic cancer treatment. Integrative Cancer Therapies. Jan-Dec 2021;**20**:1534735420986615. DOI: 10.1177/1534735420986615. PMID: 33870744; PMCID: PMC8056559

[106] Solheim TS, Laird BJA, Balstad TR, Stene GB, Bye A, Johns N, et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle. 2017;**8**(5):778-788

[107] Naito T, Mitsunaga S, Miura S, Tatematsu N, Inano T, Mouri T, et al. Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-smallcell lung cancer. Journal of Cachexia, Sarcopenia and Muscle. 2019;**10**(1):73-83

#### **Chapter 3**

## Epidemiology and Risk Factors of Pancreatic Cancer

*Michele Molinari, Hao Liu and Christof Kaltenmeier*

#### **Abstract**

Pancreatic cancer (PC) is among the most common tumors of the gastrointestinal system in the world. In the United States and in other industrialized countries, it represents the fourth leading cause of cancer-related mortality. The incidence of PC increases with age and most patients are diagnosed after the age of 50. The overall prognosis of PC is poor. Most tumors are silent and they often present when metastatic. Only less than 15% of patients can undergo surgery, which represents the only potential cure for PC, and less than 10% of patients are alive after 5 years. In this chapter, we present the epidemiology of PC and its most common risk factors.

**Keywords:** pancreatic cancer, risk factors, epidemiology, screening for pancreatic cancer, nutritional status and pancreatic cancer

#### **1. Introduction**

Worldrwide, pancreatic cancer (PC) is the 12th most common cancer [1] and the fourth leading cause of cancer-related mortality in the United States with estimated 42,500 new cases and 35,000 deaths each year [2] (**Figure 1**). The agestandardized incidence of PC is 4.9 per 100,000 individuals [1] (**Figure 2**). There are significant variations in the incidence of PC among different geographical areas (**Figure 3**). In high-income countries, the incidence of PC is much higher than in low-income countries (11 vs. 3 per 100,000 individuals). PC ranks fifth after colorectal cancer, gastric cancer, hepatic cancer, and esophageal cancer among all gastrointestinal malignancies [3] (**Table 1**). Over time, the mortality rate for males has decreased by 0.4% while the mortality rate for females has increased by 4.4% [2]. More than 80% of PCs are diagnosed in patients older than 60 and almost 50% have distant metastases at the time of their clinical presentation [3–5]. Men are more frequently affected than women (Relative Risk (RR) = 1.3) and individuals of African American descent are at a higher risk in comparison to Caucasians (RR = 1.5) [3]. Despite some improvements in early diagnosis, surgical therapy, neoadjuvant therapy, adjuvant therapy and palliative interventions, the overall survival of patients with PC is still quite poor with only 6-9% of all patients being alive after 5 years (**Figure 4**) [6].

#### *Pancreatic Cancer – Updates in Pathogenesis, Diagnosis and Therapies*

#### **Figure 1.**

*Estimated age-standardized mortality rates of the most common types of malignancies in 2020 for patients older than 50 years in Canada and in the United States (data from the World Health Organization; https://gco.iarc.fr/).*

#### **Figure 2.**

*Age-standardized incidence of pancreatic cancer in the world (4.9 per 100,000 individuals) and in selected countries with high incidence of the tumor (data from the World Health Organization; https://gco.iarc.fr/).*

#### **Figure 3.**

*Estimated age-standardized incidence of pancreatic cancer in the world for individuals older than 50 years (data from the World Health Organization; https://gco.iarc.fr/).*

*Epidemiology and Risk Factors of Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.109778*


*All ages, crude, and age-standardized rates per 100,000 individuals (data from the World Health Organization; https:// gco.iarc.fr/).*

#### **Table 1.**

*Estimated number of patients diagnosed with cancer with exclusion of nonmelanoma skin cancer, worldwide in 2020.*

#### **Figure 4.**

*Estimated age-standardized mortality rate of pancreatic cancer in different parts of the world for individuals older than 50 years (data from the World Health Organization; https://gco.iarc.fr/).*

#### **2. Risk factors**

The strongest risk factor for PC is age. The incidence of PC increases significantly after the age of 50 and over 80% of PCs are diagnosed in patients older than 60 [7] (**Figure 5**).

**Figure 5.**

*Incidence of pancreatic cancer in Canada during the period between 2011 and 2013 per 100,000 individuals stratified by age.*

#### **2.1 Smoking**

The risk of PC in smokers ranks second to lung cancer [8] and it is proportionate to the frequency (≥30 cigarettes per day: Odds Ratio (OR) = 1.75), duration (≥50 years: OR = 2.13), and cumulative smoking dose (≥40 pack/years: OR = 1.78) [9]. A meta-analysis of 82 studies from 4 continents has shown that cigarette smokers were diagnosed at significantly younger ages and had a 75% increased risk of developing PC in comparison to the regular population [10], and the risk persisted for 5 to 15 years after cessation [11]. In a case–control study of 808 PC patients matched against 808 healthy controls, in comparison to male counterparts, female smokers were at increased risk of developing PC as they suffered from a synergistic interaction between cigarette smoking, diabetes mellitus (OR = 9.3), and family history of PC (OR = 12.8) [12].

#### **2.2 Diabetes**

Nearly 80% of PC patients have either frank diabetes or impaired glucose tolerance at the time of their diagnosis [13]. Diabetes is often found concomitantly or during the two years preceding the diagnosis of PC [14]. Several studies have assessed the link between diabetes and PC with conflicting results. A meta-analysis of 11 cohort studies found that the relative risk for diabetic patients was 2.1 (95% CI 1.6–2.8) in comparison to nondiabetic individuals [15]. These findings were supported by another cohort study of 100,000 Danish diabetic patients that found a standardized incidence ratio of 2.1 (95% CI 1.9–2.4) [16]. A large prospective cohort study of 20,475 men and 15,183 women in the United States, has shown that the relative risk of dying from PC adjusted for age, race, history of cigarette smoking, and body mass index (BMI) was proportionate to the severity of diabetes. The RR was 1.65 for post-load plasma glucose levels between 6.7 and 8.8 mmol/L, 1.60 for levels between 8.9 and 11.0 mmol/L, and 2.15 for levels equal or more than 11.1 mmol/L [17]. Diabetes can present as an early manifestation of PC. Approximately 1% of new onset of diabetes in patients older than 50 is linked to PC [18]. Despite these findings, there is no evidence that screening patients for PC when newly diagnosed with diabetes [19] could reduce their mortality risk [5].

It is important to highlight that the link between abnormal glycemia and PC exists only for type II diabetes. A meta-analysis of 36 studies indicated that the OR of PC for patients with type II diabetes was 2.1 [20] while there are no reports showing an association between PC and type I diabetes [21].

Family history of diabetes does not appear to be a risk factor for PC [22]. On the other hand, a recent prospective study found that women with gestational diabetes are at a higher risk of developing PC with an estimated relative risk of 7.1 (95% CI = 2.8–18.0) [23]. Gapstur and colleagues [17] have proposed that high levels of insulin can cause abnormalities in the regulation of the insulin-like growth factor I (IGF1) receptor [19] that down-regulates the IGF binding protein 1, (IGFBP1) [20] causing an increase cell growth in PC cell lines [24, 25].

#### **2.3 Alcohol**

The role of alcohol in the predisposition of PC is controversial. Several studies have shown inconsistent findings due to multiple associations between alcohol consumption and other confounders such as cigarette smoking, lower socioeconomic status [26], and history of pancreatitis and diabetes [25]. A recent pooled analysis of 14 cohort studies with a sample of 862,664 individuals has shown a slight positive association

between PC and alcohol consumption when larger than 30 gm/day (RR 1.22; 95% CI 1.03–1.45) [27]. On the other hand, a smaller epidemiological European study of 555 patients did not show any association between PC and alcohol consumption [28]. Yet, there is some evidence that compared with light drinkers, men consuming a large amount of hard liquor suffered from 62% increased risk of PC (95% CI 1.24–2.10) [11, 29] but this did not pan out for women and for beer and wine drinkers [29].

Although moderate alcohol consumption is not a risk factor, African Americans seem to be at a significantly higher risk of developing PC after adjusting for their drinking habits suggesting that racial differences play a role [30].

#### **2.4 Pancreatitis**

Several studies have shown a positive association between PC and history of pancreatitis. However, the magnitude of this phenomenon remains poorly understood [31, 32]. An international epidemiological study reported that both genders with chronic pancreatitis had an increased risk of developing PC independently from the cause of the disease [32]. A large case–control study indicated that chronic pancreatitis lasting more than 7 years was associated with a higher risk of PC (RR = 2.04; 95% CI 1.53–2.72) [33]. A large Italian study from 1983 to 1992 found similar results reporting that the risk increased after 5 or more years of chronic pancreatitis (RR in the first 4 years = 2.1, RR after 5 years = 6.9) [29]. These findings have been challenged by a more recent international study that showed that the risk was significantly increased only in the early years after the onset of pancreatitis. This observation suggested that pancreatitis might represent a manifestation of PC that becomes apparent only several years later rather than an independent risk factor for PC.

#### **2.5 Hereditary pancreatitis**

Hereditary pancreatitis affects 0.3 per 100,000 [34]. In 1996, it was found that hereditary pancreatitis was due to an autosomal dominant defect of the cationic trypsinogen gene (PRSS1) in 7q35 chromosome region [35]. Since then, more than 30 different PRSS1 mutations have been identified and reported in a few families. The risk of developing PC is particularly high for patients affected by hereditary pancreatitis who are at 53 times higher risk of developing the tumor in comparison to individuals without history of hereditary pancreatitis [36]. This observation was confirmed by another study that estimated a 40% cumulative risk of PC in patients with hereditary pancreatitis by the age of 70 [37]. For patients with paternal inheritance of hereditary pancreatitis, the cumulative risk of PC was even higher with a risk of up to 75% [37]. Patients with hereditary pancreatitis have high concentrations of cytokines, reactive oxygen molecules, and pro-inflammatory compounds that can lead to DNA damage, and despite DNA repair systems, these mechanisms seem responsible for the higher risk of genetic mutations leading to PC [33, 38].

#### **2.6 Intraductal papillary mucinous neoplasms**

The definition of intraductal papillary mucinous neoplasm (IPMN) is applied to a family of benign pancreatic cysts that can transform into PC [39]. The risk factors and the true incidence of IPMN are still unclear. These cysts produce mucin and are divided into two groups: IPMNs that affect the side branches of the pancreatic ducts and IPMN that affect the main pancreatic duct. Some patients have mixed IPMNs as they have

#### *Epidemiology and Risk Factors of Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.109778*

cystic lesions in both the side branch and main pancreatic duct. IPMNs are responsible for 20–30% of PC cases. Current evidence suggests that only IPMNs affecting the main pancreatic duct are at high risk for malignant transformation. A recent meta-analysis [39] of 2411 patients with low-risk IPMNs and 825 patients with high-risk IPMNs has shown that the cumulative incidence of PC was significantly different between the two groups. For low-risk IPMNs, the cumulative incidence of PC was 0.02% at 1 year, 1.4% at 3 years, 3.1% at 5 years, and 7.7% at 10 years. On the other hand, for high-risk IPMNs, the cumulative incidence of PC was 1.9% at 1 year, 5.7% at 3 years, 9.7% at 5 years, and 24.6% at 10 years.

#### **2.7 Genetic predisposition for pancreatic cancer**

The presence of genetic predisposing factors for the development of PC has been an area of intense research during the last few decades. Case reports of families with multiple members diagnosed with PC suggest that for some patients, PC might be hereditary [40]. A large population study on twins identified hereditary factors for prostatic, breast, and colorectal cancers, however, this was not detected for PC [41]. A Canadian study on patients with suspected hereditary cancer syndromes found that the standardized incidence of PC was 4.5 (CI 0.54–16.) when cancer affected one 1st degree relative; the standardized incidence increased to 6.4 (CI 1.8–16.4) and 32 (CI 10.4–74.7) when two and three 1st degree relatives were affected, respectively [42]. This translates to an estimated incidence of PC of 41, 58, and 288 per 100,000 individuals, respectively, compared to 9 per 100,000 for the general population [43].

Brentnall et al. [44] and Meckler and colleagues [45] described examples of autosomal dominant PC in individuals presenting at early age (median age 43 years) and with high genetic penetrance (more than 80%). A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) within a highly conserved region of the gene encoding paladin (PALLD) was found in all affected family members (family X). Another study has shown that the P239S mutation was only specific for the family X while it was not a common finding in other individuals with suspected familial PC [46]. Currently, genetic predisposition is thought to be responsible for 7–10% of all PC [47]. Genetic factors including germline mutations in p16/CDKN2A [48], BRCA2 [49–51], and STK 11 [52] genes are thought to increase the risk of PC. The combination of all these known genetic factors accounts for less than 20% of the familial aggregation of PC, suggesting that other genes play a role in the development of familial PC.

A systematic review and meta-analysis of studies on familial PC has shown that individuals with positive family history have nearly two-fold increased risk of developing PC (RR = 1.80, CI 1.48–2.12) [53]. Therefore, families with two or more cases may benefit from a comprehensive risk assessment involving collection of detailed family history information and data regarding other risk factors for PC [54]. A case– control study of PC in two Canadian provinces (Ontario and Quebec) assessed a total of 174 PC cases and 136 healthy controls. Information regarding the ages and sites of cancer was taken in 966 first-degree relatives of PC patients and for 903 first-degree relatives of the control group. PC was the only malignancy in excess in relatives of patients with PC, compared to the control group (RR = 5, p = 0.01). The lifetime risk of PC was 4.7% for the first-degree relatives and the risk was 7.2% for relatives of patients diagnosed before the age of 60 [55].

Besides the isolated aggregation of PC in some families, several other hereditary disorders predispose the development of PC in known familial cancer conditions [56]. These include hereditary pancreatitis, Peutz-Jeghers syndrome (STK11 mutation), familial atypical multiple mole melanoma (FAMMM mutation), familial breast cancer (BRCA1, BRCA2, PALB2, CDKN2A, ATM mutations) and ovarian cancer, Li-Fraumeni syndrome (TP53 mutation), Fanconi anemia, ataxia-telangiectasia, familial adenomatous polyposis, cystic fibrosis, and possible hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM mutations) [4, 54, 57–59].

#### **2.8 Familial pancreatic cancer registries**

As the prognosis of PC is generally poor, there has been a strong interest to detect genes or other markers that could help identify high-risk patients in early stage. Although a precise genetic marker for this scope is not currently available, geneticists and epidemiologists have been profiling traits of high-risk families enrolled in registries established in North America and Europe [60]. Even if there is no standardized definition for familial PC, most authors apply the term to families with at least two first-degree relatives affected by PC in the absence of other predisposing familial conditions [60]. The creation of familial PC registries has been used not only for identification of genetic mutations but also for the screening of high-risk individuals. In selected centers in North America and Europe, screening programs for high-risk individuals have been implemented with the use of endoscopic ultrasound and computed tomography (CT) scan or magnetic resonance imaging (MRI). Such early diagnosis of PC within a comprehensive screening program is hoped to ultimately result in improved survival [61]. The discovery of the genetic bases of inherited PC continues to be an active area of research and in 2001 a multi-center linkage was formed to conduct studies aimed at the localization and identification of PC susceptibility genes (PACGENE) [62]. The complex nature of pedigree data makes it difficult to accurately assess risk based upon the simple counting of the number of affected family members, as it does not adjust for family size, age of onset of PC, and exact relationship between affected family members. Therefore, computer programs have been developed to integrate these complex risk factors and pedigree data. In April 2007 the 1st risk prediction tool for PC, PancPro (https://projects.iq.harvard.edu/ bayesmendel/pancpro) was released [63]. This model provides accurate risk assessment for kindreds with familial PC as the receiver operating characteristic (ROC) curve was 0.75, which is considered good for predictive models.

#### **3. Nutritional status**

Several studies have explored the relationship between body mass index (BMI) lifestyle, diet, and the risk of PC, but uncertainty regarding the strength of this relationship still exists. A recent case–control study of 841 patients and 754 healthy controls showed that individuals with BMI of 25–29.9 had an OR of 1.67 (95% CI = 1.20–2.34) in comparison to obese patients (BMI of ≥30) who had an OR of 2.58 (95% CI = 1.70–3.90) independently of their diabetes status [64]. The duration of being overweight was significantly longer among patients with PC than among controls. Being obese or overweight, particularly in early adulthood, resulted in earlier onset of PC (age at presentation of PC was 61 years for overweight patients and 59 years for obese) when compared to the median age of diagnosis being 64 in the general population [65]. A few studies reported that central weight gain measured by


#### **Table 2.**

*Known risk factors for pancreatic cancer.*

waist circumference and/or waist-to-hip ratio had a statistically significant increased risk compared to those with peripheral weight gain (RR = 1.45, 95% CI 1.02–2.07) [66, 67]. All the known risk factors for PC are summarized in **Table 2**.

#### **4. Screening for pancreatic cancer**

The role of screening for PC is not recommended for asymptomatic average-risk individuals [68, 69] as it is estimated that it would generate more harm than good. With an incidence of only 1.6% of individuals developing PC during their lifetime, Lucas et al. [68] estimated that even with an ideal screening tool with 99% sensitivity and 99% specificity, 1000 false positive results would be generated when the test is applied to 100,000 individuals. Current guidelines recommend that only healthy individuals with at least a 5% or higher risk of developing PC should be considered for screening programs [70] at age 50, or 10 years younger than the earliest diagnosis of PC in the family. These individuals must have two or more blood relatives diagnosed with PC with at least one affected first-degree relative [70, 71].

Guidelines also recommend that individuals with germline mutations in the genes listed above should consider screening beginning at age 50, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, if they have a family history of PC. Some experts have recommended that all individuals with germline mutations in *STK11* (which causes Peutz-Jeghers syndrome) or *CDKN2A* (which causes familial atypical multiple mole melanoma [FAMMM] syndrome), ATM, BRCA1, BRCA2, CDKN2A, PALB2, PRSS1, STK11, TP53, and the Lynch syndrome mismatch repair genes undergo screening for PC regardless of their family history. Peutz-Jeghers syndrome patients are recommended to begin screening at ages 30 to 35. FAMMM syndrome patients are recommended to begin screening for PC at age 40. Magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS) is the two radiological modalities recommended for the screening of patients considered at increased risk of developing PC.

#### **5. Conclusions**

PC is among the most common malignancies of the gastrointestinal system. Its incidence increases after the age of 50. Most patients diagnosed with PC have advanced disease at the time of their presentation. Age, cigarette smoking, alcohol abuse, chronic pancreatitis, and genetic factors are well-known predisposing factors for PC. Screening protocols for PC in the general population are not recommended as the incidence of PC is relatively low. The use of screening programs for high-risk patients is still under investigation.

#### **Author details**

Michele Molinari\*, Hao Liu and Christof Kaltenmeier Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

\*Address all correspondence to: molinarim@upmc.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Epidemiology and Risk Factors of Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.109778*

#### **References**

[1] International WCRF. Pancreatic Cancer Statistics. 2022. Available from: https:// www.wcrf.org/cancer-trends/pancreaticcancer-statistics/#:~:text=pancreatic%20 cancer%20data-,Pancreatic%20 cancer%20is%20the%2012th%20 most%20common%20cancer%20 worldwide.,most%20common%20 cancer%20in%20women [Accessed: October 2, 2022]

[2] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: A Cancer Journal for Clinicians. 2009;**59**(4):225-249

[3] Shaib YH, Davila JA, El-Serag HB. The epidemiology of pancreatic cancer in the United States: Changes below the surface. Alimentary Pharmacology & Therapeutics. 2006;**24**(1):87-94

[4] Ghadirian P, Lynch HT, Krewski D. Epidemiology of pancreatic cancer: An overview. Cancer Detection and Prevention. 2003;**27**(2):87-93

[5] Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Practice & Research. Clinical Gastroenterology. 2006;**20**(2):197-209

[6] Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World Journal of Oncology. 2019;**10**(1):10-27

[7] Lin RT, Chen PL, Yang CY, Yeh CC, Lin CC, Huang WH, et al. Risk factors related to age at diagnosis of pancreatic cancer: A retrospective cohort pilot study. BMC Gastroenterology. 2022;**22**(1):243

[8] Neugut AI, Ahsan H, Robinson E. Pancreas cancer as a second primary

malignancy. A population-based study. Cancer. 1995;**76**(4):589-592

[9] Lynch SM, Vrieling A, Lubin JH, Kraft P, Mendelsohn JB, Hartge P, et al. Cigarette smoking and pancreatic cancer: A pooled analysis from the pancreatic cancer cohort consortium. American Journal of Epidemiology. 2009;**170**(4):403-413

[10] Brand RE, Greer JB, Zolotarevsky E, Brand R, Du H, Simeone D, et al. Pancreatic cancer patients who smoke and drink are diagnosed at younger ages. Clinical Gastroenterology and Hepatology. 2009;**7**(9):1007-1012

[11] Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: A review and meta-analysis. Langenbeck's Archives of Surgery. 2008;**393**(4):535-545

[12] Hassan MM, Bondy ML, Wolff RA, Abbruzzese JL, Vauthey JN, Pisters PW, et al. Risk factors for pancreatic cancer: Case-control study. The American Journal of Gastroenterology. 2007;**102**(12):2696-2707

[13] Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnqvist HJ, Larsson J. Pancreatic cancer is associated with impaired glucose metabolism. The European Journal of Surgery. 1993;**159**(2):101-107

[14] Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. The New England Journal of Medicine. 1994;**331**(2):81-84

[15] Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. JAMA. 1995;**273**(20):1605-1609

[16] Wideroff L, Gridley G, Mellemkjaer L, Chow WH, Linet M, Keehn S, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. Journal of the National Cancer Institute. 1997;**89**(18):1360-1365

[17] Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. Journal of the American Medical Association. 2000;**283**(19):2552-2558

[18] Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: A populationbased study. Gastroenterology. 2005;**129**(2):504-511

[19] Ogawa Y, Tanaka M, Inoue K, Yamaguchi K, Chijiiwa K, Mizumoto K, et al. A prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus. Cancer. 2002;**94**(9):2344-2349

[20] Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: A meta-analysis of 36 studies. British Journal of Cancer. 2005;**92**(11):2076-2083

[21] Yalniz M, Pour PM. Diabetes mellitus: A risk factor for pancreatic cancer? Langenbeck's Archives of Surgery. 2005;**390**(1):66-72

[22] Silverman DT, Schiffman M, Everhart J, Goldstein A, Lillemoe KD, Swanson GM, et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. British Journal of Cancer. 1999;**80**(11):1830-1837

[23] Perrin MC, Terry MB, Kleinhaus K, Deutsch L, Yanetz R, Tiram E, et al.

Gestational diabetes as a risk factor for pancreatic cancer: A prospective cohort study. BMC Medicine. 2007;**5**:25

[24] Fisher WE, Boros LG, Schirmer WJ. Insulin promotes pancreatic cancer: Evidence for endocrine influence on exocrine pancreatic tumors. The Journal of Surgical Research. 1996;**63**(1):310-313

[25] Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of pancreatic cancer. International pancreatitis study group. The New England Journal of Medicine. 1993;**328**(20):1433-1437

[26] Jiao L, Silverman DT, Schairer C, Thiebaut AC, Hollenbeck AR, Leitzmann MF, et al. Alcohol use and risk of pancreatic cancer: The NIH-AARP diet and health study. American Journal of Epidemiology. 2009;**169**(9):1043-1051

[27] Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, et al. Alcohol intake and pancreatic cancer risk: A pooled analysis of fourteen cohort studies. Cancer Epidemiology, Biomarkers & Prevention. 2009;**18**(3):765-776

[28] Rohrmann S, Linseisen J, Vrieling A, Boffetta P, Stolzenberg-Solomon RZ, Lowenfels AB, et al. Ethanol intake and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition (EPIC). Cancer Causes & Control. 2009;**20**(5):785-794

[29] Fernandez E, La Vecchia C, Porta M, Negri E, d'Avanzo B, Boyle P. Pancreatitis and the risk of pancreatic cancer. Pancreas. 1995;**11**(2):185-189

[30] Silverman DT, Brown LM, Hoover RN, Schiffman M, Lillemoe KD, Schoenberg JB, et al. Alcohol and pancreatic cancer in blacks and whites

*Epidemiology and Risk Factors of Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.109778*

in the United States. Cancer Research. 1995;**55**(21):4899-4905

[31] Bansal P, Sonnenberg A. Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology. 1995;**109**(1):247-251

[32] Karlson BM, Ekbom A, Josefsson S, McLaughlin JK, Fraumeni JF Jr, Nyren O. The risk of pancreatic cancer following pancreatitis: An association due to confounding? Gastroenterology. 1997;**113**(2):587-592

[33] Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surgical Oncology. 2002;**10**(4):153-169

[34] Weiss FU. Pancreatic cancer risk in hereditary pancreatitis. Frontiers in Physiology. 2014;**5**:70

[35] Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics. 1996;**14**(2):141-145

[36] Whitcomb DC, Applebaum S, Martin SP. Hereditary pancreatitis and pancreatic carcinoma. Annals of the New York Academy of Sciences. 1999;**880**:201-209

[37] Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International hereditary pancreatitis study group. Journal of the National Cancer Institute. 1997;**89**(6):442-446

[38] Hingorani SR, Wang LF, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53(R172H) and KraS(G12D) cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7(5):469-483.

[39] Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of Unresected Intraductal papillary mucinous neoplasms of the pancreas to cancer: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology. 2017;**15**(10):1509-20 e4

[40] Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Falatko F, et al. Familial pancreatic cancer. Annals of Oncology. 1999;**10**(Suppl. 4):69-73

[41] O'Brien JM. Environmental and heritable factors in the causation of cancer: Analyses of cohorts of twins from Sweden, Denmark, and Finland, by P. Lichtenstein, N.V. holm, P.K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, and K. Hemminki. N Engl J med 343:78-84, 2000. Survey of Ophthalmology. 2000;**45**(2):167-168

[42] Lilley M, Gilchrist D. The hereditary spectrum of pancreatic cancer: The Edmonton experience. Canadian Journal of Gastroenterology. 2004;**18**(1):17-21

[43] Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Research. 2004;**64**(7):2634-2638

[44] Brentnall TA, Bronner MP, Byrd DR, Haggitt RC, Kimmey MB. Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer. Annals of Internal Medicine. 1999;**131**(4):247-255

[45] Meckler KA, Brentnall TA, Haggitt RC, Crispin D, Byrd DR, Kimmey MB, et al. Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma. The American Journal of Surgical Pathology. 2001;**25**(8):1047-1053

[46] Zogopoulos G, Rothenmund H, Eppel A, Ash C, Akbari MR, Hedley D, et al. The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer. Human Genetics. 2007;**121**(5):635-637

[47] Lynch HT, Fitzsimmons ML, Smyrk TC, Lanspa SJ, Watson P, McClellan J, et al. Familial pancreatic cancer: Clinicopathologic study of 18 nuclear families. The American Journal of Gastroenterology. 1990;**85**(1):54-60

[48] Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. The New England Journal of Medicine. 1995;**333**(15):970-974

[49] Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Research. 1996;**56**(23):5360-5364

[50] Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, et al. BRCA2 germline mutations in familial pancreatic carcinoma. Journal of the National Cancer Institute. 2003;**95**(3):214-221

[51] Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%. Cancer Research. 2002;**62**(13):3789-3793

[52] Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.

The American Journal of Pathology. 1999;**154**(6):1835-1840

[53] Permuth-Wey J, Egan KM. Family history is a significant risk factor for pancreatic cancer: Results from a systematic review and meta-analysis. Familial Cancer. 2009;**8**(2):109-117

[54] Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Archives of Pathology & Laboratory Medicine. 2009;**133**(3):365-374

[55] Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, et al. Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. International Journal of Cancer. 2002;**97**(6):807-810

[56] Bartsch DK, Kress R, Sina-Frey M, Grutzmann R, Gerdes B, Pilarsky C, et al. Prevalence of familial pancreatic cancer in Germany. International Journal of Cancer. 2004;**110**(6):902-906

[57] Bartsch DK. Familial pancreatic cancer. The British Journal of Surgery. 2003;**90**(4):386-387

[58] Landi S. Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature. Mutation Research. 2009;**681**(2-3):299-307

[59] van der Heijden MS, Yeo CJ, Hruban RH, Kern SE. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Research. 2003;**63**(10):2585-2588

[60] Rieder H, Sina-Frey M, Ziegler A, Hahn SA, Przypadlo E, Kress R, et al. German national case collection of familial pancreatic cancer - clinicalgenetic analysis of the first 21 families. Onkologie. 2002;**25**(3):262-266

*Epidemiology and Risk Factors of Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.109778*

[61] Hruban RH, Canto MI, Yeo CJ. Prevention of pancreatic cancer and strategies for management of familial pancreatic cancer. Digestive Diseases. 2001;**19**(1):76-84

[62] Petersen GM, de Andrade M, Goggins M, Hruban RH, Bondy M, Korczak JF, et al. Pancreatic cancer genetic epidemiology consortium. Cancer Epidemiology, Biomarkers & Prevention. 2006;**15**(4):704-710

[63] Wang W, Chen S, Brune KA, Hruban RH, Parmigiani G, Klein AP. PancPRO: Risk assessment for individuals with a family history of pancreatic cancer. Journal of Clinical Oncology. 2007;**25**(11):1417-1422

[64] Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, et al. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. Journal of the American Medical Association. 2009;**301**(24):2553-2562

[65] Patel AV, Rodriguez C, Bernstein L, Chao A, Thun MJ, Calle EE. Obesity, recreational physical activity, and risk of pancreatic cancer in a large U.S. cohort. Cancer Epidemiology, Biomarkers & Prevention. 2005;**14**(2):459-466

[66] Larsson SC, Permert J, Hakansson N, Naslund I, Bergkvist L, Wolk A. Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. British Journal of Cancer. 2005;**93**(11):1310-1315

[67] Berrington de Gonzalez A, Spencer EA, Bueno-de-Mesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, et al. Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiology, Biomarkers & Prevention. 2006;**15**(5):879-885

[68] Lucas AL, Kastrinos F. Screening for pancreatic cancer. JAMA. 2019;**322**(5):407-408

[69] Tracer H, Sanou A. Screening for pancreatic cancer. American Family Physician. 2019;**100**(12):771-772

[70] Henrikson NB, Bowles EJA, Blasi PR, Morrison CC, Nguyen M, Pillarisetty VG, et al. Screening for pancreatic cancer: Updated evidence report and systematic review for the US preventive services task force. JAMA. 2019;**322**(5):445-454

[71] Canto MI, Harinck F, Hruban RH. International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2014;**63**(1):178

## Section 3
