4. Risk Factors, Risk Groups and Screening – Pancreatic Cancer
4.1 Risk Factors for Sporadic Pancreatic Carcinoma in the Normal Population
Established risk factors for the development of pancreatic cancer include:
- Smoking
- Heavy/excessive alcohol consumption
- Obesity
Certain diseases (diabetes mellitus, chronic pancreatitis) also increase the risk. Occupational exposure to certain substances are discussed as risk factors as well.
There is evidence that a healthy lifestyle with sufficient exercise and a healthy, varied diet is protective. No drug prophylaxis is available to date.
Based on the available data, concrete recommendations for risk reduction through lifestyle modification can only be made for abstaining from alcohol and tobacco consumption.
4.1.1 Diet/Nutrition
As early as 1997, a detailed literature review by the World Cancer Research Fund (WCRF) found no convincing evidence for links between certain dietary factors and pancreatic cancer [3]. This result was confirmed by an updated WCRF review from 2018 [4] – the evidence remains limited. The results of a systematic search for meta-analyses and systematic reviews during the last 5 years (search period until 08/2021) also do not allow for a more precise definition of individual dietary factors in relation to pancreatic cancer risk.
Background
In 2018, a detailed literature review by the World Cancer Research Fund considered some associations between dietary factors and pancreatic cancer to be probable, but did not classify any of the associations as convincing.
A generally healthy diet (vegetables, fruit, whole grain products, olive oil, fish, soy, poultry and low-fat dairy products) appears to make sense, as supported by two meta-analyses. One describes a significantly lower risk of pancreatic cancer with an OR of 0.86 (95% CI 0.77-0.95; p=0.004) [7]. In the second meta-analysis, a favorable dietary pattern (fruits, vegetables, vitamins and fiber) was associated with a lower relative risk of developing pancreatic cancer (RR 0.51-0.55) [8]. In another meta-analysis, a lower risk of pancreatic cancer is described with a relative risk of 0.67 (95% CI 0.50–0.91) when a healthy lifestyle is followed [6]. However, in another meta-analysis, a Mediterranean diet was not significantly associated with a lower risk of pancreatic cancer (RR 0.80; 95% CI 0.60-1.06) [5].
The meta-analyses and systematic reviews on specific food groups or individual foods on which the above statement 4.1 is based are presented in the table "Risk of Developing Pancreatic Carcinoma Depending on Individual Types of Food" and summarized below.
Evidence on Individual Foods and Nutrients
Meat and Fish
In one meta-analysis, a relative risk of 1.82 (95% CI 1.08-3.08; p=0.03) for the development of pancreatic cancer was described for men with a high consumption of poultry [9]. This result should be interpreted with caution, as the proportion of different preparation methods (e.g. roasted, grilled or cured) is unclear and therefore the proportion of carcinogens due to different processing methods could not be taken into account. It has been discussed that the correlation in men compared to women is also due to the fact that more men than women eat processed foods. Overall, it cannot be assumed that there is a definite link based on the available data.
In one further meta-analysis of case-control studies, a relative risk of 1.38 (95% CI 1.05-1.81) was described for men with a high consumption of red meat. An increasing risk (RR 1.62; 95% CI 1.17-2.26) of pancreatic cancer was also seen with increasing consumption of processed meat. These associations were not observed in women [10].
No association was found between fish consumption and pancreatic cancer risk [9].
Fruit, Vegetables, Legumes, and Nuts
In one systematic review of case-control studies, the association between the consumption of dried fruit and cancer risk was investigated. In one study from Australia, a risk-reducing effect was observed through the consumption of raisins (p<0.01) [11]. In meta-analyses, the association between the consumption of fruit and vegetables and a lower risk of pancreatic cancer is inconsistent [12], [10]. No association with pancreatic cancer risk was seen for the consumption of potatoes either [13]. Overall, the data from the available studies are very heterogeneous and only allow direct conclusions to be drawn to a limited extent. Nevertheless, regular fruit and vegetable consumption is considered sensible.
Nut consumption, such as the consumption of walnuts, almonds, hazelnuts, cashews, could be associated with a slightly lower relative risk of 0.89 (95% CI 0.81–0.98) for the occurrence of pancreatic cancer. In a supplementary dose-response analysis, the authors recommended an increase in nut consumption of 15g/day for general health promotion [14].
Cereal Products
There are two meta-analyses on cereal products and dietary fiber that conclude that an increased intake of whole grain cereal products and dietary fiber could reduce the risk of developing pancreatic cancer [15], [16]. However, both analyses point to imprecise definitions of dietary fiber and cereal products in the primary studies.
Sweet Drinks and Sugar Intake
The consumption of sweet drinks (beverages sweetened with sugar, fruit juices, and artificially sweetened beverages) was not associated with a statistically significant increased risk of pancreatic cancer. The relatively small number of included studies and the low significance of the primary studies themselves are limiting factors [17], [18].
There are indications that high sugar consumption is associated with an increased risk of pancreatic cancer. However, a statistically significant association was only reported for women with a higher BMI (≥25 kg/m²) and a lack of exercise [19], [20], [21].
Fats and Cholesterol
In a cohort study of male smokers, increased saturated fat intake was associated with an increased risk of pancreatic cancer [22]. No such association was described in other cohort studies [23].
In a case-control study, an increased risk of pancreatic cancer was found in the group with a high cholesterol intake [24], but this observation could not be confirmed in a cohort study [25].
Milk and Dairy Products
A protective effect with regard to the risk of pancreatic cancer has been described for cheese and fermented milk products [26]. However, as these data only apply to certain dairy products, no general recommendation can be made. This is particularly the case as current meta-analyses do not make a general statement on dairy products and the consumption of low-fat dairy products is part of a recommended healthy lifestyle [27].
Micronutrients and Food Supplements
Antioxidants (selenium, vitamin C, vitamin E, vitamin A, carotene)
Several meta-analyses indicate a protective association between a higher intake of antioxidants such as selenium [28], [29], vitamin C [28], [30], [31], vitamin E [28], [31], vitamin A [32], [33], carotene [28], [32] and the risk of pancreatic cancer. A general recommendation cannot be made due to the small number of studies included and the lack of subgroup analyses.
Folic Acid
There are indications in three meta-analyses that a high folic acid intake can contribute to the prevention of pancreatic cancer. However, the subgroup analyses carried out to date are inconsistent and do not allow a differentiated recommendation to be made [34], [35], [31]. The recommendation of the German Nutrition Society is a daily intake of 300 µg folate equivalent, corresponding to 150 µg synthetic folic acid for an adult [36].
Nicotinic Acid/Niacin (B3) and Thiamine (B1)
A lower risk of pancreatic cancer was described in a meta-analysis for high doses of nicotinic acid (30 mg/day) and thiamine (2 mg/day). Due to the heterogeneous studies on which this analysis was based and a short follow-up period, a general recommendation for substitution cannot be made [31].
Vitamin B6
A high vitamin B6 intake is associated with a lower risk of pancreatic cancer. However, the different substitution doses are not precisely described and in some cases, at up to 500 mg/day, are far above the current recommendations [37], [38], [39]. Therefore, the German Nutrition Society’s recommendation of a daily intake of 1.4-1.8 mg applies [36].
Vitamin B12
The data on vitamin B12 intake is contradictory; only one study in a meta-analysis describes a lower risk of pancreatic cancer with an intake of 10 µg/day [31], another meta-analysis does not confirm this [37].
Vitamin D
The study situation on vitamin D is inconsistent. One meta-analysis describes a lower risk of pancreatic cancer with vitamin D supplementation (10 µg/day = 400 IU) [31]. This result was not confirmed in another meta-analysis [40].
Zinc
A meta-analysis described a lower risk of pancreatic cancer with a high zinc intake in Americans. This association could not be shown in the European studies, so that no recommendation can be derived from this [41].
Total Antioxidant Capacity (TAC) of Foods
The total antioxidant capacity (TAC) of foods was examined in a meta-analysis. This analysis suggests a reduced risk of pancreatic cancer with a high TAC value with an OR of 0.68 (95% CI 0.53–0.89). However, due to the heterogeneous primary data situation, no recommendation can be made [42].
Dietary Inflammatory Index (DII)
Certain foods are associated with the triggering of high inflammatory activity. The biomarkers CRP, TNF-α, IL-1β, IL-4, IL-6 and IL-10 are included in the determination of the inflammatory index. Foods that increase DII include sugar, saturated fats, refined carbohydrates, gluten and casein. A meta-analysis suggests that dietary habits with a high DII may increase the risk of pancreatic cancer (RR=1.45; 95% CI 1.11-1.90). Due to the small number of studies included, the data are not sufficient to make a recommendation [43].
Nitrate/Nitrite
In an available meta-analysis, an increased intake of nitrate is associated with a slightly higher risk for the occurrence of tumor diseases with an RR of 1.04 (95% CI 0.99-1.08). This was not confirmed for pancreatic cancer [44].
Table 4: Risk of Developing Pancreatic Carcinoma Depending on Individual Types of Food
| Type of Food | PDAC Risk |
| White meat | Highest vs. lowest consumption of poultry in men RR=1.82 (95% CI 1.08-3.08) p=0.03 [45] |
| Fish | Highest vs. lowest consumption of fish RR=1.00 (95% CI 0.93-1.07) [9] |
| Red meat |
Red meat: highest vs. lowest consumption Gender: highes vs. lowest consumption: |
| Processed meat | Highest vs. lowest consumption: RR=1.62 (95% CI 1.17-2.26) [10] |
| Fruit and vegetables |
Protective effect of raisin consumption (p<0.01) Fruit and vegetables + vs. fruit and vegetables - : RR=0.92 (95% CI 0.78-1.08) Fruit and vegetables + vs. fruit and vegetables - : RR=0.73 (95% CI 0.53-1.00) Lowest overall potato consumption (OPC-) vs. highest overall potato consumption (OPC+) |
| Legumes | Beans, lentils, peas <1x/week: RR=1.00 1-2x/week: RR=0.47 (0.21-1.02) ≥3x/week: RR=0.43 (0.16-1.13) [48] |
| Nuts | N+ vs. N- : RR=0.89 (95% CI 0.81-0.98) [14] |
| Dietary fiber |
Whole grain foods: DIetary fiber: |
| Sweetened beverages |
SB + vs. SB - : RR=1.28 (95% CI 0.95–1.72) SB + vs. SB - : RR=1.06 (95% CI 0.87–1.29) |
| Sugar consumption |
Sugar + vs. sugar - Glycemic load/ fructose consumption high vs. low in women with a BMI ≥ 25 kg/m² and a lack of exercise Glycemic index/glycemic load: high vs. low |
| MIcronutrients |
Selenium + vs. selenium - : OR=0.47 (95% CI 0.26–0.85) VitA + vs. VitA - : OR=0.85 (95% CI 0.74–0.97) Folate / dose: n/a. high dose vs. low dose: RR=0.84 (95% CI 0.75–0.95) VitA+ vs. VitA-: RR=0.839 (95% CI 0.712-0.988) VitC+ vs. VitC-: RR=0.66 (95% CI 0.58–0.75) |
| Nitrate/Nitrite | Nitrate intake highest vs. lowest: RR=0.97 (95% CI 0.83-1.13) Nitrite intake hightes vs. lowest: RR=0.96 (95% CI 0.82-1.12) [44] |
| Folic acid |
Hightes folate intake vs. lowest folate intake: OR=0.82 (95% CI 0.69-0.97) Highest folate intake vs. lowest folate intake: OR=0.731 (95% CI 0.555-0.907) Folate / dose: n/a, high dose vs. low dose: RR=0.84 (95% CI 0.75–0.95) |
| Vitamin B6 |
VItB6 + vs. VitB6 - :RR=0.63 (95% CI 0.48-0.79) VitB6 + vs. VitB6 - : RR=0.65 (95% CI 0.53-0.80) VitB6 + vs. VitB6 - : RR=0.64 (95% CI 0.44–0.93) |
| Vitamin B12 |
VitB+ vs. VitB-: RR=0.77 (95% CI 0.67–0.89) VitB12+ vs. VitB12- (6 studies): RR=0.97 (95% CI 0.78-1.16) |
| Vitamin D |
Vitamin D/ 10 μg/day, high dose vs. low dose: RR=0.75 (95% CI 0.60–0.93) 25(OHD) + vs. 25(OHD) - : HR=1.02 (95% CI 0.66-1.57) |
| Zinc | Highest zinc intake vs. lowest zinc intake: RR=0.798 (95% CI 0.621-0.984) [41] |
| TAC | High TAC vs. low TAC: OR=0.68 (95% CI 0.53–0.89) [42] |
| DII | DII+ vs. DII- : RR=1.45 (95% CI 1.11–1.90) [43] |
4.1.2 Stimulants
In order to reduce the risk of developing pancreatic cancer, high alcohol and tobacco consumption shall be avoided.
Background
In various meta-analyses, certain stimulants (alcohol, tobacco) are discussed as possible risk factors for the development of pancreatic cancer. Abstinence from alcohol and nicotine is seen as a preventive measure to reduce the risk of pancreatic cancer [Ordóñez-Mena, JM et al. 2016], [54]. See also the guideline „Smoking and Tobacco Dependency: Screening, Diagnosis and Treatment" (https://www.awmf.org/leitlinien/detail/ll/076-006.html) for this.
The meta-analyses and systematic reviews on which recommendation 4.2 above is based are summarized below. In addition, we would like to refer to the appendix.
Special Recommendations for Individual Stimulants
Alcohol Consumption
According to a meta-analysis of 19 prospective studies with a total of 4,211,129 individuals, the consumption of more than 15 g of alcohol per day is associated with an increased risk of pancreatic cancer. In people with a high alcohol consumption (≥ 24 g per day), the relative risk is 1.15 (95% CI 1.06-1.25), and 1.43 (95% CI 1.17-1.74) if high-proof alcohol is consumed [50].
Tobacco Consumption
The relative risk of developing pancreatic cancer in active smokers is 1.8 (95% CI 1.7-1.9) compared to never-smokers. It increases with the duration of exposure and the number of cigarettes smoked per day (10 cigarettes/day = RR 1.6; 95% CI 1.5-1.8), 30 cigarettes/day = RR 2.2 (95% CI 1.9-2.4). Considering the duration of exposure, there is a statistically significant continuous increase in risk with a relative risk of 1.3 (95% CI 1.3-1.4) from an exposure duration of approx. 10 years up to a relative risk of 1.8 (95% CI 1.6-2.0) at 30 years. On the other hand, the relative risk can be rapidly reduced by quitting smoking: after 10 years of abstinence, the relative risk in former smokers is 0.7 (95% CI, 0.6-0.7) compared to active smokers. After 20 years of abstinence, the relative risk for former smokers is 0.6 (95% CI 0.5-0.7) and corresponds to the risk of never-smokers [51]. Active smoking increases the risk of developing a pancreatic tumor with an HR=1.9 (95% CI 1.48–2.43). Whereas quitting smoking for 10-19 years has an HR=0.71 (95% CI 0.52–0.96), and quitting smoking for more than 20 years has an HR=0.47 (95%CI 0.31–0.70) [Ordóñez-Mena, JM et al. 2016]. The risk of pancreatic cancer can therefore be reduced by giving up tobacco consumption.
A meta-analysis shows no significant correlation between exposure to secondhand smoke – during exposure, even when age is taken into account [54].
Two studies from Sweden describe an increased risk of developing pancreatic cancer with snus consumption (snuff), so that the German guideline recommends avoiding such smokeless tobacco consumption as well [55].
Coffee
In the meta-analyses available to date, it is not possible to assess whether increased coffee consumption has a protective effect or leads to an increased risk of pancreatic cancer. The available studies are inconsistent and sometimes describe an increased risk, but also a lower risk when consuming coffee, with inclusion and evaluation criteria that are not always clearly comprehensible [56].
Tea
There is no meta-analysis that proves a reliable link between tea consumption and the risk of developing pancreatic cancer.
Table 5: Risk of Developing Pancreatic Carcinoma Depending on the Consumption of Stimulants
| Type | PDAC Risk |
| Alcohol | High alcohol consumption (³ 24 g per day), RR=1.15 (95% CI 1.06–1.25) p=0.001 High-proof alcohol consumption, RR 1.43; 95% CI 1.17–1.74 High alcohol consumption >15 g/day increased PDAC risk [50] |
| Smoking |
Active smokers: RR=1.8 (95% CI 1.7-1.9) Dose-response relationship: Exposure duration (10 studies) Quit smoking Active smokers vs. never-smokers Quit smoking 10-19 years ago Quit smoking >20 years ago |
| Environmental Tobacco Smoke | Environmental tobacco smoke vs. no environmental tobacco smoke: RR=1.16 (95% CI 0.92-1.47) [54] |
| Snus | Consumption of smokeless tobacco OR=2,1 (95% CI 1,2-3,6) OR=1,6 (95% CI 1,0-2,55) [52] |
| Coffee |
Highest vs. lowest coffee consumption: RR=1.08 (95% CI 0.94–1.25) Highest (K+) vs. lowest coffee consumption (K-): RR=0.75 (95% CI 0.63–0.86) |
4.1.3 Occupational Risk Factors
Exposure to pesticides, herbicides and fungicides could potentially increase pancreatic cancer risk. Other potential risk factors may include chlorinated hydrocarbons, chromium and chromium compounds, electromagnetic fields, as well as fuel vapors.
Background
Some occupations and work settings appear to be associated with a slightly increased risk of disease [68], [69], [70]. Particular risk factors may include the above chemicals [71], [72], [73], [74], [75], [76], [77].
According to a meta-analysis, night work that is associated with a change in the circadian rhythm does not increase the risk of developing pancreatic cancer with an odds ratio of 1.007; 95% CI=0.910-1.104. This meta-analysis must be evaluated critically, as neither the duration of the individual night shift nor the lifetime duration of night work is further specified [78].
4.1.4 Physical Activity and Further Risk Factors
Regular physical activity reduces the risk of developing pancreatic cancer.
- Level of evidence
- 1
- Consensus
- Strong consensus
- References
- [79]
Background
The metabolic equivalent (MET) can be used as a measure of physical activity. It is defined by the oxygen consumption of a 70 kg 40-year-old man at rest and corresponds to 3.5 ml of oxygen per kilogram of body weight per minute. For women, the value is 3.15 ml/kg bw/min.
Regular physically demanding activity (>3000 MET) is associated with a reduced risk of pancreatic cancer: RR 0.85; 95% CI, 0.78-0.93 [79]. A physical activity of 3000 MET can be achieved, for example, by climbing stairs continuously for 10 min, or cycling for 30 min per day.
A meta-analysis based on the WCRF (World Cancer Research Fund) / AICR (American Institute for Cancer Research) score, which primarily analyzes the parameters of body weight, physical activity, and nutritional factors, however, showed no statistical correlation between the level of the score and the risk of developing pancreatic cancer. The data are heterogeneous overall and the recommendations used to form the score date back to 2007 [80].
A higher age of women at first birth is associated with a higher risk of pancreatic cancer. The relative risk was 1.21 (95% CI: 1.01-1.45; P=0.314, I2=13.7%) when comparing the highest (≥ 30 years) with the lowest age category (<23 years) [81]. The mechanism is unclear, but based on the data available, a hormonal dependence of pancreatic cancer could be possible [82].
Table 6: Risk of Developing Pancreatic Carcinoma Depending on Lifestyle Habits
| Habit | PDAC Risk | Literature |
| Physical activity | Statistically significant lower risk with high physical activity RR=0.85 (95% CI 0.78-0.93 High physical activity corresponds to >3000 METs (weekly metabolic equivalent tasks) |
Xie, F., Y. You, J. Huang, C. Guan, Z. Chen, et al., Association between physical activity and digestive- system cancer: An updated systematic review and meta- analysis. Journal of Sport & Health Science, 2021. 10(1): p. 4-13. |
| Lifestyle |
Night Shift Work No significant difference in the risk of pancreatic cancer for night shift work (rotating or fixed night shift) compared to no night shift (overall result) |
Dun, A., X. Zhao, X. Jin, T. Wei, X. Gao, et al., Association between night-shift work and cancer risk: Updated systematic review and meta- analysis. Frontiers in Oncology, 2020. 10: p. 1-15. |
4.1.5 Pre-existing Conditions
An increased risk of developing pancreatic cancer is postulated for certain conditions. The evidence on which the pancreatic cancer risk described is based is in part very weak and in part controversial.
Certain pre-existing conditions (obesity, diabetes mellitus, PSC, gallstones/cholecystectomy, cystic fibrosis, periodontitis/tooth loss, systemic lupus erythematosus, psoriasis, infections (hepatitis, TB, helicobacter pylori), ovarian cancer, non-alcoholic fatty liver disease, kidney transplantation) are associated with an increased risk of pancreatic cancer.
The association between these pre-existing conditions and the occurrence of pancreatic cancer is weak.
Background
The meta-analyses and systematic reviews on the risk of pancreatic cancer for patients with certain pre-existing conditions on which the statement made in 4.5. is based are summarized below. In addition, reference is made to Table 7 below, which shows the complexity and variability of the data that must be taken into account when evaluating the risks.
Specific Recommendations on Individual Pre-existing Conditions:
Metabolic Diseases
A total of four meta-analyses and systematic reviews indicate that obesity is associated with a higher risk of developing pancreatic cancer. Visceral obesity in particular appears to be associated with a statistically significant higher risk (RR up to 1.19) [83]. Every increase in BMI by 5 kg/m² at a young age appears to be associated with an increase in risk (RR up to 1.17 in men) up until the age of 30 [84]. In a meta-analysis of young Chinese adults (18 - 25 years), an RR of 1.18 is described for an increase in BMI of 5 kg/m² [99]. This is not confirmed in a sub-analysis of another meta-analysis for Asians, but only for Caucasians, and without taking ethnic origin into account for adult men with an RR of up to 1.10 [100]. Overall, the study situation is very heterogeneous, but indicates that obesity, and visceral obesity in particular, appear to be associated with a higher risk.
Furthermore, several systematic reviews and meta-analyses show that both type 2 diabetes mellitus and, in one study, type 1 diabetes mellitus are associated with an increased risk of pancreatic cancer [101], [102]. The highest risk (RR = 4.92) was described in a study from China in patients with new onset diabetes mellitus (NOD) within the first two years after diagnosis of diabetes mellitus [86]. The longer the diabetes persists, the lower the risk of developing pancreatic cancer. 10 years after the onset of diabetes, there is no longer a statistically significant increased risk. Data from a registry study at the Mayo Clinic show that of patients with NOD who are older than 50 years, around 1 % develop pancreatic cancer within 3 years [103]. Suresh Chari's group has developed a model (END-PAC model) based on weight changes, changes in blood glucose, and age at onset of NOD to better estimate the risk of pancreatic cancer. Validation is planned in the USA in a prospective randomized study, the study protocol of which has since been published [104].
However, the population of over 50-year-olds with NOD is too large to recommend screening measures in the overall context (e.g. in view of the quality of currently available procedures). In addition, there are currently no established screening procedures that can detect or rule out pancreatic cancer with sufficient sensitivity and specificity using non-invasive measures. In other studies, no connection between diabetes and the occurrence of carcinomas was seen [105], [106]. One meta-analysis describes a similar risk of developing pancreatic cancer for men and women with diabetes mellitus [107].
One meta-analysis postulated a link between diabetes mellitus and an increased BMI and the occurrence of carcinomas. However, with regard to the risk of developing pancreatic cancer, no significant correlation was found with a high degree of heterogeneity in the data [108].
According to one meta-analysis, patients with diabetes mellitus and IPMN (intraductal papillary mucinous neoplasia) have a higher risk of developing more aggressive pancreatic cancer (RR of 1.29-1.61) [109].
No statistically significant correlation was found between gestational diabetes and the risk of pancreatic cancer [110].
Hepato-biliary Diseases
Patients with PSC (primary sclerosing cholangitis) have a statistically significant increased risk of pancreatic cancer with an RR of 7.56. However, it should be noted that in the three studies included in this meta-analysis, only 15 patients out of 2,736 patients with PSC developed pancreatic cancer [87]. General recommendations can therefore not be derived.
An increased risk of pancreatic cancer was also described in patients with gallstones and a cholecystectomy, with an RR of 1.39 (gallstone carriers with cholecystectomy vs. people without gallstones and cholecystectomy) [88]. A general recommendation for screenings cannot be made, as other potential risk factors such as diabetes mellitus, obesity, and/or tobacco smoking were not sufficiently taken into account.
In one meta-analysis, a risk of developing pancreatic cancer with an OR of 2.12 was described for patients with non-alcoholic fatty liver disease (NAFLD) [93].
Autoimmune Diseases
In individual reviews and meta-analyses, a slightly increased risk of developing pancreatic cancer was described for systemic lupus erythematosus (HR 1.42) [85] and psoriasis (HR 1.41) [89]. In the presence of atopic dermatitis, the available cohort studies and case-control studies showed an inconsistent picture [98].
Infectious Diseases
Infectious diseases such as hepatitis C, tuberculosis, and hepatitis B are associated with a higher risk of pancreatic cancer.
Patients with a hepatitis C virus infection appear to have a higher risk of pancreatic cancer with an OR of 1.51 (95% CI 1.31–1.74), even after adjustment for diabetes, alcohol, and smoking [90].
This also applies to patients with tuberculosis with an RR of 1.58 (95% CI 1.28–1.96) [91].
The picture for hepatitis B infection is not uniform. In the Asian population, hepatitis B infection is associated with a statistically significant increased risk with an RR of 1.34 (95% CI 1.15–1.57), while this association is not found in Europe and Oceania [94].
A meta-analysis also showed an increased risk of pancreatic cancer with Helicobacter pylori infestation of the stomach (OR 1.45) [111], but a second meta-analysis did not confirm this [92].
Dental Health
The WHO classifies dental health as one of the „top ten“ criteria for health. Periodontitis and tooth loss are the two most common measures of dental health. Three meta-analyses/systematic reviews have shown a statistically significant increased risk of pancreatic cancer for patients with periodontitis (RR 1.25-1.74) [95], edentulism (RR 1.54) [97] and periodontal disease (RR up to 4.56) [96]. Here, the different study designs are noteworthy, as well as the sometimes low numbers of pancreatic cancer cases in the study population and different classifications of dental diseases. Another meta-analysis showed a „dose-response curve“ with a 7% increase in the risk of pancreatic cancer for every 10 teeth lost [97]. Periodontitis increases the risk of developing gastrointestinal carcinomas, but a statistically significant increase was not seen in a subgroup analysis for pancreatic cancer [112].
Other Pre-existing Conditions
Chronic pancreatitis is also associated with a slightly increased risk of pancreatic cancer. This connection is discussed in detail in the DGVS S3 guideline on pancreatitis, so that it will not be discussed in detail here [113].
In one meta-analysis, patients with cystic fibrosis (also: cystic fibrosis: CF) had a standardized incidence ratio (SIR) for pancreatic cancer of 6.18, which was even higher in patients with a lung transplant [114]. The authors of this meta-analysis recommend screening for pancreatic cancer (sonography, MRI or EUS and CA 19-9) every 2-3 years in CF patients without a lung transplant, and even every 1-2 years after transplantation. Such screening examinations should only be carried out in specialized centers as part of CF registries or studies.
Individual reviews and meta-analyses have shown an association with a slightly increased risk of pancreatic cancer for ovarian cancer (SIR 1.42; 95% CI 1.13-1.71) [115], but also after kidney transplantation (SIR 1.53; 95% CI 1.23-1.91) [116].
Diseases With Indications of a Reduced Risk of Pancreatic Carcinoma
The systematic literature review also provided evidence for pre-existing conditions that are associated with a reduced risk of pancreatic cancer. The reduced risk of pancreatic cancer in allergic diseases/atopias such as patients with rhinoconjunctivitis (OR 0.57; 95% CI 0.50-0.64) [117] or patients with allergic diseases/asthma (OR up to 0.56) [118], as shown in several systematic reviews and meta-analyses, is worth mentioning. However, there were also heterogeneous and partly contradictory analyses (e.g. [119]).
Table 7: Risk of Developing Pancreatic Carcinoma Depending on Pre-existing Conditions
| Pre-existing Condition | PDAC Risk |
| Obesity | Visceral obesity: Waist circumference per 10 cm increase RR 1.11 (95% CI 1.05-1.18) Waist-to-hip ratio per 0.1 units RR 1.19 (95% CI 1.09-1.31) [83] |
| Increased BMI (age ≤ 30 years): every 5 kg/m² Increase in BMI: RR=1.17 (95% CI 1.11-1.24) Subgroup analyses Men: RR=1.17 (95% CI 1.10-1.24) Women: RR=1.10 (95% CI 1.07-1.14) [84] |
|
| Every 5 kg/m² Increase in BMI Age 18-25 years (4 studies): RR=1.18 (95% CI 1.12-1.24) Adults (31 studies): RR=1.09 (95% CI 1.08-1.11) [120] |
|
| Increased BMI, every 5 kg/m² increase: in men RR=1.10 (95% CI 1.01-1.19) in women RR=1.08 (95% CI 1.02-1.13) [100] |
|
| Diabetes mellitus |
DM2+ >5 years vs. DM2+ 2-5 years: OR=0.77 (95% CI 0.70-0.86) DM2+ >5 years vs. new-onset DM2+ <2 years: OR=1.63 (95% CI 1.47-1.80) DM2+ 2-5 years vs. new-onset DM2+ <2 years: OR=0.82 (95% CI 0.75-0.90)
|
|
DM1+ vs. DM1-: RR=1.34 (95% CI 1.18-1.52) |
|
|
Patients with diabetes mellitus (DM+) vs. people without diabetes mellitus (DM-) in China: DM+ vs. DM-: OR=3.69 (95% CI 3.12-4.37)
|
|
|
DM: as a risk factor for pancreatic cancer in women vs. DM as a risk factor for pancreatic cancer in men: RRR=1.00 (95% CI 0.93-1.07) |
|
|
Patients with type 2 diabetes mellitus and increased BMI Per 5 kg/m² increased BMI: RR=0.97 (95% CI 0.84-1.11) |
|
|
Patients with diabetes mellitus (DM+) vs. people without diabetes mellitus (DM-) High-grade dysplasia/invasive carcinoma: RR=1.29 (95% CI 1.16-1.43) Invasive carcinoma: RR=1.61 (95% CI 1.33-1.95) High-grade dysplasia: RR=1.27 (95% CI 1.01-1.59)
|
|
|
Patients with gestational diabetes (DMG+) vs. persons without gestational diabetes (DMG-): RR=3.49 (95% CI 0.80-15.23) p=0.097 |
|
| PSC |
People with primary sclerosing cholangitis (PSC+) vs. people without primary sclerosing cholangitis (PSC): PSC+, RR=7.56 (95% CI 2.42–23.62) |
| Gallstones, cholecystectomy |
People with gallstones (GS) and/or cholecystectomy (CC) (GS+, CC+, GS+CC) vs. people without gallstones or cholecystectomy (GS/CC-): GS+ vs. GS/CC-: RR=1.70 (95% CI 1.30–2.21) p<0.001 |
| Cystic fibrosis |
People with cystic fibrosis (CF+) vs. people without cystic fibrosis (CF-): SIR=6.18 (95% CI 1.31 – 29.27) p=0.022 Subgroup analyses Patients with lung transplant SIR=1.82 (95% CI 0.27–3.38) |
| Non-alcoholic fatty liver disease |
Patients with non-alcoholic fatty liver disease (NAFLD+) vs. people without non-alcoholic fatty liver disease (NAFLD-): NAFLD+ OR=2.12 (95% CI 1.58-2.83) |
| Systemic lupus erythematosus (SLE) |
SLE+ vs. SLE: SLE+,HR=1.42 (95% CI 1.32-1.53) |
| Psoriasis |
Patients with psoriasis (P+) vs. people without psoriasis (P-): Pancreatic cancer risk P+ vs. P- P+, RR=1.41 (95% CI 1.16–1.73) Pancreatic cancer mortality: P+ vs. P-: P+, RR=1.31 (95% CI 1.02–1.69) |
| Atopic dermatitis |
AD+ vs. AD-: OR=0.81 (95% CI 0.66–0.98) AD+ vs. AD-: SIR=1.90 (95% CI 1.03–3.50) |
| Infectious diseases (hepatitis c and b, tuberculosis) |
Patients with hepatitis C infection (HCV+) vs. persons without hepatitis C infection (HCV-): HCV+, OR=1.51 (95% CI 1.31–1.74) Statistically significant higher risk even after adjustment for diabetes, alcohol, smoking. No statistically significant difference after adjustment for chronic pancreatitis (two studies). |
|
Patients with tuberculosis (T+) vs. persons without tuberculosis (T-): T+, RR=1.58 (95% CI 1.28–1.96) |
|
|
Patients with hepatitis B infection (HBV+) vs. persons without hepatitis B infection (HBV-): HBV+, RR=1.39 (95% CI 1.19–1.63) Regional subgroup analyses Europe: HBV+ vs. HBV-: no statistically significant difference, RR=1.44 (95% CI 0.88–2.34) Oceania: HBV+ vs. HBV-: no statistically significant difference, RR=1.47 (95% CI 0.38–5.71) Asia: HBV+ vs . HBV-: statistically significant higher risk with HBV+, RR=1.34 (95% CI 1.15–1.57) |
|
| Heliobacter pylori infection |
Patients with helicobacter pylori infection (HP+) vs. people without helicobacter pylori infection (HP-): HP, OR=1.45 (95% CI 1.09–1.92) |
|
Patients with helicobacter pylori infection (HP+) vs. people without helicobacter pylori infection (HP-) (8 studies): OR=1.09 (95% CI 0.81–1.47) p=0.58 |
|
| Periodontitis and tooth loss |
Patients with periodontitis PD+ vs. persons without periodontitis PD-: PD+: RR=1.74 (95% CI 1.41-2.15) Patients with edentulism E+ vs. persons without edentulism E-: E+ RR=1.54 (95% CI 1.16-2.05) |
|
Patients with periodontal disease PDD+ vs. people without periodontal disease PDD+ vs. PDD- : RR max. 4.56 (95% Cl 0.93-22.29)
|
|
|
Patients with periodontitis PD+ vs. people without periodontitis PD- PD+ vs. PD- Incidence HR=1.25 (95% CI 0.84-1.85)
|
|
|
Patients with tooth loss (TL+) vs. people without tooth loss (TL-)RR=1.15 (95% CI 1.05-1.19) |
|
| Ovarian cancer |
Patients with ovarian cancer (OC+) vs. people without ovarian cancer (OC-): OC+, SIR=1.42 (95% CI 1.13-1.71) p=0.523 |
| Kidney transplant |
Patients with kidney transplant (KT+) vs. persons without kidney transplant (KT-): KT+, SIR=1.53 (95% CI 1.23-1.91) p<0.001 |
4.1.6 Hereditary Chronic Pancreatitis
Background
Details on hereditary pancreatitis can be found in the current S3 guideline on pancreatitis [113]. According to international doctrine and particularly with regard to the risk of carcinoma, hereditary pancreatitis is diagnosed if at least one first-degree or two second-degree relatives have chronic pancreatitis, or a PRSS1 mutation is detected. The PRSS1 (cationic trypsinogen) mutation follows an autosomal dominant mode of inheritance and 80% penetrance. The term idiopathic pancreatitis is used when genetic susceptibility factors are present that increase the risk of chronic pancreatitis, but do not follow an autosomal dominant pattern of inheritance and the penetrance cannot be specified. Examples are mutations in the SPINK1, CTRC, CFTR, or CPA1 gene. A multifactorial genetic basis also seems likely in early onset disease [113]. Patients with hereditary chronic pancreatitis have an increased risk of developing pancreatic cancer. The cumulative risk, up to the age of 70, is between 40 % and 44 % [123], [122]. The cause of pancreatic cancer development in patients with hereditary chronic pancreatitis has not yet been clarified and could be independent of the underlying mutation. Patients without evidence of a PRSS1 mutation also developed pancreatic cancer in a study published in 2004 [123].
There is an increased risk of developing pancreatitis with probable pathogenic/definite pathogenic germline variants in the PRSS1, CPA1, and CTRC genes [124], [125], [126]. Variants in CPA1 and CPB1 may be associated with an increased risk of pancreatic cancer without pancreatitis episodes being observed first [127]. The UK NICE guideline [128] only recommends screening for pancreatic cancer, e.g. by CT, in patients with hereditary pancreatitis - due to a PRSS1 mutation - as the risk appears to be particularly high in this patient group [129]. Germline gene variants associated with an increased risk of pancreatitis are not part of the gene panel recommended by ASCO-PCO and CAPS 2020 for determining pathogenic germline variants with an increased risk of pancreatic cancer (see Table 5).
4.2 Individuals with an Increased Risk for Hereditary Pancreatic Cancer
4.2.1 Familial Pancreatic Cancer
Regardless of the status of pathogenic gene variants, an individual has a significantly increased risk of also developing pancreatic cancer:
- If pancreatic cancer has occurred in two blood relatives who are first-degree related to each other and at least one of whom is first-degree related to the individual being evaluated.
- If two or more blood relatives on the same side of the family have been diagnosed with pancreatic cancer, one of whom is first-degree related to the individual being evaluated.
Background
Familial pancreatic cancer (FPC) is always assumed if the familial clustering of pancreatic cancer described in statement 4.7 is present without the family fulfilling the clinical or family history criteria of another hereditary syndrome (Table 5).
In the clinical evaluation of suspected familial pancreatic cancer, a detailed history should be taken regarding the familial clustering of other cancers, including the tumor type and the age at onset of all first- and second-degree relatives, as a genetic tumor risk syndrome (see Table 5) may also be present. In around 90% of families that meet the criteria for familial pancreatic cancer, no probable pathogenic/pathogenic germline variant can be detected. Family members of a patient with pancreatic cancer with the criteria described in Statement 4.7 should be offered comprehensive genetic diagnostics due to the suspicion of a genetic tumor risk syndrome in the family.
FPC tumors cannot be distinguished histologically from sporadic tumors. The mean age of onset of FPC does not differ significantly from the age of sporadic cases (± 62 years of age). However, initial data seem to indicate that children of FPC patients may develop pancreatic cancer up to 10 years earlier (anticipation) [133].
The number of first- and second-degree related family members and their age of onset can be used to estimate the risk of pancreatic cancer in families in which no pathogenic/probably pathogenic germline variant has yet been found. Individuals with two first-degree family members with pancreatic cancer have a 6.4-fold increased risk of developing pancreatic cancer themselves (lifetime risk 8-12%), with three or more first-degree relatives with pancreatic cancer the risk increases 32-fold (40% lifetime risk) [134]. The risk also increases if one of the members of an FPC family is diagnosed with pancreatic cancer at an early age (< 50 years RR 9.3) [135].
As with all genetic diseases, members of FPC families should also be offered genetic counseling. A specific probable pathogenic/pathogenic germline variant for FPC has only been identified in a subgroup (approx. 10 %) of FPC families so far [136].
For individuals in a family with a cluster of pancreatic cancer cases on the same side of the family who also meet the criteria listed in Statement 4.7, all guidelines used (CAPS, NICE, NCCN, ASCO-PCO) recommend performing a germline mutation analysis with an NGS panel of genes associated with familial pancreatic cancer or hereditary tumor syndromes. According to ASCO-PCO [136], Table 8 summarizes the genes that should also be analyzed in individuals with an increased familial risk of pancreatic cancer in accordance with recommendation 4.7.
Other likely pathogenic/pathogenic germline variants were found in the following genes in pancreatic cancer patients: BARD1, CHEK2 [Park, Wungki et al. 2020] and WT1 [138]. The composition of the gene panel should correspond to the current state of scientific knowledge.
Individuals who have not yet developed pancreatic cancer and who have an increased familial risk according to statement 4.7 shall be offered genetic testing.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Consent
- References
- [136]
4.2.2 Genetic Tumor Risk Syndromes with an Increased Risk of Pancreatic Cancer
An increased risk of pancreatic cancer has been observed in a number of genetic tumor risk syndromes in which pancreatic cancer is not one of the leading clinical/phenotypic manifestations. Pancreatic cancer in individuals with such a genetic syndrome in the family is differentiated from familial pancreatic cancer (FPC) as defined in 4.2.1. Individuals from families that meet the criteria of the genetic tumor risk syndromes listed in Table 8 should be offered a germline analysis with an NGS panel in accordance with recommendation 4.9. The use of the NGS gene panel can be dispensed with if the probable pathogenic/pathogenic gene variant is known. Detailed information on genetic tumor risk syndromes associated with pancreatic cancer, in particular on the management of other tumor types occurring in the syndrome, can be found in the NCCN Guideline: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic (BOP) 1/2022 and [139] as well as in the CAPS (2019) [132] and NICE (2018) [128] guidelines.
Genetic testing shall be offered to the following individuals without manifest or symptomatic cancer:
- Members of families with a known, likely pathogenic/pathogenic gene variant predisposing to pancreatic cancer (Table 8).
- Individuals who have not yet developed pancreatic cancer from families who meet the criteria for genetic testing for known genetic tumor risk syndromes associated with pancreatic cancer (Table 8).
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 5
- Consensus
- Strong consensus
- References
- [136]
A number of genes have been associated with an increased risk of pancreatic cancer (Table 8). Except in cases where a genetic diagnosis has previously been made in a family member, the individuals listed in Recommendation 4.9 should undergo germline genetic testing using a multigene panel containing the genes listed in Table 8.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- References
- [136]
Background
Probable pathogenic/pathogenic germline variants in the genes known to predispose to cancer are responsible for around 10-20% of familial clusters of pancreatic cancer [140], [141].
ASCO-PCO writes about this in a qualifying statement: „It is important to note that in 90% of families that meet the criteria for familial pancreatic cancer, no pathogenic mutations are found (Table 8), so that additional common epigenetic, genetic or environmental factors are likely to contribute to the risk of pancreatic cancer“ [136]. Probable pathogenic/pathogenic germline variants associated with an increased risk of pancreatic cancer are also found in about 5-10% of patients with sporadic pancreatic cancer [142], [Lowery, M. A. et al. 2018], [144], [145], [146]. As these germline variants are also associated with an increased risk of other cancers [147], ASCO-PCO suggests genetic testing of all first-degree relatives of germline mutation carriers who are eligible for pancreatic cancer surveillance [148], [149].
Germline analysis of the genes listed in Table 8 will also lead to the identification of variants of unclear significance whose relevance to pancreatic cancer disease is unproven or unclear. The significance of the finding of a germline variant with unclear significance should be evaluated taking into account the familial risk and explained to the tested individuals during genetic counseling.
Table 8: Genes and Syndromes Associated with an Increased Risk of Pancreatic Cancer [based on Table 1 from Stoffel et al. 2018 [122]]
| Gene | Syndrome | PDAC Risk | Other Associated Cancers* |
| APC | Familial adenomatous polyposis | 1-5% | Colorectal, upper GI, thyroid, brain |
| ATM | Ataxia telangiectasia (biallelic)† | 1-5% | Breast, prostate, gastric |
| BRCA2 | Hereditary breast ovarian cancer syndrome | 5-10% | Breast, ovary, prostate, melanoma |
| BRCA1 | Hereditary breast ovarian cancer syndrome | 2% | Breast, ovary, prostate, melanoma |
| CDKN2A | Familial atypical multiple mole melanoma (FAMMM) |
10-30% | Melanoma |
| MLH1, MSH2, MSH6, PMS2, EPCAM |
Lynch syndrome | 5-10% | Colorectal, uterine, upper GI, ovary, urinary tract, brain, sebaceous neoplasms |
| PALB2 | 5-10% | Breast, prostate | |
| STK11 | Peutz Jeghers syndrome | 10-30% | Breast, colorectal, upper GI, lung, reproductive tract |
| TP53 | Li Fraumeni syndrome | n/a | Breast, brain, sarcoma, adrenocortical carcinoma |
*Most commonly associated cancers.
†Biallelic ATM mutation carriers have ataxia telangiectasia, but a single ATM mutation is associated with increased risk for pancreatic cancer.
4.3 Prophylaxis and Prevention for Patients at Risk
A recommendation for primary prevention of relatives of a patient with pancreatic cancer, deviating from the recommendations for primary prevention of the normal population, cannot be given.
- Consensus
- Strong consensus
Background
In general, the recommendations for the normal population also apply to the relatives of a pancreatic cancer patient. There is currently no scientific evidence for the benefit of measures that deviate from these recommendations.
4.4 Screening
4.4.1 Screening in an Asymptomatic Population
Recommendations for screening asymptomatic individuals who are not at increased risk of developing pancreatic cancer.
Screening tests shall not be carried out in asymptomatic individuals without an increased risk of pancreatic cancer.
- Consensus
- Strong consensus
Background
Due to the low prevalence of pancreatic cancer, screening of the asymptomatic normal population does not appear sensible. This includes laboratory tests such as the determination of CA19-9, any form of imaging examination, as well as molecular biological biomarker analyses in blood and tissue samples. The following considerations on a hypothetical screening test with excellent sensitivity and specificity for pancreatic cancer illustrate the problem [154]: The age-adjusted incidence of pancreatic cancer in individuals aged 50 years or older is 37 per 100,000 population [103]. If a hypothetical test with 99% sensitivity and 99% specificity for pancreatic cancer is used to screen 100,000 individuals aged 50 years or older, the test would detect almost all pancreatic cancers in this population (n= 36 of 37 pancreatic cancers in 100,000), but it would also be false positive in 1,000 individuals. This risk-benefit ratio is not acceptable.
At the time of the 2006 guideline recommendation, two studies with large numbers of cases were available which showed that screening of asymptomatic individuals is not justified due to the very low positive predictive value of CA19-9 [155], [156].
The US Preventive Services Task Force (USPSTF) formulates recommendations on the effectiveness of specific preventive measures for individuals without obvious disease-related findings or symptoms. In 2004, the USPSTF recommended against screening for pancreatic cancer in the asymptomatic general population. In 2019, the USPSTF reviewed the new evidence (2004 - June 2019) and found no studies demonstrating that screening for pancreatic cancer, or treatment of screening-detected pancreatic cancer, improves disease-specific morbidity or mortality or all-cause mortality in the adult asymptomatic normal population. No adequate evidence was found on the accuracy of imaging screening tests (computed tomography, endoscopic ultrasound and magnetic resonance imaging) in this indication. However, adequate evidence was found that pancreatic cancer screening tests are associated with at least a moderate risk of harm, while the benefit is small. Harm can result from false positive screening results as well as from treatment.
The USPSTF therefore reiterated its 2004 conclusion that the potential benefits of screening for pancreatic cancer in asymptomatic adults do not outweigh the potential harms. The USPSTF thus recommends against screening for pancreatic cancer in asymptomatic adults. With moderate or high certainty, these screenings have no net benefit or the harms outweigh the benefits [157], [158].
The CAPS-2020 consensus recommendations (International Cancer of the Pancreas Screening Consortium) also describe the mean lifetime risk of developing pancreatic cancer (~1 in 64 in the USA) as too low to justify population-wide screening [132].
There is currently no scientific evidence to justify screening the asymptomatic normal population with molecular biology tests.
4.4.2 Screening Examinations/Programs for Individuals with an Increased Risk of Pancreatic Cancer
4.4.2.1 Risk Groups for Sporadic Pancreatic Cancer
Recommendation for screening asymptomatic individuals who are at increased risk (Statement 4.5) such as diabetes, advanced age, nicotine consumption, obesity, and/or chronic pancreatitis.
Screening tests shall not be performed on asymptomatic individuals who are known or suspected to have an increased risk of sporadic pancreatic cancer, as these factors only slightly increase the risk.
- Consensus
- Strong consensus
Background
As described in Chapter 4.1.5, there are a number of conditions for which an increased risk of developing sporadic pancreatic cancer has been described. With partly contradictory results, weak data and only slightly increased risks (see Chapter 4.1.5), no recommendation for screening can be made here for asymptomatic individuals.
4.4.2.2 Individuals with an Increased Risk of Familial Pancreatic Carcinoma
The care of individuals at increased risk of familial pancreatic cancer (Statement 4.7), or pancreatic cancer in a genetic tumor risk syndrome should preferably be carried out at centers that have experience in the management of these high-risk individuals and have prospective studies or registries at their disposal.
Surveillance examinations can be offered to individuals who meet the criteria for familial pancreatic cancer (see statement on familial pancreatic cancer).
- Consensus
- Strong consensus
According to the latest national and international studies, the risk of developing pancreatic cancer is significantly lower in FPC family members compared to carriers of probable pathogenic/pathogenic germline gene variants, in particular STK11 and CDKN2A. The affected individuals develop the disease late in life (usually between 65-70 years of age). The evidence for recommending screening is therefore weak, particularly with regard to the expected benefit [159], [160], [161], [148], [162]. In this context, the recently published data of a cohort from the Netherlands with 366 high-risk individuals show particularly impressively that after an average follow-up of 63 months, pancreatic carcinomas developed only in the group of 165 carriers of probable pathogenic/pathogenic germline variants, while no pancreatic carcinoma was found in 201 individuals from FPC families [163]. Similar data were already reported when comparing the screening results of CDKN2A germline variant carriers with at-risk individuals from FPC families at the centers in Marburg, Madrid, and Leyden [161], where a clear benefit of surveillance examinations was only evident in CDKN2A variant carriers.
All published surveillance studies show that benign lesions (e.g. serous cystic adenomas or local fibrosis) or low-grade precursor lesions (e.g. PanIN 1-2, BD-IPMN) are found in up to 50 % of pancreatic resections performed due to abnormal surveillance findings [159], [160], [164], [131]. The CAPS consensus conference defined that screening programs must detect T1 N0 M0 pancreatic cancer or IPMN or PanIN with high grade dysplasia (HGD) to be considered successful [132]. According to a recently published summary of the surveillance results of 16 international programs with 2,522 high-risk individuals mainly from FPC families [159], this requirement was rarely achieved. More than 70% of the 28 incident pancreatic carcinomas were diagnosed at a tumor stage > T1 N0 M0 - often in the interval between surveillance examinations.
The guidelines included in the analysis are also reluctant to recommend surveillance examinations for asymptomatic members of FPC families. ASCO-PCO and NICE recommend that surveillance tests can be offered to members of FPC families. The CAPS consensus conference recommended that screening can be considered for these at-risk individuals from FPC families. For these reasons, the working group of the DGVS guideline for this risk group of patients (FPC according to recommendation 4.15) also recommends that surveillance examinations can be offered, whereby the expected benefit should be discussed and weighed up with the patients. Surveillance examinations should be carried out at centers that have extensive experience in screening individuals at risk of pancreatic cancer.
4.4.2.3 Individuals from Families with Genetic Tumor Risk Syndromes Associated with an Increased Risk of Pancreatic Cancer
Screening examinations should be offered at specialized centers.
Surveillance examinations shall be offered to individuals who are carriers of a probable pathogenic/pathogenic germline variant in one of the predisposing genes APC, ATM, BARD1, BRCA1, BRCA2, CHEK2, CDKN2A, MLH1, MSH2, MSH6, PMS2, EPCAM, PALB2, TP53, WT1 and who are first-degree relatives of at least one family member with pancreatic cancer.
- Consensus
- Strong consensus
Surveillance examinations shall be offered to the following individuals due to the high risk of developing pancreatic cancer:
- all patients with Peutz-Jeghers syndrome or carriers of a probable pathogenic/pathogenic germline variant in the STK11 gene,
- all carriers of a probable pathogenic/pathogenic germline variant in the CDKN2A gene.
- Consensus
- Consent
Background
As described in the previous chapter, the risk of developing pancreatic cancer is significantly higher in carriers of probable pathogenic/pathogenic germline gene variants - in particular STK11/LKB1 and CDKN2a gene variants - than in FPC family members (see [159], [160], [161], [148], [162]). Thus, the recommendations of the guidelines consulted regarding the performance of surveillance examinations for carriers of germline variants are stronger and more differentiated than for FPC family members. CAPS, NCCN, ASCO and NICE recommend surveillance tests for carriers of STK11 variants and all guidelines except NICE also recommend surveillance tests for carriers of CDKN2A gene variants due to the high risk of pancreatic cancer, even if no first-degree relative has pancreatic cancer.
For individuals with a known probable pathogenic/pathogenic germline variant in predisposing genes, the risk of developing pancreatic cancer is higher than in FPC families without a probable pathogenic/pathogenic germline variant, but is very heterogeneous and variable. Thus, individuals with a likely pathogenic/pathogenic BRCA1/ BRCA2/ PALB2 germline variant usually develop pancreatic cancer later and the risk is only slightly higher than in FPC without likely pathogenic/pathogenic germline variants (see [163], [162], [161]). The ASCO, NCCN, CAPS and NICE guidelines recommend considering surveillance examinations for carriers of the different germline variants.
Further background information on families with genetic tumor risk syndromes associated with an increased risk of pancreatic cancer can be found in chapter 4.2.2 of this guideline.
Table 8 of this guideline (Chapter 4.2.2) summarizes the genetic tumor risk syndromes associated with pancreatic cancer and the associated risk genes, in accordance with the ASCO-PCO recommendations [136]. These include: APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PMS2, EPCAM, PALB2, STK11 and TP53. Other likely pathogenic/pathogenic germline variants were found in the following genes in pancreatic cancer patients: BARD1, CHEK2 [Park, Wungki et al. 2020], WT1 [138].
4.4.2.4 Individuals with Hereditary Chronic Pancreatitits
Surveillance testing can be offered to individuals with hereditary chronic pancreatitis regardless of the likely underlying pathogenic/pathogenic germline variant.
- Consensus
- Strong consensus
Background
CAPS-2020 recommends that pancreatic cancer screening should also be considered in patients with hereditary pancreatitis [132]. NCCN also states the same for patients with mutations in PRSS1 or other HP-associated genes and a clinical phenotype consistent with hereditary pancreatitis. Only NICE 2018 makes a stronger recommendation for screening, but only for patients with hereditary pancreatitis and a probable pathogenic/pathogenic variant in the PRSS1 gene. The available guidelines mention screening from the age of 40 or 20 years after the onset of the disease [132]. In addition to patients with a probable pathogenic/pathogenic variant in the PRSS1 gene, these recommendations also include carriers of probable pathogenic/pathogenic variants of chymotrypsinogen C (CTRC), carboxypeptidase A1 (CPA1), „cystic fibrosis transmembrane conductance regulator“ (CFTR) and serine protease inhibitor, Kazal type 1 (SPINK1) that predispose to hereditary chronic pancreatitis [165]. As it is unlikely that the individual probable pathogenic/pathogenic variant or the combination of probable pathogenic/pathogenic variants explains the development of pancreatic cancer, screening can be recommended to all patients with hereditary chronic pancreatitis.
4.4.2.5 Screening Methods
During the initial examination of high-risk individuals, MRI/MRCP and/or endoscopic ultrasound should be used as the imaging method for the surveillance examinations.
- Consensus
- Strong consensus
Background
Various guidelines (ASCO-PCO [136] CAPS-2020 [132]) recommend MRI/MRCP and/or endoscopic ultrasound for the initial examination of individuals with a familial or hereditary increased risk of pancreatic cancer (high-risk individuals, HRI). In addition to the lack of radiation exposure, both procedures are able to detect smaller lesions, e.g. cysts [132]. The superiority of the procedures over CT has not been clearly proven, but the reduction in radiation exposure speaks in favor of their use in the initial examination. In patients with hereditary chronic pancreatitis and morphological changes in the pancreas, the informative value of imaging procedures with regard to the early detection of pancreatic cancer is limited [166], [167], [168], [169].
If the findings are unremarkable in the initial and follow-up examinations, annual monitoring is advisable [132]. Small (less than 1 cm) neuroendocrine tumors of the pancreas are often detected as solid masses as incidental findings in the patients examined [170]. In this case, the procedure should be carried out according to the current guideline (ENETS consensus guideline, DGVS S2K guideline NET) [171]. The same applies to cystic pancreatic lesions (European guideline on cystic pancreatic lesions, Gut 2018). In the case of abnormal findings that do not yet provide an immediate indication for surgery, e.g. pancreatic duct changes, new cystic lesions (no clear solid parts can be delineated), further examinations should be considered (e.g. CT) and the follow-up interval shortened to 3-6 months. However, new data [159] show that patients with a hereditary risk of pancreatic cancer in surveillance programs also develop so-called interval carcinomas, i.e. an advanced tumor is diagnosed before the next scheduled examination if the surveillance examination is normal.
There is no clear evidence for an additional benefit of HbA1c and fasting blood glucose testing in high-risk individuals who receive imaging as a screening test. Nevertheless, the expert consensus is that if HbA1c and fasting blood glucose values are abnormal, further examinations can be adapted, e.g. with regard to the examination interval and the addition of further imaging [132].
Routine determination of the CA 19-9 value is not recommended.
4.4.2.6 Starting with Screening Procedures
Screening/surveillance examinations should be carried out at the following ages:
- in high-risk individuals for familial pancreatic cancer without a known germline mutation: from 50-55 years of age. or at an age of 10 years before the youngest age of onset in the family.
- in individuals with probable pathogenic/pathogenic CDKN2A germline variants or Peutz-Jeghers syndrome (probable pathogenic/pathogenic germline variants STK11 gene): From 40 years of age or at 10 years before the youngest age of onset in the family.
- for carriers of a probable pathogenic/pathogenic variant in the germline in one of the predisposing genes APC, ATM, BARD1, BRCA1, BRCA2, CHEK2, CDKN2A, MLH1, MSH2, MSH6, PMS2, EPCAM, PALB2, TP53, WT1 and at least one first-degree relative with pancreatic cancer: From the age of 50 or 10 years before the youngest age of onset of the disease in the family.
- in patients with hereditary pancreatitis: from the age of 40 if the onset of the disease is unknown, or 20 years after the onset of the disease if this is before the age of 40.
- Consensus
- Strong consensus
Background
The best age to start screening examinations in patients at risk for hereditary pancreatic cancer is controversial. The recommendations are based on consensus decisions, e.g. [172], [132]. In individuals from FPC families, the mean age at diagnosis of pancreatic cancer is 68 years; pancreatic cancer does not usually occur before the age of 50 [131], [173], [135]. At the CAPS consensus conference, 51% of participants recommended starting screening at the age of 50 for individuals from FPC families [132]. In carriers of likely pathogenic/pathogenic CDKN2A and STK11 gene variants, some patients were diagnosed with pancreatic cancer between 30-44 years of age [132], so that an earlier start of screening is justified. In patients with hereditary chronic pancreatitis, the risk of developing pancreatic cancer increases from the age of 50. In one study, the cumulative risk was 3.4% at the age of 50 years, 18.8% at the age of 70 years and 33.3% at the age of 80 years [123]. As the duration of the disease appears to be an important factor for the risk, it makes sense to take this into account when the onset of the disease is known. This is the basis for the recommendation to start screening patients with hereditary pancreatitis from the age of 40 if the onset of the disease is unknown or 20 years after the onset of the disease if this is before the age of 40. Smokers have almost twice the risk of developing pancreatic cancer and it can occur up to 20 years earlier [174], [123]. However, the underlying guidelines do not advocate an earlier start of surveillance examinations in smokers.
References
[3] Glade, M. J., Food, nutrition, and the prevention of cancer: a global perspective. American Institute for Cancer Research/World Cancer Research Fund, American Institute for Cancer Research, 1997, Nutrition, 1999. 15(6): p. 523-6., https://pubmed.ncbi.nlm.nih.gov/10378216/
[4] WCRF, AICR, Diet, nutrition, physical activity and pancreatic cancer, Diet, Nutrition, Physical Activity and Cancer: a Global Perspective, 2018., https://www.wcrf.org/wp-content/uploads/2021/02/pancreatic-cancer-report.pdf
[5] Morze, J., Danielewicz, A., Przybyłowicz, K., Zeng, H., Hoffmann, G., Schwingshackl, L., An updated systematic review and meta‑analysis on adherence to mediterranean diet and risk of cancer, 2020., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987633/pdf/394_2020_Article_2346.pdf
[6] Grosso, G, Bella, F, Godos, J, Sciacca, S, Del Rio, D, Ray, S, et.al. Possible role of diet in cancer: systematic review and multiple meta-analyses of dietary patterns, lifestyle factors, and cancer risk., Nutr Rev, 2017. 75 (6)(6): p. 405-419., https://pubmed.ncbi.nlm.nih.gov/28969358/
[7] Lu, PY, Shu, L, Shen, SS, Chen, XJ, Zhang, XY, Dietary Patterns and Pancreatic Cancer Risk: A Meta-Analysis., Nutrients, 2017. 9 (1)(1):, https://pubmed.ncbi.nlm.nih.gov/28067765/
[8] Zheng, J, Guinter, MA, Merchant, AT, Wirth, MD, Zhang, J, Stolzenberg-Solomon, RZ, et.al. Dietary patterns and risk of pancreatic cancer: a systematic review., Nutr Rev, 2017. 75 (11)(11): p. 883-908., https://pubmed.ncbi.nlm.nih.gov/29025004/
[9] Gao, Y, Ma, Y, Yu, M, Li, G, Chen, Y, Li, X, et.al. Poultry and Fish Intake and Pancreatic Cancer Risk: A Systematic Review and Meta-Analysis., Nutr Cancer, 2022. 74 (1)(1): p. 55-67., https://pubmed.ncbi.nlm.nih.gov/33432844/
[10] Zhao, Z., Yin, Z., Pu, Z., Zhao, O., Association Between Consumption of Red and Processed Meat and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis, 2017. p. 486 - 493., http://www.elsevier.com/inca/publications/store/6/7/2/7/4/3/index
[11] Mossine, VV, Mawhinney, TP, Giovanucci, EL, Dried Fruit Intake and Cancer: A Systematic Review of Observational Studies, 2020. p. 237 - 250., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442373/pdf/nmz085.pdf
[12] Wu, QJ, Wu, L, Zheng, LQ, Xu, X, Ji, C, Gong, TT, Consumption of fruit and vegetables reduces risk of pancreatic cancer: evidence from epidemiological studies., Eur J Cancer Prev, 2016. 25 (3)(3): p. 196-205., https://pubmed.ncbi.nlm.nih.gov/26075658/
[13] Darooghegi Mofrad, M, Mozaffari H, Askari MR, Amini MR, Jafari A, Surkan PJ, Potato Consumption and Risk of Site-Specific Cancers in Adults: A Systematic Review and Dose-Response Meta-Analysis of Observational Studies, 2021., https://academic.oup.com/advances/article-abstract/12/5/1705/6228237?redirectedFrom=fulltext
[14] Zhang, D, Dai, C, Zhou, L, Li, Y, Liu, K, Deng, YJ, Meta-analysis of the association between nut consumption and the risks of cancer incidence and cancer-specific mortality, 2020. p. 10772 - 10794., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346045/pdf/aging-12-103292.pdf
[15] Gaesser, GA, Whole grains, refined grains, and cancer risk: A systematic review of meta-analyses of observational studies, 2020. p. 1 - 23., https://www.mdpi.com/2072-6643/12/12/3756/pdfhttps://mdpi-res.com/d_attachment/nutrients/nutrients-12-03756/article_deploy/nutrients-12-03756.pdf
[16] McRae, MP, The Benefits of Dietary Fiber Intake on Reducing the Risk of Cancer: An Umbrella Review of Meta-analyses, 2018. p. 90 - 96., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112064/pdf/main.pdf
[17] Llaha, F., Gil-Lespinard, M., Unal, P., de Villasante, I., Castaneda, J., Zamora-Ros, R., Consumption of sweet beverages and cancer risk A systematic review and meta-analysis of observational studies, 2021. p. 1 - 35., htps://mdpi-res.com/d_attachment/nutrients/nutrients-13-00516/article_deploy/nutrients-13-00516-v3.pdf
[18] Milajerdi, A., Larijani, B., Esmaillzadeh, A., Sweetened Beverages Consumption and Pancreatic Cancer: A Meta-Analysis, 2019. p. 375 - 384., https://www.tandfonline.com/doi/full/10.1080/01635581.2019.1578390
[19] Ghadirian, P., Baillargeon, J., Simard, A., Perret, C., Food habits and pancreatic cancer: a case-control study of the Francophone community in Montreal, Canada, Cancer Epidemiol Biomarkers Prev, 1995. 4(8): p. 895-9., https://pubmed.ncbi.nlm.nih.gov/8634663/
[20] Michaud, D. S., Liu, S., Giovannucci, E., Willett, W. C., Colditz, G. A., Fuchs, C. S., Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study, J Natl Cancer Inst, 2002. 94(17): p. 1293-300., https://pubmed.ncbi.nlm.nih.gov/12208894/
[21] Silvera, S. A., Rohan, T. E., Jain, M., Terry, P. D., Howe, G. R., Miller, A. B., Glycemic index, glycemic load, and pancreatic cancer risk (Canada), Cancer Causes Control, 2005. 16(4): p. 431-6., https://pubmed.ncbi.nlm.nih.gov/15953985/
[22] Stolzenberg-Solomon, R. Z., Pietinen, P., Taylor, P. R., Virtamo, J., Albanes, D., Prospective study of diet and pancreatic cancer in male smokers, Am J Epidemiol, 2002. 155(9): p. 783-92., https://pubmed.ncbi.nlm.nih.gov/11978580/
[23] Nothlings, U., Wilkens, L. R., Murphy, S. P., Hankin, J. H., Henderson, B. E., Kolonel, L. N., Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study, J Natl Cancer Inst, 2005. 97(19): p. 1458-65., https://pubmed.ncbi.nlm.nih.gov/16204695/
[24] Lin, Y., Tamakoshi, A., Hayakawa, T., Naruse, S., Kitagawa, M., Ohno, Y., Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan, J Gastroenterol, 2005. 40(3): p. 297-301., https://pubmed.ncbi.nlm.nih.gov/15830290/
[25] Michaud, D. S., Giovannucci, E., Willett, W. C., Colditz, G. A., Fuchs, C. S., Dietary meat, dairy products, fat, and cholesterol and pancreatic cancer risk in a prospective study, Am J Epidemiol, 2003. 157(12): p. 1115-25., https://pubmed.ncbi.nlm.nih.gov/12796048/
[26] Bueno de Mesquita, H. B., Maisonneuve, P., Runia, S., Moerman, C. J., Intake of foods and nutrients and cancer of the exocrine pancreas: a population-based case-control study in The Netherlands, Int J Cancer, 1991. 48(4): p. 540-9., https://pubmed.ncbi.nlm.nih.gov/1646177/
[27] Lu, PY, Shu, L, Shen, SS, Chen, XJ, Zhang, XY, Dietary Patterns and Pancreatic Cancer Risk: A Meta-Analysis., Nutrients, 2017. 9 (1)(1):, https://pubmed.ncbi.nlm.nih.gov/28067765/
[28] Chen, J, Jiang, W, Shao, L, Zhong, D, Wu, Y, Cai, J, Association between intake of antioxidants and pancreatic cancer risk: a meta-analysis, 2016. p. 744 - 753., https://www.tandfonline.com/doi/full/10.1080/09637486.2016.1197892
[29] Wang, L, Wang, J, Liu, X, Liu, Q, Zhang, G, Liang, L, Association between selenium intake and the risk of pancreatic cancer: a meta-analysis of observational studies., Biosci Rep, 2016. 36 (5)(5):, https://pubmed.ncbi.nlm.nih.gov/27623938/
[30] Hua, YF, Wang, GQ, Jiang, W, Huang, J, Chen, GC, Lu, CD, Vitamin C Intake and Pancreatic Cancer Risk: A Meta-Analysis of Published Case-Control and Cohort Studies., PLoS One, 2016. 11 (2)(2): p. e0148816., https://pubmed.ncbi.nlm.nih.gov/26859881/
[31] Liu, Y, Wang, X, Sun, X, Lu, S, Liu, S, Vitamin intake and pancreatic cancer risk reduction: A meta-analysis of observational studies, 2018., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895396/pdf/medi-97-e0114.pdf
[32] Huang, X, Gao, Y, Zhi, X, Ta, N, Jiang, H, Zheng, J, Association between vitamin A, retinol and carotenoid intake and pancreatic cancer risk: Evidence from epidemiologic studies, 2016., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150257/pdf/srep38936.pdf
[33] Zhang, T, Chen, H, Qin, S, Wang, M, Wang, X, Zhang, X, et.al. The association between dietary vitamin A intake and pancreatic cancer risk: a meta-analysis of 11 studies., Biosci Rep, 2016. 36 (6)(6):, https://pubmed.ncbi.nlm.nih.gov/27756825/
[34] Fu, H, Zeng, J, Liu, C, Gu, Y, Zou, Y, Chang, H, Folate Intake and Risk of Pancreatic Cancer: A Systematic Review and Updated Meta-Analysis of Epidemiological Studies., Dig Dis Sci, 2021. 66 (7)(7): p. 2368-2379., https://pubmed.ncbi.nlm.nih.gov/32770489/
[35] Liu, W, Zhou, H, Zhu, Y, Tie, C, Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis., Oncotarget, 2017. 8 (49)(49): p. 86828-86842., https://pubmed.ncbi.nlm.nih.gov/29156838/
[36] DGE, 13. DGE-Ernährungsbericht, 2016.
[37] Wei, DH, Mao, QQ, Vitamin B6, vitamin B12 and methionine and risk of pancreatic cancer: a meta-analysis., Nutr J, 2020. 19 (1)(1): p. 111., https://pubmed.ncbi.nlm.nih.gov/33012287/
[38] Peng, YF, Han, MM, Huang, R, Dong, BB, Li, L, Vitamin B6 Intake and Pancreatic Carcinoma Risk: A Meta-Analysis., Nutr Cancer, 2019. 71 (7)(7): p. 1061-1066., https://pubmed.ncbi.nlm.nih.gov/31226890/
[39] Mocellin, S, Briarava, M, Pilati, P, Vitamin B6 and Cancer Risk: A Field Synopsis and Meta-Analysis., J Natl Cancer Inst, 2017. 109 (3)(3): p. 1-9., https://pubmed.ncbi.nlm.nih.gov/28376200/
[40] Zhang, X, Huang, XZ, Chen, WJ, Wu, J, Chen, Y, Wu, CC, et.al. Plasma 25-hydroxyvitamin D levels, vitamin D intake, and pancreatic cancer risk or mortality: a meta-analysis., Oncotarget, 2017. 8 (38)(38): p. 64395-64406., https://pubmed.ncbi.nlm.nih.gov/28969079/
[41] Li, L, Gai, X, The association between dietary zinc intake and risk of pancreatic cancer: a meta-analysis., Biosci Rep, 2017. 37 (3)(3):, https://pubmed.ncbi.nlm.nih.gov/28428431/
[42] Abbasalizad Farhangi, M, Vajdi, M, Dietary Total Antioxidant Capacity (TAC) Significantly Reduces the Risk of Site-Specific Cancers: An Updated Systematic Review and Meta-Analysis., Nutr Cancer, 2021. 73 (5)(5): p. 721-739., https://pubmed.ncbi.nlm.nih.gov/32462920/
[43] Guo, Z, Hong, Y, Cheng, Y, Dietary inflammatory index and pancreatic cancer risk: a systematic review and dose-response meta-analysis., Public Health Nutr, 2021. 24 (18)(18): p. 6427-6435., https://pubmed.ncbi.nlm.nih.gov/33843543/
[44] Xie, L, Mo, M, Jia, HX, Liang, F, Yuan, J, Zhu, J, Association between dietary nitrate and nitrite intake and sitespecific cancer risk: evidence from observational studies., Oncotarget, 2016. 7 (35)(35): p. 56915-56932., https://pubmed.ncbi.nlm.nih.gov/27486968/
[45] Gao, Y., Ma, Y., Yu, M., Li, G., Chen, Y., Li, X., Poultry and Fish Intake and Pancreatic Cancer Risk: A Systematic Review and Meta-Analysis, 2021. p. 1 - 13.
[46] Zhao, Z., Yu, P., Feng, X., Yin, Z., Wang, S., Qiu, Z., No associations between fruit and vegetable consumption and pancreatic cancer risk: A meta-analysis of prospective studiesOncotarget, 2018. p. 32250 - 32261., https://www.oncotarget.com/article/23128/pdf/
[47] Wu, QJ, Wu, L, Zheng, LQ, Xu, X, Ji, C, Gong, TT, Consumption of fruit and vegetables reduces risk of pancreatic cancer: evidence from epidemiological studies., Eur J Cancer Prev, 2016. 25 (3)(3): p. 196-205., https://pubmed.ncbi.nlm.nih.gov/26075658/
[48] Mills, P. K., Beeson, W. L., Abbey, D. E., Fraser, G. E., Phillips, R. L., Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists, Cancer, 1988. 61(12): p. 2578-85., https://pubmed.ncbi.nlm.nih.gov/3365678/
[49] Silvera, S. A., Rohan, T. E., Jain, M., Terry, P. D., Howe, G. R., Miller, A. B., Glycemic index, glycemic load, and pancreatic cancer risk (Canada), Cancer Causes Control, 2005. 16(4): p. 431-6., https://pubmed.ncbi.nlm.nih.gov/15953985/
[50] Wang, YT, Gou, YW, Jin, WW, Xiao, M, Fang, HY, Association between alcohol intake and the risk of pancreatic cancer: a dose-response meta-analysis of cohort studies., BMC Cancer, 2016. 16 (): p. 212., https://pubmed.ncbi.nlm.nih.gov/26968702/
[51] Lugo, A, Peveri, G, Bosetti, C, Bagnardi, V, Crippa, A, Orsini, N, et.al. Strong excess risk of pancreatic cancer for low frequency and duration of cigarette smoking: A comprehensive review and meta-analysis., Eur J Cancer, 2018. 104 (): p. 117-126., https://pubmed.ncbi.nlm.nih.gov/30347287/
[52] Gupta, S, Gupta, R, Sinha, DN, Mehrotra, R, Relationship between type of smokeless tobacco & risk of cancer: A systematic review., Indian J Med Res, 2018. 148 (1)(1): p. 56-76., https://pubmed.ncbi.nlm.nih.gov/30264755/
[53] Ordóñez-Mena, JM, Schöttker, B, Mons, U, Jenab, M, Freisling, H, Bueno-de-Mesquita, B, et.al. Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium., BMC Med, 2016. 14 (): p. 62., https://pubmed.ncbi.nlm.nih.gov/27044418/
[54] Lee, PN, Thornton, AJ, Hamling, JS, Epidemiological evidence on environmental tobacco smoke and cancers other than lung or breast., Regul Toxicol Pharmacol, 2016. 80 (): p. 134-63., https://pubmed.ncbi.nlm.nih.gov/27321059/
[55] Gupta, S, Gupta, R, Sinha, DN, Mehrotra, R, Relationship between type of smokeless tobacco & risk of cancer: A systematic review., Indian J Med Res, 2018. 148 (1)(1): p. 56-76., https://pubmed.ncbi.nlm.nih.gov/30264755/
[56] Li, TD, Yang, HW, Wang, P, Song, CH, Wang, KJ, Dai, LP, et.al. Coffee consumption and risk of pancreatic cancer: a systematic review and dose-response meta-analysis., Int J Food Sci Nutr, 2019. 70 (5)(5): p. 519-529., https://pubmed.ncbi.nlm.nih.gov/30632827/
[57] Ran, HQ, Wang, JZ, Sun, CQ, Coffee Consumption and Pancreatic Cancer Risk: An Update Meta-analysis of Cohort Studies., Pak J Med Sci, 2016. 32 (1)(1): p. 253-9., https://pubmed.ncbi.nlm.nih.gov/27022386/
[58] Alguacil, J., Pollan, M., Gustavsson, P., Occupations with increased risk of pancreatic cancer in the Swedish population, Occup Environ Med, 2003. 60(8): p. 570-6., https://www.ncbi.nlm.nih.gov/pubmed/12883017
[59] Alguacil, J., Porta, M., Benavides, F. G., Malats, N., Kogevinas, M., Fernandez, E., et.al. Occupation and pancreatic cancer in Spain: a case-control study based on job titles. PANKRAS II Study Group, Int J Epidemiol, 2000. 29(6): p. 1004-13., https://www.ncbi.nlm.nih.gov/pubmed/11101541
[60] Laakkonen, A., Kauppinen, T., Pukkala, E., Cancer risk among Finnish food industry workers, Int J Cancer, 2006. 118(10): p. 2567-71., https://pubmed.ncbi.nlm.nih.gov/16380992/
[61] Fryzek, J. P., Garabrant, D. H., Harlow, S. D., Severson, R. K., Gillespie, B. W., Schenk, M., et.al. A case-control study of self-reported exposures to pesticides and pancreas cancer in southeastern Michigan, Int J Cancer, 1997. 72(1): p. 62-7., https://www.ncbi.nlm.nih.gov/pubmed/9212224
[62] Ji, B. T., Silverman, D. T., Stewart, P. A., Blair, A., Swanson, G. M., Baris, D., et.al. Occupational exposure to pesticides and pancreatic cancer, Am J Ind Med, 2001. 39(1): p. 92-9., https://pubmed.ncbi.nlm.nih.gov/11148019/
[63] Ojajarvi, I. A., Partanen, T. J., Ahlbom, A., Boffetta, P., Hakulinen, T., Jourenkova, N., et.al. Occupational exposures and pancreatic cancer: a meta-analysis, Occup Environ Med, 2000. 57(5): p. 316-24., https://pubmed.ncbi.nlm.nih.gov/10769297/
[64] Ojajarvi, A., Partanen, T., Ahlbom, A., Boffetta, P., Hakulinen, T., Jourenkova, N., et.al. Risk of pancreatic cancer in workers exposed to chlorinated hydrocarbon solvents and related compounds: a meta-analysis, Am J Epidemiol, 2001. 153(9): p. 841-50., https://pubmed.ncbi.nlm.nih.gov/11323314/
[65] Weiderpass, E., Vainio, H., Kauppinen, T., Vasama-Neuvonen, K., Partanen, T., Pukkala, E., Occupational exposures and gastrointestinal cancers among Finnish women, J Occup Environ Med, 2003. 45(3): p. 305-15., https://pubmed.ncbi.nlm.nih.gov/12661188/
[66] Yassi, A., Tate, R. B., Routledge, M., Cancer incidence and mortality in workers employed at a transformer manufacturing plant: update to a cohort study, Am J Ind Med, 2003. 44(1): p. 58-62., https://pubmed.ncbi.nlm.nih.gov/12822136/
[67] Ji, J., Hemminki, K., Socioeconomic and occupational risk factors for pancreatic cancer: a cohort study in Sweden, J Occup Environ Med, 2006. 48(3): p. 283-8., https://pubmed.ncbi.nlm.nih.gov/16531832/
[68] Alguacil, J., Pollan, M., Gustavsson, P., Occupations with increased risk of pancreatic cancer in the Swedish population, Occup Environ Med, 2003. 60(8): p. 570-6., https://pubmed.ncbi.nlm.nih.gov/12883017/
[69] Alguacil, J., Porta, M., Benavides, F. G., Malats, N., Kogevinas, M., Fernandez, E., et.al. Occupation and pancreatic cancer in Spain: a case-control study based on job titles. PANKRAS II Study Group, Int J Epidemiol, 2000. 29(6): p. 1004-13., https://pubmed.ncbi.nlm.nih.gov/11101541/
[70] Laakkonen, A., Kauppinen, T., Pukkala, E., Cancer risk among Finnish food industry workers, Int J Cancer, 2006. 118(10): p. 2567-71., https://pubmed.ncbi.nlm.nih.gov/16380992/
[71] Fryzek, J. P., Garabrant, D. H., Harlow, S. D., Severson, R. K., Gillespie, B. W., Schenk, M., et.al. A case-control study of self-reported exposures to pesticides and pancreas cancer in southeastern Michigan, Int J Cancer, 1997. 72(1): p. 62-7., https://pubmed.ncbi.nlm.nih.gov/9212224/
[72] Ji, B. T., Silverman, D. T., Stewart, P. A., Blair, A., Swanson, G. M., Baris, D., et.al. Occupational exposure to pesticides and pancreatic cancer, Am J Ind Med, 2001. 39(1): p. 92-9., https://pubmed.ncbi.nlm.nih.gov/11148019/
[73] Ojajarvi, I. A., Partanen, T. J., Ahlbom, A., Boffetta, P., Hakulinen, T., Jourenkova, N., et.al. Occupational exposures and pancreatic cancer: a meta-analysis, Occup Environ Med, 2000. 57(5): p. 316-24., https://pubmed.ncbi.nlm.nih.gov/10769297/
[74] Ojajarvi, A., Partanen, T., Ahlbom, A., Boffetta, P., Hakulinen, T., Jourenkova, N., et.al. Risk of pancreatic cancer in workers exposed to chlorinated hydrocarbon solvents and related compounds: a meta-analysis, Am J Epidemiol, 2001. 153(9): p. 841-50., https://pubmed.ncbi.nlm.nih.gov/11323314/
[75] Weiderpass, E., Vainio, H., Kauppinen, T., Vasama-Neuvonen, K., Partanen, T., Pukkala, E., Occupational exposures and gastrointestinal cancers among Finnish women, J Occup Environ Med, 2003. 45(3): p. 305-15., https://pubmed.ncbi.nlm.nih.gov/12661188/
[76] Yassi, A., Tate, R. B., Routledge, M., Cancer incidence and mortality in workers employed at a transformer manufacturing plant: update to a cohort study, Am J Ind Med, 2003. 44(1): p. 58-62., https://pubmed.ncbi.nlm.nih.gov/12822136/
[77] Ji, J., Hemminki, K., Socioeconomic and occupational risk factors for pancreatic cancer: a cohort study in Sweden, J Occup Environ Med, 2006. 48(3): p. 283-8., https://pubmed.ncbi.nlm.nih.gov/16531832/
[78] Dun, A, Zhao, X, Jin, X, Wei, T, Gao, X, Wang, Y, et.al. Association Between Night-Shift Work and Cancer Risk: Updated Systematic Review and Meta-Analysis., Front Oncol, 2020. 10 (): p. 1006., https://pubmed.ncbi.nlm.nih.gov/32656086/
[79] Xie, F, You, Y, Huang, J, Guan, C, Chen, Z, Fang, M, et.al. Association between physical activity and digestive-system cancer: An updated systematic review and meta-analysis., J Sport Health Sci, 2021. 10 (1)(1): p. 4-13., https://pubmed.ncbi.nlm.nih.gov/33010525/
[80] Solans, M, Chan, DSM, Mitrou, P, Norat, T, Romaguera, D, A systematic review and meta-analysis of the 2007 WCRF/AICR score in relation to cancer-related health outcomes., Ann Oncol, 2020. 31 (3)(3): p. 352-368., https://pubmed.ncbi.nlm.nih.gov/32067678/
[81] Luo, AJ, Feng, RH, Wang, XW, Wang, FZ, Older age at first birth is a risk factor for pancreatic cancer: a meta-analysis., Hepatobiliary Pancreat Dis Int, 2016. 15 (2)(2): p. 125-30., https://pubmed.ncbi.nlm.nih.gov/27020627/
[82] Prizment, AE, Anderson, KE, Hong, CP, Folsom, AR, Pancreatic cancer incidence in relation to female reproductive factors: Iowa Women's Health Study., JOP, 2007. 8 (1)(1): p. 16-27., https://pubmed.ncbi.nlm.nih.gov/17228129/
[83] Silveira, EA, Kliemann, N, Noll, M, Sarrafzadegan, N, de Oliveira, C, Visceral obesity and incident cancer and cardiovascular disease: An integrative review of the epidemiological evidence., Obes Rev, 2021. 22 (1)(1): p. e13088., https://pubmed.ncbi.nlm.nih.gov/32692447/
[84] Hidayat, K, Du, X, Shi, BM, Body fatness at a young age and risks of eight types of cancer: systematic review and meta-analysis of observational studies., Obes Rev, 2018. 19 (10)(10): p. 1385-1394., https://pubmed.ncbi.nlm.nih.gov/30047231/
[85] Seo, MS, Yeo, J, Hwang, IC, Shim, JY, Risk of pancreatic cancer in patients with systemic lupus erythematosus: a meta-analysis., Clin Rheumatol, 2019. 38 (11)(11): p. 3109-3116., https://pubmed.ncbi.nlm.nih.gov/31270697/
[86] Zhang, JJ, Jia, JP, Shao, Q, Wang, YK, Diabetes mellitus and risk of pancreatic cancer in China: A meta-analysis based on 26 case-control studies., Prim Care Diabetes, 2019. 13 (3)(3): p. 276-282., https://pubmed.ncbi.nlm.nih.gov/30553699/
[87] Aune, D, Sen, A, Norat, T, Riboli, E, Folseraas, T, Primary sclerosing cholangitis and the risk of cancer, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of cohort studies., Sci Rep, 2021. 11 (1)(1): p. 10646., https://pubmed.ncbi.nlm.nih.gov/34017024/
[88] Fan, Y, Hu, J, Feng, B, Wang, W, Yao, G, Zhai, J, et.al. Increased Risk of Pancreatic Cancer Related to Gallstones and Cholecystectomy: A Systematic Review and Meta-Analysis., Pancreas, 2016. 45 (4)(4): p. 503-9., https://pubmed.ncbi.nlm.nih.gov/26684857/
[89] Trafford, AM, Parisi, R, Kontopantelis, E, Griffiths, CEM, Ashcroft, DM, Association of Psoriasis With the Risk of Developing or Dying of Cancer: A Systematic Review and Meta-analysis., JAMA Dermatol, 2019. 155 (12)(12): p. 1390-1403., https://pubmed.ncbi.nlm.nih.gov/31617868/
[90] Arafa, A, Eshak, ES, Abdel Rahman, TA, Anwar, MM, Hepatitis C virus infection and risk of pancreatic cancer: A meta-analysis., Cancer Epidemiol, 2020. 65 (): p. 101691., https://pubmed.ncbi.nlm.nih.gov/32088651/
[91] Leung, CY, Huang, HL, Rahman, MM, Nomura, S, Krull Abe, S, Saito, E, et.al. Cancer incidence attributable to tuberculosis in 2015: global, regional, and national estimates., BMC Cancer, 2020. 20 (1)(1): p. 412., https://pubmed.ncbi.nlm.nih.gov/32398031/
[92] Liu, H, Chen, YT, Wang, R, Chen, XZ, Helicobacter pylori infection, atrophic gastritis, and pancreatic cancer risk: A meta-analysis of prospective epidemiologic studies., Medicine (Baltimore), 2017. 96 (33)(33): p. e7811., https://pubmed.ncbi.nlm.nih.gov/28816977/
[93] Liu, SS, Ma, XF, Zhao, J, Du, SX, Zhang, J, Dong, MZ, et.al. Association between nonalcoholic fatty liver disease and extrahepatic cancers: a systematic review and meta-analysis., Lipids Health Dis, 2020. 19 (1)(1): p. 118., https://pubmed.ncbi.nlm.nih.gov/32475354/
[94] Liu, X, Zhang, ZH, Jiang, F, Hepatitis B virus infection increases the risk of pancreatic cancer: a meta-analysis., Scand J Gastroenterol, 2021. 56 (3)(3): p. 252-258., https://pubmed.ncbi.nlm.nih.gov/33399501/
[95] Maisonneuve, P, Amar, S, Lowenfels, AB, Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis., Ann Oncol, 2017. 28 (5)(5): p. 985-995., https://pubmed.ncbi.nlm.nih.gov/28453689/
[96] Michaud, DS, Fu, Z, Shi, J, Chung, M, Periodontal Disease, Tooth Loss, and Cancer Risk., Epidemiol Rev, 2017. 39 (1)(1): p. 49-58., https://pubmed.ncbi.nlm.nih.gov/28449041/
[97] Shi, J, Leng, W, Zhao, L, Deng, C, Xu, C, Wang, J, et.al. Tooth loss and cancer risk: a dose-response meta analysis of prospective cohort studies., Oncotarget, 2018. 9 (19)(19): p. 15090-15100., https://pubmed.ncbi.nlm.nih.gov/29599929/
[98] Wang, L, Bierbrier, R, Drucker, AM, Chan, AW, Noncutaneous and Cutaneous Cancer Risk in Patients With Atopic Dermatitis: A Systematic Review and Meta-analysis., JAMA Dermatol, 2020. 156 (2)(2): p. 158-171., https://pubmed.ncbi.nlm.nih.gov/31825457/
[99] Pang, Y, Kartsonaki, C, Guo, Y, Bragg, F, Yang, L, Bian, Z, et.al. Diabetes, plasma glucose and incidence of pancreatic cancer: A prospective study of 0.5 million Chinese adults and a meta-analysis of 22 cohort studies., Int J Cancer, 2017. 140 (8)(8): p. 1781-1788., https://pubmed.ncbi.nlm.nih.gov/28063165/
[100] Wang, J, Yang, DL, Chen, ZZ, Gou, BF, Associations of body mass index with cancer incidence among populations, genders, and menopausal status: A systematic review and meta-analysis., Cancer Epidemiol, 2016. 42 (): p. 1-8., https://pubmed.ncbi.nlm.nih.gov/26946037/
[101] Kaleru, T, Vankeshwaram, VK, Maheshwary, A, Mohite, D, Khan, S, Diabetes Mellitus in the Middle-Aged and Elderly Population (>45 Years) and Its Association With Pancreatic Cancer: An Updated Review., Cureus, 2020. 12 (6)(6): p. e8884., https://pubmed.ncbi.nlm.nih.gov/32742851/
[102] Sona, MF, Myung, SK, Park, K, Jargalsaikhan, G, Type 1 diabetes mellitus and risk of cancer: a meta-analysis of observational studies., Jpn J Clin Oncol, 2018. 48 (5)(5): p. 426-433., https://pubmed.ncbi.nlm.nih.gov/29635473/
[103] Sharma, A., Kandlakunta, H., Nagpal, S. J. S., Feng, Z., Hoos, W., Petersen, G. M., et.al. Model to Determine Risk of Pancreatic Cancer in Patients With New-Onset Diabetes, Gastroenterology, 2018. 155(3): p. 730-739.e3., https://pubmed.ncbi.nlm.nih.gov/29775599/
[104] Chari, ST, Maitra, A, Matrisian, LM, Shrader, EE, Wu, BU, Kambadakone, A, et.al. Early Detection Initiative: A randomized controlled trial of algorithm-based screening in patients with new onset hyperglycemia and diabetes for early detection of pancreatic ductal adenocarcinoma., Contemp Clin Trials, 2022. 113 (): p. 106659., https://pubmed.ncbi.nlm.nih.gov/34954100/
[105] Hatami Marbini, M, Amiri, F, Sajadi Hezaveh, Z, Dietary glycemic index, glycemic load, insulin index, insulin load and risk of diabetes-related cancers: A systematic review of cohort studies., Clin Nutr ESPEN, 2021. 42 (): p. 22-31., https://pubmed.ncbi.nlm.nih.gov/33745582/
[106] Ling, S, Brown, K, Miksza, JK, Howells, LM, Morrison, A, Issa, E, et.al. Risk of cancer incidence and mortality associated with diabetes: A systematic review with trend analysis of 203 cohorts., Nutr Metab Cardiovasc Dis, 2021. 31 (1)(1): p. 14-22., https://pubmed.ncbi.nlm.nih.gov/33223399/
[107] Fang, HJ, Shan, SB, Zhou, YH, Zhong, LY, Diabetes mellitus and the risk of gastrointestinal cancer in women compared with men: a meta-analysis of cohort studies., BMC Cancer, 2018. 18 (1)(1): p. 422., https://pubmed.ncbi.nlm.nih.gov/29661174/
[108] Soltani, S, Abdollahi, S, Aune, D, Jayedi, A, Body mass index and cancer risk in patients with type 2 diabetes: a dose-response meta-analysis of cohort studies., Sci Rep, 2021. 11 (1)(1): p. 2479., https://pubmed.ncbi.nlm.nih.gov/33510262/
[109] Pergolini, I, Schorn, S, Jäger, C, Göß, R, Novotny, A, Friess, H, et.al. Diabetes mellitus in intraductal papillary mucinous neoplasms: A systematic review and meta-analysis., Surgery, 2021. 169 (2)(2): p. 411-418., https://pubmed.ncbi.nlm.nih.gov/32838986/
[110] Wang, Y, Yan, P, Fu, T, Yuan, J, Yang, G, Liu, Y, et.al. The association between gestational diabetes mellitus and cancer in women: A systematic review and meta-analysis of observational studies., Diabetes Metab, 2020. 46 (6)(6): p. 461-471., https://pubmed.ncbi.nlm.nih.gov/32097717/
[111] Guo, Y, Liu, W, Wu, J, None, J Cancer Res Ther, 2016. 12 (Supplement)(Supplement): p. C229-C232., https://pubmed.ncbi.nlm.nih.gov/28230023/
[112] Zhang, Y, Sun, C, Song, EJ, Liang, M, Shi, T, Min, M, et.al. Is periodontitis a risk indicator for gastrointestinal cancers? A meta-analysis of cohort studies., J Clin Periodontol, 2020. 47 (2)(2): p. 134-147., https://pubmed.ncbi.nlm.nih.gov/31697412/
[113] Beyer, G, Hoffmeister, A, Michl, P, Gress, TM, Huber, W, Algül, H, et.al. [Not Available]., Z Gastroenterol, 2022. 60 (3)(3): p. 419-521., https://pubmed.ncbi.nlm.nih.gov/35263785/
[114] Yamada, A, Komaki, Y, Komaki, F, Micic, D, Zullow, S, Sakuraba, A, Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis., Lancet Oncol, 2018. 19 (6)(6): p. 758-767., https://pubmed.ncbi.nlm.nih.gov/29706374/
[115] Heydari K., Rismantab S., Alizadeh-Navaei R., Shamshirian A., Shadmehri N., Lotfi P., Risk of secondary malignancies in patients with ovarian cancer: a systematic review and meta-analysis, 2021. p. 234 - 244., https://www.ejgo.net/articles/10.31083/j.ejgo.2021.02.2238
[116] Wang, Y, Lan, GB, Peng, FH, Xie, XB, Cancer risks in recipients of renal transplants: a meta-analysis of cohort studies., Oncotarget, 2018. 9 (20)(20): p. 15375-15385., https://pubmed.ncbi.nlm.nih.gov/29632651/
[117] Wang, G, Xu, Z, Zhu, J, Ren, J, Chen, M, He, G, et.al. Decreased Risk in the Pancreatic Cancer With History of Hay Fever: A Meta-Analysis., Front Public Health, 2020. 8 (): p. 551490., https://pubmed.ncbi.nlm.nih.gov/33117769/
[118] Karim, AF, Westenberg, LEH, Eurelings, LEM, Otten, R, Gerth van Wijk, R, The association between allergic diseases and cancer: a systematic review of the literature., Neth J Med, 2019. 77 (2)(2): p. 42-66., https://pubmed.ncbi.nlm.nih.gov/30895928/
[119] Cui, Y, Hill, AW, Atopy and Specific Cancer Sites: a Review of Epidemiological Studies., Clin Rev Allergy Immunol, 2016. 51 (3)(3): p. 338-352., https://pubmed.ncbi.nlm.nih.gov/27277132/
[120] Pang, Y, Holmes, MV, Kartsonaki, C, Guo, Y, Yang, L, Bian, Z, et.al. Young adulthood and adulthood adiposity in relation to incidence of pancreatic cancer: a prospective study of 0.5 million Chinese adults and a meta-analysis., J Epidemiol Community Health, 2017. 71 (11)(11): p. 1059-1067., https://pubmed.ncbi.nlm.nih.gov/28900029/
[121] Tan, J, You, Y, Guo, F, Xu, J, Dai, H, Bie, P, Association of elevated risk of pancreatic cancer in diabetic patients: A systematic review and meta-analysis., Oncol Lett, 2017. 13 (3)(3): p. 1247-1255., https://pubmed.ncbi.nlm.nih.gov/28454242/
[122] Lowenfels, A. B., Maisonneuve, P., DiMagno, E. P., Elitsur, Y., Gates, L. K., Jr., Perrault, J., et.al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group, J Natl Cancer Inst, 1997. 89(6): p. 442-6., https://pubmed.ncbi.nlm.nih.gov/9091646/
[123] Howes, N., Lerch, M. M., Greenhalf, W., Stocken, D. D., Ellis, I., Simon, P., et.al. Clinical and genetic characteristics of hereditary pancreatitis in Europe, Clin Gastroenterol Hepatol, 2004. 2(3): p. 252-61., https://pubmed.ncbi.nlm.nih.gov/15017610/
[124] Rosendahl, J., Witt, H., Szmola, R., Bhatia, E., Ozsvári, B., Landt, O., et.al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis, Nat Genet, 2008. 40(1): p. 78-82., https://pubmed.ncbi.nlm.nih.gov/18059268/
[125] Witt, H., Beer, S., Rosendahl, J., Chen, J. M., Chandak, G. R., Masamune, A., et.al. Variants in CPA1 are strongly associated with early onset chronic pancreatitis, Nat Genet, 2013. 45(10): p. 1216-20., https://pubmed.ncbi.nlm.nih.gov/23955596/
[126] Whitcomb, D. C., Genetic risk factors for pancreatic disorders, Gastroenterology, 2013. 144(6): p. 1292-302., https://pubmed.ncbi.nlm.nih.gov/23622139/
[127] Tamura, K., Yu, J., Hata, T., Suenaga, M., Shindo, K., Abe, T., et.al. Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer, Proc Natl Acad Sci U S A, 2018. 115(18): p. 4767-4772., https://pubmed.ncbi.nlm.nih.gov/29669919/
[128] National Institute for, Health, Care, Excellence, Pancreatic cancer in adults: diagnosis and management. NICE Guideline NG85NICE, 2018., https://www.nice.org.uk/guidance/ng85
[129] Raimondi, S, Lowenfels, AB, Morselli-Labate, AM, Maisonneuve, P, Pezzilli, R, Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection., Best Pract Res Clin Gastroenterol, 2010. 24 (3)(3): p. 349-58., https://pubmed.ncbi.nlm.nih.gov/20510834/
[130] Klein, A. P., Brune, K. A., Petersen, G. M., Goggins, M., Tersmette, A. C., Offerhaus, G. J., et.al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds, Cancer Res, 2004. 64(7): p. 2634-8., https://pubmed.ncbi.nlm.nih.gov/15059921/
[131] Bartsch, D. K., Slater, E. P., Carrato, A., Ibrahim, I. S., Guillen-Ponce, C., Vasen, H. F., et.al. Refinement of screening for familial pancreatic cancer, Gut, 2016. 65(8): p. 1314-21., https://www.ncbi.nlm.nih.gov/pubmed/27222532
[132] Goggins, M., Overbeek, K. A., Brand, R., Syngal, S., Del Chiaro, M., Bartsch, D. K., et.al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium, Gut, 2020. 69(1): p. 7-17., https://www.ncbi.nlm.nih.gov/pubmed/31672839
[133] McFaul, C. D., Greenhalf, W., Earl, J., Howes, N., Neoptolemos, J. P., Kress, R., et.al. Anticipation in familial pancreatic cancer, Gut, 2006. 55(2): p. 252-8., https://pubmed.ncbi.nlm.nih.gov/15972300/
[134] Grover, S, Syngal, S, Hereditary pancreatic cancer., Gastroenterology, 2010. 139 (4)(4): p. 1076-80, 1080.e1-2., https://pubmed.ncbi.nlm.nih.gov/20727885/
[135] Brune, KA, Lau, B, Palmisano, E, Canto, M, Goggins, MG, Hruban, RH, et.al. Importance of age of onset in pancreatic cancer kindreds., J Natl Cancer Inst, 2010. 102 (2)(2): p. 119-26., https://pubmed.ncbi.nlm.nih.gov/20068195/
[136] Stoffel, E. M., McKernin, S. E., Brand, R., Canto, M., Goggins, M., Moravek, C., et.al. Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion, Journal of Clinical Oncology, 2019. 37(2): p. 153-164., https://pubmed.ncbi.nlm.nih.gov/30589608/
[138] Jahn, A, Rump, A, Widmann, TJ, Heining, C, Horak, P, Hutter, B, et.al. Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers., Ann Oncol, 2022. 33 (11)(11): p. 1186-1199., https://pubmed.ncbi.nlm.nih.gov/35988656/
[139] Daly, MB, Pal, T, Berry, MP, Buys, SS, Dickson, P, Domchek, SM, et.al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology., J Natl Compr Canc Netw, 2021. 19 (1)(1): p. 77-102., https://pubmed.ncbi.nlm.nih.gov/33406487/
[140] Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R., Gallinger, S., et.al. Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer, Cancer Discov, 2016. 6(2): p. 166-75., https://pubmed.ncbi.nlm.nih.gov/26658419/
[141] Chaffee, K. G., Oberg, A. L., McWilliams, R. R., Majithia, N., Allen, B. A., Kidd, J., et.al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history, Genetics in Medicine, 2018. 20(1): p. 119-127., https://pubmed.ncbi.nlm.nih.gov/28726808/
[142] Shindo, K., Yu, J., Suenaga, M., Fesharakizadeh, S., Cho, C., Macgregor-Das, A., et.al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma, Journal of Clinical Oncology, 2017. 35(30): p. 3382-3390., https://pubmed.ncbi.nlm.nih.gov/28767289/
[144] Wood, L. D., Yurgelun, M. B., Goggins, M. G., Genetics of Familial and Sporadic Pancreatic Cancer, Gastroenterology, 2019. 156(7): p. 2041-2055., https://pubmed.ncbi.nlm.nih.gov/30660730/
[145] Yurgelun, M. B., Chittenden, A. B., Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., et.al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer, Genetics in Medicine, 2019. 21(1): p. 213-223., https://pubmed.ncbi.nlm.nih.gov/29961768/
[146] Bannon, S. A., Montiel, M. F., Goldstein, J. B., Dong, W., Mork, M. E., Borras, E., et.al. High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer, Cancer Prev Res (Phila), 2018. 11(11): p. 679-686., https://www.ncbi.nlm.nih.gov/pubmed/30274973
[147] Lucas, A. L., Frado, L. E., Hwang, C., Kumar, S., Khanna, L. G., Levinson, E. J., et.al. BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts, Cancer, 2014. 120(13): p. 1960-1967., https://pubmed.ncbi.nlm.nih.gov/24737347/
[148] Abe, T., Blackford, A. L., Tamura, K., Ford, M., McCormick, P., Chuidian, M., et.al. Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019. p. JCO1801512., https://pubmed.ncbi.nlm.nih.gov/30883245/
[149] Konings, Ingrid C. A. W., Harinck, Femme, Poley, Jan Werner, Aalfs, Cora M., van Rens, Anja, Krak, Nanda C., et.al. Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer, Pancreas, 2017. 46(1): p. 28-34., https://pubmed.ncbi.nlm.nih.gov/27846136/
[150] Bjelakovic, G., Nikolova, D., Simonetti, R. G., Gluud, C., Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis, Lancet, 2004. 364(9441): p. 1219-28., https://pubmed.ncbi.nlm.nih.gov/15464182/
[151] Coogan, P. F., Rosenberg, L., Palmer, J. R., Strom, B. L., Zauber, A. G., Stolley, P. D., et.al. Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel, Cancer Epidemiol Biomarkers Prev, 2000. 9(1): p. 119-23., https://pubmed.ncbi.nlm.nih.gov/10667472/
[152] Harris, R. E., Beebe-Donk, J., Doss, H., Burr Doss, D., Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review), Oncol Rep, 2005. 13(4): p. 559-83., https://pubmed.ncbi.nlm.nih.gov/15756426/
[153] Jacobs, E. J., Connell, C. J., Rodriguez, C., Patel, A. V., Calle, E. E., Thun, M. J., Aspirin use and pancreatic cancer mortality in a large United States cohort, J Natl Cancer Inst, 2004. 96(7): p. 524-8., https://pubmed.ncbi.nlm.nih.gov/15069114/
[154] Hart, P. A., Chari, S. T., Is Screening for Pancreatic Cancer in High-Risk Individuals One Step Closer or a Fool's Errand?, Clin Gastroenterol Hepatol, 2019. 17(1): p. 36-38., https://www.ncbi.nlm.nih.gov/pubmed/30268560
[155] Homma, T., Tsuchiya, R., The study of the mass screening of persons without symptoms and of the screening of outpatients with gastrointestinal complaints or icterus for pancreatic cancer in Japan, using CA19-9 and elastase-1 or ultrasonography, Int J Pancreatol, 1991. 9: p. 119-24., https://pubmed.ncbi.nlm.nih.gov/1744437/
[156] Kim, J. E., Lee, K. T., Lee, J. K., Paik, S. W., Rhee, J. C., Choi, K. W., Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population, J Gastroenterol Hepatol, 2004. 19(2): p. 182-6., https://pubmed.ncbi.nlm.nih.gov/14731128/
[157] Owens, D. K., Davidson, K. W., Krist, A. H., Barry, M. J., Cabana, M., Caughey, A. B., et.al. Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement, Jama, 2019. 322(5): p. 438-444., https://pubmed.ncbi.nlm.nih.gov/31386141/
[158] Siegel, R. L., Miller, K. D., Jemal, A., Cancer statistics, 2019, CA Cancer J Clin, 2019. 69(1): p. 7-34., https://pubmed.ncbi.nlm.nih.gov/30620402/
[159] Overbeek, KA, Goggins, MG, Dbouk, M, Levink, IJM, Koopmann, BDM, Chuidian, M, et.al. Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals., Gastroenterology, 2022. 162 (3)(3): p. 772-785.e4., https://pubmed.ncbi.nlm.nih.gov/34678218/
[160] Bartsch, DK, Matthäi, E, Mintziras, I, Bauer, C, Figiel, J, Sina-Boemers, M, et.al. The German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa)—Knowledge Gained in 20 Years., Dtsch Arztebl Int, 2021. 118 (10)(10): p. 163-8., https://pubmed.ncbi.nlm.nih.gov/33531114/
[161] Vasen, H, Ibrahim, I, Ponce, CG, Slater, EP, Matthäi, E, Carrato, A, et.al. Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers., J Clin Oncol, 2016. 34 (17)(17): p. 2010-9., https://pubmed.ncbi.nlm.nih.gov/27114589/
[162] Antwi, SO, Fagan, SE, Chaffee, KG, Bamlet, WR, Hu, C, Polley, EC, et.al. Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status., J Natl Cancer Inst, 2019. 111 (3)(3): p. 264-271., https://pubmed.ncbi.nlm.nih.gov/29982661/
[163] Overbeek, KA, Levink, IJM, Koopmann, BDM, Harinck, F, Konings, ICAW, Ausems, MGEM, et.al. Long-term yield of pancreatic cancer surveillance in high-risk individuals., Gut, 2022. 71 (6)(6): p. 1152-1160., https://pubmed.ncbi.nlm.nih.gov/33820756/
[164] Canto, M. I., Almario, J. A., Schulick, R. D., Yeo, C. J., Klein, A., Blackford, A., et.al. Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance, Gastroenterology, 2018. 155(3): p. 740., https://pubmed.ncbi.nlm.nih.gov/29803839/
[165] Rebours, V, Boutron-Ruault, MC, Schnee, M, Férec, C, Le Maréchal, C, Hentic, O, et.al. The natural history of hereditary pancreatitis: a national series., Gut, 2009. 58 (1)(1): p. 97-103., https://pubmed.ncbi.nlm.nih.gov/18755888/
[166] Canto, M. I., Goggins, M., Yeo, C. J., Griffin, C., Axilbund, J. E., Brune, K., et.al. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach, Clin Gastroenterol Hepatol, 2004. 2(7): p. 606-21., https://pubmed.ncbi.nlm.nih.gov/15224285/
[167] Canto, M. I., Goggins, M., Hruban, R. H., Petersen, G. M., Giardiello, F. M., Yeo, C., et.al. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study, Clin Gastroenterol Hepatol, 2006. 4(6): p. 766-81; quiz 665., https://pubmed.ncbi.nlm.nih.gov/16682259/
[168] Brentnall, T. A., Management strategies for patients with hereditary pancreatic cancer, Curr Treat Options Oncol, 2005. 6(5): p. 437-45., https://pubmed.ncbi.nlm.nih.gov/16107246/
[169] Kimmey, M. B., Bronner, M. P., Byrd, D. R., Brentnall, T. A., Screening and surveillance for hereditary pancreatic cancer, Gastrointest Endosc, 2002. 56(4 Suppl): p. S82-6., https://pubmed.ncbi.nlm.nih.gov/12297755/
[170] Canto, MI, Hruban, RH, Fishman, EK, Kamel, IR, Schulick, R, Zhang, Z, et.al. Frequent detection of pancreatic lesions in asymptomatic high-risk individuals., Gastroenterology, 2012. 142 (4)(4): p. 796-804; quiz e14-5., https://pubmed.ncbi.nlm.nih.gov/22245846/
[171] Falconi, M, Eriksson, B, Kaltsas, G, Bartsch, DK, Capdevila, J, Caplin, M, et.al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors., Neuroendocrinology, 2016. 103 (2)(2): p. 153-71., https://pubmed.ncbi.nlm.nih.gov/26742109/
[172] Canto, M. I., Harinck, F., Hruban, R. H., Offerhaus, G. J., Poley, J. W., Kamel, I., et.al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer, Gut, 2013. 62(3): p. 339-47., https://www.ncbi.nlm.nih.gov/pubmed/23135763
[173] Corral, JE, Mareth, KF, Riegert-Johnson, DL, Das, A, Wallace, MB, Diagnostic Yield From Screening Asymptomatic Individuals at High Risk for Pancreatic Cancer: A Meta-analysis of Cohort Studies., Clin Gastroenterol Hepatol, 2019. 17 (1)(1): p. 41-53., https://pubmed.ncbi.nlm.nih.gov/29775792/
[174] Lowenfels, AB, Maisonneuve, P, Whitcomb, DC, Lerch, MM, DiMagno, EP, Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis., JAMA, 2001. 286 (2)(2): p. 169-70., https://pubmed.ncbi.nlm.nih.gov/11448279/