Pancreatic cancer is the sixth most common cause of cancer death in the world, 1 and it ranks among the top 10 leading causes of cancer death in Israel. 2 Pancreatic cancer is considered 1 of the cancers for which there is strong evidence of an association between adult obesity and an increased risk for its occurrence. 3 - 10 There also are data supporting an association of overweight and obesity during adolescence or early adulthood as well as in childhood. 6 , 7 , 11 - 15 Childhood obesity is a global problem. 4 In the United States alone, approximately 17% of children and adolescents aged 2 to 19 years have obesity (defined as an age‐specific and sex‐specific body mass index [BMI] in the 95th percentile or greater, based on year 2000 US Centers for Disease Control and Prevention [CDC] growth charts). 16 Obesity in childhood and adolescence may continue into adulthood and lead to adverse cardiovascular outcomes or other obesity‐related morbidity. 17 - 19 In the current report, we extend our previous work on the association between measured BMI in adolescence and the risk of pancreatic cancer among men 14 by incorporating data for women from a total of 1.79 million adolescents who were followed and updating our cancer registry linkage data, thus enlarging the number of incident pancreatic cancer cases from 98 to 551.

Kaplan‐Meier life‐table analysis for the unadjusted cumulative incidence of pancreatic cancer according to baseline BMI was undertaken with years of follow‐up grouped in intervals of 0.5 years. We used Cox proportional‐hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer outcomes. Follow‐up terminated at the date of any cancer diagnosis, or death, or December 31, 2012, whichever occurred first. In the main analysis, Cox models were fitted with BMI using the CDC 4‐group classification unadjusted and adjusted for birth year, sex, and education. During the follow‐up period, 48,818 other cancers occurred, and 31,013 patients died. Cox models were repeated to account for the competing risk of death or other cancer. 26 Models also were repeated with the WHO BMI classification (4 groups) and the CDC in a 7‐group BMI classification. Data were missing from 11,939 examinees (0.7%) for residential SES, from 988 (0.1%) for country of birth, and from 1462 (0.1%) for education. Because SES and country of birth were not associated with cancer in the univariate analysis, in the final model, only country of birth (with 0.1% missing data) was included. The missing group did not include cancer cases. In the main model, we regarded the missing values as missing. Because lower education was independently associated with cancer risk, in a secondary analysis, we input missing education as low education. The multivariable‐adjusted population‐attributable fraction (PAF) of overweight and obesity to incident cancer cases was calculated according to Laaksonen et al 27 A spline analysis (log of HRs) for pancreatic cancer was prepared according to baseline BMI (kg/m 2 ) at age 17 years for men and women. The assumption of proportionality of the hazards was visually confirmed for all variables. An assessment of age at cancer diagnosis according to weight status was performed using an analysis of variance with Duncan post hoc analysis. A sensitivity analysis included individuals who had been followed up to age 50 years, which, for those with cancer, would mean a diagnosis before this age. For most analyses, we used IBM‐SPSS software (version 22; IBM Corporation, Armonk, NY). For spline analysis, PAF, and the competing risk calculations, SAS statistical software was used (version 9.3; SAS Institute, Inc., Cary, NC).

We calculated the BMI from weight and height measured by means of a beam balance and stadiometer, with each participant barefoot and wearing underwear. Physicians reviewed medical records, performed the health examinations, and provided standardized diagnostic codes where applicable. Data regarding residential socioeconomic status (SES), country of birth, and place of origin were recorded. The age at the time of examination, year of birth, and height were treated as continuous variables. Residential SES was determined according to residential locality, 23 with participants grouped into low, medium, and high categories. Birth country was categorized into Israel, the former Union of Soviet Socialist Republics (USSR), Asia‐Africa and Europe (including countries of emigration from Europe—the Americas, South Africa and Australia, and excluding the former USSR). Education was categorized according to the number of years of schooling attained up to age 18 years (11 to 12 years or ≤9 to 10 years). BMI values were grouped according to percentiles for age and sex, as established by the US Centers for Disease Control and Prevention (CDC) 24 as follows: less than 5th percentile (underweight), 5th to <85th percentile (“normal” weight reference group), 85th to <95th percentile (overweight), and 95th percentile or higher (obese). A conversion table was prepared for each participant according to his or her exact age at the time of measurement (in months) with respect to the CDC percentiles. A sensitivity analysis of BMI was performed according to 7 CDC percentile groups (<5th, 5th‐24th, 25th‐49th, 50th‐74th, 75th‐84th, 85th‐94th, and ≥95th). Deaths in the cohort and their dates were obtained from the national population (death) registry. In a secondary analysis, we also assessed associations with BMI according to the World Health Organization (WHO) definitions: <18.5 kg/m 2 (underweight), 18.5 to 24.9 kg/m 2 (normal weight), 25 to 29.9 kg/m 2 (overweight), and ≥30 kg/m 2 (obese). 25

By linkage with the Israeli National Cancer Registry (INCR) database, we included only cases of verified adenocarcinoma based on histology ( International Classification of Diseases for Oncology , third edition; site codes C25.0‐C25.3 and C25.7‐C25.9) with a histologic report of adenocarcinoma (codes 80003, 80013, 80103, 81403, and 84803), and we excluded all other histologic codes, such as insulinoma, carcinoid tumors, and neuroendocrine tumors (codes 8146, 8150, 8151, 8153, 8155, 8240, and 8146) diagnosed and reported to the INCR during the period up to December 31, 2012. The INCR was established in 1960; and, since 1982, reporting of all newly diagnosed cancers in Israeli residents to the registry has been mandatory by law. There have been major changes in the method of reporting since the INCR was established, and its completeness has been consistently high (both before and after 1982) and is estimated to be approximately 97% for solid tumors. 22

We analyzed a cohort of Israeli Jewish adolescents aged 16 to 19 years who underwent a compulsory examination in late adolescence (predominantly at age 17 years) to determine their fitness for military service and had at least 10 years of follow‐up. Between January 1967 to December 31, 2010, in total, 2,454,693 adolescents were evaluated, irrespective of whether they actually served in the military, as recently described. 20 After excluding 64,186 individuals who were missing height or weight data and 82,377 non‐Jewish examinees (because of the nonrepresentativeness of their source populations), 2,298,130 participants remained. We then excluded 503,560 individuals who were evaluated after December 2002 and did not have the opportunity for at least 10 years of follow‐up. These exclusions resulted in a study sample of 1,794,570 participants, which included a nationally representative sample of Jewish men (but not Jewish women), because ultra‐orthodox and orthodox religious women are exempt from military service and are not obligated to undergo medical examinations (estimated as 15% of Jewish women aged 15 years 21 ).

The single variable and multivariable analyses according to the CDC BMI classification with covariates other than BMI are presented in Supporting Table 5. Country of birth, country of origin, and SES were not associated with the incidence of pancreatic cancer. Low education (ie, ≤9 or 10 years of schooling) was significantly associated with an increased HR for pancreatic cancer (adjusted HR, 1.36; 95% CI, 1.14‐1.63) as well as male sex (adjusted HR, 1.35; 95% CI, 1.10‐1.66). A test for interaction of sex with CDC BMI classification was not significant ( P = .683).

An analysis according to the WHO 4‐group BMI classification yielded consistent results (Supporting Table 1). A competing risk analysis did not materially affect the strength of the associations (Supporting Table 2). A subanalysis of the cohort age ≤50 years (254 cases) demonstrated that the associations of overweight and obesity with cancer were somewhat higher (adjusted HR, 1.73 [95% CI, 1.15‐2.61] and 4.52 [95% CI, 2.88‐7.11], respectively) (Supporting Table 3). Repeated analysis of adjusted HRs according to baseline BMI CDC percentiles that included imputations did not change these results (Supporting Table 4).

An analysis of the association of the CDC BMI 7 percentile grouping for men indicated that, compared with low‐normal BMI (≥5th to <25th percentile), high‐normal BMI (≥75th to <85th percentile) also was associated with the risk for pancreatic cancer (HR, 1.49; 95% CI, 1.04‐2.13), as were overweight (HR, 1.97; 95% CI, 1.39‐2.80) and obesity (HR, 3.88; 95% CI, 2.58‐5.83) (Table 3 and Fig. 3 ).

This is a spline analysis (log of hazard ratios) for pancreatic cancer according to baseline body mass index (BMI) (in kg/m 2 ) at age 17 years for men and women. A minimal risk of pancreatic cancer was observed for a BMI of 19.8 kg/m 2 , whereas a significantly elevated risk was evident for BMI values greater than 23.0 kg/m 2 .

The Kaplan‐Meier analysis for cumulative pancreatic cancer incidence across BMI categories revealed overt divergence of the curves beginning at about 25 years of follow‐up (Fig. 1 ). The unadjusted and adjusted HRs according to baseline CDC BMI percentiles divided into BMI categories are presented in Table 2 . A spline analysis is presented in Figure 2 . For men and women combined, overweight and obesity were associated with HRs for pancreatic cancer of 1.68 (95% CI, 1.27‐2.21) and 3.89 (95% CI, 2.76‐5.50), respectively, and a BMI 23.0 kg/m 2 or greater was identified as statistically significant in spline analysis. Among men, HRs for overweight and obesity were 1.86 (95% CI, 1.36‐2.45) and 3.67 (95% CI, 2.52‐5.34), respectively, and the HRs for women were 1.21 (95% CI, 0.66‐2.26) and 4.07 (95% CI, 1.78‐9.29), respectively. On the basis of the adjusted model, the estimated PAF caused by overweight and obesity was 10.9% (95% CI, 6.1%‐15.6%).

Over a median of 23.3 years of follow‐up and a total of 44,563,618 person‐years of follow‐up, 551 patients were identified who had pancreatic cancer, including 423 cancers among men and 128 among women. The median age at pancreatic cancer diagnosis was 51.0 years (interquartile range, 44.0‐55.0 years) and did not differ between BMI categories (Duncan test; P = .44).

Baseline characteristics of the study participants are listed in Table 1 . The mean age at the baseline examination was 17.4 ± 0.4 years. Women comprised 39.4% of the cohort, 84.4% were Israeli born, and 6.4% were immigrants from the former USSR. According to the CDC classification, in total, 140,467 examinees (7.8%) were overweight, and 54,224 (3.0%) were obese.

Discussion

In this large, prospective, population‐based study using measured heights and weights, we observed that BMI at age 17 years was significantly and positively associated with pancreatic cancer in early adulthood among both men and women. For men, the analysis was robust enough to demonstrate a dose‐response pattern, which started in the range of high‐normal BMI (≥75th to <85th percentile; HR, 1.53), then progressed to overweight (HR, 2.02), and to obese (HR, 3.95). The overall PAF of pancreatic cancer caused by adolescent overweight and obesity was 13.0% among this Israeli Jewish population.

Pancreatic cancer is 1 of the cancers with strong evidence for an association with BMI and a dose‐response relation, as stated above.3-9 In addition, previous studies that used pooled data from large analyses using recalled BMI reported associations of early age obesity with pancreatic cancer with HRs ranging from 1.15 to 1.53.6, 7, 11-14 The largest study of pooled data from 20 prospective cohort studies (including mostly self‐reported, recalled weight during early adulthood) reported that being either overweight (BMI ≥25 to <30 kg/m2) or obese (BMI ≥30 kg/m2) during early adulthood was associated with an approximately 40% higher risk of pancreatic cancer mortality. Another 2 studies that analyzed recalled BMI from the National Institutes of Health‐AARP Diet and Health Study cohort and the American Cancer Society Cancer Prevention Study II nutrition cohort reported similar positive associations between overweight and obesity in early adulthood, with approximately 30% to 50% excess incidence for the obese.12, 28 A recent report from Japan suggested that, among men, compared with normal weight at baseline (reported/recalled weight at age 20 years), obesity was associated with an HR of 1.71 for pancreatic cancer.15 In our previous report, which included only 98 cases of pancreatic cancer among men, we reported an approximately 2‐fold increased risk of pancreatic cancer for men who were overweight or obese at adolescence.14 In the current study, we demonstrate a higher risk for pancreatic cancer compared with previous studies. The explanation for this difference may relate to our study population. The Cancer Prevention Study II cohort reported that, after adjusting for age, sex, smoking, BMI, and diabetes, pancreatic cancer mortality was higher among Jewish participants than among non‐Jewish whites (relative risk, 1.43; 95% CI, 1.30‐1.57).29 Another possible explanation is that weight and height were measured in our current cohort, thus avoiding recall bias, which is likely to increase the risk of misclassification and reduce estimates toward the null. Furthermore, the young age of the cohort at the termination of follow‐up and the young mean age of the individuals may have played a role.

Several mechanisms have been proposed to explain the increased risk of pancreatic cancer related to obesity. A hallmark of obesity is adipose tissue inflammation, which can promote cancer growth through the secretion of proinflammatory cytokines like tumor necrosis factor α, transforming growth factor β, interleukin‐6, and leptin.30, 31 Obesity also is associated with insulin resistance and elevated levels of insulin and insulin‐like growth factor 1 (IGF‐1), which, in turn, can stimulate proliferation and inhibit apoptosis.30, 31

It is noteworthy that our data suggest a trend toward a moderately increased risk among individuals who are underweight and revealed a trend toward an increased risk of pancreatic cancer among both men and women, as reported in a study of Japanese pooled data among men.15 We expect to produce more conclusive results at the next linkage of cancer cases planned in our cohort.

Limitations to our study exist. We did not have data about weight change over time, although 2 meta‐analyses reported that BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer incidence or mortality.7, 32 We also did not have data on the waist‐to‐hip ratio or waist circumference, which are independently associated with an increased risk of pancreatic cancer.7, 33, 34 However, this information is more important for patterns of weight gain later in life because, unlike adolescent adipose gain, which is distributed primarily on the hips and thighs (pear‐shaped), during adulthood, fat accumulates preferentially around the waist (apple‐shaped), which is metabolically more detrimental.32, 35, 36

We did not have data on the smoking status of participants, and smoking is a well known risk factor for pancreatic cancer in a dose‐dependent manner.37-39 In this context, it should be noted that, in Israel, smoking rates among adults trended toward a decrease, from 43.0% for Jewish men in 1972 to 27.8% in a recent report.40 The absence of data on other possible confounders, such as alcohol use, diabetes, physical activity, and dietary composition, is also a limitation.37, 41-46 Smoking by itself also may interact with obesity to potentiate oxidative stress.39 However, it has been demonstrated that SES (which was accounted for in our analysis) is strongly associated with smoking.47-49 This association may be mediated by several factors, including parental smoking, friends’ smoking, cigarette availability, and depression.48 In the current study, the increased HR was controlled for education and income to eliminate these potential confounding effects.

Our study also was limited by the modest number of cases among obese women. In addition, we did not have information about family history of pancreatic cancer, although it is believed that most cases are sporadic, and only up to 10% of ductal adenocarcinomas may be caused by an inherited predisposition based on familial clustering.50 However, in a subanalysis of the cohort among those aged ≤50 years, which probably reflects a higher proportion of cancers with genetic origin,51 the association of BMI with cancer was not attenuated.

Finally, we did not have information about BRCA mutation status. Genetic mutations in BRCA2 and BRCA1 are associated with a 3.5‐fold to 2.25‐fold increase in the risk for pancreatic cancer, but they are prevalent in only approximately 2% of Ashkenazi Jews.29, 51-54 We observed no evidence of an excess incidence among European (predominantly Ashkenazi) Jews.

In our study, incomplete schooling was associated significantly with the risk of pancreatic cancer. This is not surprising, because a low level of educational is associated with alcohol abuse and smoking.55 Our findings for BMI were unaffected by adjustment for education.

A notable strength of this analysis is its historical prospective design in a large cohort with measured BMI and long term follow‐up. To our knowledge, this is the largest analysis to date of measures of adolescent obesity in association with the risk for pancreatic cancer. The large sample size enabled us to examine whether lesser degrees of obesity are associated with the risk of pancreatic cancer. In addition, we included information on potential confounding factors like SES, education, and country of birth.

In conclusion, our data suggest that adolescent obesity is associated with up to a 4‐fold increased risk for pancreatic cancer. Furthermore, men who are overweight, and even among those who have a higher BMI within the “normal” weight range, are at increased risk for pancreatic cancer in a graded manner. On a practical note, the current study further emphasizes the need for effective interventions to prevent childhood and adolescent obesity.