Teenage Obesity & Fourfold Increase in Risk for Pancreatic Cancer

A nationwide Israeli study has found that persons who were obese during adolescence had an approximately fourfold increased risk of developing pancreatic cancer later in life; those who were overweight had a twofold increased risk.

The study analyzed data on nearly 1.8 million adolescents who were followed for a medium of 23 years.

"This is the largest analysis to date of measures of adolescent obesity in association with risk for pancreatic cancer," say the authors, led by Zohar Levi, MD, MHA, of the Rabin Medical Center, Tikva, Israel.

"We observed that BMI [body mass index] at age 17 years was significantly and positively associated with pancreatic cancer in early adulthood among both men and women," they note.

The study also reports that the association with pancreatic cancer is dose dependent &mdash higher percentiles in the higher BMI group were associated with higher probabilities of risk. A minimal risk was observed in individuals with a BMI of 19.8 kg/m²; significantly elevated risks were seen at values greater than 23.0 mg/m².

The study was published online November 12 in Cancer.

An accompanying editorial suggests that the study is important for two reasons. Because the study used two large Israeli databases that are relatively complete, the results may be extrapolated to the general Israeli population. In addition, the study confirms findings from other studies that establish obesity as a risk factor for pancreatic cancer.

"The identification of risk factors for this pathological entity is greatly needed because, to date, these factors have been attributed only to a small part of the patient population and have included various biologic, social, and hereditary risk factors, although they account for only modest increases in risk," writes editorialist Chanan Meydan, MD, of the Department of Internal Medicine, Mayanei HaYeshua Medical Center, Bnei Brak, Israel.

Study Details

The researchers linked two large Israeli databases. One was the database of Israeli Jewish adolescents aged 16 years to 19 years who underwent compulsory examination in late adolescence to determine fitness for military service. The other was the Israeli National Cancer Registry database, from which only verified reports of pancreatic adenocarcinomas were included.

For the analysis, the researchers grouped BMI values in percentiles established by the Center for Diseases Control and Prevention classification (CDC): <5th percentile was considered underweight; 5th to <85th percentile was the reference group ("normal" weight); 85th to the 95th percentile was considered overweight; and 95th percentile or higher was considered obese.

The study included an analysis of 1,794,570 individuals (1,087,358 males; 707,212 females). The mean age of the participants at the time of baseline examination was 17 years.

According to the CDC-BMI classification, 54,224 individuals (3%) were obese, and 140,467 individuals (7.8%) were overweight.

After a median of 23.3 years of follow-up (44,563,618 person-years), 551 cases of pancreatic cancer were identified (423 among men, 128 among women). The median age at diagnosis was 51 years.

The Kaplan-Meier cumulative incidence of pancreatic cancer curves showed a divergence at about 25 years' follow-up.

The hazard ratios for pancreatic cancer were as follows (95% confidence intervals are indicated in parentheses) :

For obese individuals in the overall population: 3.89 (2.76 – 5.50)
For overweight individuals in the overall population: 1.68 (1.27 – 2.21)
For obese males: 3.67 (2.52 – 5.34)
For overweight males: 1.86 (1.36 – 2.45)
For obese females: 4.07 (1.78 – 9.29)
For overweight females: 1.21 (0.66 – 2.26)

On the basis of an analysis of BMI percentiles, individuals with high-normal BMI were also found to be at increased risk for pancreatic cancer compared with persons with low-normal BMI.

Similar findings emerged when the researchers used the World Health Organization's four-group BMI classification instead of the CDC-BMI classification.

Country of birth, country of origin, and socioeconomic status were not associated with increased risk.

Study Limitations

The researchers acknowledge several limitations of their study. Weight change over time was not available, and therefore the association of pancreatic cancer risk with weight change over time could not be determined. An analysis of risk for pancreatic cancer with hip-to-waist ratio or waist circumference, which is an independent correlate for pancreatic cancer, was also not possible owing to lack of information.

Information of other confounders (eg, smoking, alcohol use, diabetes, physical activity, dietary composition, BRCA mutation status) was not available and hence their contribution to pancreatic cancer risk could not be assessed. However, the researchers note that BRCA mutations, which are associated with an increased risk for pancreatic cancer, are present in approximately 2% of Ashkenazi Jews.

In his editorial, Meydan also notes the limitation inherent in big data analyses. "The core questions asked by researchers are sometimes established long after the data are collected, formulated, and waiting to be unveiled," Meydan writes. "In this manner, the initial tenants of the database may not fulfill the future needs of researchers, limiting its relevance," he adds.

Comments From the Editorialist

Meydan notes that the large, population-based Israeli databases reflect a society in development from rural to urban, from austerity to economic boom, and from physical labor to sedentary occupations &mdash all of which are associated with a progressive increase in the prevalence of obesity.

Meydan speculates that obesity is a component of the metabolic syndrome, which is being established as a modifying factor in the pathogenesis of pancreatic cancer and "must be considered as part of the spectrum of inflammation."

The focus of obesity is shifting from vasculopathy to encompass dysmetabolism, Meydan suggests. He points out that a growing body of evidence suggests that adipose tissue is an endocrine organ, with adiponectin and leptin as mediators of adipocyte regulation; adiponectin affects insulin resistance, and leptin affects hunger. He highlights the fact that noncoding RNA-associated signaling pathways are associated with the pathogenesis of pancreatic cancer.

"In the context of pancreatic cancer, these molecular elements [metabolic syndrome, inflammation, noncoding RNA] are emerging as diagnostic, prognostic, and therapeutic roles," Meydan notes.

The study was supported by research grants from the Israel Cancer Research Fund (New York City) and the Environment and Health Fund (Jerusalem, Israel). The study authors have disclosed no relevant financial relationships. Dr Meydan has received personal fees from Raziel Therapeutics Ltd.

Cancer. Published online November 12, 2018. Abstract, Editorial

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