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Pooled data were analyzed from the NCI Pancreatic Cancer Cohort Consortium (PanScan) to study the association between pre-diagnostic anthropometric measures and risk of pancreatic cancer.
PanScan applied a nested case-control study design and included 2,170 cases and 2,209 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI), weight, height, waist circumference, and waist-to-hip ratio (WHR), as well as conventional BMI categories: underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obese (30.0-34.9 kg/m2), and severely obese (≥35.0 kg/m2). Models were adjusted for potential confounders.
Among all subjects, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs. lowest BMI quartile = 1.33, 95% CI = 1.12-1.58, Ptrend < 0.001). Among men, the adjusted OR for pancreatic cancer for the highest vs. lowest quartile of BMI was 1.33 (95% CI = 1.04-1.69, Ptrend <0.03). Among women, the adjusted OR for pancreatic cancer for the highest quartile of BMI was 1.34 (95% CI = 1.05-1.70, Ptrend = 0.01). Increased WHR was associated with increased risk of pancreatic cancer among women (adjusted OR for the highest vs. lowest quartile = 1.87, 95% CI = 1.31-2.69, Ptrend = 0.003) but less so in men.
The findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.
Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States 1 and is responsible for about 227,000 deaths per year worldwide 2. Because of the lack of effective screening tests for pancreatic cancer, it is often diagnosed at an advanced stage, contributing to a five-year survival rate that is less than 5% 3. The incidence of pancreatic cancer is higher in men compared with women, and within the United States, it is higher in Blacks compared to Caucasians 3. Smoking, diabetes, and family history of pancreatic cancer are known risk factors 4,5 but these factors do not account for all the cases of pancreatic cancer.
Obesity and high body mass index (BMI) have been proposed as additional risk factors for pancreatic cancer. Prospective studies have yielded conflicting results concerning the association between BMI and risk of pancreatic cancer. A majority of prospective epidemiological studies 6-15 have found that a high body mass index and/or a lack of physical activity are associated with an increased risk of pancreatic cancer incidence or mortality, independently of prior history of diabetes. However, several prospective studies have not confirmed a significant role of BMI in pancreatic cancer 16-23 or found that effect of BMI varied according to smoking status 24,25 or gender 26-28.
The purpose of the current study was to examine the association between BMI, other anthropometric factors, and pancreatic cancer risk by pooling data from nested case-control studies included in the NCI Pancreatic Cancer Cohort Consortium (PanScan). With 2,170 cases, this is one of the largest analyses to date of BMI and pancreatic cancer.
PanScan is an initiative that was funded jointly by the National Cancer Institute’s Division of Cancer Control and Population Sciences and the Division of Cancer Epidemiology and Genetics in 2006. PanScan includes investigators from 12 prospective epidemiologic cohorts and one case-control study and was created to identify genetic markers of susceptibility through a genome-wide association scan and to investigate environmental, lifestyle, and genetic causes of pancreatic cancer.
Studies in the pooled analysis included: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) 29, CLUE II 30, Cancer Prevention Study II (CPS II) 31, European Prospective Investigation into Cancer and Nutrition (EPIC) 32, the Health Professionals Follow-up Study (HPFS) 33, the Mayo Clinic study (MAYO) 34, the New York University Women’s Health Study (NYUWHS) 35, the Nurses’ Health Study (NHS) 36, the Physicians’ Health Study (PHS I) 37, the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) 38, Shanghai Men’s and Women’s Health Studies (SMWHS) 39,40, the Women’s Health Initiative (WHI) 41, and the Women’s Health Study (WHS) 42. A total of 2,170 cases and 2,209 controls were eligible for the current study (Table 1).
Cases included all incident primary pancreatic adenocarcinoma (ICD-O-3 codes C25.0-C25.3, C25.7-C25.9). Endocrine pancreatic tumors (ICD-O-3 code C25.4, histology types 8150, 8151, 8153, 8155, 8240, and 8246) were excluded because the etiology of these cancers is thought to be different from that of exocrine tumors, which account for the vast majority of pancreatic tumors. Case ascertainment varied between studies but included linking participants to cancer registries and national death indices, and self and next of kin report. Most cases were histologically confirmed (ATBC, CLUE II, EPIC, NYUWHS, SMWHS, WHI) or confirmed through cancer registries (ATBC, CPS II, EPIC, SMWHS), death certificates (CPS II, EPIC), or review of medical records by medical personnel (ATBC, CPS II, EPIC, PLCO, SMWHS).
Controls were incidence density-sampled with a 1-to-1 control-to-case ratio and were alive and cancer-free on the date of diagnosis of the matched case. At a minimum, controls were matched to cases on calendar year of birth (±5 years), gender, race and ethnicity. Some cohorts employed more stringent matching on age and, additionally, on other relevant factors (for comparisons of blood levels of analytes of interest) such as age at baseline or age at blood draw (±5 years), date/time of day of blood draw, fasting blood draw, and length of follow-up (Table 1).
Data on anthropometry, demographics and possible confounders were collected through self-administered written questionnaires or in-person interviews. Detailed descriptions of data collection methods have been published previously by the individual studies 29,30,32,33,35-44. From each study, baseline information on body mass index (BMI), weight, height, waist circumference, waist-to-hip ratio (WHR), history of cigarette smoking, gender, age, race, family history of pancreatic cancer, alcohol consumption, pancreatitis, and history of diabetes was requested. Individual datasets were checked for consistency with previously published results. A total of forty cases and forty six controls had missing data on BMI, resulting in 2,130 cases and 2,163 controls available for the main analyses.
The Special Studies Institutional Review Board (SSIRB) of the National Cancer Institute approved the pooled PanScan study. Each study also was approved by its local IRB.
Odds ratios (OR) and 95% confidence intervals (95% CI) for pancreatic cancer risk were calculated using unconditional logistic regression, adjusting for cohort, age (categorical), gender, BMI source (self-reported, measured), and smoking (never, former, current) (Model 1). Several multivariate models were assessed to control the effects of potential confounders. Model 2 was additionally adjusted for diabetes history (yes, no). In model 3, cases diagnosed within the first 2 years of follow-up were excluded to address the possibility of an effect of early undiagnosed disease. In model 4, current smokers (at baseline) were excluded, and in model 5, both cases diagnosed within the first 2 years of follow-up and current smokers were excluded. Furthermore, models including waist circumference and waist-to-hip ratio were additionally adjusted for height to remove extraneous variation due to body size. There was no adjustment for family history of pancreatic cancer as few cohorts had this information. Trend tests were conducted using cohort-specific quartiles of BMI, weight, height, waist circumference, and WHR, as well as descriptive BMI categories: underweight (<18.5 kg/m2), normal (reference, 18.5-<25.0 kg/m2), overweight (25.0-<30.0 kg/m2), obese (30.0-<35.0 kg/m2), and severely obese (≥35.0 kg/m2). To test for heterogeneity BMI quartile categories were modeled as a continuous variable and the risk estimates and standard errors from the cohort-specific models were used to generate the Q statistic.
The association between BMI and time of onset for pancreatic cancer was also examined using logistic regression modeling. Differences in time of onset were examined for normal versus overweight versus obese categories of BMI as well as in a combined category of overweight and obese. The analyses were conducted using the SAS program version 9.1.3.
The study included 2,170 pancreatic cancer cases and 2,209 controls aged between 37 and 94 years (Table 1). Of the 2,170 pancreatic cancer cases, 1,059 were males and 1,111 were females. Cases and controls were similar in terms of age and racial distribution (Table 2). The majority of subjects were Caucasian, and 86% of the study population was 60 years of age or older. Compared to the controls, cases had a higher prevalence of current smoking (18% and 25%, respectively), diabetes (7% and 14%, respectively), history of pancreatitis (0.4% and 11%, respectively), and family history of pancreatic cancer (2% and 6%, respectively) based on data from cohorts with available information. The average age of pancreatic cancer onset among cases was 68.3 years and the average lag time between cohort enrollment and diagnosis of pancreatic cancer among cases was 6.3 years.
Table 3 describes baseline anthropometric characteristics of cases and controls. Weight, height, and corresponding BMI were self-reported in about 50% of subjects, measured in 29% of subjects, and measured and subsequently adjusted for difference in clothing in about 20% of subjects. Thirty-six percent of cases and 39% of controls had BMI in the normal range, 41% of cases and 39% of controls were overweight, and 21% of cases and 19% of controls were obese (Table 3). Cases had slightly higher mean weight compared to controls (76.8 kg and 75.5 kg, respectively), and larger mean waist circumference (86.9 and 85.7, respectively). Mean WHR and height were similar.
Table 4 displays odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer according to baseline anthropometric factors for all subjects in the study. Among all subjects, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs. lowest BMI quartile = 1.33, 95% CI = 1.12-1.58, Ptrend < 0.001 in model 1). Statistically significant trends of increasing risk of pancreatic cancer with increasing BMI (both quartiles and clinical categories) were observed in all five models analyzed.
Further adjustment for diabetes history (model 2) resulted in attenuation of risk estimates compared to model 1 but P values for trend were statistically significant for BMI quartiles and categories (Table 4). In addition, waist circumference and waist-to-hip ratio were positively associated with risk of pancreatic cancer among all subjects with top versus bottom quartile ORs = 1.23 (95% CI = 0.94-1.62) and 1.71 (95% CI = 1.27-2.30), respectively (Table 4). Stratification by BMI source (self-reported, measured) resulted in similar risk estimates: ORs (95% CIs) for obese vs. normal BMI were 1.24 (0.92-1.68) for measured BMI and 1.21 (0.95-1.53) for self-reported BMI. The OR per 5 kg/m2 increase in BMI was 1.13 (95% CI = 1.11-1.14).
The risk estimates did not change significantly in the sensitivity analysis excluding the Mayo Clinic case-control study (data not shown), therefore we decided to include the Mayo subjects in the final analyses. There was no evidence of significant heterogeneity between different cohorts for the BMI-pancreatic cancer results (P heterogeneity = 0.36).
Tables 55 and and66 show ORs and 95% CIs of pancreatic cancer among males and females, respectively. Among men, adjusted risk estimate (model 1) for the top versus bottom quartile of BMI was 1.33 (95% CI = 1.04-1.69). Higher risk estimates were observed after exclusion of current smokers (model 4). Among males who never smoked, there was a statistically significant trend of increasing risk with increasing BMI (P trend = 0.007) with the top versus bottom quartile OR = 1.51 (95% CI = 1.13-2.03). Height, waist circumference, and waist-to-hip ratio were not significantly associated with pancreatic cancer among males (Table 5).
Among women, statistically significant trends of increasing risk of pancreatic cancer with increasing BMI were observed overall (model 1) and after exclusion of cases diagnosed within the first 2 years of follow-up (model 3) or current and former smokers (model 4) (Table 6). Compared to normal BMI (model 1), the ORs of pancreatic cancer were 1.31 (95% CI = 1.07-1.60) for overweight women and 1.61 (95% CI = 1.12-2.33, P trend = 0.003) for severely obese women. Increasing waist circumference and WHR were significantly associated with pancreatic cancer risk in women. Compared to the reference group, women in the highest quartile of WHR had an OR of 1.87 (95% CI = 1.31-2.69) after adjustment for cohort, age, BMI source, and smoking status. Inclusion of both BMI (categorical) and WHR (quartiles) in the same model suggested that the effect of increasing WHR is stronger (P = 0.006) compared to that of BMI categories (P = 0.44) after adjustment for cohort, age, gender, BMI source, smoking, and diabetes history.
We did not observe clinically meaningful differences in time of onset for pancreatic cancer between normal and overweight/obese individuals. Overweight and obese individuals together were diagnosed approximately 4 months earlier than normal weight individuals (data not shown). When comparing obese individuals only with normal weight individuals, obese subjects were diagnosed on average about one year earlier than normal weight individuals and the difference was statistically significant (p = 0.03).
Results from this large, pooled set of studies support the hypothesis that obesity is associated with an increased risk of pancreatic cancer. The present findings are consistent with the majority of previous epidemiologic studies that found a positive association between BMI and pancreatic cancer risk 45 and support the conclusion from a recent review panel from the World Cancer Research Fund that the strength of the evidence supporting an association between obesity and pancreatic cancer is convincing 45.
Previous studies that did not observe a positive association between body mass index and pancreatic cancer were often limited by use of proxy respondents 46-49 or by inadequate statistical power to examine associations at BMI levels that correspond with obesity (fewer than 10 cases with BMI > 30.0) 7,10,17,50. Controversy regarding the role of smoking in the BMI and pancreatic cancer relationship still remains. Many previous studies that did not observe an association with obesity did not properly control for smoking history 7,47,48,50. It is possible that residual confounding due to improper adjustment for smoking history may have biased the association between body mass index and pancreatic cancer toward the null. When stratifying on smoking status, some previous studies found the relationship between BMI and pancreatic cancer was strongest among never smokers 24,25. Our findings are consistent with previous reports that the association between BMI and pancreatic cancer is stronger among non-smokers (adjusted OR for BMI ≥30 = 1.37, 95% CI = 1.06-1.78) than smokers (adjusted OR for BMI ≥30 = 1.14, 95% CI = 0.91-1.78).
Unlike a recent report where the authors reported that individuals who were overweight or obese from the ages of 20 to 49 had an earlier onset of pancreatic cancer compared to those with normal body weight 51, we did not find a substantial difference in age of diagnosis between normal weight and the combined group of overweight/obese individuals.
In our study, BMI was assessed between the ages 37 and 94 and overweight or obese individuals were diagnosed on average 4 months earlier than normal weight individuals. The previous report by Li et al. 51, using a hospital-based case-control study design, found that overweight or obese patients from the ages 20 to 49 had a median age of pancreatic cancer onset 2 to 6 years earlier than normal weight patients. However, these differences were based on BMI as recalled from early adulthood and may have been subject to recall bias. Nevertheless, as suggested by Li et al., obesity at younger ages might have a more profound effect on risk and age of onset of pancreatic cancer than obesity at older ages.
There are established biologic pathways to support a relationship between excess body weight and the development of pancreatic cancer. Body fatness has a direct linear relationship with insulin production and is related to the development of insulin resistance 52. Furthermore, insulin resistance and abnormal glucose metabolism, even in the absence of diabetes, is associated with pancreatic cancer risk 8,53,54. In vitro studies have also shown that insulin has growth-promoting effects in the pancreas 55. A hyperinsulinemic state allows increased insulin to pass through the pancreas and trigger mitotic activity 8,53,56. Additionally, excess insulin can also down-regulate insulin-like growth factor-I binding proteins, which would result in more bioavailable insulin-like growth factor-I that has been associated with cell proliferation and pancreatic cancer risk 54,57.
The results of this study also support a specific role of central adiposity in pancreatic cancer risk, especially among women. In addition to general body fatness, there is a direct linear relationship between intra-abdominal fat deposits, insulin production, and the development of insulin resistance 52.
There are several strengths of the current study including the very large sample size, the wide range of BMI, and the ability to control for most known or suspected pancreatic cancer risk factors. Additionally, our population was largely a nested sample from various prospective cohort studies, so that BMI was measured prior to pancreatic cancer diagnosis, thus reducing differential reporting of past exposure information. Limitations include the use of some self-reported exposure information; however, adjusting for source of exposure information (self-reported or measured), did not alter the association. Another potential limitation is the wide range of lag periods between BMI measurement (collected at baseline for each cohort) and the date of diagnosis; however, sensitivity analyses examining this lag time by excluding the first 2 years of follow-up did not change the point estimates appreciably, thus arguing against an influence of pre-diagnostic disease-related changes in anthropometric measures (reverse causation). Participating cohorts had different coding systems for physical activity that were not readily comparable; therefore we could not assess whether the association between BMI and pancreatic cancer vary by level of physical activity. To address potential residual confounding by smoking, we have performed the analyses in never smokers and found slightly stronger association between BMI and pancreatic risk. Lastly, only a few cohorts had data available on waist and hip circumference, so that there was limited statistical power to examine these relationships.
In summary, the results of this study provide additional evidence that obesity is associated with increased risk of pancreatic cancer. In addition, the association between waist circumference and pancreatic cancer risk, especially in women, suggests a possible association with the distribution of body fat. These findings, along with those from previous studies, strongly support the role of obesity in pancreatic cancer development.
The authors thank the investigators from the PanScan Cohort Consortium centers and the study participants, without whom this study would have not been possible.
Funding/Grant Support: This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial was supported by funding provided by the Intramural Research Program of the National Cancer Institute, and the U.S. Public Health Service contracts [(N01-CN-45165, N01-RC-45035, N01-RC-37004].
CLUE II was supported by National Institute of Aging [5U01AG018033] and National Cancer Institute [CA105069, CA73790].
European Prospective Investigation into Cancer and Nutrition was supported by the European Commission: Public Health and Consumer Protection Directorate 1993-2004; Research Directorate-General 2005; Ligue contre le Cancer; Societé 3M; Mutuelle Générale de l’Education Nationale; Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center, Federal Ministry of Education and Research (Germany); Danish Cancer Society (Denmark); Health Research Fund (FIS) of the Spanish Ministry of Health, The participating regional governments and institutions (Spain); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (United Kingdom); Greek Ministry of Health and Social Solidarity, Hellenic Health Foundation and Stavros Niarchos Foundation (Greece); Italian Association for Research on Cancer (AIRC) (Italy); Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland) (the Netherlands); Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skane and Västerbotten (Sweden); World Cancer Research Fund (WCRF).
The New York University Women’s Health Study is supported by the National Cancer Institute research grants [R01CA034588, R01CA098661, P30CA016087] and the National Institute of Environmental Health Sciences Center grant [ES000260].
The Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial was supported by contracts from the National Cancer Institute [University of Colorado Denver, NO1-CN-25514, Georgetown University NO1-CN-25522, Pacific Health Research Institute NO1-CN-25515, Henry Ford Health System NO1-CN-25512, University of Minnesota, NO1-CN-25513, Washington University NO1-CN-25516, University of Pittsburgh NO1-CN-25511, University of Utah NO1-CN-25524 Marshfield Clinic Research Foundation NO1-CN-25518, University of Alabama at Birmingham NO1-CN-75022, Westat, Inc. NO1-CN-25476, University of California, Los Angeles NO1-CN-25404].
The Shanghai Men’s and Women’s Health Studies were supported by the National Cancer Institute extramural research grants [R01 CA82729, R01 CA70867] and by the Intramural Research Program of National Cancer Institute (Division of Cancer Epidemiology and Genetics).
The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute through contracts [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221].
Role of the Sponsors: This project has been funded with federal funds from the National Cancer Institute, National Institutes of Health. The funding agency had no role in the conduct of the study, the interpretation of the data, or the decision to submit the manuscript for publication.
Dr. Arslan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.
Conception and Design: Patricia Hartge, Demetrius Albanes, Laufey Amundadottir, Stephen J. Chanock, Robert N. Hoover, Amy Hutchinson, Kevin B. Jacobs, Julie B. Mendelsohn, Gilles Thomas, Geoffrey S. Tobias, Kai Yu
Analysis and Interpretation of Data: Alan A. Arslan, Alpa V. Patel, Emily Steplowski, Charles Kooperberg, Kathy J. Helzlsouer, Xiao-Ou Shu
Drafting of the article: Alan A. Arslan, Alpa V. Patel, Kathy J. Helzlsouer, Charles Kooperberg, Xiao-Ou Shu, Emily Steplowski
Critical revision of the article for important intellectual content: Alan A. Arslan, Kathy J. Helzlsouer, Charles Kooperberg, Xiao-Ou Shu, Emily Steplowski, H. Bas Bueno-de-Mesquita, Eric J. Jacobs, Heiner Boeing, Edward L. Giovannucci, Amy Hutchinson, JoAnn E. Manson, Anne McTiernan, Julie B. Mendelsohn, Dominique S. Michaud, Thomas E. Rohan, Geoffrey S. Tobias, Dimitrios Trichopoulos, Jarmo Virtamo, Alpa V. Patel
Final approval of the article: Alan A. Arslan, Kathy J. Helzlsouer, Charles Kooperberg, Xiao-Ou Shu, Emily Steplowski, H. Bas Bueno-de-Mesquita, Charles S. Fuchs, Myron D. Gross, Eric J. Jacobs, Andrea LaCroix, Gloria M. Petersen, Rachael Z. Stolzenberg-Solomon, Wei Zheng, Demetrius Albanes, Laufey Amundadottir, William R. Bamlet, Aurelio Barricarte, Sheila A. Bingham, Heiner Boeing, Marie-Christine Boutron-Ruault, Julie E. Buring, Stephen J. Chanock, Sandra Clipp, J. Michael Gaziano, Edward L. Giovannucci, Susan E. Hankinson, Patricia Hartge, Robert N. Hoover, David J. Hunter, Amy Hutchinson, Kevin B. Jacobs, Peter Kraft, Shannon M. Lynch, Jonas Manjer, JoAnn E. Manson, Anne McTiernan, Robert R. McWilliams, Julie B. Mendelsohn, Dominique S. Michaud, Domenico Palli, Thomas E. Rohan, Nadia Slimani, Gilles Thomas, Anne Tjønneland, Geoffrey S. Tobias, Dimitrios Trichopoulos, Jarmo Virtamo, Brian M. Wolpin, Kai Yu, Anne Zeleniuch-Jacquotte, Alpa V. Patel
Provision of study materials or patients: Demetrius Albanes, Eric J. Jacobs, H. Bas Bueno-de-Mesquita, Aurelio Barricarte, Heiner Boeing, Marie-Christine Boutron-Ruault, Jonas Manjer, Dominique S. Michaud, Domenico Palli, Nadia Slimani, Anne Tjønneland, Dimitrios Trichopoulos, Jarmo Virtamo, Kathy J. Helzlsouer, Charles S. Fuchs, Gloria M. Petersen, Anne Zeleniuch-Jacquotte, Susan E. Hankinson, J. Michael Gaziano, Wei Zheng, Xiao-Ou Shu, Andrea LaCroix
Statistical expertise: Charles Kooperberg, Emily Steplowski, Peter Kraft, Kai Yu
Obtaining of funding: Patricia Hartge, Demetrius Albanes, Laufey Amundadottir, Stephen J. Chanock, Robert N. Hoover, Amy Hutchinson, Kevin B. Jacobs, Julie B. Mendelsohn, Gilles Thomas, Geoffrey S. Tobias, Kai Yu
Administrative, technical, or logistical support: Geoffrey S. Tobias, Julie B. Mendelsohn Collection and assembly of data: Geoffrey S. Tobias, Julie B. Mendelsohn, Emily Steplowski
Financial Disclosure: None reported.