Is the Women’s Health Initiative (WHI) Dietary Modification Associated With a Reduced Risk of Pancreatic Cancer?

JNCI: Journal of the National Cancer Institute, Jan 2018

Stolzenberg-Solomon, Rachael Z, Katki, Hormuzd A

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Is the Women’s Health Initiative (WHI) Dietary Modification Associated With a Reduced Risk of Pancreatic Cancer?

JNCI J Natl Cancer Inst ( Is the Women's Health Initiative (WHI) Dietary Modification Associated With a Reduced Risk of Pancreatic Cancer? Rachael Z. Stolzenberg-Solomon 0 1 Hormuzd A. Katki 0 1 0 Institute, National Institutes of Health , 9609 Medical Center Drive, Room 6E420, Rockville, MD 20850 , USA 1 Affiliations of authors: Metabolic Epidemiology Branch and Biostatics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Rockville MD , USA - Diet may play a role in the prevention of pancreatic cancer ( 1,2 ); however, healthy patterns have variably been associated with pancreatic cancer in case-control and cohort studies ( 3–7 ). Dietary exposures are challenging to study in epidemiologic studies due to measurement error, and large studies are needed to detect modest magnitudes of risk. Diet is particularly difficult to examine in epidemiologic studies of pancreatic cancer because cases often have symptoms of latent disease such as diabetes, gastrointestinal issues, and weight loss, which can influence dietary intake. Randomized trials are considered the “gold standard” of study designs in determining the efficacy of interventions. The study reported by Jiao et al. ( 8 ) in this issue of the Journal is a worthy effort to evaluate whether a healthy lowfat dietary pattern affects incident pancreatic cancer. Jiao et al. ( 8 ) report findings from the Women’s Health Initiative (WHI) Dietary Modification Trial that evaluated the effects of a low-fat dietary pattern and subsequent risk of incident pancreatic cancer in postmenopausal women with extended follow-up for an additional nine years after the intervention ended. The dietary intervention promoted reducing total fat intake to 20% of energy and increasing consumption of vegetables and fruit to at least five servings per day and grains to at least six servings per day ( 9 ). The comparison group was asked not to make dietary changes ( 9 ). Consistent with the original WHI report ( 9 ), no statistically significant association (hazard ratio [HR] ¼ 0.86, 95% confidence interval [CI] ¼ 0.67 to 1.11) was observed for the effect of the low-fat dietary intervention on subsequent incident pancreatic cancer during the core intervention up to 2005 or during the extended follow-up through 2014 (weighted log-rank P ¼ .23). The authors did, however, observe a protective association (HR ¼ 0.71, 95% CI ¼ 0.53 to 0.96) for the low-fat diet intervention among participants who were overweight or obese (body mass index [BMI] > 25 kg/m2). They also showed a positive association (HR ¼ 1.62, 95% CI ¼ 0.97 to 2.71) among women who were normal weight (BMI < 25 kg/m2) at baseline (Pinteraction ¼ .01). We agree with the authors regarding the limitations of conducting post hoc analyses of the WHI Dietary Modification Trial and that caution needs to be taken in interpreting study findings based on subgroup analyses. A concern about the present study is that pancreatic cancer is a secondary outcome of the WHI Dietary Modification Trial. In addition, participants in the trial had less than optimal adherence to the dietary modification, and the differences between the intervention and control groups fell short of the goal for which the study was designed ( 10 ). The number of pancreatic cancer cases included in the present study is modest (n ¼ 257). The trial was not powered to examine pancreatic cancer as an outcome or an interaction of the trial intervention with other variables. When a study detects an effect that it is not adequately powered for, the observed effect may be stronger than the truth. That is, in underpowered studies, observed statistically significant effects, either protective or harmful, are often too pronounced. Extreme care is warranted in the interpretation of the inverse associations in the subgroup of women who were overweight or obese at baseline (n ¼ 197), as well as the positive associations observed among the normal weight women (n ¼ 60). Subgroup associations found in trials are known to be unreliable, and one might expect spurious subgroup effects to be identified when none exist ( 11,12 ). Further, given the multiple comparisons from the other stratified analyses and interactions that were tested, the interaction by baseline body mass index may be due to chance. Although the results in the subgroup of women who were overweight or obese are suggestive, they could be misleading. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US. E D I T O R I A L In our judgment, the results from this randomized trial do not clearly support that adhering to a low-fat healthy dietary pattern reduces the risk of pancreatic cancer. As it is unlikely that large dietary trials will be conducted with pancreatic cancer as an outcome, additional studies are needed to demonstrate associations between healthy dietary patterns and risk of pancreatic cancer. Note The authors have no conflicts of interest to declare. 1. World Cancer Research Fund/American Institute for Cancer Research. Pancreas. In: Food, Nutrition, Physical Activity , and the Prevention of Cancer: A Global Perspective . Washington, DC: AICR; 2007 : 271 - 274 . 2. World Cancer Research Fund/American Institute of Cancer Research [Internet]. Pancreatic cancer 2012 summary: Food, nutrition, physical activity and the prevention of pancreatic cancer, continuous update project . 2012 . http://www.aicr. org/assets/docs/pdf/education/cup-pancreatic-cancer -2012.pdf . Accessed May 2017 . 3. Arem H , Reedy J , Sampson J , et al. The Healthy Eating Index 2005 and risk for pancreatic cancer in the NIH-AARP study . J Natl Cancer Inst . 2013 ; 105 ( 17 ): 1298 - 1305 . 4. Michaud DS , Skinner HG , Wu K , et al. Dietary patterns and pancreatic cancer risk in men and women . J Natl Cancer Inst . 2005 ; 97 ( 7 ): 518 - 524 . 5. Inoue-Choi M , Flood A , Robien K , Anderson K. Nutrients , food groups, dietary patterns, and risk of pancreatic cancer in postmenopausal women . Cancer Epidemiol Biomarkers Prev . 2011 ; 20 ( 4 ): 711 - 714 . 6. Chan JM , Gong Z , Holly EA , Bracci PM . Dietary patterns and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area . Nutr Cancer . 2013 ; 65 ( 1 ): 157 - 164 . 7. Jiao L , Mitrou PN , Reedy J , et al. A combined healthy lifestyle score and risk of pancreatic cancer in a large cohort study . Arch Intern Med . 2009 ; 169 ( 8 ): 764 - 770 . 8. Jiao L , Chen L , DLW , et al. Low-fat dietary pattern and pancreatic cancer risk in the Women's Health Initiative Dietary Modification randomized controlled trial . J Natl Cancer Inst . 2018 ; 110 ( 1 ): 49 - 56 . 9. Prentice RL , Thomson CA , Caan B , et al. Low-fat dietary pattern and cancer incidence in the Women's Health Initiative Dietary Modification randomized controlled trial . J Natl Cancer Inst . 2007 ; 99 ( 20 ): 1534 - 1543 . 10. Women 's Health Initiative Study G. Dietary adherence in the Women's Health Initiative Dietary Modification Trial . J Am Diet Assoc . 2004 ; 104 ( 4 ): 654 - 658 . 11. Brookes ST , Whitley E , Peters TJ , Mulheran PA , Egger M , Davey Smith G. Subgroup analyses in randomised controlled trials: Quantifying the risks of false-positives and false-negatives . Health Technol Assess . 2001 ; 5 ( 33 ): 1 - 56 . 12. Brookes ST , Whitely E , Egger M , Smith GD , Mulheran PA , Peters TJ . Subgroup analyses in randomized trials: Risks of subgroup-specific analyses; power and sample size for the interaction test . J Clin Epidemiol . 2004 ; 57 ( 3 ): 229 - 236 .


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Stolzenberg-Solomon, Rachael Z, Katki, Hormuzd A. Is the Women’s Health Initiative (WHI) Dietary Modification Associated With a Reduced Risk of Pancreatic Cancer?, JNCI: Journal of the National Cancer Institute, 2018, 9-10, DOI: 10.1093/jnci/djx139