AS755 - Nutrition and Physical Activity Assessment Study (NPAAS Competitive renewal)

Investigator Names and Contact Information

Marian Neuhouser (mneuhous@fredhutch.org) Johanna Lampe (jlampe@fredhutch.org )

Introduction/Intent

This competing renewal of CA119171-17 “Nutrition and Physical Activity Assessment Study” (NPAAS) continues to focus on dietary biomarker discovery and application of biomarkers to investigations of diet and risk of cancer and other chronic diseases in the Women’s Health Initiative (WHI). Here we will focus on the WHI Dietary Modification Trial where gaps remain in understanding the biology of intervention effects (both a priori hypothesized and those observed with further interrogations of the data), and in the contribution of fat reduction per se to intervention effects. Our overall goal for this renewal is to delineate biological mechanisms underlying dietary intervention effects of the WHI Dietary Modification (DM) Trial. We will use metabolomics to interrogate archived biospecimens collected at baseline, year 1, and end of study among women in the intervention and comparison groups to elucidate pathways related to downstream risk for breast, colorectal, endometrial, and total cancer, as well as obesity and other chronic diseases. These and currently available data will be used to objectively assess the magnitude of fat density difference between randomization groups, and to project corresponding changes in cancer incidence for the estimated fat density reduction. The WHI-DM randomized 48,835 postmenopausal women to an intervention group (DM-I) whose participants followed a low-fat/high fruit and vegetable dietary pattern (n=19,541) or a usual diet comparison group (DM-C) (n=29,294).1 Recruitment and randomization took place 1993-1998 at 40 US clinical centers (CCs) and ended in 2005 after a mean 8.5 year intervention period. Neither invasive breast cancer nor colorectal cancer were statistically significantly reduced by the intervention (P=0.09 and P=0.45, respectively),2, 3 However, all-cause mortality after a breast cancer diagnosis was significantly reduced for those diagnosed during the intervention period (P=0.02).4 Additionally, intervention women who reduced fat by increasing plant protein had a coronary heart disease (CHD) hazard ratio of 0.39 (95%CI 0.22-0.71) compared to women who did not make these changes.5 Further, after nearly 20 years of long-term follow-up, there was a sustained reduction in mortality attributed to breast cancer for those who were in the DM-I compared to the DM-C (HR=0.85, 95%CI 0.74-0.96, p<0.01).6 Other novel and important clinical findings for the DM-I compared to DM-C were reductions in body weight even though the trial did not instruct on weight loss and had no weight loss goals,7 more favorable lean and fat measures of body composition,8 less urinary incontinence,9 and suggestively less age-related cognitive impairment.10 In terms of metabolic health, women in the WHI DM-I arm did not have higher Type 2 diabetes (T2D) risk (potential concern with higher carbohydrate diet), and among those who did develop T2D during the trial, intervention arm women were less likely to have disease progression requiring insulin.11 Three years into the trial, intervention effects yielded lower diastolic blood pressure, Factor VIIC, total and LDL-cholesterol, body weight, waist circumference and body mass index (BMI),12 and the intervention had notable effects on risk of metabolic syndrome.13 Taken together, the WHI-DM had clinically meaningful intervention effects on important measures of metabolic health and on long term health and mortality outcomes. **Gaps remain in identifying specific biological pathways affected by the WHI-DM, and in identifying the importance of the fat reduction intervention component specifically, gaps that will be addressed with this proposal. **We will utilize baseline and year 1 biospecimens from the WHI-DM blood draw cohort, and end-of-intervention specimens from the Nutritional Biomarkers Study (NBS) whose participants were all enrolled in the DM.

The specific aims for the upcoming grant period are:

1. Evaluate the effect of the WHI DM intervention on the targeted serum metabolome and lipidome and metabolic pathways in WHI-DM participants. 1a. Measure metabolomics at baseline and year 1 in 500 DM-I and 500 DM-C participants (n=535 from 6% blood draw cohort and n=465 from NBS). 1b. Measure metabolomics at end-of-intervention in 233 DM-I and 232 DM-C participants (NBS). Aim 1b is exploratory. Hypothesis: WHI participants in the DM-I will have metabolomics profiles downregulated in pathways related to insulin resistance and metabolic syndrome compared to WHI participants in DM-C.

2. Investigate how the metabolites mediate the effects of the intervention on intermediate biomarkers and body measurements of metabolic health. 2a. Measure the mediation effect of metabolites on weight, waist circumference and BMI (blood draw cohort). 2b. Measure the mediation effect of metabolites on existing measure of glucose, insulin, computed HOMA-IR, and lipids (blood draw cohort with core analytes). Hypothesis: Metabolites will mediate the intervention effects on body measurements and on glucose, insulin, and lipids favoring the DM-I compared to the DM-C.

3. Elucidate the contribution of fat reduction to DM intervention effects. 3a. Estimate a serum metabolomics-based estimate of the fat density difference between the DM-I and DM-C randomization groups at 1-year post-randomization. 3b. Assess the mediation of DM intervention effects on clinical outcomes by biomarker-calibrated changes in fat density. Hypothesis: Reduction in fat density in the DM-I will provide an explanation for most intervention effects, including those related to breast cancer.