Diet Composition, Weight Control, and Breast Carcinogenesis

Overview

In the United States, overweight (BMI \> 25 but \< 30 Kg/m2) and obesity (BMI \> 30Kg/m2) are increasing at epidemic rates. A significant association exists between being overweight or obese and breast cancer recurrence and survival. However, evidence continues to accumulate indicating that achieving or maintaining a healthy weight for height (Body Mass Index, BMI, 18.5-25Kg/m2) is associated with a reduced risk for breast cancer and with a decrease in breast cancer associated mortality. Despite this, there is a lack of randomized controlled trials exploring this association and how the process of fat loss or being successful in actually reaching a healthy weight for height differentially affects biomarkers for cancer recurrence. Many dietary approaches for weight loss are currently available to the public, and each purports to offer advantages. However, there is little scientific evidence to indicate how these dietary approaches, some of which vary markedly in the foods that they limit or exclude, affect biomarkers for breast cancer risk. In particular, it is not know whether the critical factor in relation to weight and breast cancer is simply weight loss (negative energy balance), irrespective of the manner in which it is achieved, or if certain dietary approaches affect breast cancer risk biomarkers more favorably than others. Published data from our laboratory suggest that dietary pattern does matter, and therefore the goal of this study is to investigate the effects of two popular weight loss dietary approaches that differ in the extent to which they limit carbohydrate or fat consumption (with effects on dietary glycemic load) compared to a usual care group on prognostic markers for cancer recurrence in postmenopausal breast cancer survivors. The investigators hypothesize that in addition to the anticipated effects of fat loss on circulating levels of bioavailable sex steroid hormones, that the effects of excess fat on breast cancer prognosis can be attributed to three interrelated metabolic processes that affect cancer progression: altered glucose metabolism, chronic inflammation and excessive cellular oxidation.

This study is designed to answer questions about how a dietary pattern either high or low in dietary carbohydrate and fat availability and fat loss influence metabolic and hormonal processes that may affect breast cancer recurrence. The investigators hypothesize that in addition to the anticipated effects of fat loss on circulating levels of bioavailable sex steroids, that the effects of excess fat on breast cancer prognosis can be attributed to three interrelated metabolic processes: altered glucose metabolism (IGF-1, IGFBP-3, glycated proteins), chronic inflammation (C-reactive protein, IL-6, TNF-alpha) and excessive cellular oxidation (8-hydroxy-2-deoxyguanosine and 8-isoprostane F-2 alpha). A 6 month intervention study involving 370 post menopausal women who have been treated for breast cancer is proposed. Randomized women, stratified by resected stage, systemic adjuvant therapy and body mass index (\> 25 and \< 35 Kg/m2), will serve as either a non-intervention control group or will follow a tailored diet-physical activity program designed to create a weekly negative energy balance equivalent to 3500 kcal. The intervention groups will receive the same physical activity protocol, but one of two diets that differ in dietary pattern. The specific aims are: Aim 1. Does a dietary pattern either high or low in available carbohydrate and fat alter the pattern of change observed in circulating factors involved in glucose homeostasis, chronic inflammation, cellular oxidation, and steroid hormone metabolism during progressive loss of body fat? The investigators will also examine how observed changes in these circulating factors related to changes indicators of breast cancer recurrence. Aim 2. Do circulating factors associated with glucose homeostasis, chronic inflammation, and cellular oxidation display the same pattern of change in response to progressive fat loss as circulating analytes associated with sex steroid metabolism? Analytes of interest will be measured monthly throughout the study. Aim 3. Does dietary glycemic load affect the magnitude or rate of fat loss? Plasma adipokines such as leptin and adiponectin and plasma ghrelin will be measured to provide biological determinants that may help explain differences in response. The work proposed in this application should provide quantitative data about the importance of the magnitude of fat loss on metabolic and hormonal processes involved in cancer recurrence and provide guidance about effective dietary approaches that maximize weight loss benefits on breast cancer prognosis.