Adriana Villaseñor

Postdiagnosis C-Reactive Protein and Breast Cancer Survivorship: Findings from the WHEL Study

Background: Serum C-reactive protein (CRP) is a marker of acute inflammatory response and has been associated with health outcomes in some studies. Inflammation and immune response may have potential prognostic implications for breast cancer survivors. Methods: The Womens Healthy Eating and Living Study includes 2,919 early-stage breast cancer survivors with serum collected 2 years postdiagnosis and follow-up for clinical outcomes over approximately 7 years. CRP concentrations were measured using high-sensitivity electrochemiluminescence assay. Outcomes, including all-cause mortality, breast cancer–specific mortality, and additional breast cancer events were oncologist verified from medical records and death certificates. Cox proportional hazards models were conducted with adjustment for potential confounding factors to generate HRs and 95% confidence intervals (CI). Results: CRP concentrations in women diagnosed with breast cancer were associated with death due to any cause, death due to breast cancer, and additional breast cancer events, after adjustment for sociodemographic and cancer characteristics (lnCRP: P < 0.05 for all three outcomes). The HR for women with (vs. without) acute inflammation suggests a threshold effect on overall survival, rather than a dose–response relationship (≥10.0 mg/L vs. <1 mg/L: HR, 1.96; 95% CI, 1.22–3.13). Associations were similar for breast cancer–specific mortality (HR, 1.91; 95% CI, 1.13–3.23) and any additional breast cancer–related event (HR, 1.69; 95% CI, 1.17–2.43). Conclusions: Acute inflammation status (CRP ≥ 10 mg/L) may be an important independent biomarker for long-term survival in breast cancer survivors. Impact: Interventions to decrease circulating CRP concentrations in breast cancer survivors with acute inflammation may improve prognosis. Cancer Epidemiol Biomarkers Prev; 23(1); 189–99. ©2013 AACR.

Intermittent Fasting and Human Metabolic Health

Periods of voluntary abstinence from food and drink (i.e., intermittent fasting) has been practiced since earliest antiquity by peoples around the globe. Books on ethnology and religion describe a remarkable variety of fasting forms and practices.1 Renewed interest in fasting regimens is evidenced by a plethora of popular press publications and diet recommendations. For example, in 2013, Mosley and Spencer published a best-selling book titled “The Fast Diet,” which touts the benefits of restricting energy intake severely for two days a week while eating normally the rest of the week.2 Dozens of books promote various fasting dietary patterns and the web offers hundreds of fasting-related sites. However, scientific evidence for the health benefits of intermittent fasting in humans is often extrapolated from animal studies, based on observational data on religious fasting (particularly Ramadan), or derived from experimental studies with modest sample sizes. The overall objective of this paper is to provide an overview of intermittent fasting regimens (Table 1) and summarize the evidence on the health benefits of intermittent fasting with a focus on human intervention studies. Because much of the data on intermittent fasting is from research in animal models, we briefly summarize key rodent studies and reviews. Health outcomes of interest are changes in weight and metabolic parameters associated with type 2 diabetes, cardiovascular disease, and cancer. We also present an overview of the major mechanisms hypothesized to link fasting regimens with human health: (1) circadian biology, (2) the gastrointestinal microbiota, and (3) modifiable lifestyle behaviors such as diet, activity, and sleep. Finally, we present conclusions regarding the evidence-base for intermittent fasting as an intervention for improving human health and propose a research agenda. Table 1 Types of intermittent fasting regimens that are hypothesized to impact health outcomes This paper provides a uniquely broad synthesis of the scientific evidence linking intermittent fasting with human health and a framework for future research on this topic.

Metabolic responses to a traditional Mexican diet compared with a commonly consumed US diet in women of Mexican descent: a randomized crossover feeding trial,

BACKGROUND Mexican immigrants are disproportionally affected by diet-related risk of metabolic dysfunction. Whether adhering to a traditional Mexican diet or adopting a US diet contributes to metabolic changes associated with future risk of type 2 diabetes and other chronic diseases has not been investigated. OBJECTIVE The purpose of this study was to test in a randomized crossover feeding trial the metabolic responses to a Mexican diet compared with a commonly consumed US diet. DESIGN First- and second-generation healthy women of Mexican descent (n = 53) were randomly assigned in a crossover design to consume a Mexican or US diet for 24 d each, separated by a 28-d washout period. Diets were eucaloric and similar in macronutrient composition. The metabolic responses to diets were assessed by measuring fasting serum concentrations of glucose, insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6), as well as the homeostasis model assessment of insulin resistance (HOMA-IR) at the beginning and end of each period. Linear mixed models tested the intervention effect on the biomarkers, while adjusting for diet sequence, feeding period, baseline and washout biomarker concentrations, age, acculturation, and BMI. RESULTS Compared with the US diet, the Mexican diet reduced insulin by 14% [geometric means (95% CIs): 9.3 (8.3, 10.3) compared with 8.0 (7.2, 8.9) μU/mL; P = 0.02], HOMA-IR by 15% [2.0 (1.8, 2.3) compared with 1.7 (1.6, 2.0); P = 0.02], and IGFBP-3 by 6% (mean ± SEM: 2420 ± 29 compared with 2299 ± 29 ng/mL; P < 0.01) and tended to reduce circulating concentrations of IGF-1 by 4% (149 ± 2.6 compared with 144 ± 2.5 ng/mL; P = 0.06). There was no significant intervention effect on serum concentrations of glucose, adiponectin, CRP, or IL-6 in the US compared with the Mexican diet. CONCLUSION Compared with the commonly consumed US diet, the traditional Mexican diet modestly improved insulin sensitivity under conditions of weight stability in healthy women of Mexican descent, while having no impact on biomarkers of inflammation. This trial was registered at clinicaltrials.gov as NCT01369173.

Recruitment strategies, design, and participant characteristics in a trial of weight-loss and metformin in breast cancer survivors

Weight loss and metformin are hypothesized to improve breast cancer outcomes; however the joint impacts of these treatments have not been investigated. Reach for Health is a randomized trial using a 2 × 2 factorial design to investigate the effects of weight loss and metformin on biomarkers associated with breast cancer prognosis among overweight/obese postmenopausal breast cancer survivors. This paper describes the trial recruitment strategies, design, and baseline sample characteristics. Participants were randomized in equal numbers to (1) placebo, (2) metformin, (3) weight loss intervention and placebo, or (4) weight-loss intervention and metformin. The lifestyle intervention was a personalized, telephone-based program targeting a 7% weight-loss in the intervention arm. The metformin dose was 1500 mg/day. The duration of the intervention was 6 months. Main outcomes were biomarkers representing 3 metabolic systems putatively related to breast cancer mortality: glucoregulation, inflammation, and sex hormones. Between August 2011 and May 2015, we randomized 333 breast cancer survivors. Mass mailings from the California Cancer Registry were the most successful recruitment strategy with over 25,000 letters sent at a cost of

The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes

191 per randomized participant. At baseline, higher levels of obesity were significantly associated with worse sleep disturbance and impairment scores, lower levels of physical activity and higher levels of sedentary behavior, hypertension, hypercholesterolemia, and lower quality of life (p<0.05 for all). These results illustrate the health burden of obesity. Results of this trial will provide mechanistic data on biological pathways and circulating biomarkers associated with lifestyle and pharmacologic interventions to improve breast cancer prognosis.

Trends in lung cancer and cigarette smoking: California compared to the rest of the United States

Background This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis. Methods Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomly assigned to metformin vs placebo and to a weight loss intervention vs control (ie, usual care). The 2 × 2 factorial design allows a single randomized trial to investigate the effect of two factors and interactions between them. Outcomes were changes in fasting insulin, glucose, C-reactive protein (CRP), estradiol, testosterone, and sex-hormone binding globulin (SHBG). The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control. All tests of statistical significance were two-sided. Results A total of 313 women (94.0%) completed the six-month trial. High prescription adherence (ie, ≥80% of pills taken) ranged from 65.9% of participants in the metformin group to 81.3% of those in the placebo group (P < .002). Mean percent weight loss was statistically significantly higher in the weight loss group (-5.5%, 95% confidence interval [CI] = -6.3% to -4.8%) compared with the control group (-2.7%, 95% CI = -3.5% to -1.9%). Statistically significant group differences (ie, percent change in metformin group minus placebo group) were -7.9% (95% CI = -15.0% to -0.8%) for insulin, -10.0% (95% CI = -18.5% to -1.5%) for estradiol, -9.5% (95% CI = -15.2% to -3.8%) for testosterone, and 7.5% (95% CI = 2.4% to 12.6%) for SHBG. Statistically significant group differences (ie, percent change in weight loss group minus placebo group) were -12.5% (95% CI = -19.6% to -5.3%) for insulin and 5.3% (95% CI = 0.2% to 10.4%) for SHBG. Conclusions As adjuvant therapy, weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality.

Genetic ancestry in relation to the metabolic response to a US versus traditional Mexican diet: a randomized crossover feeding trial among women of Mexican descent

Three cigarette smoking behaviors influence lung cancer rates: how many people start, the amount they smoke, and the age they quit. California has reduced smoking faster than the rest of the United States and trends in these three smoking behaviors should inform lung cancer trends. We examined trends in smoking behavior (initiation, intensity, and quitting) in California and the rest of United States by regression models using the 1974–2014 National Health Interview Surveys (n = 962,174). Lung cancer mortality data for 1970–2013 was obtained from the National Surveillance, Epidemiology, and End Results (SEER) Program. Among those aged 18 to 35 years, California had much larger declines than the rest of the United States in smoking initiation and intensity, and increased quitting. In 2012–2014, among this age group, only 18.6% [95% confidence interval (CI), 16.8%–20.3%] had ever smoked; smokers consumed only 6.3 cigarettes/day (95% CI, 5.6–7.0); and 45.7% (95% CI, 41.1%–50.4%) of ever-smokers had quit by age 35. Each of these metrics was at least 24% better than in the rest of the United States. There was no marked California effect on quitting or intensity among seniors. From 1986 to 2013, annual lung cancer mortality decreased more rapidly in California and by 2013 was 28% lower (62.6 vs. 87.5/100,000) than in the rest of the United States. Californias tobacco control efforts were associated with a major reduction in cigarette smoking among those under age 35 years. These changes will further widen the lung cancer gap that already exists between California and the rest of the United States.

Abstract A68: Does genetic ancestry influence the metabolic response to a traditional Mexican versus U.S. diet? A randomized crossover feeding trial among first and second generation women of Mexican descent

Background/Objectives:Certain populations with a large proportion of indigenous American (IA) genetic ancestry may be evolutionarily adapted to traditional diets high in legumes and complex carbohydrates, and may have a detrimental metabolic response to US diets high in refined carbohydrates and added sugars. We tested whether IA ancestry modified the metabolic response to a US versus traditional Mexican diet in a controlled dietary intervention.Subjects/Methods:First and second generation Mexican immigrant women (n=53) completed a randomized crossover feeding trial testing the effects of a US versus traditional Mexican diet. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), adiponectin, C-reactive protein, interleukin-6 and computed homeostasis model assessment for insulin resistance (HOMAIR). Blood collected at baseline was used for genotyping, and estimation of African, European and IA ancestries with the use of 214 ancestry informative markers.Results:The genetic ancestral background was 56% IA, 38% European and 6% African. Women in the highest IA ancestry tertile (>62%) were shorter in height, less educated and less acculturated to the US lifestyle, and tended to have higher waist-to-hip ratio compared with women in the middle and lowest IA ancestry tertiles, respectively. Compared with the US diet, the traditional Mexican diet tended to reduce glucose, insulin, IGF-1, IGFBP-3 and HOMAIR among women in the middle IA ancestry group (IA ancestry ⩽45–62%), whereas having no effect on biomarkers related to inflammation.Conclusions:We observed modest interactions between IA ancestry and the metabolic response to a US versus traditional Mexican diet among Mexican immigrant women.

Chapter 4 - Overview of Nutritional Epidemiology

Background: Greater acculturation to the U.S. dietary habits has been suggested to contribute to the high rates of obesity, insulin resistance, and therefore, potential risk of type 2 diabetes (T2D) and breast cancer. Mexican immigrants may be evolutionary adapted to traditional diets high in legumes and complex carbohydrates. When consuming an inexpensive, readily available U.S. diet high in refined carbohydrates and added sugars they may experience a detrimental metabolic and/or inflammatory response, placing them at a disproportionately higher risk of certain cancers. To better understand these biological mechanisms that may underlie immigrant-related health disparities, we tested whether genetic ancestry modified the metabolic response to a traditional Mexican versus U.S. diet in a controlled feeding trial. Methods: First and second generation, female, Mexican immigrants (n=53) completed a randomized, crossover feeding trial testing the response to a Mexican versus U.S. diet for 24 days each, separated by a 28-day washout period. The trial diets were designed to provide energy content for weight maintenance and were similar in macronutrient composition. Participants were instructed to consume only study provided foods. The traditional Mexican diet was high in corn tortillas, beans, Mexican soups, fruits, vegetables, animal fats, full-fat milk, and Mexican cheeses; in contrast, the U.S. diet was high in refined carbohydrates, vegetable oils, nonfat or low-fat milk, processed foods, processed meats and sugar-sweetened beverages. The metabolic response to the diets was measured by fasting serum concentrations of glucose, insulin, insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6), and the calculated homeostasis model assessment of insulin resistance (HOMA-IR) at the beginning and end of each feeding period. DNA was extracted from baseline blood for genotyping and estimation of each participant9s proportion of genetic ancestry from four populations – Indigenous American (IA), European, African, and Asian – with the use of 218 Informative Ancestry Markers. Linear mixed models were adjusted for diet sequence, feeding period, baseline and washout biomarker concentrations, age, body weight, and acculturation. Results: The overall genetic ancestral background of the study sample was 53% IA and 36% European ancestry. In general, genetic ancestry did not modify the metabolic responses to the Mexican versus U.S. diet. However, genetic ancestry was associated with some baseline participant9s characteristics and measures. Greater IA ancestry trended toward a positive association with waist-to-hip ratio (P=0.08) and was inversely associated with both education and acculturation (P Conclusions: Genetic ancestry suggested differences in baseline measures of several biomarkers that have been identified as cancer susceptibility biomarkers. Although, we found a significant metabolic response to the traditional Mexican versus U.S. diet, overall, we did not observe correlations between genetic ancestry and this response. Nonetheless, the results from the study may inform our understanding of variation in cancer susceptibility biomarkers in vulnerable populations. Additional research is needed to further investigate whether genetic ancestry modifies the associations of other lifestyle exposures, such as physical activity or smoking, with cancer susceptibility biomarkers in Mexican immigrants and other minority groups. Citation Format: Margarita Santiago-Torres, Jean De Dieu Tapsoba, Mario Kratz, Johanna W. Lampe, Kara L. Breymeyer, Lisa Levy, Xiaoling Song, Adriana Villasenor, Ching-Yun Wang, Christopher Carlson, Marian L. Neuhouser. Does genetic ancestry influence the metabolic response to a traditional Mexican versus U.S. diet? A randomized crossover feeding trial among first and second generation women of Mexican descent. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A68.

Disentangling the body weight-bone mineral density association among breast cancer survivors: an examination of the independent roles of lean mass and fat mass

Nutritional epidemiology is the study of how diet affects health and disease in human populations, or the science of public health nutrition. The general approach to these studies consists of assessing dietary intake in groups of people and then examining disease rates. Statistical models are used to quantify the associations between diet and disease. A major challenge in nutritional epidemiology is that self-reported dietary intake is subject to random and systematic bias. In addition, people who adhere to healthy dietary patterns often have other healthy lifestyle behaviors, such as engaging in leisure physical activity; disentangling these exposures in relation to health outcomes is difficult. Although the complete elimination of error in dietary assessment methods is not a realistic objective, a better understanding of these errors (based on objective biomarkers) combined with statistical methods to address these errors may be an attainable goal. In addition, future research on diet and disease should focus on study designs that do not rely on self-reported diet as a measure of intervention adherence or an outcome. These research approaches include use of randomized trial designs, inclusion of dietary biomarkers, and use of disease biomarkers such as insulin resistance. Despite the challenges, nutritional epidemiology has made major contributions to general dietary recommendations as well as legislative and policy matters related to diet and health.