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1.  Metabolism and Breast Cancer Risk: Frontiers in Research and Practice 
Fifty years ago, the causes of cancer were largely unknown. Since then, it has become clear that a strong relationship exists between obesity and many cancers, particularly postmenopausal breast cancer. A major challenge in understanding the link between obesity and cancer risk has been elucidating the biological basis underlying the association. Although this remains unresolved, the main candidate systems linking adiposity and cancer risk are (1) insulin and the insulin-like growth factor-I (IGF-I) axis, (2) endogenous reproductive hormones, and (3) chronic inflammation. The purpose of this paper is to provide a mechanistic overview of the hypothesized relationship between diet, physical activity, and obesity with breast cancer risk and progression. In addition, we will provide examples of recently funded randomized clinical trials examining metabolic risk factors in relation to breast cancer risk and survival. Additional research is warranted to validate the strength and consistency of the relationships among diet, these biomarkers, and breast cancer risk. As these relationships become clearer, future studies will be needed to develop effective intervention programs to prevent breast cancer and improve cancer prognosis by promoting a healthy lifestyle.
PMCID: PMC3557584  PMID: 23127511
Obesity; Diet; Physical Activity; Metabolism; Breast Cancer
Cancer causes & control : CCC  2013;24(4):695-704.
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
3.  Post-diagnosis Alcohol Consumption and Breast Cancer Prognosis in the After Breast Cancer Pooling Project 
Alcohol consumption is an established risk factor for incident breast cancer. However, its role in breast cancer prognosis remains unclear.
We conducted an investigation of post-diagnosis alcohol consumption with recurrence and mortality among 9,329 breast cancer patients in the After Breast Cancer Pooling Project. Women were diagnosed from 1990-2006 with AJCC Stage I-III breast tumors from three prospective U.S. cohorts. Alcohol intake was assessed at cohort entry (mean 2.1 years post-diagnosis) using a food frequency questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using delayed entry Cox proportional hazards models with adjustment for known prognostic factors.
After a mean follow-up of 10.3 years, 1,646 recurrences and 1,543 deaths were ascertained. 5,422 women (58%) were considered drinkers (≥0.36 g/day of alcohol, ≥0.25 drinks/week) with a median of 5.3 g/day. Overall, compared with non-drinking, regular alcohol intake (≥6.0 g/day) was not associated with risk of recurrence (HR for 6-<12 g/day=1.03; 95% CI: 0.86, 1.24; HR for 12-<24 g/day=1.12; 95% CI: 0.93, 1.34; HR for ≥24 g/day=1.04; 95% CI: 0.84, 1.31). However, risk varied significantly by menopausal status (p for interaction<0.05). Postmenopausal women who regularly consumed alcohol (≥6.0 g/day) had increased risk of recurrence (HR=1.19; 95% CI: 1.01, 1.40). Alcohol intake was not associated with mortality.
Regular alcohol consumption was not associated with breast cancer recurrence and total mortality overall, yet recurrence risk was only elevated in postmenopausal women.
The association between alcohol intake and recurrence may depend on menopausal status at breast cancer diagnosis.
PMCID: PMC3538884  PMID: 23150063
alcohol; ethanol; estrogen; breast cancer; recurrence; mortality; prognosis
Archives of internal medicine  2009;169(3):10.1001/archinternmed.2008.540.
Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease.
To examine associations between multivitamin use and risk of cancer, cardiovascular disease and mortality in postmenopausal women.
Design, Setting and Participants
161,808 participants from the Women’s Health Initiative Clinical Trials (n=68,132 in three overlapping trials of hormone therapy, dietary modification and calcium-vitamin D) or Observational Study (n=93,676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993–1998; women were followed for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease endpoints were collected through 2005.
Outcome Measures
Cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary and lung; cardiovascular disease (myocardial infarction, stroke, venous thrombosis); and total mortality.
41.5% of participants used multivitamins. After a median of 8.0 years of follow-up in the CT and 7.9 years in the OS, 9,619 cases of breast, colorectal, endometrium, kidney, bladder, stomach lung or ovary cancer; 8,751 CVD events and 9,865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamins with risk of cancer (breast HR=0.98, 95%CI 0.91–1.05; colorectal HR = 0.99, 95% CI 0.88–1.11; endometrial HR = 1.05, 95%CI= 0.90–1.21; lung HR = 1.0, 95% CI=0.88–1.13; ovary HR = 1.07, 95%CI =0.88–1.29); CVD (MI HR= 0.96, 95%CI= 0.89–1.03; stroke HR = 0.99, 95%CI =0.91–1.07; VT HR = 1.05, 95%CI =0.85–1.29); or mortality (HR = 1.02, 95% CI=0.97–1.07).
After a median follow-up of 8.0 and 7.9 years in the CT and OS, respectively, the WHI cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of common cancers, cardiovascular disease or total mortality in postmenopausal women.
Clinical Trial Registration identifier: NCT00000611
PMCID: PMC3868488  PMID: 19204221
dietary supplements; vitamins; minerals; breast cancer; lung cancer; colon cancer; myocardial infarction; stroke
5.  Improvement in Self-Reported Physical Health Predicts Longer Survival Among Women with a History of Breast Cancer 
Physical health-related quality of life scores have been, inconsistently, associated with breast cancer prognosis. This analysis examined whether change in physical health scores were related to outcomes in women with a history of breast cancer.
2343 breast cancer survivors in a randomized diet trial provided self-reported assessment of physical health-related quality of life at baseline and year 1. Based on change in physical health score, participants were grouped into subpopulations of decreased physical health, no/minimal changes, and increased physical health. Cox regression analysis assessed whether change in physical health (from baseline to year 1) predicted disease-free and overall survival; hazard ratio (HR) was the measure of association.
There were 294 additional breast cancer events and 162 deaths among women followed for 7.3 years. Improvements in physical health were associated with younger age, lower BMI, being employed, not receiving tamoxifen, lower physical activity, and lower baseline physical and mental health. There was no association of change in physical health with additional breast cancer events or mortality among women diagnosed ≤ 2 years before study enrollment. However, among women who entered the study >2 years post diagnosis, the HR for increased compared to decreased physical health was 0.38 (95% CI, 0.16 to 0.85) for all-cause mortality.
These results appear to support testing an intervention to improve physical health in breast cancer patients among patients after the acute stage of treatment.
PMCID: PMC3306248  PMID: 21042931
breast cancer; physical health; survival; mortality
6.  Prognosis following the use of complementary and alternative medicine in women diagnosed with breast cancer 
The purpose of this study was to assess whether CAM use affected breast cancer prognosis in those who did not receive systemic therapy.
Secondary data analysis of baseline/survey data from the Women's Healthy Eating and Living Study (WHEL). 2562 breast cancer survivors participating in the study completed baseline assessments and a CAM use questionnaire. Cox regression models were conducted to evaluate the use of CAM modalities and dietary supplements on time to an additional breast cancer event (mean follow-up = 7.3 years).
A US-based multi-site randomized dietary trial.
Time to additional breast cancer events.
The women who did not receive any systemic treatment had a higher risk for time to additional breast cancer events (HR=1.9, 95% CI: 1.32, 2.73) and for all-cause mortality (HR=1.7, 95% CI: 1.06, 2.73) compared to those who had received systemic treatment. Among 177 women who did not receive systemic treatment, CAM use was not significantly related to additional breast cancer events. There were no significant differences between high supplement users ( ≥ 3 formulations per day) and low supplement users in either risk for additional breast cancer events.
The risk for an additional breast cancer event and/or death was higher for those who did not receive any systemic treatments; the use dietary supplements or CAM therapies did not change this risk. This indicates that complementary and alternative therapies did not alter the outcome of breast cancer and should not be used in place of standard treatment.
PMCID: PMC3413169  PMID: 22863642
breast cancer; complementary and alternative medicine; dietary supplements; long- term prognosis; alternative cancer treatment
7.  Dietary-Related and Physical Activity-Related Predictors of Obesity in Children: A 2-Year Prospective Study 
Childhood Obesity  2012;8(2):110-115.
This observational study examined cross-sectional and 24-month longitudinal associations of physical activity and dietary behaviors with change in BMI and percent body fat among children aged 6–9 years old.
Data were from the control group (n=271; 48% Latino) of a community-based childhood obesity prevention program. Assessments were conducted at baseline and at 24 months and included height and weight, bioelectrical impedance–derived percent body fat, and 10 physical activity and dietary behaviors measured via parent report of their child. Cross-sectional analysis of variances (ANOVA) (normal weight, overweight, obese) and longitudinal mixed-effects linear regression models were used to investigate the relation of each physical activity and dietary behavior with BMI and percent body fat.
At baseline, obese children engaged in less physical activity and more sedentary behavior than normal-weight children (p<0.05). Increased physical activity (p<0.01) and number of breakfasts eaten with family (p<0.05) were associated with decreased BMI z-score and percent body fat. Decreased sedentary behavior and sugar-sweetened beverage consumption were associated with decreased percent body fat (p<0.05) but not BMI.
In this cohort of 271 children, increased physical activity and eating breakfast with family and reduced screen-based sedentary behaviors and sugar-sweetened beverage consumption were associated with more favorable trends in adiposity. Therefore, attention to these behaviors may be of particular importance. Results also suggest that future studies should include percent body fat as an outcome for a more precise assessment of the association of behavior with adiposity.
PMCID: PMC3647527  PMID: 22799510
8.  Weight Change and Survival after Breast Cancer in the After Breast Cancer Pooling Project 
Weight change after a breast cancer diagnosis has been linked to lower survival. To further understand effects of post-diagnostic weight variation on survival, we examined the relationship by comorbid status and initial BMI.
The current analysis included 12,915 breast cancer patients diagnosed between 1990 and 2006 with Stage I–III tumors from four prospective cohorts in the US and China Hazard ratios (HR) and 95% confidence intervals (CI) representing the associations of five weight change categories (within <5% [reference]; 5–<10% and ≥10% loss and gain) with mortality were estimated using Cox proportional hazards models.
Mean weight change was 1.6 kg. 14.7% of women lost and 34.7% gained weight. Weight stability in the early years post-diagnosis was associated with the lowest overall mortality risk. Weight loss ≥10% was related to a 40% increased risk of death (HR=1.41; 95% CI: 1.14, 1.75) in the US and over three times the risk of death (HR=3.25; 95% CI: 2.24, 4.73) in Shanghai. This association varied by pre-diagnosis BMI, and in the US lower survival were seen for women who lost weight and had comorbid conditions. Weight gain ≥10% was associated with a non-significant increased risk of death.
Prevention of excessive weight gain is a valid public health goal for breast cancer survivors. Although intentionality of weight loss could not be determined, women with comorbid conditions may be particularly at risk of weight loss and mortality.
Weight control strategies for breast cancer survivors should be personalized to the individual’s medical history.
PMCID: PMC3433249  PMID: 22695738
9.  Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer 
Intestinal tumors in ApcMin/+ mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D2 (PGD2). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 °C, the wild-type enzyme lost 15% of its activity in one hour, whereas the Val187Ile form remained >95% active. At 50 °C, the half life of native HPGDS was 9 minutes, compared to 42 minutes for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75–1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.
PMCID: PMC3226866  PMID: 21821144
glutathione transferase; HPGDS; prostaglandin D2; colon cancer
10.  The After Breast Cancer Pooling Project: Rationale, Methodology, and Breast Cancer Survivor Characteristics 
Cancer causes & control : CCC  2011;22(9):1319-1331.
The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER−/PR−. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2− and 18.5% were HER-2+. At 1–2 years post-diagnosis (on average) 17.9% of participants were obese (BMI ≥30 kg/m2), 32.6% were overweight (BMI 25–29 kg/m2) and 59.9% met the 2008 Physical Activity Guidelines for Americans (≥ 2.5 hours per week of moderate activity). During follow-up (mean=8.4 years), 3,736 deaths (2,614 from breast cancer), and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five-year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post-diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone-receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes.
PMCID: PMC3169084  PMID: 21710192
Breast neoplasm; Survival; Recurrence; Life style
11.  Classification of CAM Use and its Correlates in Early Stage Breast Cancer Patients 
Integrative cancer therapies  2011;10(2):138-147.
Self-reported use of complementary and alternative medicine (CAM) has been shown to increase following a cancer diagnosis, and breast cancer survivors are the heaviest users among cancer survivors. The aim of this study was to determine whether the prevalence estimate of CAM use varied according to classification of CAM. We used a comprehensive system to classify CAM users and test differences in demographic, lifestyle, quality of life, and cancer characteristics among them.
Study Design and Methods
Participants were 2562 breast cancer survivors participating in the Women's Healthy Eating and Living (WHEL) Study, aged 28-74 years. A structured telephone interview assessed CAM use, questioning about specific CAM practices, and whether use was related to cancer. We examined CAM use in relation to demographics, health behaviors, and quality of life.
Approximately 80% of the women used CAM for general purposes but only 50% reported CAM use for cancer purposes. Visual imagery, spiritual healing, and meditation were the most frequently used practices for cancer purposes. CAM use, defined as consulting a CAM practitioner and regular use, was significantly related to younger age, higher education, increased fruit & vegetable intake, and lower body mass index (p < .05). CAM users who had seen a practitioner were also more likely to report poor physical and mental health than non-CAM users (p < .05). CAM use was not associated with changes in physical and mental health between study baseline and 1-year follow-up.
This study addressed important differences in the classification of CAM use among breast cancer survivors. Future studies need to further test the potential benefits and risks associated with CAM use.
PMCID: PMC3126886  PMID: 21382963
12.  Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes 
We examined if the reduced risk of breast cancer events seen among women without baseline hot flash symptoms in the Women’s Healthy Eating and Living (WHEL) dietary intervention trial was related to changes in sex hormone concentrations.
Baseline and year one concentrations of total and bioavailable estradiol and testosterone and sex hormone binding globulin (SHBG) were compared by intervention arm among 447 postmenopausal women without hot flashes. Cox proportional hazard models tested interaction terms between study arm and baseline hormone concentrations adjusted for study site, anti-estrogen use, positive nodes, tumor size, oophorectomy status, and hormone replacement therapy use.
Sex hormone concentrations did not differ by study arm at baseline nor at year one. Twenty-two (9.8%) events occurred in the intervention arm vs. 42 (18.9%) in the comparison arm (p=0.009). Baseline bioavailable testosterone was significantly, positively associated with additional events (HR 1.69, 95% CI: 1.00-2.84; p=0.049). There were significant interactions between the intervention and total (p=0.015) and bioavailable (p=0.050) testosterone: the intervention was more protective among participants with higher baseline total (HR 0.3, 95% CI: 0.2-0.7) or bioavailable (HR 0.4, 95%CI: 0.2-0.7) testosterone than for participants with lower baseline total (HR 0.8, 95% CI: 0.4-1.5) or bioavailable (HR 0.8, 95%CI: 0.4-1.5) testosterone. No significant effects were seen for estradiol or SHBG.
The WHEL dietary intervention may have modified other risk factors of recurrence correlated with testosterone.
Sex hormones should be considered as part of a larger biological system related to the risk of breast cancer recurrence.
PMCID: PMC3089679  PMID: 21415358
Postmenopausal; hot flashes; sex hormones; breast cancer
13.  Non-steroidal Anti-inflammatory Drugs and Cancer Incidence by Sex in the VITamins And Lifestyle (VITAL) Cohort 
Cancer causes & control : CCC  2012;23(3):431-444.
Use of NSAIDs may reduce the risk of several cancers. A recent meta-analysis of randomized trials of aspirin reported a reduction in cancer mortality; however few studies have investigated whether aspirin or other NSAIDs reduce overall cancer risk. 64,847 residents of western Washington State, ages 50-76 years, completed a baseline questionnaire in 2000-2002 and reported on their use of individual NSAIDs over the past 10 years. Behavior was categorized as non-use, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). Over 7 years of follow-up 5,946 incident invasive cancer cases were identified. Multivariable proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Relative to non-use, high 10-year use of regular-strength NSAIDs was inversely associated with total cancer risk in men (HR 0.88, 95% CI: 0.79-0.97) and suggestive of a positive association in women (HR 1.10, 95% CI: 0.96-1.25; P interaction <0. 01). Use of regular-strength NSAIDs was strongly and inversely associated with colorectal cancer risk in men and women, but differentially associated with sex-specific risk of shared cancer sites other than colorectal cancer (men: HR 0.84, 95% CI: 0.72-0.97; women: HR 1.18, 95% CI: 0.97-1.44; P interaction <0.01). Long-term use of NSAIDs reduces the risk of total cancer among men and colorectal cancer among both sexes. Our findings do not support NSAID use for overall cancer prevention among women. Additional high-quality studies with long-term follow-up for cancer among women are needed before a public health recommendation can be made.
PMCID: PMC3319091  PMID: 22212612
14.  Dietary Intake, Supplement Use, and Survival Among Women Diagnosed with Early Stage Breast Cancer 
Nutrition and cancer  2011;63(3):327-333.
Previous studies examining the relationship between micronutrient intakes and survival following diagnosis of breast cancer have reported mixed results. This may be partly due to considerable variance in amounts of micronutrients consumed from diet and supplements across studies.
Early stage breast cancer survivors (n=3081) completed four 24-hour dietary and supplement recalls at the baseline assessment (1995 to 2000) and were followed for a median of 9.0 years. Mean micronutrient intakes were compared to dietary reference intakes (DRI) to assess micronutrient adequacy for both users and non-users of supplements. Cox regressions were performed to assess whether intakes of selected micronutrients were associated with all-cause mortality.
412 deaths occurred between baseline and August 2009. Among these women, more supplement users had adequate micronutrient intakes than non-users for 15 out of 17 micronutrients. Less than 10% of supplement users (< 2% of non-supplement users) reported levels that exceeded the tolerable upper limit for each micronutrient except magnesium. After adjusting for age, tumor characteristics, and health status variables, micronutrient intakes were not significantly associated with all-cause mortality.
Dietary supplements may improve overall micronutrient intakes of breast cancer survivors. However, vitamin and mineral intakes were not associated with all-cause mortality.
PMCID: PMC3078826  PMID: 21391124
dietary intake; supplement use; breast cancer survival
15.  Poor Physical Health Predicts Time to Additional Breast Cancer Events and Mortality in Breast Cancer Survivors 
Psycho-Oncology  2011;20(3):252-259.
Health-related quality of life (HRQOL) has been hypothesized to predict time to additional breast cancer events and all-cause mortality in breast cancer survivors.
Women with early stage breast cancer (n=2967) completed the SF-36 (mental and physical health-related quality of life) and standardized psychosocial questionnaires to assess social support, optimism, hostility, and depression prior to randomization into a dietary trial. Cox regression was performed to assess whether these measures of quality of life and psychosocial functioning predicted time to additional breast cancer events and all-cause mortality; hazard ratios were the measure of association.
There were 492 additional breast cancer events and 301 deaths occurred over a median 7.3 years (range: 0.01–10.8 years) of follow-up. In multivariate models, poorer physical health was associated with both decreased time to additional breast cancer events and all-cause mortality (p trend=0.005 and 0.004, respectively), while greater hostility predicted additional breast cancer events only (p trend=0.03). None of the other psycho-social variables predicted either outcome. The hazard ratios comparing persons with poor (bottom two quintiles) to better (top three quintiles) physical health were 1.42 (95% CI: 1.16, 1.75) for decreased time to additional breast cancer events and 1.37 (95% CI: 1.08, 1.74) for all-cause mortality. Potentially modifiable factors associated with poor physical health included higher BMI, lower physical activity, lower alcohol consumption, and more insomnia (p<0.05 for all).
Interventions to improve physical health should be tested as a means to increase time to additional breast cancer events and mortality among breast cancer survivors.
PMCID: PMC3297415  PMID: 20878837
physical health; breast cancer; oncology; survival
16.  Meeting the Physical Activity Guidelines and Survival After Breast Cancer: Findings from the After Breast Cancer Pooling Project 
The 2008 Physical Activity (PA) Guidelines recommend engaging in at least 2.5 hours (10 MET-hours/week) of moderate intensity PA per week (defined as 4 METs) to reduce risk of morbidity and mortality. This analysis was conducted to investigate whether this recommendation can be extended to breast cancer survivors. Data from four studies of breast cancer survivors measuring recreational PA from semi-quantitative questionnaires a median of 23 months post-diagnosis (interquartile range 18 to 32 months) were pooled in the After Breast Cancer Pooling Project (n=13,302). Delayed entry Cox proportional hazards models were applied in data analysis with adjustment for age, post-diagnosis body mass index, race/ethnicity, menopausal status, TNM stage, cancer treatment, and smoking history. Engaging in at least 10 MET-hours/week of PA was associated with a 27% reduction in all-cause mortality (n=1,468 events, Hazard Ratio (HR) = 0.73, 95% CI, 0.66–0.82) and a 25% reduction in breast cancer mortality (n=971 events, HR=0.75, 95% CI 0.65–0.85) compared to women who did not meet the PA Guidelines (< 10 MET-hours/week). Risk of breast cancer recurrence (n=1,421 events) was not associated with meeting the PA Guidelines (HR=0.96, 95% CI, 0.86–1.06). These data suggest that adhering to the PA Guidelines may be an important intervention target for reducing mortality among breast cancer survivors.
PMCID: PMC3272362  PMID: 21935600
physical activity guidelines; breast cancer survival; mortality; epidemiology
17.  Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2010;29(1):54-60.
Self-reported diabetes has been associated with poor breast cancer outcomes. Research is needed to investigate the relationship between biologically determined glycemic control and breast cancer prognosis.
Archived baseline blood samples from the Women's Healthy Eating and Living Study were used to measure hemoglobin A1C (HbA1C) among 3,003 survivors of early-stage breast cancer (age of diagnosis, 28 to 70 years) observed for a median of 7.3 years for additional breast cancer events and 10.3 years for all-cause mortality. HbA1C levels provide an accurate, precise measure of chronic glycemic levels. Cox regression analysis was performed to assess whether baseline HbA1C levels predicted disease-free and overall survival.
Only 5.8% of women had chronic hyperglycemia (defined as HbA1C levels ≥ 6.5%). Those with HbA1C ≥ 6.5% were older and more likely to be less educated, have nonwhite ethnicity, be obese, and have more advanced breast cancer at diagnosis. HbA1C was significantly associated with overall survival (Ptrend < .001). After adjusting for confounders, risk of all-cause mortality was twice as high in women with HbA1C ≥ 7.0% compared with women with HbA1C less than 6.5% (hazard ratio [HR], 2.35; 95% CI, 1.56 to 3.54). For disease-free survival, there was a nonsignificant 30% increase in risk for HbA1C levels ≥ 7.0% (HR, 1.26; 95% CI, 0.78 to 2.02). During study follow-up, previously diagnosed rather than undiagnosed diabetes seemed to account for the increased risk.
Chronic hyperglycemia is statistically significantly associated with reduced overall survival in survivors of early-stage breast cancer. Further study of diabetes and its relationship to breast cancer outcomes is warranted.
PMCID: PMC3055860  PMID: 21115861
18.  Measurement Error of Dietary Self-Report in Intervention Trials 
American Journal of Epidemiology  2010;172(7):819-827.
Dietary intervention trials aim to change dietary patterns of individuals. Participating in such trials could impact dietary self-report in divergent ways: Dietary counseling and training on portion-size estimation could improve self-report accuracy; participant burden could increase systematic error. Such intervention-associated biases could complicate interpretation of trial results. The authors investigated intervention-associated biases in reported total carotenoid intake using data on 3,088 breast cancer survivors recruited between 1995 and 2000 and followed through 2006 in the Women's Healthy Eating and Living Study, a randomized intervention trial. Longitudinal data from 2 self-report methods (24-hour recalls and food frequency questionnaires) and a plasma carotenoid biomarker were collected. A flexible measurement error model was postulated. Parameters were estimated in a Bayesian framework by using Markov chain Monte Carlo methods. Results indicated that the validity (i.e., correlation with “true” intake) of both self-report methods was significantly higher during follow-up for intervention versus nonintervention participants (4-year validity estimates: intervention = 0.57 for food frequency questionnaires and 0.58 for 24-hour recalls; nonintervention = 0.42 for food frequency questionnaires and 0.48 for 24-hour recalls). However, within- and between-instrument error correlations during follow-up were higher among intervention participants, indicating an increase in systematic error. Diet interventions can impact measurement errors of dietary self-report. Appropriate statistical methods should be applied to examine intervention-associated biases when interpreting results of diet trials.
PMCID: PMC3025654  PMID: 20720101
bias (epidemiology); diet; intervention studies; Markov chain Monte Carlo; measurement error; nutrition assessment; reproducibility of results; validity
19.  Medical Comorbidities Predict Mortality in Women with a History of Early Stage Breast Cancer 
This analysis was conducted to determine whether comorbid medical conditions predict additional breast cancer events and all-cause mortality in women with a history of early stage breast cancer.
Women (n=2542) participating in a randomized diet trial completed a selfadministered questionnaire regarding whether they were currently being treated for a wide variety of diseases (cardiovascular, diabetes, gallbladder, gastrointestinal, arthritis, and osteoporosis) and conditions (high blood pressure, elevated cholesterol level). Height and weight were measured at baseline. Participants were followed for a median of 7.3 years (range 0.8 to 15.0). Cox regression analysis was performed to assess whether comorbidities predicted disease-free and overall survival; hazard ratio (HR) was the measure of association.
Overall, there were 406 additional breast cancer events and 242 deaths. Participants with diabetes had over 2-fold the risk of additional breast cancer events (HR 2.1, 95% CI: 1.3, 3.4) and mortality (HR 2.5, 95% CI: 1.4, 4.4). The presence of multiple comorbidities did not statistically significantly predict additional breast cancer events. However, compared to no comorbidities, participants with 3 or more comorbidities had a HR of 2.1, 95% CI: 1.3, 3.3 for mortality.
Type 2 diabetes was associated with poor breast cancer prognosis. Given that 85 percent of deaths were caused by breast cancer, these findings suggest that multiple comorbidities may reduce the likelihood of surviving additional breast cancer events.
PMCID: PMC2895945  PMID: 20077000
comorbidities; breast cancer; mortality
20.  Association of glycemic load with cardiovascular disease risk factors: the Women's Health Initiative Observational Study 
Associations between dietary glycemic load (GL) and cardiovascular disease (CVD) risk factors, including plasma lipoprotein/lipid levels, blood pressure (BP), and glucose metabolism factors, in the Women's Health Initiative Observational Study were examined.
A random sample of 878 Observational Study participants (postmenopausal women age 50 to 79 years) with baseline blood measures (647 White, 104 Black, 127 Hispanic) was included. Dietary GL was estimated from baseline food frequency questionnaires, which assessed dietary intake over the previous three months. At the baseline visit, participants completed demographic and health habit questionnaires, fasting blood samples were collected, anthropometric measurements were completed, and BP was assessed.
In all participants combined, GL was inversely associated with high-density lipoprotein (HDL) cholesterol (P for trend = 0.004) and positively associated with log10-transformed triglycerides (P = 0.008). While there were no statistically significant interactions of race/ethnicity with associations between GL and CVD risk factors, stratified results were suggestive, showing that GL was positively associated with total cholesterol (P = 0.018) and low-density lipoprotein (LDL) cholesterol (P = 0.038) in Hispanics. In Whites, there was a trend of reduced HDL cholesterol with higher GL (P = 0.003), while GL was positively associated with log10-transformed triglycerides (P = 0.015). Associations between GL and HDL cholesterol and GL and triglycerides also varied by BMI, although the interactions were not statistically significant.
Among these generally healthy postmenopausal women, GL was associated with HDL cholesterol and triglycerides. Suggestive effects of race/ethnicity and BMI on these associations need to be confirmed in larger studies.
PMCID: PMC2866821  PMID: 20053533
Glycemic load; Glycemic index; Carbohydrate; Cardiovascular disease; Women's Health Initiative
21.  Low To Moderate Alcohol Intake Is Not Associated with Increased Mortality after Breast Cancer 
Both alcohol consumption and obesity have been linked with breast cancer morbidity and mortality. An inverse association between alcohol intake and obesity suggests possible confounding between these variables (and perhaps other factors) with breast cancer outcomes.
Alcohol intake (beer, wine, spirits, and total) was examined in 3088 women previously diagnosed and treated for breast cancer, within an intervention trial that targeted vegetables, fiber, and fat but not alcohol or weight loss. Factors associated with baseline alcohol intake were included in Cox proportional hazards models for recurrence and mortality.
Alcohol intake was significantly associated with higher education and physical activity levels. Neither light alcohol intake nor obesity was significantly associated with breast cancer recurrence, but moderate alcohol intake > 300 g/month was protective against all-cause mortality (HR = 0.69, CI=0.49-0.97) in a proportional hazards model adjusted for obesity. Obese women were 61% more likely to be nondrinkers than drinkers, and 76% more likely to be light drinkers than moderate/heavy drinkers. In non-obese women, alcohol intake > 10 g/month was associated with lower risk of all-cause mortality (HR = 0.68, 95% CI = 0.51-0.91).
Light alcohol intake, regardless of body weight, did not increase the risk of breast cancer recurrence or all-cause mortality in this cohort of middle-aged women previously diagnosed with breast cancer. Alcohol intake was associated with other favorable prognostic indicators that may explain its apparent protective effect in non-obese women.
PMCID: PMC2836421  PMID: 20160253
alcohol; breast cancer; obesity; mortality; recurrence
22.  Physical activity, additional breast cancer events, and mortality among early-stage breast cancer survivors: findings from the WHEL Study 
Cancer Causes & Control  2010;22(3):427-435.
Research suggests that physical activity is associated with improved breast cancer survival, yet no studies have examined the association between post-diagnosis changes in physical activity and breast cancer outcomes. The aim of this study was to determine whether baseline activity and 1-year change in activity are associated with breast cancer events or mortality.
A total of 2,361 post-treatment breast cancer survivors (Stage I–III) enrolled in a randomized controlled trial of dietary change completed physical activity measures at baseline and one year. Physical activity variables (total, moderate–vigorous, and adherence to guidelines) were calculated for each time point. Median follow-up was 7.1 years. Outcomes were invasive breast cancer events and all-cause mortality.
Those who were most active at baseline had a 53% lower mortality risk compared to the least active women (HR = 0.47; 95% CI: 0.26, 0.84; p = .01). Adherence to activity guidelines was associated with a 35% lower mortality risk (HR = 0.65, 95% CI: 0.47, 0.91; p < .01). Neither baseline nor 1-year change in activity was associated with additional breast cancer events.
Higher baseline (post-treatment) physical activity was associated with improved survival. However, change in activity over the following year was not associated with outcomes. These data suggest that long-term physical activity levels are important for breast cancer prognosis.
PMCID: PMC3042101  PMID: 21184262
Exercise; Recurrence; Survival; Behavior; Lifestyle
23.  Increased Risk of Acute Pancreatitis and Biliary Disease Observed in Patients With Type 2 Diabetes 
Diabetes Care  2009;32(5):834-838.
The objective of this study was to assess the risk of acute pancreatitis in patients with type 2 diabetes compared with that in patients without diabetes. We also examined the risk of biliary disease (defined as occurrence of cholelithiasis, acute cholecystitis, or cholecystectomy), which is a major cause of pancreatitis.
We conducted a retrospective cohort study using a large, geographically diverse U.S. health care claims database. Eligible patients (≥18 years) were enrolled for at least 12 continuous months (1999–2005), with no incident events of pancreatitis or biliary disease during that 1 year baseline period. ICD-9 codes and prescription data were used to identify patients with type 2 diabetes; ICD-9 codes were also used to identify cases of pancreatitis and biliary disease. Overall, 337,067 patients with type 2 diabetes were matched on age and sex with 337,067 patients without diabetes. Incidence rates of disease and 95% CI were calculated per 100,000 person-years of exposure.
The type 2 diabetic cohort had a 2.83-fold (95% CI 2.61–3.06) greater risk of pancreatitis and 1.91-fold (1.84–1.99) greater risk of biliary disease compared with the nondiabetic cohort. Relative to patients of corresponding age without diabetes, younger type 2 diabetic patients had the highest risk of pancreatitis (<45 years: incidence rate ratio [IRR] 5.26 [95% CI 4.31–6.42]; ≥45 years: 2.44 [2.23–2.66]).
These data suggest that patients with type 2 diabetes may have an increased risk of acute pancreatitis and biliary disease.
PMCID: PMC2671118  PMID: 19208917
24.  Biomarker-calibrated Energy and Protein Consumption and Increased Cancer Risk Among Postmenopausal Women 
American Journal of Epidemiology  2009;169(8):977-989.
The authors previously reported equations, derived from the Nutrient Biomarker Study within the Women's Health Initiative, that produce calibrated estimates of energy, protein, and percentage of energy from protein consumption from corresponding food frequency questionnaire estimates and data on other factors, such as body mass index, age, and ethnicity. Here, these equations were applied to yield calibrated consumption estimates for 21,711 women enrolled in the Women's Health Initiative dietary modification trial comparison group and 59,105 women enrolled in the observational study. These estimates were related prospectively to total and site-specific invasive cancer incidence (1993–2005). In combined cohort analyses that do not control for body mass, uncalibrated energy was not associated with total cancer incidence or site-specific cancer incidence for most sites, whereas biomarker-calibrated energy was positively associated with total cancer (hazard ratio = 1.18, 95% confidence interval: 1.10, 1.27, for 20% consumption increase), as well as with breast, colon, endometrial, and kidney cancer (respective hazard ratios of 1.24, 1.35, 1.83, and 1.47). Calibrated protein was weakly associated, and calibrated percentage of energy from protein was inversely associated, with total cancer. Calibrated energy and body mass index associations were highly interdependent. Implications for the interpretation of nutritional epidemiology studies are described.
PMCID: PMC2732977  PMID: 19258487
bias (epidemiology); biological markers; diet; energy intake; epidemiologic methods; neoplasms; nutrition assessment; proteins
25.  Dietary intake of specific fatty acids and breast cancer risk among postmenopausal women in the VITAL cohort 
Nutrition and cancer  2012;64(8):1131-1142.
Studies of dietary fat intake and breast cancer have been inconsistent and few have examined specific fatty acids. We examined the association between specific monounsaturated (MUFA), polyunsaturated (PUFA), saturated (SFA), and trans-fatty acids (TFA) and breast cancer risk. Participants, 50–76y, were female members of the VITamins And Lifestyle (VITAL) Cohort, who were postmenopausal at baseline. In 2000–2002, participants completed a food frequency questionnaire. 772 incident, primary breast cancer cases were identified using a population-based cancer registry. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between fatty acid intake and breast cancer risk. Intake of total MUFAs (Highest vs. lowest quintile: HR=1.61, 95% CI: 1.08–2.38, P-trend=0.02), particularly myristoleic and erucic acids, was associated with increased breast cancer risk. Whereas total SFA was suggestive of an increased risk (HR=1.47, 95% CI: 1.00–2.15, P-trend=0.09), strong associations were observed for palmitic, margaric, and stearic acids. Total TFA and PUFA intake were not associated with breast cancer. However, among TFAs, linolelaidic acid was positively associated with risk; among PUFAs, intake of eicosapentaenoic and docosahexaenoic acids were inversely associated with risk. Our findings show that fatty acids are heterogeneous in their association with postmenopausal breast cancer risk.
PMCID: PMC3633593  PMID: 23137008

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