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1.  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 Women’s Healthy Eating and Living (WHEL) Study includes 2919 early stage breast cancer survivors with serum collected 2 years post-diagnosis 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 hazard ratios (HR) 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 (versus without) acute inflammation suggests a threshold effect on overall survival, rather than a dose-response relationship (≥10.0 mg/L v <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.
doi:10.1158/1055-9965.EPI-13-0852
PMCID: PMC3911892  PMID: 24220913
C-reactive protein; all-cause mortality; breast cancer-specific mortality; recurrence
2.  Lifetime Cigarette Smoking and Breast Cancer Prognosis in the After Breast Cancer Pooling Project 
Background
There is controversy on whether former smokers have increased risk for breast cancer recurrence or all-cause mortality, regardless of how much they smoked.
Methods
Data were from three US cohorts in the After Breast Cancer Pooling Project, with detailed information on smoking among 9975 breast cancer survivors. Smoking was assessed an average of 2 years after diagnosis. Delayed entry Cox proportional hazards models were used to examine the relationships of smoking status, cigarettes per day, years of smoking, and pack years with breast cancer prognosis. Endpoints included breast cancer recurrence (n = 1727), breast cancer mortality (n = 1059), and overall mortality (n = 1803).
Results
Compared with never smokers, former smokers with less than 20 pack-years of exposure had no increased risk of any outcome. However, former smokers with 20 to less than 34.9 pack-years of exposure had a 22% increased risk of breast cancer recurrence (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.01 to 1.48) and a 26% increased risk of all-cause mortality (HR = 1.26; 95% CI = 1.07 to 1.48). For former smokers with 35 or more pack-years of exposure, the probability of recurrence increased by 37% (HR = 1.37; 95% CI = 1.13 to 1.66), breast cancer mortality increased by 54% (HR = 1.54; 95% CI = 1.24 to 1.91), and all-cause mortality increased by 68% (HR = 1.68; 95% CI = 1.44 to 1.96). Current smoking increased the probability of recurrence by 41% (HR = 1.41; 95% CI = 1.16 to 1.71), increased breast cancer mortality by 60% (HR = 1.61; 95% CI = 1.28 to 2.03), and doubled the risk of all-cause mortality (HR = 2.17; 95% CI = 1.85 to 2.54).
Conclusions
Lifetime cigarette smoking was statistically significantly associated with a poor prognosis among women diagnosed with breast cancer, dose-dependent increased risks of recurrence, and breast cancer and all-cause mortality.
doi:10.1093/jnci/djt359
PMCID: PMC3906992  PMID: 24317179
3.  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.
doi:10.1016/j.jand.2012.08.015
PMCID: PMC3557584  PMID: 23127511
Obesity; Diet; Physical Activity; Metabolism; Breast Cancer
4.  Endogenous Estradiol Is Not Associated with Poor Physical Health in Postmenopausal Breast Cancer Survivors 
Journal of Women's Health  2013;22(12):1043-1048.
Abstract
Background
Among postmenopausal breast cancer survivors, poor physical health has been associated with higher risks of breast cancer events. Obesity and physical inactivity are known risk factors for poor physical health, while circulating estrogen is an additional potential risk factor. We tested the hypothesis that the relationship between poor physical health and worse breast cancer outcomes is mediated by higher estrogen concentrations associated with body size and physical inactivity.
Methods
We used data from 1030 postmenopausal breast cancer survivors to examine the association between serum estradiol levels, body mass index (BMI), physical activity, and RAND-36-item Health Survey (SF-36) physical health.
Results
In univariate analysis, poor physical health was associated with higher estradiol levels, in addition to obesity and low physical activity. Higher estradiol levels were significantly associated with higher odds of poor physical health (odds ratio, OR, 1.20 [95% confidence interval 1.03–1.39]) in a multivariable model adjusting for age, cancer stage and treatment, alcohol use, and physical activity. However, the relationship between estradiol levels and poor physical health was no longer significant (OR 1.06 [0.91–1.24]) after adding BMI in the model. In multivariate analysis, only poor physical health resulted in higher risks of recurrence (hazard ratio 1.33 [95% CI 1.08–1.64]).
Conclusions
These findings indicate that estradiol is related to poor physical health, but is not an independent risk factor from body size or inactivity. While obesity and physical activity in survivorship are potential targets for improving physical health, other biological processes that impact physical health, e.g. inflammation, remain to be identified.
doi:10.1089/jwh.2013.4375
PMCID: PMC3852607  PMID: 24111813
5.  Eating frequency and risk of colorectal cancer 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0288-8.
Purpose
Eating frequency is a modifiable aspect of dietary behavior that may affect risk of colorectal cancer (CRC). Although most previous case-control studies indicate a positive association, two prospective studies suggest an inverse association between eating frequency and CRC risk, with evidence of effect modification by diet composition. We examined the association between eating frequency and CRC in a large, prospective cohort study, and explored whether this relationship was modified by sex, coffee consumption or dietary glycemic load.
Methods
Between 2000 and 2002, 67,912 western Washington residents aged 50–76 reported average daily meal and snack frequency using a mailed questionnaire as part of the VITamins And Lifestyle (VITAL) study. Participants were followed for CRC through linkage with SEER through 2008, over which time 409 CRC cases developed. Hazard Ratios and 95% Confidence Intervals were obtained using Cox regression.
Results
In age and sex adjusted models higher (5+ times/d) vs lower (1–2 times/d) eating frequency was associated with a HR of 0.62 (95% CI 0.43–0.88, P trend =0.001). However, following further adjustment for BMI, race/ethnicity, alcohol and other known CRC risk factors the relationship was no longer statistically significant (HR: 0.76; 95% CI: 0.51, 1.14). No effect modification was observed by sex (Pinteraction=0.45), coffee consumption (Pinteraction=0.44) or dietary glycemic load (Pinteraction=0.90). In subgroup analyses by tumor site, higher vs. lower eating frequency was associated with lower risk for colon (HR 0.65 95% CI 0.39–1.07, Ptrend=0.04), but not rectal cancers (HR = 1.08 95% CI 0.54–2.18, Ptrend=0.94).
Conclusion
The weak inverse association observed between eating frequency and CRC is consistent with findings from other prospective studies. Modification of this relationship by diet quality and participant characteristics should be considered in future studies.
doi:10.1007/s10552-013-0288-8
PMCID: PMC3875335  PMID: 24057417
Eating frequency; meal frequency; nutrition; colorectal cancer
6.  Objectively Measured Physical Activity is Related to Cognitive Function in Older Adults 
Journal of the American Geriatrics Society  2013;61(11):10.1111/jgs.12524.
Background/Objectives
To explore the relationship between cognitive functioning and the time spent at different intensities of physical activity (PA) in free-living older adults.
Design, Setting
Cross sectional analyses of participants enrolled in a randomized controlled trial set in continuing care retirement communities.
Participants
215 older adults residing in 7 continuing care retirement communities in San Diego County: average age 83 years, 70% female and 35% with graduate level education.
Measurements
PA was measured objectively by hip worn accelerometers with data aggregated to the minute level. Three cut points were used to assess low-light, high-light, and moderate-to-vigorous intensity PA (MVPA). Trail Making Tests A and B were completed and time for each test (sec) and test B-minus- A time (sec) were used as measures of cognitive functioning. Variables were log transformed and entered into linear regression models adjusting for demographic factors (age, education, gender) and other PA intensity variables.
Results
Low-light PA was not related to any Trails test score. High-light PA was significantly related to Trails A, B and B-minus-A; but only in unadjusted models. MVPA was related to Trails B and B-minus-A after adjusting for demographic variables.
Conclusion
These data suggest there may be a dose response between PA intensity and cognitive functioning in older adults. The stronger findings supporting a relationship between MVPA and cognitive functioning are consistent with previous observational and intervention studies.
doi:10.1111/jgs.12524
PMCID: PMC3858204  PMID: 24219194
Physical Activity; Cognition; Older Adults
7.  Using doubly labeled water to validate associations between sugar-sweetened beverage intake and body mass among White and African-American adults 
BACKGROUND
Evidence is mixed regarding sugar-sweetened beverage (SSB) intake and adiposity among adults, perhaps due to reporting bias.
OBJECTIVE
To determine the impact of reporting bias on any associations between increased SSB intake and overweight/obesity.
DESIGN
Beverage intake and overweight/obese status (BMI ≥25 kg/m2) was examined among adults from a dietary assessment and doubly labeled water study (n=250). Four web-based, 24-hour recalls assessed dietary intake. SSB intake was categorized as no intake, 1–99 kcals per day, and >99 kcals per day. Logistic regression models adjusted for total caloric intake, age, race, education and diet quality compared SSB intake to overweight/obese status. To investigate dietary self-reporting bias, analyses were replicated in a subset of “true reporters”: those with self-reported total caloric intake within 25% of total energy expenditure per doubly labeled water assessments (n=108).
RESULTS
One-half of participants were overweight/obese; more overweight/obese participants consumed SSB than normal weight participants (69% vs. 47%; p<0.001). Intake of other beverages did not differ by adiposity. Less White participants (48%) consumed SSB compared to African-American participants (68%; p=0.002). Compared to no intake, SSB intake up to the median intake doubled the risk of being overweight/obese (OR: 2.1, 95% CI: 1.0–4.3; p=0.046), and SSB intake over the median more than doubled the risk (OR: 2.6, 95% CI: 1.2–6.0; p=0.018). When limited to true reporters, SSB intake significantly increased the risk of being overweight/obese by nearly 4 fold.
CONCLUSION
Underreporting of SSB intake may be attenuating true associations of SSB intake and the risk of being overweight/obese.
doi:10.1038/ijo.2013.130
PMCID: PMC3872257  PMID: 23867782
Sugar-sweetened beverages; obesity; African-American; high-fructose corn syrup
8.  Adherence to WCRF/AICR cancer prevention recommendations and risk of post-menopausal breast cancer 
Background
In 2007 the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) released eight recommendations related to body fatness, physical activity and diet aimed at preventing the most common cancers worldwide. However, limited information exists on the association between meeting these recommendations and risks of specific cancers, including breast cancer.
Methods
We operationalized six recommendations (related to body fatness, physical activity, foods that promote weight gain, plant foods, red and processed meats, and alcohol) and examined their association with invasive breast cancer incidence over 6.7 years of follow-up in the VITamins And Lifestyle (VITAL) study cohort. Participants included 30,797 post-menopausal women ages 50–76 years at baseline in 2000–2002 with no history of breast cancer. Breast cancers (n=899) were tracked through the Western Washington Surveillance, Epidemiology and End Results (SEER) database.
Results
Breast cancer risk was reduced by 60% in women who met at least five recommendations compared to those who met none (HR: 0.40; 95% CI: 0.25–0.65; Ptrend<0.001). Further analyses that sequentially removed individual recommendations least associated with reduced risk suggested that this reduction is due to meeting recommendations related to body fatness, plant foods and alcohol (HR for meeting vs. not meeting these three recommendations: 0.38; 95% CI: 0.25–0.58; Ptrend <0.001).
Conclusions
Meeting the WCRF/AICR cancer prevention recommendations, specifically those related to alcohol, body fatness and plant foods, is associated with reduced post-menopausal breast cancer incidence.
Impact
Increased adherence to the WCRF/AICR cancer prevention recommendations could substantially reduce post-menopausal breast cancer risk in US women.
doi:10.1158/1055-9965.EPI-13-0210
PMCID: PMC3774119  PMID: 23780838
cancer prevention; breast cancer; recommendations; diet; alcohol
9.  Sleep, Type 2 Diabetes, Dyslipidemia, and Hypertension in Elderly Alzheimer’s Caregivers 
Research indicates that very short or long durations of sleep and inefficient sleep, are associated with higher total cholesterol and risk of type 2 diabetes and hypertension. This study tested the hypothesis that inefficient sleep or short/long sleep durations are associated with an elevated prevalence of type 2 diabetes, dyslipidemia, and hypertension in a community-dwelling sample of elderly Alzheimer’s caregivers. Participants were 126 caregivers for spouses with Alzheimer’s disease who underwent in-home sleep assessment by wrist actigraphy for 72 consecutive hours. Sleep data were averaged across the 3 days/nights; nighttime sleep and daytime napping were computed. Morning fasting blood samples were collected to determine measures of blood lipids and glucose. The average of three resting blood pressure measurements was used to estimate mean resting blood pressure. Logistic regression models including covariates related to sleep and metabolic regulation indicated that nighttime sleep duration, percent sleep at night, and daytime naps were not significantly associated with odds of having diabetes (OR, 0.92; 95%CI, 0.56–1.53; OR, 0.93; 95%CI, 0.83–1.03; OR, 1.75; 95%CI, 0.74–4.11, respectively), dyslipidemia (OR, 0.83; 95%CI, 0.57–1.20; OR, 0.99; 95%CI, 0.92–1.07; OR, 0.64; 95%CI: 0.33–1.24, respectively), or hypertension (OR, 0.97; 95%CI, 0.62–1.52; OR, 1.02; 95%CI, 0.93–1.11; OR, 1.10; 95%CI, 0.44–2.74, respectively). When categorical and combined sleep parameters were examined, there were no significant associations with any of the metabolic conditions (all p>0.05). The current study suggests that in an elderly sample of Alzheimer’s caregivers, nighttime sleep duration, nighttime sleep efficiency and daytime naps are not significantly associated with prevalent type 2 diabetes, dyslipidemia, or hypertension. As several of the associations demonstrated clinically relevant magnitudes of the associations, larger studies to more fully test these hypotheses are warranted.
doi:10.1016/j.archger.2013.02.008
PMCID: PMC3696346  PMID: 23522093
Sleep; type 2 diabetes; hypertension; dyslipidemia; caregivers
10.  Improvement in Self-Reported Physical Health Predicts Longer Survival Among Women with a History of Breast Cancer 
Purpose
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.
Methods
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.
Results
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.
Conclusions
These results appear to support testing an intervention to improve physical health in breast cancer patients among patients after the acute stage of treatment.
doi:10.1007/s10549-010-1236-x
PMCID: PMC3306248  PMID: 21042931
breast cancer; physical health; survival; mortality
11.  THE 2011-2016 TRANSDISCIPLINARY RESEARCH IN ENERGETICS AND CANCER (TREC) INITIATIVE: RATIONALE AND DESIGN 
Cancer causes & control : CCC  2013;24(4):695-704.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s10552-013-0150-z
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
12.  Medical Comorbidities Predict Mortality in Women with a History of Early Stage Breast Cancer 
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s10549-010-0732-3
PMCID: PMC2895945  PMID: 20077000
comorbidities; breast cancer; mortality
13.  Post-diagnosis Alcohol Consumption and Breast Cancer Prognosis in the After Breast Cancer Pooling Project 
Background
Alcohol consumption is an established risk factor for incident breast cancer. However, its role in breast cancer prognosis remains unclear.
Methods
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.
Results
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.
Conclusions
Regular alcohol consumption was not associated with breast cancer recurrence and total mortality overall, yet recurrence risk was only elevated in postmenopausal women.
Impact
The association between alcohol intake and recurrence may depend on menopausal status at breast cancer diagnosis.
doi:10.1158/1055-9965.EPI-12-1022
PMCID: PMC3538884  PMID: 23150063
alcohol; ethanol; estrogen; breast cancer; recurrence; mortality; prognosis
14.  MULTIVITAMIN USE AND RISK OF CANCER AND CARDIOVASCULAR DISEASE IN THE WOMEN’S HEALTH INITIATIVE COHORTS 
Archives of internal medicine  2009;169(3):10.1001/archinternmed.2008.540.
Context
Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease.
Objective
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.
Results
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).
Conclusion
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
clinicaltrials.gov identifier: NCT00000611
doi:10.1001/archinternmed.2008.540
PMCID: PMC3868488  PMID: 19204221
dietary supplements; vitamins; minerals; breast cancer; lung cancer; colon cancer; myocardial infarction; stroke
15.  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.
doi:10.1080/01635581.2012.718033
PMCID: PMC3633593  PMID: 23137008
16.  Prognosis following the use of complementary and alternative medicine in women diagnosed with breast cancer 
Objective
The purpose of this study was to assess whether CAM use affected breast cancer prognosis in those who did not receive systemic therapy.
Design
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).
Setting
A US-based multi-site randomized dietary trial.
Outcome
Time to additional breast cancer events.
Results
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.
Conclusion
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.
doi:10.1016/j.ctim.2012.04.002
PMCID: PMC3413169  PMID: 22863642
breast cancer; complementary and alternative medicine; dietary supplements; long- term prognosis; alternative cancer treatment
17.  Dietary-Related and Physical Activity-Related Predictors of Obesity in Children: A 2-Year Prospective Study 
Childhood Obesity  2012;8(2):110-115.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1089/chi.2011.0071
PMCID: PMC3647527  PMID: 22799510
18.  Weight Change and Survival after Breast Cancer in the After Breast Cancer Pooling Project 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Impact
Weight control strategies for breast cancer survivors should be personalized to the individual’s medical history.
doi:10.1158/1055-9965.EPI-12-0306
PMCID: PMC3433249  PMID: 22695738
19.  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.
doi:10.1016/j.prostaglandins.2011.07.006
PMCID: PMC3226866  PMID: 21821144
glutathione transferase; HPGDS; prostaglandin D2; colon cancer
20.  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.
doi:10.1007/s10552-011-9805-9
PMCID: PMC3169084  PMID: 21710192
Breast neoplasm; Survival; Recurrence; Life style
21.  Classification of CAM Use and its Correlates in Early Stage Breast Cancer Patients 
Integrative cancer therapies  2011;10(2):138-147.
Hypothesis
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.
Results
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.
Conclusion
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.
doi:10.1177/1534735410392578
PMCID: PMC3126886  PMID: 21382963
22.  Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes 
Background
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.
Methods
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.
Results
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.
Conclusions
The WHEL dietary intervention may have modified other risk factors of recurrence correlated with testosterone.
Impact
Sex hormones should be considered as part of a larger biological system related to the risk of breast cancer recurrence.
doi:10.1158/1055-9965.EPI-10-1240
PMCID: PMC3089679  PMID: 21415358
Postmenopausal; hot flashes; sex hormones; breast cancer
23.  Specialty Supplements and Prostate Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort 
Nutrition and cancer  2011;63(4):573-582.
Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have anti-inflammatory, anti-oxidant, or other anti-cancer properties, few epidemiologic studies have examined the association between non-vitamin, non-mineral, “specialty” supplement use and prostate cancer risk. Participants, 50–76 years, were 35,239 male members of the VITamins And Lifestyle (VITAL) cohort who were residents of western Washington State, and who completed an extensive baseline questionnaire in 2000–2002. Participants responded about their frequency (days/week) and duration (years) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40–0.86) reduced risk of total prostate cancer. There were no associations for use of chondroitin, co-enzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent, however as current evidence is limited, it should not yet be promoted for prevention of prostate cancer.
doi:10.1080/01635581.2011.553022
PMCID: PMC3100666  PMID: 21598177
Botanical; Epidemiologic; Nutraceutical; Prostate; Supplements
24.  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.
doi:10.1007/s10552-011-9891-8
PMCID: PMC3319091  PMID: 22212612
25.  Dietary Intake, Supplement Use, and Survival Among Women Diagnosed with Early Stage Breast Cancer 
Nutrition and cancer  2011;63(3):327-333.
Background
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.
Methods
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.
Results
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.
Conclusion
Dietary supplements may improve overall micronutrient intakes of breast cancer survivors. However, vitamin and mineral intakes were not associated with all-cause mortality.
doi:10.1080/01635581.2011.535957
PMCID: PMC3078826  PMID: 21391124
dietary intake; supplement use; breast cancer survival

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