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1.  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
2.  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
3.  Depressed Mood and Flow-Mediated Dilation: A Systematic Review and Meta-Analysis 
Psychosomatic medicine  2011;73(5):360-369.
Objective
This systematic and quantitative review evaluates the literature on associations between depressed mood and flow-mediated dilation (FMD), a measure of endothelial function, in adults.
Methods
Published English-language articles (through December 2010) were identified from literature searches, assessed for data extraction, and evaluated for quality.
Results
The literature includes cross-sectional (n = 9) and retrospective examinations (n = 3) of how FMD correlates with clinical or subclinical depression in healthy adults and cardiovascular patients (total N across 12 studies = 1491). FMD was assessed using a variety of methodologies. Samples were predominately older white and Asian subjects with higher socioeconomic status. In eight of the 12 articles selected for this review, at least one significant inverse association was noted between depressed mood and FMD, with primarily moderate effect sizes. The overall meta-analysis (random-effects model) revealed a combined effect size of correlation coefficient r = 0.19 (95% confidence interval = 0.08–0.29, p = .001). Significant combined effects were found for subgroups of studies that a) received better quality ratings (r = 0.29), b) examined patients with cardiovascular disease or with cardiovascular disease risk factors/comorbidity (r = 0.29), c) used maximum vasodilation to quantify FMD (r = 0.27), and d) assessed samples that had a mean age of 55 years and older (r = 0.15).
Conclusions
Diverse studies support the inverse correlation between depressed mood and endothelial function, as measured by FMD. This literature would be strengthened by prospective studies, increased methodological consistency in FMD testing, and broader sampling (e.g., African Americans, younger age, lower socioeconomic status).
doi:10.1097/PSY.0b013e31821db79a
PMCID: PMC4266566  PMID: 21636660
review; meta-analysis; depression; mood; flow-mediated dilation; vasodilation
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.  Mortality Risk in Former Smokers with Breast Cancer: Pack-years vs. Smoking Status 
It is unclear why successful quitting at time of breast cancer diagnosis should remove risk from a significant lifetime of smoking. Studies concluding this may be biased by how smoking is measured in many epidemiological cohorts. In the late 1990s, a randomized trial of diet and breast cancer outcomes enrolled early-stage female breast cancer survivors diagnosed within the previous 4 years. Smoking history and key covariate measures were available at study entry for 2953 participants. Participants were followed for an average of 7.3 years (96% response rate). There were 10.1% deaths (83% from breast cancer). At enrollment, 55.2% were never smokers, 41.2% former smokers, and 4.6% current smokers. Using current smoking status in a Cox regression, there was no increased risk for former smokers for either all-cause mortality (HR=1.11; 95% CI=0.87, 1.41; p-value = 0.42) or breast cancer mortality. However, when we categorized on extensive lifetime exposure, former smokers with 20+ pack-years of smoking (25.8%) had a significantly higher risk of both all-cause (HR=1.77; 95% CI =1.17, 2.48; p-value = 0.0007) and breast cancer specific mortality (HR=1.62; 95% CI =1.11, 2.37; p-value = 0.01). Lifetime smoking exposure, not current status should be used to assess mortality risk among former smokers.
doi:10.1002/ijc.28241
PMCID: PMC3770774  PMID: 23649774
Breast cancer; smoking status; pack-years; mortality
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.  Reproductive Factors, Heterogeneity, and Breast Tumor Subtypes in Women of Mexican Descent 
Background
Published data support the presence of etiologic heterogeneity by breast tumor subtype, but few studies have assessed this in Hispanic populations.
Methods
We assessed tumor subtype prevalence and associations between reproductive factors and tumor subtypes in 1041 women of Mexican descent enrolled in a case-only, binational breast cancer study. Multinomial logistic regression comparing human epidermal growth factor receptor 2 positive (HER2+) tumors and triple negative breast cancer (TNBC) to luminal A tumors was conducted.
Results
Compared to women with luminal A tumors, those with a later age at first pregnancy were less likely to have TNBC (odds ratio [OR], 0.61; 95% CI, 0.39–0.95), whereas those with ≥ 3 full-term pregnancies were more likely to have TNBC (OR, 1.68; 95% CI, 1.10–2.55). A lower odds of TNBC was shown for longer menstruation duration, whether prior to first pregnancy (OR, 0.78; 95% CI, 0.65–0.93 per 10 years) or menopause (OR, 0.79; 95% CI, 0.69–0.91 per 10 years). Patients who reported breastfeeding for >12 months were over twice as likely to have TNBC than luminal A tumors (OR, 2.14; 95% CI, 1.24–3.68). Associations comparing HER2+ to luminal A tumors were weak or non-existent except for the interval between last full-term pregnancy and breast cancer diagnosis.
Conclusions
Findings show etiologic heterogeneity by tumor subtype in a population of Hispanic women with unique reproductive profiles.
Impact
Identification of etiologically distinct breast tumor subtypes can further improve our understanding of the disease and help provide personalized prevention and treatment regimens.
doi:10.1158/1055-9965.EPI-13-0560
PMCID: PMC3799795  PMID: 23950213
Breast cancer; Breastfeeding; Hispanics; Parity; Reproductive Factors; Tumor Subtype
8.  A Randomized Pilot Trial of Dietary Modification for the Chemoprevention of Non-invasive Bladder Cancer: The Dietary Intervention in Bladder Cancer Study (DIBS) 
Cancer prevention research (Philadelphia, Pa.)  2013;6(9):10.1158/1940-6207.CAPR-13-0050.
Epidemiological data suggest robust associations of high vegetable intake with decreased risks of bladder cancer incidence and mortality, but translational prevention studies have yet to be performed. We designed and tested a novel intervention to increase vegetable intake in patients with non-invasive bladder cancer. We randomized 48 patients aged 50 to 80 years with biopsy-proven non-invasive (Ta, T1, or carcinoma in situ) urothelial cell carcinoma to telephone- and Skype-based dietary counseling or a control condition that provided print materials only. The intervention behavioral goals promoted 7 daily vegetable servings, with at least 2 of these as cruciferous vegetables. Outcome variables were self-reported diet and plasma carotenoid and 24-hour urinary isothiocyanate (ITC) concentrations. We used 2-sample t-tests to assess between-group differences at 6-month follow-up. After 6 months, intervention patients had higher daily intakes of vegetable juice (p=0.02), total vegetables (p=0.02), and cruciferous vegetables (p=0.07); lower daily intakes of energy (p=0.007), (p=0.002) and energy from fat (p=0.06); and higher plasma alpha-carotene concentrations (p=0.03). Self-reported cruciferous vegetable intake correlated with urinary ITC concentrations at baseline (p<0.001) and at 6 months (p=0.03). Although urinary ITC concentrations increased in the intervention group and decreased in the control group, these changes did not attain between-group significance (p=0.32). In patients with non-invasive bladder cancer, our novel intervention induced diet changes associated with protective effects against bladder cancer. These data demonstrate the feasibility of implementing therapeutic dietary modifications to prevent recurrent and progressive bladder cancer.
doi:10.1158/1940-6207.CAPR-13-0050
PMCID: PMC3857028  PMID: 23867158
9.  Prevention of quality of life deterioration with light therapy is associated with changes in fatigue in women with breast cancer undergoing chemotherapy 
Purpose
During chemotherapy, women with breast cancer not only experience poor quality of life (QOL), they also have little exposure to bright light, which has been shown to be associated with depression, fatigue and poor sleep in other chronic illnesses. This study examined whether increased light exposure would have a positive effect on QOL.
Methods
39 women with Stage I–III breast cancer scheduled to receive ≥4 cycles of chemotherapy were randomized to a bright white light (BWL, n=23) or dim red light (DRL, n=16) treatment group. Data were collected before (baseline) and during cycles 1 and 4 of chemotherapy. Light was administered via a light box (Litebook®, Ltd.). QOL was assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) and the Functional Outcomes of Sleep Questionnaire (FOSQ).
Results
Compared to baseline, the DRL group demonstrated significant decline in QOL during the treatment weeks of both cycles (all p’s<0.02), whereas the BWL group had no significant decline (all p’s>0.05). Mixed model analyses revealed that there was a group-by-time interaction for FOSQ at the treatment week of cycle 4 and this interaction was mediated by fatigue.
Conclusion
The data suggest that increased exposure to bright light during chemotherapy may prevent the decline in QOL via preventing the increase of fatigue.
doi:10.1007/s11136-012-0243-2
PMCID: PMC3780416  PMID: 22865153
breast cancer; chemotherapy; light therapy; quality of life; fatigue; depression
10.  Decreased Health-Related Quality of Life in Women with Breast Cancer is Associated with Poor Sleep 
Behavioral sleep medicine  2012;11(3):189-206.
This study examined the longitudinal relationship between health-related quality of life (HR-QOL) and subjective and objective sleep quality in 166 women with newly diagnosed stage I-III breast cancer who were scheduled to receive ≥4 cycles of adjuvant/neoadjuvant chemotherapy. HR-QOL was assessed with the Medical Outcomes Study-Short Form Physical Component Scale and Mental Component Scale scores. Subjective sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI); objective sleep was measured with actigraphy. Data were collected before starting chemotherapy and during the last week of cycle 4 of chemotherapy. Patients reported poor HR-QOL and poor sleep quality before and during chemotherapy. Short sleep time and long naps were recorded at both time points. The Mental Component score was related to reports of poor sleep but not to recorded sleep, worse Physical Component scores were associated with reports of poor sleep and less recorded nap time, suggesting sleep plays an important role in cancer patients’ HR-QOL.
doi:10.1080/15402002.2012.660589
PMCID: PMC3594390  PMID: 23205513
11.  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
12.  HYPOTHESIZED ROLE OF PREGNANCY HORMONES ON HER2+ BREAST TUMOR DEVELOPMENT 
Breast cancer incidence rates have declined among older but not younger women; the latter are more likely to be diagnosed with breast cancers carrying a poor prognosis. Epidemiological evidence supports an increase in breast cancer incidence following pregnancy with risk elevated as much as 10 years postpartum. We investigated the association between years since last full-term pregnancy at the time of diagnosis (≤10 or >10 years) and breast tumor subtype in a case series of premenopausal Hispanic women (n = 627). Participants were recruited in the United States, Mexico, and Spain. Cases with known estrogen receptor (ER), progesterone receptor (PR), and HER2 status, with one or more full-term pregnancies ≥1 year prior to diagnosis were eligible for this analysis. Cases were classified into three tumor subtypes according to hormone receptor (HR+ = ER+ and/or PR+; HR− = ER− and PR−) expression and HER2 status: HR+/HER2−, HER2+ (regardless of HR), and triple negative breast cancer (TNBC). Case-only odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for HER2+ tumors in reference to HR+/HER2− tumors. Participants were pooled in a mixed-effects logistic regression model with years since pregnancy as a fixed effect and study site as a random effect. When compared to HR+/HER2− cases, women with HER2+ tumors were more likely be diagnosed in the postpartum period of ≤10 years (OR=1.68; 95% CI, 1.12–2.52). The effect was present across all source populations and independent of the HR status of the HER2+ tumor. Adjusting for age at diagnosis (≤45 or >45 years) did not materially alter our results (OR=1.78; 95% CI, 1.08–2.93). These findings support the novel hypothesis that factors associated with the postpartum breast, possibly hormonal, are involved in the development of HER2+ tumors.
doi:10.1007/s10549-012-2313-0
PMCID: PMC4054812  PMID: 23135573
breast cancer; breast tumor subtypes; etiologic heterogeneity; HER2; Hispanic; parity
13.  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
14.  Risk Factors Associated with Breast Cancer-Related Lymphedema in the WHEL Study 
Introduction
Lymphedema is a significant health problem faced by a large percentage of breast cancer survivors. The Women’s Healthy Eating and Living (WHEL) Study has a unique data set collected after the completion of breast cancer treatment, which allowed a focused analysis of risk factors for breast cancer-related lymphedema.
Methods
Participant characteristics, treatment modalities, and health behaviors were examined as potential predictors of lymphedema among breast cancer survivors with univariate analyses and multivariate logistic regression.
Results
Lymphedema status was assessed for 83% of the study cohort (2431 of the 2917 WHEL participants). Among these respondents, 692 (28.5%) women reported yes to either a physician’s diagnosis of lymphedema or a question on arm/hand swelling. When compared to other participants, women with lymphedema were diagnosed at a younger age, more likely to have a higher body mass index, had a larger tumor size, had more lymph nodes removed, more likely to have a mastectomy with radiation therapy, and more likely to have chemotherapy. In the final multivariate-adjusted model, body mass index greater than 25 kg/m2 (p<0.01), the removal of 11 or more lymph nodes (p<0.01), and breast cancer surgery plus radiation therapy (p<0.01) showed a strong independent association with developing breast cancer-related lymphedema.
Conclusions
The results of this study highlight the importance of educating breast cancer survivors about the modifiable risk factors (e.g., body mass index) associated with the development of lymphedema.
Implications for Cancer Survivors
Breast cancer survivors at risk for lymphedema may benefit from interventions aimed at achieving or maintaining a healthy body weight.
doi:10.1007/s11764-012-0251-9
PMCID: PMC3568206  PMID: 23212606
Breast cancer survivors; Lymphedema; Risk factors; Body mass index; Lymph node removal; Breast cancer treatment
15.  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
16.  Fatigue and Circadian Activity Rhythms in Breast Cancer Patients Before and After Chemotherapy: A Controlled Study 
Fatigue (Abingdon, Eng. Print)  2013;1(1-2):12-26.
Background
Breast cancer (BC) patients often experience cancer-related fatigue (CRF) before, during, and after their chemotherapy. Circadian rhythms are 24-hour cycles of behavior and physiology that are generated by internal pacemakers and entrained by zeitgebers (e.g., light). A few studies have suggested a relationship between fatigue and circadian rhythms in some clinical populations.
Methods
One hundred and forty-eight women diagnosed with stage I-III breast cancer and scheduled to receive at least four cycles of adjuvant or neoadjuvant chemotherapy, and 61 controls (cancer-free healthy women) participated in this study. Data were collected before (Baseline) and after four cycles of chemotherapy (Cycle-4). Fatigue was assessed with the Short Form of Multidimensional Fatigue Symptom Inventory (MFSI-SF); circadian activity rhythm (CAR) was recorded with wrist actigraphy (six parameters included: amplitude, acrophase, mesor, up-mesor, down-mesor and F-statistic). A mixed model analysis was used to examine changes in fatigue and CAR parameters compared to controls, and to examine the longitudinal relationship between fatigue and CAR parameters in BC patients.
Results
More severe CRF (total and subscale scores) and disrupted CAR (amplitude, mesor and F-statistic) were observed in BC patients compared to controls at both Baseline and Cycle-4 (all p's<0.05); BC patients also experienced more fatigue and decreased amplitude and mesor, as well as delayed up-mesor time at Cycle-4 compared to Baseline (all p's<0.05). The increased total MFSI-SF scores were significantly associated with decreased amplitude, mesor and F-statistic (all p's<0.006).
Conclusion
CRF exists and CAR is disrupted even before the start of chemotherapy. The significant relationship between CRF and CAR indicate possible underlying connections. Re-entraining the disturbed CAR using effective interventions such as bright light therapy might also improve CRF.
doi:10.1080/21641846.2012.741782
PMCID: PMC3568994  PMID: 23412418
breast cancer; fatigue; circadian activity rhythm; chemotherapy
17.  Effect of continuous positive airway pressure on day/night rhythm of prothrombotic markers in obstructive sleep apnea 
Sleep medicine  2012;14(1):58-65.
Objective
Obstructive sleep apnea (OSA) has been associated with an increased risk of atherothrombotic events. A prothrombotic state might partially explain this link. This study investigated OSA patients’ day/night rhythm of several prothrombotic markers and their potential changes with therapeutic continuous positive airway pressure (CPAP).
Methods
The study included 51 OSA patients [apnea hypopnea index (AHI) ≥10] and 24 non-OSA controls (AHI <10). Of the 51 OSA patients, 25 were randomized to CPAP and 26 to placebo-CPAP. Twelve blood samples were collected over a 24 h period to measure prothrombotic markers. For the apneic patients these samples were collected before treatment and after 3 weeks of treatment with either CPAP or placebo-CPAP. Day/night variation in prothrombotic markers was examined using a cosinor analysis.
Results
Compared with controls, OSA patients showed lower mesor (mean) and amplitude (difference between maximum and minimum activity) of D-dimer. In unadjusted (but not in adjusted) analysis, patients showed higher mesor of plasminogen activator inhibitor-1 (p < 0.05 in all cases). No significant group differences were seen in mesor and amplitude for either soluble tissue factor or von Willebrand factor, or the acrophase (time of the peak) and periodic pattern for any prothrombotic markers. There were no significant differences in changes of periodic pattern and in day/night rhythm parameters of prothrombotic markers pre- to post-treatment between the CPAP and placebo condition.
Conclusions
There may be altered day/night rhythm of some prothrombotic markers in OSA patients compared with controls. CPAP treatment for 3 weeks did not affect day/night rhythm of prothrombotic markers in OSA patients differently from placebo-CPAP.
doi:10.1016/j.sleep.2012.07.009
PMCID: PMC3540139  PMID: 23036264
Day/night rhythm; Continuous positive airway pressure; Hemostasis; Polysomnography; Sleep apnea; Treatment
18.  Moderate-to-high levels of exercise are associated with higher resting energy expenditure in community-dwelling postmenopausal women 
Postmenopausal women experience an age-related decline in resting energy expenditure (REE), which is a risk factor for energy imbalance and metabolic disease. Exercise, by association with greater lean tissue mass and other factors, has the potential to mediate REE decline, but the relationship between exercise and REE in postmenopausal women is not well characterized. This study tests the hypothesis that exercise energy expenditure (EEE) is positively associated with REE, opposing the effects of age and menopause. The study tests this hypothesis in a cross-sectional sample of healthy postmenopausal women (N = 31, aged 49 - 72 years) with habitual exercise volumes at or above levels consistent with current clinical recommendations. Subjects kept four weeks of exercise diaries quantifying exercise activity, and were measured for body composition, maximal oxygen uptake, and REE. Multiple regression analysis was used to test for relationships between EEE, age, body composition, and REE. EEE and lean tissue mass (fat-free mass: FFM; and fat-free mass index: FFMI) exhibited significant, positive relationships with REE. The relationship between REE and EEE remained significant even after controlling for lean tissue mass. These results support the hypothesis that exercise is positively associated with REE, counter to the negative effects of age and menopause, and indicate a continuous relationship between exercise and REE across the moderate-to-high exercise range. Exercise at levels at and above current clinical guidelines may, in part, ameliorate risk for energy imbalance and metabolic disease through a positive relationship with REE.
doi:10.1139/apnm-2013-0063
PMCID: PMC3865986  PMID: 24053522
exercise; metabolic rate; energy expenditure; menopause; fat-free mass; aging
19.  RELATIONSHIPS BETWEEN CLINICAL CHARACTERISTICS AND NOCTURNAL CARDIAC AUTONOMIC ACTIVITY IN PARKINSON’S DISEASE 
Background
The aim of the present study was to explore the association between Parkinson’s disease (PD) clinical characteristics and cardiac autonomic control across sleep stages.
Methods
Frequency-domain heart rate variability (HRV) measures were estimated in 18 PD patients undergoing a night of polysomnography.
Results
Significant relationships were found between PD severity and nocturnal HRV indices. The associations were restricted to rapid eye movement (R) sleep.
Conclusions
The progressive nocturnal cardiac autonomic impairment occurring with more severe PD can be subclinical emerging only during conditions requiring active modulation of physiological functions such as R-sleep.
doi:10.1016/j.autneu.2012.10.003
PMCID: PMC3501606  PMID: 23141523
Heart rate variability; Parkinson’s disease; polysomnography; sleep
20.  ASSOCIATIONS OF SOLUBLE FIBER, WHOLE FRUITS/VEGETABLES, AND JUICE WITH PLASMA BETA-CAROTENE CONCENTRATIONS IN A FREE-LIVING POPULATION OF BREAST CANCER SURVIVORS 
Women & health  2012;52(8):731-743.
Objective
Soluble fiber and the physical state of fruits/vegetables affect plasma ß-carotene concentrations; however, most of this research was conducted in laboratory-based settings. These analyses investigated the relationship between soluble fiber and juiced vs. whole fruits/vegetables to plasma ß-carotene concentrations in a free-living population.
Method
This cross-sectional analysis used 12-month follow-up data from the Women’s Healthy Eating & Living Study (WHEL) (1995-2006), a study to improve diet in breast cancer survivors in the Western United States. The dietary nutrients considered in this analysis included intake of soluble fiber (g), ß-carotene from fruit/vegetable juice (mg), and ß-carotene from whole fruits/vegetables (mg). A linear regression model was used to assess the relationship of the variables to plasma ß-carotene concentrations.
Results
Out of 3,088 women enrolled in WHEL 2,397 women had complete data (mean age=54). The final model accounted for approximately 49% of the explained variance in plasma ß-carotene concentrations. Fruit/vegetable juice had the largest, positive relation to plasma ß-carotene concentrations (standardized parameter estimate=0.23, p < 0.01) followed by whole fruits/vegetables (standardized parameter estimate=0.09, p < 0.01). Conclusion: Soluble fiber may inhibit ß-carotene absorption; therefore, consumption of juice may increase plasma ß-carotene concentrations more than whole fruits/vegetables in free-living populations.
doi:10.1080/03630242.2012.728189
PMCID: PMC3491579  PMID: 23127215
Dietary fiber; carotenoids; antioxidants; diet; food
22.  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
23.  Fatigue and Sleep Quality are Associated with Changes in Inflammatory Markers in Breast Cancer Patients Undergoing Chemotherapy 
Brain, Behavior, and Immunity  2012;26(5):706-713.
Fatigue and sleep disturbances are two of the most common and distressing symptoms reported by cancer patients. Fatigue and sleep are also correlated with each other. While fatigue has been reported to be associated with some inflammatory markers, data about the relationship between cancer-related sleep disturbances and inflammatory markers are limited. This study examined the relationship between fatigue and sleep, measured both subjectively and objectively, and inflammatory markers in a sample of breast cancer patients before and during chemotherapy. Fifty-three women with newly diagnosed stage I–III breast cancer scheduled to receive at least four 3-week cycles of chemotherapy participated in this longitudinal study. Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep was measured with actigraphy. Three inflammatory markers were examined: Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1RA) and C-reactive protein (CRP). Data were collected before (baseline) and during cycle 1 and cycle 4 of chemotherapy. Compared to baseline, more fatigue was reported, levels of IL-6 increased and IL-1RA decreased during chemotherapy. Reports of sleep quality remained poor. Mixed model analyses examining changes from baseline to each treatment time point revealed overall positive relationships between changes in total MFSI-SF scores and IL-6, between changes in total PSQI scores and IL-6 and IL-1RA, and between total wake time at night and CRP (all p’s<0.05). These relationships suggest that cancer-related fatigue and sleep disturbances may share common underlying biochemical mechanisms.
doi:10.1016/j.bbi.2012.02.001
PMCID: PMC3372667  PMID: 22406004
breast cancer; chemotherapy; fatigue; sleep; inflammatory markers
24.  Long-term course of pain in breast cancer survivors: A four year longitudinal study 
Background
After successful treatment of early breast cancer, many women still report pain symptoms, and attribute them to the previous illness or its treatment. However, knowledge about the long-term course of pain in breast cancer is limited.
Methods
Baseline assessment included 3,088 women who received a breast cancer diagnosis on average 2 years prior to enrollment, and who completed typical medical treatments. After 4 years, a subsample of 2,160 recurrence-free women (70%) was re-assessed. The major outcome variable was the composite index for general pain symptoms.
Results
Over the 4 year course, a slight but significant increase in pain was reported. If only medical variables were examined, a triple interaction between surgery type, breast cancer stage, and time indicated that pain scores increased in most subgroups, while they decreased in stage II women after mastectomy and stage III women after lumpectomy. Using a regression analytical approach, psychological and other variables added significantly to the prediction of pain persistence. Regression analysis revealed that pain symptoms increased in those women taking tamoxifen at baseline, in those reporting depression at baseline or stressful life events during the first 12 months after enrollment. Exercise at baseline had a beneficial effect on pain recovery.
Conclusions
The persistence or increase of pain symptoms in women surviving breast cancer is associated with some medical factors (surgery type, tamoxifen use), but also with psychological factors. Pain should be a standard outcome variable in the evaluation of cancer treatment programs.
doi:10.1007/s10549-011-1614-z
PMCID: PMC3681533  PMID: 21656272
breast cancer; pain; depression; physical exercise
25.  Light Treatment Prevents Fatigue in Women Undergoing Chemotherapy for Breast Cancer 
Supportive Care in Cancer  2011;20(6):1211-1219.
Purpose
Fatigue is one of the most disturbing complaints of cancer patients and often is the reason for discontinuing treatment. This randomized controlled study tested the hypothesis that increased morning bright light, compared to dim light, would result in less fatigue in women with breast cancer undergoing chemotherapy.
Methods
39 women newly diagnosed with Stage I-III breast cancer were randomized to either bright white light (BWL) or dim red light (DRL) treatment and were instructed to use the light box for 30 minutes every morning throughout the first 4 cycles of chemotherapy. The Multidimensional Fatigue Symptom Inventory was administered prior to the start of chemotherapy (baseline), during the chemotherapy treatment week of cycle 1 (C1TW), the last week (recovery week) of cycle 1 (C1RW), chemotherapy treatment week of cycle 4 (C4TW), the last week (recovery week) of cycle 4 (C4RW).
Results
The DRL group reported increased fatigue at C1TW (p=0.003) and C4TW (p<0.001) compared to baseline while there was no significant change from baseline in the BWL group. A secondary analysis showed that the increases in fatigue levels in the DRL group were not mediated through associated with changes in sleep or in circadian rhythms as measured with wrist actigraphy.
Conclusions
The results of this study suggest that morning bright light treatment may prevent overall fatigue from worsening during chemotherapy. Although our hypothesis that overall fatigue would improve with bright light treatment was not supported, the lack of deterioration in total fatigue scores suggests that bright morning light may be a useful intervention during chemotherapy for breast cancer.
doi:10.1007/s00520-011-1203-z
PMCID: PMC3192914  PMID: 21660669
fatigue; breast cancer; chemotherapy; light treatment

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