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1.  Reducing Breast Cancer Recurrence with Weight Loss, a Vanguard Trial: The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) Trial 
Contemporary clinical trials  2012;34(2):282-295.
Breast cancer is the most common invasive cancer among women in developed countries. Obesity is a major risk factor for breast cancer recurrence and mortality in both pre-and postmenopausal women. Co-morbid medical conditions are common among breast cancer survivors. The Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) study is a 4-year randomized clinical trial of 693 overweight/obese women aged ≥21 years diagnosed with any early stage breast cancer (stages I[≥1 cm]-III) within the previous five years, designed to demonstrate the feasibility of achieving sustained weight loss and to examine the impact of weight loss on quality of life and co-morbidities, and to enable future exploration of biochemical mechanisms linking obesity to lower likelihood of disease-free survival. This trial is strategically designed as a vanguard for a fully-powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival. Participants were recruited between 2010 and 2012 at four sites, had completed initial therapies, and had a body mass index between 25 and 45 kg/m2. The intervention featured a group-based cognitive-behavioral weight loss program with telephone counseling and tailored newsletters to support initial weight loss and subsequent maintenance, with the goal of 7% weight loss at two years. This study has high potential to have a major impact on clinical management and outcomes after a breast cancer diagnosis. This trial initiates the effort to establish weight loss support for overweight or obese breast cancer survivors as a new standard of clinical care.
doi:10.1016/j.cct.2012.12.003
PMCID: PMC3593786  PMID: 23266440
Obesity; Weight Reduction; Breast Cancer; Quality of Life; Co-Morbidities
2.  A Comparison of Regular Consumption of Fresh Lean Pork, Beef and Chicken on Body Composition: A Randomized Cross-Over Trial 
Nutrients  2014;6(2):682-696.
Pork is the most widely eaten meat in the world and recent evidence shows that diets high in pork protein, with and without energy restriction, may have favourable effects on body composition. However, it is unclear whether these effects on body composition are specific to pork or whether consumption of other high protein meat diets may have the same benefit. Therefore we aimed to compare regular consumption of pork, beef and chicken on indices of adiposity. In a nine month randomised open-labelled cross-over intervention trial, 49 overweight or obese adults were randomly assigned to consume up to 1 kg/week of pork, chicken or beef, in an otherwise unrestricted diet for three months, followed by two further three month periods consuming each of the alternative meat options. BMI and waist/hip circumference were measured and body composition was determined using dual energy x-ray absorptiometry. Dietary intake was assessed using three day weighed food diaries. Energy expenditure was estimated from activity diaries. There was no difference in BMI or any other marker of adiposity between consumption of pork, beef and chicken diets. Similarly there were no differences in energy or nutrient intakes between diets. After three months, regular consumption of lean pork meat as compared to that of beef and chicken results in similar changes in markers of adiposity of overweight and obese Australian middle-aged men and women.
doi:10.3390/nu6020682
PMCID: PMC3942727  PMID: 24534884
pork; beef; chicken; body composition; energy intake; DEXA
3.  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
4.  Evaluation of ultra-deep targeted sequencing for personalized breast cancer care 
Breast Cancer Research : BCR  2013;15(6):R115.
Introduction
The increasing number of targeted therapies, together with a deeper understanding of cancer genetics and drug response, have prompted major healthcare centers to implement personalized treatment approaches relying on high-throughput tumor DNA sequencing. However, the optimal way to implement this transformative methodology is not yet clear. Current assays may miss important clinical information such as the mutation allelic fraction, the presence of sub-clones or chromosomal rearrangements, or the distinction between inherited variants and somatic mutations. Here, we present the evaluation of ultra-deep targeted sequencing (UDT-Seq) to generate and interpret the molecular profile of 38 breast cancer patients from two academic medical centers.
Methods
We sequenced 47 genes in matched germline and tumor DNA samples from 38 breast cancer patients. The selected genes, or the pathways they belong to, can be targeted by drugs or are important in familial cancer risk or drug metabolism.
Results
Relying on the added value of sequencing matched tumor and germline DNA and using a dedicated analysis, UDT-Seq has a high sensitivity to identify mutations in tumors with low malignant cell content. Applying UDT-Seq to matched tumor and germline specimens from the 38 patients resulted in a proposal for at least one targeted therapy for 22 patients, the identification of tumor sub-clones in 3 patients, the suggestion of potential adverse drug effects in 3 patients and a recommendation for genetic counseling for 2 patients.
Conclusion
Overall our study highlights the additional benefits of a sequencing strategy, which includes germline DNA and is optimized for heterogeneous tumor tissues.
doi:10.1186/bcr3584
PMCID: PMC3978701  PMID: 24326041
5.  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
6.  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
7.  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
8.  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
9.  Tamoxifen Metabolite Concentrations, CYP2D6 Genotype and Breast Cancer Outcomes 
We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen, and to examine potential correlates of endoxifen concentrations including CYP2D6 metabolizer phenotype and body mass index (BMI). Tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen concentrations were measured from 1370 estrogen receptor positive breast cancer patients participating in the Women’s Healthy Eating and Living (WHEL) Study, and tested for associations with breast cancer outcomes. Breast cancer outcomes were not associated with tamoxifen, 4-hydroxytamoxifen or N-desmethyltamoxifen concentrations. For endoxifen, a threshold was identified suggesting that women in the upper four quintiles of endoxifen had a 26% lower recurrence rate than women in the bottom quintile. (HR=0.74; 95% CI, [0.55, 1.00]). Predictors of membership in this higher risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and low tamoxifen concentrations. This study suggests a minimal threshold at which endoxifen is effective against breast cancer recurrence, which 80% of tamoxifen-takers achieve.
doi:10.1038/clpt.2011.32
PMCID: PMC3081375  PMID: 21430657
Cancers; CYP; Epidemiology; Pharmacogenetics; Genotype
10.  Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens 
Nucleic Acids Research  2012;40(14):e107.
The utilization of archived, formalin-fixed paraffin-embedded (FFPE) tumor samples for massive parallel sequencing has been challenging due to DNA damage and contamination with normal stroma. Here, we perform whole genome sequencing of DNA isolated from two triple-negative breast cancer tumors archived for >11 years as 5 µm FFPE sections and matched germline DNA. The tumor samples show differing amounts of FFPE damaged DNA sequencing reads revealed as relatively high alignment mismatch rates enriched for C·G > T·A substitutions compared to germline samples. This increase in mismatch rate is observable with as few as one million reads, allowing for an upfront evaluation of the sample integrity before whole genome sequencing. By applying innovative quality filters incorporating global nucleotide mismatch rates and local mismatch rates, we present a method to identify high-confidence somatic mutations even in the presence of FFPE induced DNA damage. This results in a breast cancer mutational profile consistent with previous studies and revealing potentially important functional mutations. Our study demonstrates the feasibility of performing genome-wide deep sequencing analysis of FFPE archived tumors of limited sample size such as residual cancer after treatment or metastatic biopsies.
doi:10.1093/nar/gks299
PMCID: PMC3413110  PMID: 22492626
11.  Poor Physical Health Predicts Time to Additional Breast Cancer Events and Mortality in Breast Cancer Survivors 
Psycho-Oncology  2011;20(3):252-259.
Background
Health-related quality of life (HRQOL) has been hypothesized to predict time to additional breast cancer events and all-cause mortality in breast cancer survivors.
Methods
Women with early stage breast cancer (n=2967) completed the SF-36 (mental and physical health-related quality of life) and standardized psychosocial questionnaires to assess social support, optimism, hostility, and depression prior to randomization into a dietary trial. Cox regression was performed to assess whether these measures of quality of life and psychosocial functioning predicted time to additional breast cancer events and all-cause mortality; hazard ratios were the measure of association.
Results
There were 492 additional breast cancer events and 301 deaths occurred over a median 7.3 years (range: 0.01–10.8 years) of follow-up. In multivariate models, poorer physical health was associated with both decreased time to additional breast cancer events and all-cause mortality (p trend=0.005 and 0.004, respectively), while greater hostility predicted additional breast cancer events only (p trend=0.03). None of the other psycho-social variables predicted either outcome. The hazard ratios comparing persons with poor (bottom two quintiles) to better (top three quintiles) physical health were 1.42 (95% CI: 1.16, 1.75) for decreased time to additional breast cancer events and 1.37 (95% CI: 1.08, 1.74) for all-cause mortality. Potentially modifiable factors associated with poor physical health included higher BMI, lower physical activity, lower alcohol consumption, and more insomnia (p<0.05 for all).
Conclusion
Interventions to improve physical health should be tested as a means to increase time to additional breast cancer events and mortality among breast cancer survivors.
doi:10.1002/pon.1742
PMCID: PMC3297415  PMID: 20878837
physical health; breast cancer; oncology; survival
12.  Family Factors in End-of-Life Decision-Making: Family Conflict and Proxy Relationship 
Journal of Palliative Medicine  2011;14(2):179-184.
Abstract
Background
Few studies have examined proxy decision-making regarding end-of-life treatment decisions. Proxy accuracy is defined as whether proxy treatment choices are consistent with the expressed wishes of their index elder. The purpose of this study was to examine proxy accuracy in relation to two family factors that may influence proxy accuracy: perceived family conflict and type of elder-proxy relationship.
Methods
Telephone interviews with 202 community-dwelling elders and their proxy decision makers were conducted including the Life-Support Preferences Questionnaire (LSPQ), and a measure of family conflict, and sociodemographic characteristics, including type of relationship.
Results
Elder-proxy accuracy was associated with the type of elder-proxy relationship. Adult children demonstrated the lowest elder-proxy accuracy and spousal proxies the highest elder-proxy accuracy. Elder-proxy accuracy was associated with family conflict. Proxies reporting higher family conflict had lower elder-proxy accuracy. No interaction between family conflict and relationship type was revealed.
Conclusions
Spousal proxies were more accurate in their substituted judgment than adult children, and proxies who perceive higher degree of family conflict tended to be less accurate than those with lower family conflict. Health care providers should be aware of these family factors when discussing advance care planning.
doi:10.1089/jpm.2010.0353
PMCID: PMC3037808  PMID: 21254816
13.  Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2010;29(1):54-60.
Purpose
Self-reported diabetes has been associated with poor breast cancer outcomes. Research is needed to investigate the relationship between biologically determined glycemic control and breast cancer prognosis.
Methods
Archived baseline blood samples from the Women's Healthy Eating and Living Study were used to measure hemoglobin A1C (HbA1C) among 3,003 survivors of early-stage breast cancer (age of diagnosis, 28 to 70 years) observed for a median of 7.3 years for additional breast cancer events and 10.3 years for all-cause mortality. HbA1C levels provide an accurate, precise measure of chronic glycemic levels. Cox regression analysis was performed to assess whether baseline HbA1C levels predicted disease-free and overall survival.
Results
Only 5.8% of women had chronic hyperglycemia (defined as HbA1C levels ≥ 6.5%). Those with HbA1C ≥ 6.5% were older and more likely to be less educated, have nonwhite ethnicity, be obese, and have more advanced breast cancer at diagnosis. HbA1C was significantly associated with overall survival (Ptrend < .001). After adjusting for confounders, risk of all-cause mortality was twice as high in women with HbA1C ≥ 7.0% compared with women with HbA1C less than 6.5% (hazard ratio [HR], 2.35; 95% CI, 1.56 to 3.54). For disease-free survival, there was a nonsignificant 30% increase in risk for HbA1C levels ≥ 7.0% (HR, 1.26; 95% CI, 0.78 to 2.02). During study follow-up, previously diagnosed rather than undiagnosed diabetes seemed to account for the increased risk.
Conclusion
Chronic hyperglycemia is statistically significantly associated with reduced overall survival in survivors of early-stage breast cancer. Further study of diabetes and its relationship to breast cancer outcomes is warranted.
doi:10.1200/JCO.2010.29.3183
PMCID: PMC3055860  PMID: 21115861
14.  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
15.  Physical and Mental Health Correlates of Pregnancy Following Breast Cancer 
Psycho-oncology  2010;19(5):517-524.
Introduction
The safety of pregnancy after breast cancer is an important issue for many younger breast cancer survivors and their health care providers. Current research does not indicate that pregnancy negatively affects survival, but the “healthy mother bias,” suggesting that survivors who go on to become pregnant are a self-selected healthier group based on their prognosis, has led to cautious interpretation of these findings. No studies have systematically evaluated the potential for this bias.
Methods
This nested case-control study includes 81 younger participants from the Women’s Healthy Eating and Living Study (WHEL) (N=3088). Our sample includes 27 cases who had children after breast cancer and 54 controls, matched on age and stage at diagnosis. We used hierarchical linear modeling to accommodate longitudinal data with individuals nested within matched sets (cases and controls). The primary aim was to evaluate the association between summary scores of health and childbearing after breast cancer. Covariates were added for adjustment and to improve model precision.
Results
Controlling for other variables in the model, physical health scores were not different between cases and controls (B=0.14, p=0.96). Mental health scores were marginally higher among cases (B=6.40, p=0.08), as compared to controls, a difference considered clinically significant.
Conclusion
This preliminary study did not find evidence of a healthy mother bias based on physical health. However, mental health was 6 points higher (p=0.08) among those who had children, indicating that the role of mental health needs evaluation in future research. Larger studies are needed to verify these findings.
doi:10.1002/pon.1614
PMCID: PMC2861788  PMID: 20425779
16.  Adjuvant Chemotherapy in Older Women with Early-Stage Breast Cancer 
The New England journal of medicine  2009;360(20):2055-2065.
BACKGROUND
Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older.
METHODS
We randomly assigned patients with stage I, II, IIIA, or IIIB breast cancer to standard chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide plus doxorubicin) or capecitabine. Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor–positive tumors. A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients. The primary end point was relapse-free survival.
RESULTS
When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additional year of follow-up, the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 (95% confidence interval, 1.38 to 3.17; P<0.001). Patients who were randomly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (P = 0.02). At 3 years, the rate of relapse-free survival was 68% in the capecitabine group versus 85% in the standard-chemotherapy group, and the overall survival rate was 86% versus 91%. Two patients in the capecitabine group died of treatment-related complications; as compared with patients receiving capecitabine, twice as many patients receiving standard chemotherapy had moderate-to-severe toxic effects (64% vs. 33%).
CONCLUSIONS
Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older. (ClinicalTrials.gov number, NCT00024102.)
doi:10.1056/NEJMoa0810266
PMCID: PMC3082436  PMID: 19439741
17.  Individual cognitive behavioral therapy for insomnia in breast cancer survivors: a randomized controlled crossover pilot study 
Purpose
Estimates of insomnia in breast cancer patients are high, with reports of poor sleep lasting years after completion of cancer treatment. This randomized controlled crossover pilot study looked at the effects of individual cognitive behavioral therapy for insomnia (IND-CBT-I) on sleep in breast cancer survivors.
Patients and methods
Twenty-one participants were randomly assigned to either a treatment group (six weekly IND-CBT-I sessions followed by six weeks of follow up) or a delayed treatment control group (no treatment for six weeks followed by six weekly IND-CBT-I sessions). Of these, 14 participants completed the pilot study (six in the treatment group and eight in the delayed treatment control group).
Results
Self-rated insomnia was significantly improved in the treatment group compared to the waiting period in the delayed treatment control group. The pooled pre-post-IND-CBT-I analyses revealed improvements in self-rated insomnia, sleep quality, and objective measures of sleep.
Conclusions
These preliminary results suggest that IND-CBT-I is appropriate for improving sleep in breast cancer survivors. Individual therapy in a clinic or private practice may be a more practical option for this population as it is more easily accessed and readily available in an outpatient setting.
PMCID: PMC3630926  PMID: 23616695
insomnia; breast cancer; cognitive behavioral therapy
18.  Individual cognitive behavioral therapy for insomnia in breast cancer survivors: a randomized controlled crossover pilot study 
Purpose
Estimates of insomnia in breast cancer patients are high, with reports of poor sleep lasting years after completion of cancer treatment. This randomized controlled crossover pilot study looked at the effects of individual cognitive behavioral therapy for insomnia (IND-CBT-I) on sleep in breast cancer survivors.
Patients and methods
Twenty-one participants were randomly assigned to either a treatment group (six weekly IND-CBT-I sessions followed by six weeks of follow up) or a delayed treatment control group (no treatment for six weeks followed by six weekly IND-CBT-I sessions). Of these, 14 participants completed the pilot study (six in the treatment group and eight in the delayed treatment control group).
Results
Self-rated insomnia was significantly improved in the treatment group compared to the waiting period in the delayed treatment control group. The pooled pre–post-IND-CBT-I analyses revealed improvements in self-rated insomnia, sleep quality, and objective measures of sleep.
Conclusions
These preliminary results suggest that IND-CBT-I is appropriate for improving sleep in breast cancer survivors. Individual therapy in a clinic or private practice may be a more practical option for this population as it is more easily accessed and readily available in an outpatient setting.
doi:10.2147/NSS.S8004
PMCID: PMC2953254  PMID: 20948579
insomnia; breast cancer; cognitive behavioral therapy
19.  Time-Varying Effects of Prognostic Factors Associated With Disease-Free Survival in Breast Cancer 
American Journal of Epidemiology  2009;169(12):1463-1470.
Early detection and effective treatments have dramatically improved breast cancer survivorship, yet the risk of relapse persists even 15 years after the initial diagnosis. It is important to identify prognostic factors for late breast cancer events. The authors investigated time-varying effects of tumor characteristics on breast-cancer-free survival using data on 3,088 breast cancer survivors from 4 US states who participated in a randomized dietary intervention trial in 1995–2006, with maximum follow-up through 15 years (median, 9 years). A piecewise constant penalized spline approach incorporating time-varying coefficients was adopted, allowing for deviations from the proportional hazards assumption. This method is more flexible than standard approaches, provides direct estimates of hazard ratios across time intervals, and is computationally tractable. Having a stage II or III tumor was associated with a 3-fold higher hazard of breast cancer than having a stage I tumor during the first 2.5 years after diagnosis; this hazard ratio decreased to 2.1 after 7.7 years, but higher tumor stage remained a significant risk factor. Similar diminishing effects were found for poorly differentiated tumors. Interestingly, having a positive estrogen receptor status was protective up to 4 years after diagnosis but detrimental after 7.7 years (hazard ratio = 1.5). These results emphasize the importance of careful statistical modeling allowing for possibly time-dependent effects in long-term survivorship studies.
doi:10.1093/aje/kwp077
PMCID: PMC2733768  PMID: 19403844
breast neoplasms; proportional hazards models; survival
20.  Pre-treatment Symptom Cluster in Breast Cancer Patients is Associated with Worse Sleep, Fatigue and Depression during Chemotherapy 
Psycho-oncology  2009;18(2):187-194.
Objective
The concept of symptom clusters is relatively new in cancer patients' symptom management. This study, which spanned four cycles of chemotherapy, combined three commonly seen pre-treatment symptoms in cancer patients (i.e., sleep disturbances, fatigue and depression) into one symptom cluster, to explore the associations between pre-treatment cluster categories and longitudinal profiles of these same symptoms during chemotherapy.
Methods
This was a prospective study. Seventy-six women with newly diagnosed stage I–III breast cancer, scheduled to receive at least four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Data were collected at seven time points before and during treatment. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Fatigue was measured with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Depressive symptoms were measured with the Center of Epidemiological Studies-Depression (CES-D). Patients were divided into three groups based on the number of symptoms they experienced before the start of chemotherapy (i.e., no symptoms, 1–2 symptoms or all three symptoms) and a symptom cluster index (SCI) was computed.
Results
All women reported worse sleep, more fatigue and more depressive symptoms during treatment compared to baseline (all p's <0.01); however, those women with a higher symptom cluster index (i.e., more symptoms pre-treatment) continued to experience worse symptoms during treatment compared to those who began with fewer symptoms (all p's <0.01).
Conclusions
A higher clinically relevant-based pre-treatment symptom cluster was associated with more sleep disturbances, greater fatigue and more depressive symptoms during chemotherapy. Specific interventions for these pre-treatment symptoms may improve the frequency and severity of these same symptoms during chemotherapy, when they are most severe and most disruptive to quality of life.
doi:10.1002/pon.1412
PMCID: PMC2762479  PMID: 18677716
breast cancer; symptom cluster; sleep disturbances; fatigue; depression
21.  Dietary Pattern Influences Breast Cancer Prognosis in Women Without Hot Flashes: The Women's Healthy Eating and Living Trial 
Journal of Clinical Oncology  2009;27(3):352-359.
Purpose
To determine whether a low-fat diet high in vegetables, fruit, and fiber differentially affects prognosis in breast cancer survivors with hot flashes (HF) or without HF after treatment.
Patients and Methods
A secondary analysis was conducted on 2,967 breast cancer survivors, age 18 to 70 years, who were randomly assigned between 1995 and 2000 in a multicenter, controlled trial of a dietary intervention to prevent additional breast cancer events and observed through June 1, 2006. We compared the dietary intervention group with a group who received five-a-day dietary guidelines.
Results
Independent of HF status, a substantial between-group difference among those who did and did not receive dietary guidelines was achieved and maintained at 4 years in intake of vegetable/fruit servings per day (54% higher; 10 v 6.5 servings/d, respectively), fiber (31% higher; 25.5 v 19.4 g/d, respectively), and percent energy from fat (14% lower; 26.9% v 31.3%, respectively). Adjusting for tumor characteristics and antiestrogen treatment, HF-negative women assigned to the intervention had 31% fewer events than HF-negative women assigned to the comparison group (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93; P = .02). The intervention did not affect prognosis in the women with baseline HFs. Furthermore, compared with HF-negative women assigned to the comparison group, HF-positive women had significantly fewer events in both the intervention (HR = 0.77; 95% CI, 0.59 to 1.00; P = .05) and comparison groups (HR = 0.65; 95% CI, 0.49 to 0.85; P = .002).
Conclusion
A diet with higher vegetable, fruit, and fiber and lower fat intakes than the five-a-day diet may reduce risk of additional events in HF-negative breast cancer survivors. This suggestive finding needs confirmation in a trial in which it is the primary hypothesis.
doi:10.1200/JCO.2008.16.1067
PMCID: PMC2645853  PMID: 19075284
22.  Changes in Genital Injury Patterns over Time in Women after Consensual Intercourse 
Summary
To date, there are no studies in the literature addressing whether or not microscopic genital injuries change over time or change in appearance during the 72 hours time period following intercourse. In this study, women (n=35) had two evidentiary type pelvic examinations to document injuries after consensual intercourse. At Time 1 (within 48 hours of consensual intercourse) a: larger total surface area of injury (p =.02); larger surface area of injury to the posterior fourchette (p =.02); larger surface area of abrasions (p =.04); and larger surface area of redness (p =.04) were found compared to Time 2 (24 hours after Time 1). Since this research is exploratory, larger studies are needed to explore the differences in genital injuries based on the time of examination and in women after non-consensual intercourse.
doi:10.1016/j.jflm.2007.12.007
PMCID: PMC2528252  PMID: 18511005
genital injury; colposcopy; consensual intercourse; sexual assault
23.  Tamoxifen, hot flashes and recurrence in breast cancer 
We utilized data from the comparison group of the Women's Healthy Eating and Living randomized trial to investigate an “a priori” hypothesis suggested by CYP2D6 studies that hot flashes may be an independent predictor of tamoxifen efficacy. A total of 1551 women with early stage breast cancer were enrolled and randomized to the comparison group of the WHEL multi-institutional trial between 1995 and 2000. Their primary breast cancer diagnoses were between 1991 and 2000. At study entry, 864 (56%) of these women were taking tamoxifen, and hot flashes were reported by 674 (78%). After 7.3 years of follow-up, 127 of those who took tamoxifen at baseline had a confirmed breast cancer recurrence. Women who reported hot flashes at baseline were less likely to develop recurrent breast cancer than those who did not report hot flashes (12.9% vs 21%, P = 0.01). Hot flashes were a stronger predictor of breast cancer specific outcome than age, hormone receptor status, or even the difference in the stage of the cancer at diagnosis (Stage I versus Stage II). These findings suggest an association between side effects, efficacy, and tamoxifen metabolism. The strength of this finding suggests that further study of the relationship between hot flashes and breast cancer progression is warranted. Additional work is warranted to clarify the mechanism of hot flashes in this setting.
doi:10.1007/s10549-007-9612-x
PMCID: PMC2575100  PMID: 17541741
Breast cancer; Hot flashes; Survival; Tamoxifen
24.  Predictors of Inflammation in Response to Anthracycline-Based Chemotherapy for Breast Cancer 
Brain, behavior, and immunity  2007;22(1):98-104.
Although chemotherapy for breast cancer can increase inflammation, few studies have examined predictors of this phenomenon. This study examined potential contributions of demographics, disease characteristics, and treatment regimens to markers of inflammation in response to chemotherapy for breast cancer. Thirty-five women with stage I - III-A breast cancer (mean age 50 years) were studied prior to cycle 1 and prior to cycle 4 of anthracycline-based chemotherapy. Circulating levels of inflammatory markers with high relevance to breast cancer were examined, including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), Interleukin-1 receptor antagonist (IL1-RA), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), Interleukin- (IL-6), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Chemotherapy was associated with elevations in VEGF (p≤0.01), sICAM-1 (p≤0.01), sP-selectin (p≤0.02) and vWf (p≤0.05). Multiple regression analysis controlling for age and body mass index (BMI) showed that higher post-chemotherapy levels of inflammation were consistently related to higher pre-chemotherapy levels of inflammation (p’s ≤0.05) as well as to certain disease characteristics. Post-chemotherapy IL-6 levels were higher in patients who had larger tumors (p≤0.05) while post-chemotherapy VEGF levels were higher in patients who had smaller tumors (p≤0.05). Post-chemotherapy sP-selectin levels were highest in women who had received epirubicin, cytoxan, 5fluorouracil chemotherapy (p≤0.01). These findings indicate that chemotherapy treatment can be associated with elevations in certain markers of inflammation, particularly markers of endothelial and platelet activation. Inflammation in response to chemotherapy is most significantly related to inflammation that existed prior to chemotherapy but also potentially to treatment regimen and to certain disease characteristics.
doi:10.1016/j.bbi.2007.07.001
PMCID: PMC2199880  PMID: 17706918
breast cancer; chemotherapy; inflammation; CRP; TNF-α; IL1-RA; VEGF; sICAM-1; IL-6; sP-selectin; vWf
25.  Telephone Counseling Helps Maintain Long-Term Adherence to a High-Vegetable Dietary Pattern12 
The Journal of nutrition  2007;137(10):2291-2296.
Achieving long-term adherence to a dietary pattern is a challenge in many studies investigating the relationship between diet and disease. The Women’s Healthy Eating and Living Study was a multi-institutional randomized trial in 3088 women at risk for breast cancer recurrence. At baseline, the average participant followed a healthy dietary pattern of 7 vegetable and fruit servings, 21 g/d of fiber, and 28.7% energy from fat, although fat intake increased over the enrollment period. Using primarily telephone counseling, the intervention group was encouraged to substantially increase intakes of vegetables, fruits, and fiber while decreasing fat intake. Sets of 24-h dietary recalls were completed on 90% of eligible participants at 1 y and 86% at 4 y. Using a conservative imputation analysis, at 1 y, the intervention group consumed 38% more vegetable servings (100% when including juice) than the comparison group, 20% more fruit, 38% more fiber, 50% more legumes, and 30% more whole grain foods, with a 20% lower intake of energy from fat. At 4 y, the between-group differences were 65% for vegetables (including juice), 25% fruit, 30% fiber, 40% legumes, 30% whole grain foods, and 13% lower intake of energy from fat. The intervention effect on fat intake was similar for early vs. late enrollees. Plasma carotenoid concentrations on a random 28% sample validated self-reported vegetable and fruit intake, with a between-group difference of 66% at 1 y and over 40% at 4 y. This large change will allow testing of hypotheses on the role of dietary change in preventing additional breast cancer events.
PMCID: PMC2064909  PMID: 17885013

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