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1.  Lifetime Cigarette Smoking and Breast Cancer Prognosis in the After Breast Cancer Pooling Project 
There is controversy on whether former smokers have increased risk for breast cancer recurrence or all-cause mortality, regardless of how much they smoked.
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).
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).
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.
PMCID: PMC3906992  PMID: 24317179
2.  The Effectiveness of Cigarette Price and Smoke-Free Homes on Low-Income Smokers in the United States 
American journal of public health  2013;103(12):2276-2283.
We examined the effectiveness of state cigarette price and smoke-free homes on smoking behaviors of low-income and high-income populations in the United States.
We used the 2006–2007 Tobacco Use Supplement to the Current Population Survey. The primary outcomes were average daily cigarette consumption and successful quitting. We used multivariable regression to examine the association of cigarette price and smoke-free home policies on these outcomes.
High state cigarette price (pack price ≥ $4.50) was associated with lower consumption across all income levels. Although low-income individuals were least likely to adopt smoke-free homes, those who adopted them had consumption levels and successful quit rates that were similar to those among higher-income individuals. In multivariable analysis, both policies were independently associated with lower consumption, but only smoke-free homes were associated with sustained cessation at 90 days.
High cigarette prices and especially smoke-free homes have the potential to reduce smoking behaviors among low-income individuals. Interventions are needed to increase adoption of smoke-free homes among low-income populations to increase cessation rates and prevent relapse.
PMCID: PMC3828959  PMID: 24134354
3.  Endogenous Estradiol Is Not Associated with Poor Physical Health in Postmenopausal Breast Cancer Survivors 
Journal of Women's Health  2013;22(12):1043-1048.
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.
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.
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]).
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.
PMCID: PMC3852607  PMID: 24111813
4.  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.
PMCID: PMC3770774  PMID: 23649774
Breast cancer; smoking status; pack-years; mortality
5.  Postdiagnosis C-reactive protein and Breast Cancer Survivorship: findings from the WHEL Study 
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.
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).
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).
Acute inflammation status (CRP ≥10 mg/L) may be an important independent biomarker for long-term survival in breast cancer survivors.
Interventions to decrease circulating CRP concentrations in breast cancer survivors with acute inflammation may improve prognosis.
PMCID: PMC3911892  PMID: 24220913
C-reactive protein; all-cause mortality; breast cancer-specific mortality; recurrence
6.  Risk Factors Associated with Breast Cancer-Related Lymphedema in the WHEL Study 
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.
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.
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.
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.
PMCID: PMC3568206  PMID: 23212606
Breast cancer survivors; Lymphedema; Risk factors; Body mass index; Lymph node removal; Breast cancer treatment
7.  Menthol cigarettes and smoking cessation among racial/ethnic groups in the United States 
Addiction (Abingdon, England)  2010;105(0 1):84-94.
To examine the association between smoking mentholated cigarettes and smoking cessation, separately for different racial/ethnic groups.
Secondary data analysis of the 2003 and 2006–07 Tobacco Use Supplements to the Current Population Survey.
United States.
African American, Asian American/Pacific Islander, Hispanic/Latino, Native American, non-Hispanic white adults.
Examined relations between the use of mentholated cigarettes and measures of smoking cessation.
Among African Americans (ORadj = 1.62, 95% CI: 1.35–1.95) and Hispanics/Latinos (ORadj = 1.21, 95% CI: 1.00–1.47), those who currently smoked mentholated cigarettes were more likely be seriously considering quitting in the next six months than were non-menthol smokers, after adjusting for sociodemographic factors. African Americans (ORadj = 1.87, 95% CI: 1.60– 2.19) and Hispanics/Latinos (ORadj = 1.34, 95% CI: 1.11–1.62) who smoked mentholated cigarettes were also significantly more likely to have a positive estimation of successfully quitting in the next six months compared to non-menthol smokers. These associations were not found among Asian Americans/Pacific Islanders, Native Americans/Alaska Natives and Non-Hispanic Whites. Among former smokers, across racial/ethnic groups, those who smoked mentholated cigarettes (vs. non-menthols) were significantly less likely to have successfully quit for at least six months: African Americans (ORadj = 0.23, 95% CI: 0.17–0.31), Asian Americans/Pacific Islanders (ORadj = 0.22, 95% CI: 0.11–0.45), Hispanics/Latinos (ORadj = 0.48, 95% CI: 0.34–0.69) and Non-Hispanic Whites (ORadj = 0.28, 95% CI: 0.25–0.33).
Across race/ethnic groups, those who used to regularly smoke mentholated cigarettes were less likely to have experienced long-term quitting success. Cessation programs should consider the type of cigarette typically smoked by participants, particularly menthols.
PMCID: PMC4214376  PMID: 21059139
Cessation; race/ethnicity
8.  Prognosis following the use of complementary and alternative medicine in women diagnosed with breast cancer 
The purpose of this study was to assess whether CAM use affected breast cancer prognosis in those who did not receive systemic therapy.
Secondary data analysis of baseline/survey data from the Women's Healthy Eating and Living Study (WHEL). 2562 breast cancer survivors participating in the study completed baseline assessments and a CAM use questionnaire. Cox regression models were conducted to evaluate the use of CAM modalities and dietary supplements on time to an additional breast cancer event (mean follow-up = 7.3 years).
A US-based multi-site randomized dietary trial.
Time to additional breast cancer events.
The women who did not receive any systemic treatment had a higher risk for time to additional breast cancer events (HR=1.9, 95% CI: 1.32, 2.73) and for all-cause mortality (HR=1.7, 95% CI: 1.06, 2.73) compared to those who had received systemic treatment. Among 177 women who did not receive systemic treatment, CAM use was not significantly related to additional breast cancer events. There were no significant differences between high supplement users ( ≥ 3 formulations per day) and low supplement users in either risk for additional breast cancer events.
The risk for an additional breast cancer event and/or death was higher for those who did not receive any systemic treatments; the use dietary supplements or CAM therapies did not change this risk. This indicates that complementary and alternative therapies did not alter the outcome of breast cancer and should not be used in place of standard treatment.
PMCID: PMC3413169  PMID: 22863642
breast cancer; complementary and alternative medicine; dietary supplements; long- term prognosis; alternative cancer treatment
9.  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.
PMCID: PMC3857028  PMID: 23867158
10.  Post-diagnosis Cruciferous Vegetable Consumption and Breast Cancer Outcomes: a Report from the After Breast Cancer Pooling Project 
Cruciferous vegetables are a major source of glucosinolate-derived bioactive compounds such as isothiocyanates, which have been shown in animal and in vitro studies to inhibit cancer growth and progression. Few studies have investigated cruciferous vegetable intake after diagnosis and breast cancer outcomes. Using data from the After Breast Cancer Pooling Project, which includes prospective data from US and Chinese breast cancer survivors, we evaluated the association of cruciferous vegetables with breast cancer outcomes. Analyses included 11,390 women diagnosed with stage I–III invasive breast cancer (1990–2006) from four cohorts. Cruciferous vegetable intake (g/day) was assessed using food frequency questionnaires (mean of 22 months post-diagnosis). Study heterogeneity was evaluated by the Q statistic; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using delayed-entry Cox regression models stratified by study. After a median follow-up of 9.0 years, 1,725 deaths and 1,421 recurrences were documented. In pooled analyses using study-specific quartiles, cruciferous vegetable intake was not associated with breast cancer outcomes, adjusting for known clinical prognostic factors and selected lifestyle factors. HRs (95%CIs) by increasing quartiles (reference=lowest quartile) were 1.08 (0.93–1.25), 1.01 (0.87–1.18), and 1.10 (0.95–1.28) for recurrence (Ptrend=0.34) and 1.01 (0.88–1.15), 0.97 (0.84–1.11), and 0.99 (0.86–1.13) for total mortality (Ptrend=0.84). No associations were observed for subgroups defined by ER status, stage, or tamoxifen therapy. Cruciferous vegetable intake at approximately two years after diagnosis was not associated with recurrence or mortality. Our results do not support an association between post-diagnosis cruciferous vegetable intake and breast cancer outcomes.
PMCID: PMC3732536  PMID: 23765086
dietary factors; cruciferous vegetables; breast cancer; prognosis; survival
11.  Correlates of 25-hydroxyvitamin D and breast cancer stage in the Women’s Healthy Eating and Living Study 
Nutrition and cancer  2013;65(2):188-194.
Inverse associations between circulating 25-hydroxyvitamin D [25(OH)D] and breast cancer stage have been reported, thus it is critical to understand the variables that contribute to 25(OH)D levels among women with breast cancer. Among 904 women in the Women’s Healthy Eating and Living Study, plasma 25(OH)D concentrations were measured and data on demographic characteristics, diet, physical activity, and tumor characteristics were collected at study entry. Statistically significant associations with 25(OH)D concentrations were observed for body mass index (BMI), body surface area (BSA), height, smoking, total vitamin D intake, physical activity, and race or ethnicity. Of the correlates of 25(OH)D, BMI, BSA, height, physical activity, and study site were associated with stage of breast cancer; however, concentrations of 25(OH)D were not significantly related to stage. In fully adjusted logistic regression models, the ORs (95% CIs) for the association between vitamin D deficiency and Stage II and III cancers were 0.85 (0.59-1.22) and 1.23 (0.71-2.15), respectively (p-trend=0.59), compared to Stage I. This study confirms previous work regarding the correlates of 25(OH)D concentrations but does not provide support for an association between vitamin D status and breast cancer stage.
PMCID: PMC4041275  PMID: 23441606
12.  Post-diagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project 
Vitamin supplement use after breast cancer diagnosis is common, but little is known about long-term effects on recurrence and survival. We examined post-diagnosis supplement use and risk of death or recurrence in the After Breast Cancer Pooling Project, a consortium of 4 cohorts of 12,019 breast cancer survivors from the United States and China.
Post-treatment supplement use (Vitamins A, B, C, D, E, and multivitamins) was assessed one to five years post-diagnosis. Associations with risk of recurrence, breast cancerspecific mortality, or total mortality were analyzed in Cox proportional hazards models separately by cohort. Individual cohort results were combined using random effects metaanalysis. Interactions with smoking, treatment, and hormonal status were examined.
In multivariate models, vitamin E was associated with a decreased risk of recurrence (RR: 0.88; 95% CI: 0.79–0.99) and vitamin C with decreased risk of death (RR: 0.81; 95% CI: 0.72–0.92) However, when supplements were mutually adjusted, all associations were attenuated. There were no statistically significant associations with breast cancer mortality. Use of anti-oxidant supplements (multivitamins, vitamin C or E) was not associated with recurrence, but was associated with a 16% decreased risk of death (95% CI: 0.72–0.99). Additionally, vitamin D was associated with decreased risk of recurrence among ER positive, but not ER negative tumors (p-interaction=0.01).
In this large consortium of breast cancer survivors, post-treatment use of vitamin supplements was not associated with increased risk of recurrence or death. Post-treatment use of anti-oxidant supplements were associated with improved survival, but the associations with individual supplement were difficult to determine. Stratification by ER status and considering antioxidants as a group may be more clinically relevant when evaluating associations with cancer risk and mortality.
PMCID: PMC3698864  PMID: 23660948
breast cancer; vitamins; survival; mortality
13.  Call to Action: Promoting Domestic and Global Tobacco Control by Ratifying the Framework Convention on Tobacco Control in the United States 
PLoS Medicine  2014;11(5):e1001639.
Tim K. Mackey and colleagues outline why the United States should ratify the Framework Convention on Tobacco Control (FCTC).
Please see later in the article for the Editors' Summary
PMCID: PMC4011850  PMID: 24800816
14.  Changing age-specific patterns of cigarette consumption in the United States, 1992–2002: Association with smoke-free homes and state-level tobacco control activity 
Nicotine & Tobacco Research  2009;11(2):171-177.
During the 1990s, both prevalence and average cigarette consumption declined in the United States, but age-specific changes have not been reported.
All four of the nationally and state representative U.S. Current Population Surveys—Tobacco Use Supplements from 1991–2002 (n = 542,470) were analyzed for trends in cigarette consumption among smokers in three age groups: 18–29, 30–44, and 45–64 years. A strength of tobacco control index ranking state of residence was added and weighted logistic regression analyses undertaken.
Over the decade, both prevalence and average consumption declined. Moderate-heavy smoking (≥15 cigarettes/day [CPD]) prevalence fell strongly over the period in all three age groups. For those aged ≥30 years, this reduction was accompanied by a similar drop in total smoking prevalence. For those aged 18–29 years, this reduction was associated with an increase in very light smoking (<5 CPD; 12% daily and 88% intermittent smokers) to 22.5% of current smokers with a much smaller reduction in prevalence. Smoke-free homes more than doubled in each age group and mediated the increase in very light smoking levels. Smoke-free workplaces and the strength of tobacco control in the state were also important predictors. Very light smoking was particularly prevalent among college students and graduates.
The marked reduction in prevalence of moderate-heavy smoking across age groups should translate into a reduced population risk of smoking-related disease in the near term. That this reduction is offset by an increase in light and intermittent smoking in young adults suggests the effectiveness of tobacco industry marketing and needs further research.
PMCID: PMC2658899  PMID: 19246423
15.  Classification of CAM Use and its Correlates in Early Stage Breast Cancer Patients 
Integrative cancer therapies  2011;10(2):138-147.
Self-reported use of complementary and alternative medicine (CAM) has been shown to increase following a cancer diagnosis, and breast cancer survivors are the heaviest users among cancer survivors. The aim of this study was to determine whether the prevalence estimate of CAM use varied according to classification of CAM. We used a comprehensive system to classify CAM users and test differences in demographic, lifestyle, quality of life, and cancer characteristics among them.
Study Design and Methods
Participants were 2562 breast cancer survivors participating in the Women's Healthy Eating and Living (WHEL) Study, aged 28-74 years. A structured telephone interview assessed CAM use, questioning about specific CAM practices, and whether use was related to cancer. We examined CAM use in relation to demographics, health behaviors, and quality of life.
Approximately 80% of the women used CAM for general purposes but only 50% reported CAM use for cancer purposes. Visual imagery, spiritual healing, and meditation were the most frequently used practices for cancer purposes. CAM use, defined as consulting a CAM practitioner and regular use, was significantly related to younger age, higher education, increased fruit & vegetable intake, and lower body mass index (p < .05). CAM users who had seen a practitioner were also more likely to report poor physical and mental health than non-CAM users (p < .05). CAM use was not associated with changes in physical and mental health between study baseline and 1-year follow-up.
This study addressed important differences in the classification of CAM use among breast cancer survivors. Future studies need to further test the potential benefits and risks associated with CAM use.
PMCID: PMC3126886  PMID: 21382963
16.  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.
PMCID: PMC3081375  PMID: 21430657
Cancers; CYP; Epidemiology; Pharmacogenetics; Genotype
17.  Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes 
We examined if the reduced risk of breast cancer events seen among women without baseline hot flash symptoms in the Women’s Healthy Eating and Living (WHEL) dietary intervention trial was related to changes in sex hormone concentrations.
Baseline and year one concentrations of total and bioavailable estradiol and testosterone and sex hormone binding globulin (SHBG) were compared by intervention arm among 447 postmenopausal women without hot flashes. Cox proportional hazard models tested interaction terms between study arm and baseline hormone concentrations adjusted for study site, anti-estrogen use, positive nodes, tumor size, oophorectomy status, and hormone replacement therapy use.
Sex hormone concentrations did not differ by study arm at baseline nor at year one. Twenty-two (9.8%) events occurred in the intervention arm vs. 42 (18.9%) in the comparison arm (p=0.009). Baseline bioavailable testosterone was significantly, positively associated with additional events (HR 1.69, 95% CI: 1.00-2.84; p=0.049). There were significant interactions between the intervention and total (p=0.015) and bioavailable (p=0.050) testosterone: the intervention was more protective among participants with higher baseline total (HR 0.3, 95% CI: 0.2-0.7) or bioavailable (HR 0.4, 95%CI: 0.2-0.7) testosterone than for participants with lower baseline total (HR 0.8, 95% CI: 0.4-1.5) or bioavailable (HR 0.8, 95%CI: 0.4-1.5) testosterone. No significant effects were seen for estradiol or SHBG.
The WHEL dietary intervention may have modified other risk factors of recurrence correlated with testosterone.
Sex hormones should be considered as part of a larger biological system related to the risk of breast cancer recurrence.
PMCID: PMC3089679  PMID: 21415358
Postmenopausal; hot flashes; sex hormones; breast cancer
18.  Dietary Intake, Supplement Use, and Survival Among Women Diagnosed with Early Stage Breast Cancer 
Nutrition and cancer  2011;63(3):327-333.
Previous studies examining the relationship between micronutrient intakes and survival following diagnosis of breast cancer have reported mixed results. This may be partly due to considerable variance in amounts of micronutrients consumed from diet and supplements across studies.
Early stage breast cancer survivors (n=3081) completed four 24-hour dietary and supplement recalls at the baseline assessment (1995 to 2000) and were followed for a median of 9.0 years. Mean micronutrient intakes were compared to dietary reference intakes (DRI) to assess micronutrient adequacy for both users and non-users of supplements. Cox regressions were performed to assess whether intakes of selected micronutrients were associated with all-cause mortality.
412 deaths occurred between baseline and August 2009. Among these women, more supplement users had adequate micronutrient intakes than non-users for 15 out of 17 micronutrients. Less than 10% of supplement users (< 2% of non-supplement users) reported levels that exceeded the tolerable upper limit for each micronutrient except magnesium. After adjusting for age, tumor characteristics, and health status variables, micronutrient intakes were not significantly associated with all-cause mortality.
Dietary supplements may improve overall micronutrient intakes of breast cancer survivors. However, vitamin and mineral intakes were not associated with all-cause mortality.
PMCID: PMC3078826  PMID: 21391124
dietary intake; supplement use; breast cancer survival
19.  Leveraging Epidemiology and Clinical Studies of Cancer Outcomes: Recommendations and Opportunities for Translational Research 
As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled “Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities” on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival.
PMCID: PMC3545903  PMID: 23197494
20.  Poor Physical Health Predicts Time to Additional Breast Cancer Events and Mortality in Breast Cancer Survivors 
Psycho-Oncology  2011;20(3):252-259.
Health-related quality of life (HRQOL) has been hypothesized to predict time to additional breast cancer events and all-cause mortality in breast cancer survivors.
Women with early stage breast cancer (n=2967) completed the SF-36 (mental and physical health-related quality of life) and standardized psychosocial questionnaires to assess social support, optimism, hostility, and depression prior to randomization into a dietary trial. Cox regression was performed to assess whether these measures of quality of life and psychosocial functioning predicted time to additional breast cancer events and all-cause mortality; hazard ratios were the measure of association.
There were 492 additional breast cancer events and 301 deaths occurred over a median 7.3 years (range: 0.01–10.8 years) of follow-up. In multivariate models, poorer physical health was associated with both decreased time to additional breast cancer events and all-cause mortality (p trend=0.005 and 0.004, respectively), while greater hostility predicted additional breast cancer events only (p trend=0.03). None of the other psycho-social variables predicted either outcome. The hazard ratios comparing persons with poor (bottom two quintiles) to better (top three quintiles) physical health were 1.42 (95% CI: 1.16, 1.75) for decreased time to additional breast cancer events and 1.37 (95% CI: 1.08, 1.74) for all-cause mortality. Potentially modifiable factors associated with poor physical health included higher BMI, lower physical activity, lower alcohol consumption, and more insomnia (p<0.05 for all).
Interventions to improve physical health should be tested as a means to increase time to additional breast cancer events and mortality among breast cancer survivors.
PMCID: PMC3297415  PMID: 20878837
physical health; breast cancer; oncology; survival
21.  Post-diagnosis Alcohol Consumption and Breast Cancer Prognosis in the After Breast Cancer Pooling Project 
Alcohol consumption is an established risk factor for incident breast cancer. However, its role in breast cancer prognosis remains unclear.
We conducted an investigation of post-diagnosis alcohol consumption with recurrence and mortality among 9,329 breast cancer patients in the After Breast Cancer Pooling Project. Women were diagnosed from 1990-2006 with AJCC Stage I-III breast tumors from three prospective U.S. cohorts. Alcohol intake was assessed at cohort entry (mean 2.1 years post-diagnosis) using a food frequency questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using delayed entry Cox proportional hazards models with adjustment for known prognostic factors.
After a mean follow-up of 10.3 years, 1,646 recurrences and 1,543 deaths were ascertained. 5,422 women (58%) were considered drinkers (≥0.36 g/day of alcohol, ≥0.25 drinks/week) with a median of 5.3 g/day. Overall, compared with non-drinking, regular alcohol intake (≥6.0 g/day) was not associated with risk of recurrence (HR for 6-<12 g/day=1.03; 95% CI: 0.86, 1.24; HR for 12-<24 g/day=1.12; 95% CI: 0.93, 1.34; HR for ≥24 g/day=1.04; 95% CI: 0.84, 1.31). However, risk varied significantly by menopausal status (p for interaction<0.05). Postmenopausal women who regularly consumed alcohol (≥6.0 g/day) had increased risk of recurrence (HR=1.19; 95% CI: 1.01, 1.40). Alcohol intake was not associated with mortality.
Regular alcohol consumption was not associated with breast cancer recurrence and total mortality overall, yet recurrence risk was only elevated in postmenopausal women.
The association between alcohol intake and recurrence may depend on menopausal status at breast cancer diagnosis.
PMCID: PMC3538884  PMID: 23150063
alcohol; ethanol; estrogen; breast cancer; recurrence; mortality; prognosis
22.  Young Breast Cancer Survivors: Their Perspectives on Treatment Decisions and Fertility Concerns 
Cancer nursing  2011;34(1):32-40.
Younger women diagnosed with breast cancer are more likely to have survival concerns related to fertility, which may influence their treatment decisions.
This qualitative study explores how young women make cancer treatment decisions and the role of fertility concerns in that process.
We used purposeful sampling to identify a diverse group of 20 young breast cancer survivors, half of whom had a child after breast cancer. We conducted open-ended telephone interviews and used cross-case, inductive analysis to identify themes.
The main themes were: 1) I was young, I wanted to do everything possible to move forward with my life and not to have the cancer come back, 2) Fertility concerns are different for every woman 3) My oncologist was great… a huge part of my survivorship, and 4) They didn’t tell me about my options and I didn’t think about fertility until it was too late.
While fertility was important to many participants, treatment decisions were mainly motivated by survival concerns. Fertility concerns depended on life circumstances and the timing in relation to diagnosis varied. There is a need for improved information regarding the impact of treatment on fertility and fertility preservation options, even if concerns are not expressed at diagnosis.
Implications for Practice
It is critical that cancer care providers provide timely information regarding fertility. Oncology nurses are particularly well-positioned to serve this role by communicating with patients about their fertility concerns and reproductive planning prior to treatment and throughout the course of survivorship.
PMCID: PMC2980796  PMID: 20697269
breast cancer; young women; qualitative; treatment decisions; fertility
23.  Clinically Defined Type 2 Diabetes Mellitus and Prognosis in Early-Stage Breast Cancer 
Journal of Clinical Oncology  2010;29(1):54-60.
Self-reported diabetes has been associated with poor breast cancer outcomes. Research is needed to investigate the relationship between biologically determined glycemic control and breast cancer prognosis.
Archived baseline blood samples from the Women's Healthy Eating and Living Study were used to measure hemoglobin A1C (HbA1C) among 3,003 survivors of early-stage breast cancer (age of diagnosis, 28 to 70 years) observed for a median of 7.3 years for additional breast cancer events and 10.3 years for all-cause mortality. HbA1C levels provide an accurate, precise measure of chronic glycemic levels. Cox regression analysis was performed to assess whether baseline HbA1C levels predicted disease-free and overall survival.
Only 5.8% of women had chronic hyperglycemia (defined as HbA1C levels ≥ 6.5%). Those with HbA1C ≥ 6.5% were older and more likely to be less educated, have nonwhite ethnicity, be obese, and have more advanced breast cancer at diagnosis. HbA1C was significantly associated with overall survival (Ptrend < .001). After adjusting for confounders, risk of all-cause mortality was twice as high in women with HbA1C ≥ 7.0% compared with women with HbA1C less than 6.5% (hazard ratio [HR], 2.35; 95% CI, 1.56 to 3.54). For disease-free survival, there was a nonsignificant 30% increase in risk for HbA1C levels ≥ 7.0% (HR, 1.26; 95% CI, 0.78 to 2.02). During study follow-up, previously diagnosed rather than undiagnosed diabetes seemed to account for the increased risk.
Chronic hyperglycemia is statistically significantly associated with reduced overall survival in survivors of early-stage breast cancer. Further study of diabetes and its relationship to breast cancer outcomes is warranted.
PMCID: PMC3055860  PMID: 21115861
24.  Measurement Error of Dietary Self-Report in Intervention Trials 
American Journal of Epidemiology  2010;172(7):819-827.
Dietary intervention trials aim to change dietary patterns of individuals. Participating in such trials could impact dietary self-report in divergent ways: Dietary counseling and training on portion-size estimation could improve self-report accuracy; participant burden could increase systematic error. Such intervention-associated biases could complicate interpretation of trial results. The authors investigated intervention-associated biases in reported total carotenoid intake using data on 3,088 breast cancer survivors recruited between 1995 and 2000 and followed through 2006 in the Women's Healthy Eating and Living Study, a randomized intervention trial. Longitudinal data from 2 self-report methods (24-hour recalls and food frequency questionnaires) and a plasma carotenoid biomarker were collected. A flexible measurement error model was postulated. Parameters were estimated in a Bayesian framework by using Markov chain Monte Carlo methods. Results indicated that the validity (i.e., correlation with “true” intake) of both self-report methods was significantly higher during follow-up for intervention versus nonintervention participants (4-year validity estimates: intervention = 0.57 for food frequency questionnaires and 0.58 for 24-hour recalls; nonintervention = 0.42 for food frequency questionnaires and 0.48 for 24-hour recalls). However, within- and between-instrument error correlations during follow-up were higher among intervention participants, indicating an increase in systematic error. Diet interventions can impact measurement errors of dietary self-report. Appropriate statistical methods should be applied to examine intervention-associated biases when interpreting results of diet trials.
PMCID: PMC3025654  PMID: 20720101
bias (epidemiology); diet; intervention studies; Markov chain Monte Carlo; measurement error; nutrition assessment; reproducibility of results; validity
Women & health  2012;52(8):731-743.
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.
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.
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.
PMCID: PMC3491579  PMID: 23127215
Dietary fiber; carotenoids; antioxidants; diet; food

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