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BACKGROUND: Obesity is correlated with many biomarkers, but the extent to which these correlate with underlying body composition is poorly understood. OBJECTIVES: Our objectives were to 1) describe/compare distinct contributions of fat/lean mass with BMI–metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a 2-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (in kg/m(2)) was calculated using weight and height, whereas DXA estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite concentrations. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI; kg/m(2)) and lean mass index (LMI; kg/m(2)) correlations were estimated similarly, with mutual adjustment to evaluate independent effects. RESULTS: Using a Bonferroni-corrected α level 0.20), 25 modestly (0.10 ≤ |r| ≤ 0.20), and 7 virtually null (|r| < 0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non–BMI-correlated metabolites, 6 robustly correlated with FMI (|r| = 0.24–0.31) and 2 with LMI (r = 0.25–0.26). For these, correlations for fat and lean mass were in opposing directions compared with BMI-correlated metabolites, in which correlations were mostly in the same direction. CONCLUSIONS: Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI, provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relations is important for an accurate understanding of how and why obesity is associated with disease.

The impact of patient demographics and local therapy choice on arm morbidity in young breast cancer patients is understudied despite its importance given the long survivorship period. This study assessed patient-reported arm morbidity in the Young Women’s Breast Cancer Study (YWS), a prospective cohort study. From 2006 to 2016, 1302 women with breast cancer diagnosed at the age of 40 years or younger enrolled in the YWS. The participants regularly complete surveys. The response rates are higher than 86%. Using the Breast Cancer Prevention Trial Checklist, this study examined the prevalence of patient-reported postoperative arm swelling and decreased range of motion (ROM) 1 year after diagnosis, stratified by local therapy strategy, in patients who had surgery for stages 1 to 3 disease. Logistic regression analysis was used to identify risk factors for arm morbidity. Among 888 eligible participants (median age, 37 years), 14% reported arm swelling and 34% reported decreased ROM at 1 year. Arm swelling was reported by 23.6% of the patients who had axillary lymph node dissection (ALND) and 24.6% of the patients who received ALND and post-mastectomy radiation therapy (PMRT). In the multivariable analysis, the patients who reported being financially uncomfortable or who had ALND were at higher risk of arm swelling at 1 year. Being overweight, receiving ALND after sentinel lymph node biopsy, and receiving PMRT were associated with decreased ROM at 1 year. High rates of self-reported arm morbidity in young breast cancer survivors were reported, particularly in patients receiving ALND and PMRT. Attention to the risks and benefits of differing local therapy strategies for ALND and PMRT patients is warranted.

Context Women with breast cancer treated with aromatase inhibitor (AI) therapy experience multiple concurrent symptoms or symptom clusters. Understanding of the symptom experience and identifying symptom clusters before and during AI therapy are important for the development of interventions to improve clinical outcomes. Objectives The aim of this study was to identify symptom clusters experienced by women with breast cancer treated with AI therapy from pre–adjuvant therapy up to 18 months of adjuvant therapy using a broad scope of symptoms assessment. Methods Forty-seven symptoms were evaluated in postmenopausal women with breast cancer (N = 354) who received AI therapy or chemotherapy followed by AI therapy. Symptoms were assessed at four semiannual time points with the Breast Cancer Prevention Trial Symptom Checklist, Patient's Assessment of Own Functioning Inventory, Beck Depression Inventory-II, and Profile of Mood States Tension/Anxiety and Fatigue/Inertia subscales. Exploratory factor analyses were conducted at each time point to identify symptom clusters. Results Four stable symptom clusters (i.e., musculoskeletal, vasomotor, urinary, sexual) and three relatively stable symptom clusters (i.e., psychological, neurocognitive, weight) were identified across the 18-month follow-up period. The gastrointestinal symptom cluster only appeared at after six months of adjuvant therapy (postchemotherapy). Conclusion This study helps us to better understand the most common symptom clusters over the first 18 months of adjuvant therapy among postmenopausal women with early-stage breast cancer. It is critical for health care providers to know the symptom clusters commonly experienced by women receiving AI therapy with or without chemotherapy and manage them properly over time.

Purpose The aim of the current study was to describe and compare endocrine therapy-related symptoms and quality of life in female cancer survivors taking aromatase inhibitors, tamoxifen, and no endocrine therapy, and to evaluate the effect of an exercise intervention on these symptoms and quality of life. Design Randomized controlled trial. An aerobic resistance exercise intervention group was compared with a home-based exercise control group over 1 year. The exercise intervention was supervised for the first 6 months, followed by 6 unsupervised months. Methods Perimenopausal and early postmenopausal female cancer survivors within 3 years of completing primary or adjuvant chemotherapy were selected. A total of 154 women were enrolled in the study. Type of endocrine or hormonal therapy was documented. Symptoms were measured by the Breast Cancer Prevention Trial Symptom Checklist and the Functional Assessment of Cancer Therapy-Endocrine Subscale. Quality of life was measured by the Functional Assessment of Cancer Therapy-General. Data were collected at baseline, and at 6 and 12 months. Findings Participants generally had mild symptom distress. There was no difference in symptoms by endocrine therapy group or by exercise group. Participants taking aromatase inhibitors in the aerobic resistance exercise intervention group reported significant improvement in social, family, and functional well-being and better quality of life compared to those in the control group at 6 months but not at 12 months. Conclusions Findings were similar to those of previous large clinical trials in that no significant differences were found for endocrine therapy-related symptoms and quality of life by type of endocrine therapy taken. However, exercise may improve quality of life outcomes for women taking aromatase inhibitors. Clinical relevance Exercise has established efficacy for patient outcomes such as cardiovascular fitness, fatigue, weight management, and quality of life and may provide better quality of life for women who take aromatase inhibitors as adjuvant therapy.

OBJECTIVE: To compare, in the setting of breast cancer (BrCa) prevention, the impact of estrogen-based hormone replacement therapy (E-HRT) vs. tamoxifen (TAM) on breast cancer mortality (BrCa-M) and breast cancer case fatality ratio (BrCa-CFR), by analyzing data from the Women's Health Initiative Trial 2 (WHI HRT Trial 2, E-HRT vs. placebo [P])1 and the International Breast Cancer Intervention Study 1 (IBIS-1), TAM vs. P.2 METHODS: Hazard ratios (HR) and confidence intervals (CI) for BrCa incidence and mortality were extracted from the original WHI HRT Trial 2 and IBIS-1 trials.1,2 BrCa-CFRs were estimated by dividing the mortality HR by the incidence HR. Subsequently, to compare E-HRT vs. TAM outcomes, the ratios of HRs (HR1/HR2) between the two trials were estimated separately for BrCa-M and BrCa-CFR. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported. RESULTS: Mortality and Case Fatality Outcomes: Impact of E-HRT versus TAM, expressed as ratio of HRs E-HRT vs. Placebo, HR1TAM vs. Placebo, HR2HR1/HR2pMortality0.55 (0.33-0.92)1.19 (0.68-2.10)0.46 (0.22-0.99)0.046Case Fatality0.70 (0.40-1.20)1.68 (0.93-3.01)0.42 (0.18-0.94)0.040 CONCLUSIONS: While acknowledging between-trial comparisons including eligibility differences, E-HRT yields significant reductions in BrCa mortality and case fatality as compared with TAM (54% and 58% respectively). These unexpected breast cancer mortality reductions represent major public health gains, additional to the already known superiority of E-HRT over TAM in terms of skeletal fracture rates and Alzheimer's dementia mortality reduction, and, in women entering menopause, also of cardiac and all-cause mortality reductions. REFERENCES: 1. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38. 2. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. The Lancet Oncology 2015;16:67-75. Citation Format: Ragaz J, Shakeraneh S, Qian H, Wilson KS, Wong H, Spinelli JJ. Estrogen-based hormone replacement [HRT] therapy is substantially more effective than tamoxifen in reducing breast cancer mortality and breast cancer case fatality ratio: Emergence of a new paradigm [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-06.

Purpose We evaluated demographic and clinical characteristics associated with participation in a clinical trial testing the efficacy of an online tool to support breast cancer risk communication and decision support for risk mitigation to determine the generalizability of trial results. Methods Eligible women were members of Kaiser Permanente Washington aged 40-69 years with a recent normal screening mammogram, heterogeneously or extremely dense breasts and a calculated risk of > 1.67% based on the Breast Cancer Surveillance Consortium 5-year breast cancer risk model. Trial outcomes were chemoprevention and breast magnetic resonance imaging by 12-months post-baseline. Women were recruited via mail with phone follow-up using plain language materials notifying them of their density status and higher than average breast cancer risk. Multivariable logistic regression calculated independent odds ratios (ORs) for associations between demographic and clinical characteristics with trial participation. Results Of 2,569 eligible women contacted, 995 (38.7%) participated. Women with some college (OR = 1.99, 95% confidence interval [CI] 1.34-2.96) or college degree (OR = 3.35, 95% CI 2.29-4.90) were more likely to participate than high school-educated women. Race/ethnicity also was associated with participation (African-American OR = 0.50, 95% CI 0.29-0.87; Asian OR = 0.22, 95% CI 0.12-0.41). Multivariate adjusted ORs for family history of breast/ovarian cancer were not associated with trial participation. Discussion Use of plain language and potential access to a website providing personal breast cancer risk information and education were insufficient in achieving representative participation in a breast cancer prevention trial. Additional methods of targeting and tailoring, potentially facilitated by clinical and community outreach, are needed to facilitate equitable engagement for all women.

PURPOSE: A number of studies have shown that self-rated health reliably predicts mortality. This study assessed the impact of perseveration on self-rated health, physical functioning, and physical symptoms (pain, fatigue, breast cancer symptoms) among breast cancer patients. We hypothesized that cancer-related distress would serve as an intervening variable between both worry and rumination and self-rated health, physical functioning, and physical symptoms. METHODS: Women (N=124) who were approximately seven weeks post-surgery but pre adjuvant treatment completed the Impact of Events Scale, the Penn State Worry Questionnaire, and the Rumination Scale. They also rated their pain, fatigue, physical functioning, and self-rated health using the RAND-36 and breast cancer symptoms with the Breast Cancer Prevention Trial Symptom Checklist (BCPT). Covariates included body mass index, age, cancer stage, menopause status, and physical comorbidities. RESULTS: Worry was associated with higher cancer-related distress, which in turn predicted greater pain and breast cancer symptoms, poorer physical functioning, and lower self-rated health. Rumination also predicted greater cancer-related distress, which ultimately contributed to greater pain along with poorer physical functioning and self-rated health. Models with fatigue as an outcome were not significant. CONCLUSIONS: These findings suggest that perseveration can heighten cancer-related distress and subsequent perceptions of physical symptoms and health among breast cancer patients prior to adjuvant treatment. Perseveration early in the cancer trajectory can adversely increase the impact of a cancer diagnosis and treatment on functioning and quality of life.

Background Women with breast cancer experience a wide spectrum of symptoms after diagnosis and treatment. Symptoms experienced by this specific population might not be fully assessed using available traditional Chinese-language symptom measures. Objectives The aim of this study was to examine the latent constructs and psychometric properties of the Chinese Breast Cancer Prevention Trial (C-BCPT) Symptom Scale. Methods Two hundred women with breast cancer were recruited in Taiwan. Psychometric properties, including construct validity, internal consistency, and test-retest reliability, of the C-BCPT Symptom Scale were tested after translating the original instrument. Results A 21-item C-BCPT Symptom Scale, with 7 extracted factors accounting for 72.26% of the total variance, resulted from an exploratory factor analysis. Construct validity was confirmed by significant correlations between scores on the C-BCPT Symptom Scale and the Taiwan-version Short Form-36 Health Survey (r = -0.49 to -0.53)/Greene Climacteric Scale (r = 0.81). Reliability coefficients for the overall scale/6 extracted factors (Cronbach's α = 0.72-0.88) and test-retest reliability (intraclass correlation coefficients = 0.77-0.94) of the translated instrument were satisfactory, whereas 1 reliability coefficient for 1 extracted factor was inadequate (Cronbach's α = 0.57). Conclusion An interpretable structure with preliminary acceptable psychometric properties of the C-BCPT Symptom Scale was obtained; the C-BCPT can help traditional Chinese-speaking healthcare professionals perform adequate assessments of the symptoms experienced by women with breast cancer. Implications for practice The C-BCPT Symptom Scale can be used in clinical practice and research to assess symptoms experienced by this specific population or effects of related interventions.

BACKGROUND The authors investigated disparities in the survivorship experience among Latinas with breast cancer (BC) in comparison with non-Latinas. METHODS A cross-sectional bilingual telephone survey was conducted among 212 Latina and non-Latina women within 10 to 24 months after a diagnosis of BC (AJCC TNM staging system stage 0-III) at 2 Los Angeles County public hospitals. Data were collected using the Preparing for Life as a (New) Survivor (PLANS) scale, Perceived Efficacy in Patient-Physician Interactions Questionnaire (PEPPI), Breast Cancer Prevention Trial (BCPT) Symptom Checklist, Satisfaction with Care and Information Scale, Consumer Assessment of Healthcare Providers and Systems (CAHPS) tool, Charlson Comorbidity Index adapted for patient self-report, and the 12-item Short Form Health Survey. Controlling variables included age, stage as determined by the American Joint Committee on Cancer (AJCC) TNM staging system, educational level, and study site in multivariate analyses. RESULTS The mean ages of Latinas and non-Latinas were 51.5 years and 56.6 years, respectively. Compared with non-Latinas, Latinas reported less BC survivorship knowledge (27.3 vs 30.7; P

Background: SOLE efficacy results presented at ASCO 2017 showed that extended intermittent vs continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women who had received 4-6 years of adjuvant endocrine therapy for hormone-receptor positive (HR+), lymph-node positive breast cancer. Previous studies showed that the burden by symptoms related to endocrine therapy can be substantial. Even if symptoms improve during the treatment course, extending treatment implies continuation of symptoms. We compared differences in patient-reported symptoms (PRS) and quality of life (QoL) between extended continuous and intermittent letrozole over the first two years of trial treatment. Methods: From Nov 2007 to Dec 2010, 956 postmenopausal women who were disease-free following 4-6 years of prior adjuvant endocrine therapy for HR+, node-positive breast cancer were enrolled in the QoL substudy of the randomized phase III trial SOLE at selected centers. Patients receive extended continuous letrozole (2.5 mg daily) for 5 years or intermittent letrozole, taken for the first 9 months of years 1-4, and 12 months in year 5. 955 patients completed the 18-item Breast Cancer Prevention Trial (BCPT) Symptom Scales and further symptom-specific and global QoL indicators at baseline, and at 6, 12, 18 and 24 months after randomization. Differences in change of PRS and QoL from baseline between the two administration schedules were tested at 12 and 24 months for 8 symptom scales, 4 additional symptom and 4 global QoL indicators using mixed models with repeated measures. Results: Small changes in PRS and QoL scores were observed between baseline and 12 months after randomization, i.e. at the end of the first treatment-free interval in the intermittent arm. These changes showed a consistent pattern of greater worsening for patients receiving continuous compared to patients receiving intermittent letrozole. Patients receiving continuous letrozole reported a significantly greater worsening in vaginal problems (p Conclusion: Although changes in PRS and QoL were small, there was a consistent pattern favoring the intermittent arm. For several symptoms and global QoL indicators, significantly less worsening was observed with the intermittent administration, mainly during the first year of extended treatment, due to small improvements during the treatment-free interval. Froma QoL perspective, women who suffer from endocrine side-effects in the extended setting may benefit from an intermittent administration. Citation Format: Ribi K, Luo W, Colleoni M, Karlsson P, Chirgwin J, Aebi S, Jerusalem G, Neven P, Di Lauro V, Gomez HL, Ruhstaller T, Abdi E, Di Leo A, Müller B, Maibach R, Gelber RD, Goldhirsch A, Coates AS, Regan MM, Bernhard J. Extended continuous vs intermittent adjuvant letrozole in postmenopausal women with lymph node-positive, early breast cancer (IBCSG 37-05/BIG 1-07 SOLE): Impact on patient-reported symptoms and quality of life [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-18-01.

Background: The Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) trial showed that chemoprevention can reduce the risk of invasive breast cancer by nearly 50%. Despite these results, studies have shown that while an estimated 2 million women in the United States are eligible for chemoprevention, actual acceptance of these medications is low. Improving chemoprevention utilization rates hinges on better understanding current rates of utilization and factors affecting patient acceptance. Reported rates and barriers to chemoprevention use may not accurately reflect true utilization patterns in lower socioeconomic, minority patient populations. The aim of this IRB approved retrospective study was to characterize the rate and factors associated with chemoprevention use in patients with a diagnosis of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in-situ (LCIS) at an urban hospital with a high minority population. Methods – A retrospective chart review was performed for all diagnoses of ADH, ALH, and LCIS made at the University of Maryland Medical Center between the years 2005-2015. Concurrent DCIS or invasive cancer were excluded. Demographic and clinical information including age, race, education, GAIL score, BMI, and use of chemoprevention was recorded. Univariable and multivariable logistic regression were performed to identify factors associated with chemoprevention discussion and use. Results – 301 diagnoses of ADH/ALH/or LCIS were obtained and 127 women were eligible for analysis. The median age was 53 years old with 47% of patients being premenopausal. The majority were African-American (65%) and 51% had a high school degree or less. The median 5 year risk for developing breast cancer based on the GAIL model was 2.4%. The chemoprevention utilization rate for our patient population was 28% (n=34). Race, menopausal status, and breast density were not associated with chemoprevention discussion or use. We found that patients were more likely to have a chemoprevention discussion with their provider if they were older (p=0.03) or if they were referred to medical oncology (p Conclusions - Our study evaluated chemoprevention use in an understudied predominantly African-American patient population. We found a higher rate of chemoprevention utilization (28%) compared to previously reported rates. Age and medical oncology referral had a significant impact on provider-patient chemoprevention discussion. Though limited due to small sample size, our study nonetheless provided thought provoking results. Older patients may be at higher risk for developing breast cancer, however, it is important to consider that younger patients with risk factors may have a more favorable endocrine therapy benefit-risk ratio. In addition, our results highlight the importance of encouraging all physicians who are involved in women's' breast health to have a chemoprevention discussion with eligible patients, or for these physicians to refer patients to a medical oncologist for further discussion. Citation Format: DeRidder A, Mainor C, Goloubeva O, Ioffe O, Bellavance E, Tkaczuk K, Rosenblatt P. Chemoprevention utilization in patients with a history of atypical hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in-situ: A retrospective chart review of patients diagnosed at an urban hospital with a large minority patient population [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-13-02.

OBJECTIVES: Recent metabolomics studies have identified metabolic correlates of body mass index (BMI), but the degree to which correlations are driven by fat mass as opposed to lean mass has not been established. Our objectives were to 1) replicate findings of BMI-metabolite correlations, and 2) to describe the contributions of FM and LM to the BMI-metabolite associations. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-center randomized trial of healthy but inactive, postmenopausal women (N = 304). BMI (kg/m(2)) was calculated using measured weight and height, while whole body dual X-ray absorptiometry estimated fat mass and lean mass. Serum metabolite levels were measured by ultra-performance liquid chromatography and high-resolution/accurate mass spectrometer. We estimated partial Pearson correlations between 1053 metabolites and BMI, adjusting for age, smoking, and study site. Fat mass/m(2) and lean mass/m(2) correlations were estimated similarly, with mutual adjustment for one another to evaluate independent effects after accounting for their positive intercorrelation. RESULTS: Using a Bonferroni-corrected alpha-level 0.20), and five had virtually no fat mass/m(2) correlation (|r

Background Cancer-related cognitive impairment is an emerging public health burden. Growing research suggests that sleep disturbances contribute to poor cognition. Our study aimed to evaluate the association between insomnia and cognitive impairment in breast cancer survivors. Methods We analyzed cross-sectional data from a cohort study of postmenopausal women with stage 0–III hormone receptor-positive breast cancer on aromatase inhibitor therapy. The study was conducted between November 2011 and April 2015 at an academic cancer center (Philadelphia, PA). Insomnia was assessed with the Insomnia Severity Index. Perceived cognitive impairment was assessed with the cognitive subscale of the Breast Cancer Prevention Trial Symptom Checklist. We used linear regression to evaluate the association between insomnia and perceived cognitive impairment. Results Among 1072 patients, 556 (51.9%) reported insomnia and 847 (79.0%) were bothered by cognitive symptoms (forgetfulness, difficulty concentrating, distractibility). Greater perceived cognitive impairment was reported by patients with mild insomnia (regression coefficient [β] = 0.35, 95% confidence interval [CI] = 0.23 to 0.46, P Conclusions Among postmenopausal breast cancer survivors receiving aromatase inhibitor therapy, insomnia and cognitive impairment are prevalent and characterized by a graded association, in which severity of perceived cognitive impairment increases as insomnia severity increases. Our findings warrant further research to determine whether addressing sleep is a strategy to improve management of cancer-related cognitive impairment.

The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)‐10 and IL‐4 in two randomized trials of physical activity. The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA, n = 320) and the Breast Cancer and Exercise Trial in Alberta (BETA, n = 400) were two‐center, two‐armed randomized trials in inactive, healthy, postmenopausal women. Both trials included an exercise intervention prescribed five times/week and no dietary changes. In ALPHA, the exercise group was prescribed 225 min/week versus no activity in the controls. BETA examined dose‐response effects comparing 300 (HIGH) versus 150 (MODERATE) min/week. Plasma concentrations of IL‐10 and IL‐4 were measured at baseline, 6, and 12 months. Intention‐to‐treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. Circulating anti‐inflammatory cytokine levels decreased among all groups, with percent change ranging from −3.4% (controls) to −8.2% (HIGH) for IL‐4 and −1.6% (controls) to −7.5% (HIGH) for IL‐10. No significant group differences were found for IL‐4 (ALPHA P = 0.54; BETA P = 0.32) or IL‐10 (ALPHA P = 0.84; BETA P = 0.68). Some evidence for moderation of the effect of exercise by baseline characteristics was found for IL‐10 but not for IL‐4. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL‐10 or IL‐4 in a manner consistent with chronic disease and cancer prevention.

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I–IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (

1534 Background: Women with germline BRCA1/2 (gBRCA1/2) mutations have a 70% lifetime risk of breast cancer (BC). Medical prevention by aromatase inhibitors is effective in high-risk patients (pts), including those with familial risk. However, hormone prevention has not been specifically addressed in women (wn) carrying gBRCA1/2 mutations. Methods: LIBER is a randomized, double-blind, placebo-controlled phase III trial evaluating 5-year treatment with letrozole 2.5 mg/day (L) versus placebo (P) on decreasing BC incidence in post-menopausal women with gBRCA1/2 mutations ( NCT00673335 ). Eligible wn were aged 40-70 and could have had unilateral BC > 5 years ago. Randomization was stratified on mutation ( BRCA1/BRCA2), bilateral oophorectomy and history of prior BC. Primary endpoint was 5-year invasive BC-free survival (BC-FS) in wn with or without previous BC. Main secondary endpoints were safety and quality of life (menopause rating scale, SF36). 270 pts were required to observe 37 events to show a gain in 5-year invasive BC-FS from 80% to 92% (HR=0.35) with 1-sided α=0.05 and 90% power. Results: 170 wn were randomized from 02/2008 to 02/2013; 86 and 84 were assigned to the P and L arm. Median age was 55 years (range 40-70). Pt characteristics were well balanced; 59% and 41% carried gBRCA1 and gBRCA2 mutations. In P and L arms, 47% and 43% had prior BC, 43% and 42% stopped treatment prematurely, 37 and 23 serious adverse events occurred, and during active treatment, 8 and 10 wn had grade 3/4 toxicity. Median follow-up was 72.7 months. Five-year BC-FS did not significantly differ between the P and L arms (92% vs 91%, HR 0.83; 95%CI: 0.3-2.3, p=0.73) in the overall population, nor in the subgroups of wn with and without previous BC (74% vs 91%; HR 0.43; 95% CI: 0.1-1.3; 90% vs 86%; HR 1.29; 95% CI 0.4-3.9), gBRCA1 versus gBRCA2 or hormone receptor-positive BC. Letrozole had no effect on quality of life. The two groups did not significantly differ in bone density, which decreased over time in the overall population. Conclusions: In this prospective preventive trial, BC-FS was not significantly decreased by letrozole versus placebo in women with BRCA1/2 mutations. However, the study was underpowered (170 of 270 pts expected). Despite no differences in safety and quality of life, drop-out rate was high in both P and L arms. Clinical trial information: NCT00673335.

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.

Objective: The main objective of this study was to identify the problems of Nepalese breast cancer survivors living in an urban area who had completed their treatment for at least 6 months. Methods: A cross-sectional descriptive study was conducted to assess the problems of breast cancer survivors who were registered at the Nepal Cancer Support Group. Fifty-one women who were diagnosed with breast cancer (Stage 0 to III) and were currently disease-free were enrolled in the study. They were interviewed using structured interview schedule using the Breast Cancer Prevention Trial Symptom Scale. Statistical analysis was carried out with SPSS (version 16). Results: The mean age of the women at the time of enrollment was 47.3 years. The most common modality of treatment they received was the combination of surgery, chemotherapy, and radiotherapy (84%). Top five symptoms experienced by the survivors on the basis of frequency and severity were tiredness (61%), lack of energy (57%), forgetfulness (57%), lack of interest in sex (52%), general body aches (49%), and feeling of worrisome and anxiousness about future (49%). Women with age

Background: Several randomised clinical trials have shown the benefit of tamoxifen in healthy women to reduce their risk of breast cancer. Here, we report the blinded median 16 year follow-up of the IBIS-I trial to update the long-term prevention of breast cancer with tamoxifen treatment. Methods: 7154 pre- and postmenopausal women were randomised to receive daily 20mg tamoxifen (N=3579) or matching placebo (N=3575) for 5 years. The primary endpoint of this analysis was the occurrence of breast cancer (invasive and ductal carcinoma in situ (DCIS)). Secondary endpoints included overall mortality, other cancers, and breast cancer specific mortality. Cox proportional hazard models were used to assess occurrence of breast cancer and survival. All statistical tests were two-sided. Results: After a median of 16.2 years (IQR 14.4 to 17.7) of follow-up, a total of 589 breast cancers have been reported (tamoxifen: 246 (6.9%) vs. placebo: 343 (9.6%)). Tamoxifen reduced the incidence of all breast cancer overall by 29% (HR=0.71 (0.60-0.83), P Conclusion: This updated analysis of the IBIS-I trial confirms the significant reduction in breast cancer occurrence with tamoxifen in the post-treatment follow-up period. These results indicate tamoxifen has a long-term preventive effect on invasive ER+ breast cancer in both pre- and postmenopausal women. Citation Format: Jack Cuzick, Ivana Sestak, Simon Cawthorn, Hisham Hamed, Kaija Holli, Anthony Howell, John F Forbes. 16 year long-term follow-up of the IBIS-I breast cancer prevention trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-07.

Objective The purpose of this analysis was to examine the correlates of the physical and psychosocial domains of quality of life (QOL) in a cohort of breast cancer survivors participating in a weight loss intervention trial. Methods Correlates of QOL and psychosocial functioning were examined in 692 overweight or obese breast cancer survivors at entry into a weight loss trial. QOL was explored with three measures: Short-form 36 (SF-36), Impact of Cancer scale (IOC), and the Breast Cancer Prevention Trial (BCPT) symptom scales. Available data included information on weight and physical activity, as well as demographic and medical characteristics. Multivariate analyses were used to identify associations adjusted for other characteristics. Results In multivariate analysis, younger age was associated with higher negative impact scores (p

Aim: To describe the association between adiposity and repetitive element DNA methylation in healthy postmenopausal women. Patients & methods: A cross-sectional study was conducted using baseline information from 289 women who participated in the Alberta Physical Activity and Breast Cancer Prevention trial. Results: After adjusting for important confounders, long interspersed nuclear element-1 methylation was positively associated with intra-abdominal fat area (p = 0.03), body fat percent (p = 0.048), fat mass (p = 0.01), waist circumference (p = 0.03), hip circumference (p = 0.001), BMI (p = 0.03), current weight (p = 0.002), weight at age 20 (p = 0.02) and adulthood weight gain (p = 0.03). No significant associations were found between any of the adiposity measures and Alu methylation. Conclusion: Current and historical adiposity measures are positively associated with long interspersed nuclear element-1 methylation in healthy postmenopausal women.

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510–41. ©2017 AACR.

In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients’ quality of life (QoL). In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25–30% of patients reported a clinically relevant worsening in key symptoms and global QoL. Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. Clinical trial information: NCT00553410.

Objectives: Cancersurvivorsoftenreportcognitiveproblems.Furthermore,decreasesinphysicalactivity typically occur over the course of cancer treatment. Although physical activity benefits cognitive function in noncancer populations, evidence linking physical activity to cognitive function in cancer survivors is limited. In our recent randomized controlled trial, breast cancer survivors who received a yoga intervention had lower fatigue and inflammation following the trial compared with a wait list control group. This secondary analysis of the parent trial addressed yoga’s impact on cognitive complaints. Methods: Posttreatment stage 0–IIIA breast cancer survivors (n=200) were randomized to a 12-week, twice-weekly Hatha yoga intervention or a wait list control group. Participants reported cognitive complaints using the Breast Cancer Prevention Trial Cognitive Problems Scale at baseline, immediately postintervention, and 3-month follow-up. Results: Cognitive complaints did not differ significantly between groups immediately postintervention (p=0.250). However, at 3-month follow-up, yoga participants’ Breast Cancer Prevention Trial Cognitive Problems Scale scores were an average of 23% lower than wait list participants’ scores (p=0.003). These group differences in cognitive complaints remained after controlling for psychological distress, fatigue, and sleep quality. Consistent with the primary results, those who practiced yoga more frequently reported significantly fewer cognitive problems at 3-month follow-up than those who practiced less frequently (p

Genetic testing in the modern era increasingly examines multiple genes using next generation technologies. Most assays include the high penetrance genes, which confer lifetime breast cancer risk greater than 5-fold, include BRCA1/2, TP53, CDH1 and PALB2. Moderate penetrance genes are associated with lifetime breast cancer risk in the range of 2-3 fold, and include ATM, NF1, CHEK2 (mutation-specific) and NBN, with BARD1 and others potentially joining the group. Substantial data has emerged from studies of women with BRCA1/2 mutations, evaluating the performance of screening technologies, such as mammogram, breast MRI and ultrasound, and the efficacy of risk-reducing breast and ovarian/fallopian tube surgical procedures. Guidelines exist in the NCCN (US) and ESMO guidelines in Europe, among others, trying to provide recommendations for the age at which to initiate screening or undergo risk-reducing salpingo-oophorectomies, for example. Data are increasing on the moderate penetrance genes but there is still much reliance on extrapolation from the high-penetrance genes, which should be done thoughtfully. One approach is to estimate the age at which lifetime breast cancer risk equals the risk from a high penetrance gene when screening is to begin and initiate imaging surveillance at that time. For example, initiation of annual breast imaging would be at age 40 for ATM (RR 2.8) instead of age 25 as is done for BRCA1/2 or age 20 as for TP53. However, there are no data that this is the correct age at which to initiate screening, so this practical suggestion must meet criteria for reasonableness as well as effectiveness. Other source of data may include more precise gene-specific risk estimates from focused genetic epidemiology studies, and ongoing data from studies of prospectively identified mutation carriers. Further understanding of the mechanisms of carcinogenicity for mutation carriers may also help to provide insights that can guide therapeutic and preventive approaches. For example, the work on RANK ligand by Lindeman et al has led to the development of a definitive breast cancer prevention trial examining the RANK-Ligand inhibitor Denosumab in BRCA1 mutation carriers, entitled BRCA-P, being led by C. Singer of the ABCSG and Dr. Lindeman, and to be conducted in sites around the world. Other approaches are in development and will be discussed. Citation Format: Garber JE. Managing increased breast cancer risk based on high and moderate penetrance gene mutations [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES2-3.

Little is known about the cognitive factors associated with adherence to antiestrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral antiestrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled nondemented participants ≥65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol ≥80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2 ± 4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were nonadherent. In adjusted analyses, the odds of nonadherence were lower for those with better scores on verbal memory [OR (95% confidence interval): 0.75 (0.62–0.92)]. Larger relative deficits in verbal memory compared with verbal fluency were also associated with nonadherence [1.28 (1.08–1.51)]. Among nondemented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence. Cancer Prev Res; 7(1); 161–8. ©2013 AACR.

Breast cancer is a heterogeneous disease affecting thousands of people every year. Multiple factors are responsible in causing breast cancer while a number of treatment options are also available for the disease. Tamoxifen is the most widely used anti-estrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit estrogen receptor positive breast cancer. The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6. Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy and provides effective palliation for patients with metastatic breast cancer. In this review we focus on the role of Tamoxifen in breast cancer treatment including mechanisms and side-effects. Finally, we discuss in detail the exciting prospects that lie ahead.

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.

Background Recruitment of minorities to cancer prevention trials is difficult and costly. Early-phase cancer prevention trials have fewer resources to promote recruitment. Identifying cost-effective strategies that can replace or supplement traditional recruitment methods and improve minority accrual to small, early-phase cancer prevention trials are of critical importance. Purpose To compare the costs of accrual strategies used in a small breast cancer prevention trial and assess their impact on recruitment and minority accrual. Methods A total of 1196 potential subjects with a known recruitment source contacted study coordinators about the SOY study, a breast cancer prevention trial. Recruitment strategies for this study included recruitment from within the Northwestern University network (internal strategy), advertisements placed on public transportation (Chicago Transit Authority (CTA)), health-related events, media (print/radio/television), and direct mail. Total recruitment strategy cost included the cost of study personnel and material costs calculated from itemized receipts. Incremental cost-effectiveness ratios (ICERs) were calculated to compare the relative cost-effectiveness of each recruitment strategy. If a strategy was more costly and less effective than its comparator, then that strategy was considered dominated. Scenarios that were not dominated were compared. The primary effectiveness measure was the number of consents. Separate ICERs were calculated using the number of minority consents as the effectiveness measure. Results The total cost of SOY study recruitment was US$164,585, which included the cost of materials (US$26,133) and personnel (US$138,452). The internal referral strategy was the largest source of trial contacts (748/1196; 63%), consents (107/150; 71%), and minority consents (17/34; 50%) and was the most expensive strategy (US$139,033). CTA ads generated the second largest number of trial contacts (326/1196; 27%), the most minority contacts (184/321; 57%), and 16 minority consents (16/34; 47%), at a total cost of US$15,562. The other three strategies yielded many fewer contacts and consents. The methods of health events, CTA ads, and the internal strategy showed some evidence of cost-effectiveness (ICER: US$581, US$717, and US$1524, respectively). The CTA strategy was the most cost-effective strategy for minority accrual (ICER: US$908). Limitations Recall bias may have limited the accuracy of estimated time spent on recruitment by study personnel. Also, costs spent specifically on minority accrual were unobtainable; results may not be generalizable to other settings; and cost-effectiveness data for the methods of media, health events, and direct mail should be interpreted with caution since these methods generated few consents. Conclusions Public transportation ads have the potential to generate numerous minority contacts and consents at a reasonable cost within an urban setting. Combined with traditional methods of recruitment, this method can lead to timelier study completion and increased minority accrual. Future research should prospectively track recruitment and costs in order to better assess the cost-effectiveness of recruitment methods used to target minority populations.

The dramatic increase in breast cancer incidence compels a paradigm shift in our preventive efforts. There are several barriers to overcome before prevention becomes an established part of breast cancer management. The objective of this review is to identify the clinical challenges for improved breast cancer prevention and discuss current knowledge on breast cancer risk assessment methods, risk communication, ethics, and interventional efforts with the aim of covering the aspects relevant for a breast cancer prevention trial. Herein, the following five areas are discussed: (i) Adequate tools for identification of women at high risk of breast cancer suggestively entitled Prevent! Online. (ii) Consensus on the definition of high risk, which is regarded as mandatory for all risk communication and potential prophylactic interventions. (iii) Risk perception and communication regarding risk information. (iv) Potential ethical concerns relevant for future breast cancer prevention programs. (v) Risk-reducing programs involving multileveled prevention depending on identified risk. Taken together, devoted efforts from both policy makers and health care providers are warranted to improve risk assessment and risk counseling in women at risk for breast cancer to optimize the prevention of breast cancer. Cancer Prev Res; 11(5); 255–64. ©2018 AACR.

Background Oxidative stress may contribute to cancer aetiology through several mechanisms involving damage to DNA, proteins and lipids leading to genetic mutations and genomic instability. The objective of this study was to determine the effects of aerobic exercise on markers of oxidative damage and antioxidant enzymes in postmenopausal women. Methods The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA) was a two-centre, two-armed randomised trial of 320 inactive, healthy, postmenopausal women aged 50–74 years. Participants were randomly assigned to a year-long exercise intervention (225 min/week) or a control group while being asked to maintain a normal diet. Fasting blood samples were obtained and plasma concentrations of two oxidative damage markers (8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostaglandin F2α (8-Iso-PGF2α)) and two antioxidant enzymes (superoxide dismutase and catalase) were measured at baseline, 6 months and 12 months. Intention-to-treat (ITT) and per-protocol analyses were performed using linear mixed models adjusted for baseline biomarker concentrations. A further exercise adherence analysis, based on mean minutes of exercise per week, was also performed. Results In the ITT and per-protocol analyses, the exercise intervention did not have any statistically significant effect on either oxidative damage biomarkers or antioxidant enzyme activity. Conclusions A year-long aerobic exercise intervention did not have a significant impact on oxidative stress in healthy, postmenopausal women. Trial registration number NCT00522262.

Background There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented. Methods In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37 000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation. Findings Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18 000 with ER-positive tumours, plus nearly 12 000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30 000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (χ21=52·0, 2p Interpretation For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.

Background:Few studies have examined the predictors of adherence separately for supervised and unsupervised exercise or in postmenopausal women over an extended time period. Here, we report the predictors of exercise adherence in the Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial.Methods:The ALPHA trial randomized 160 postmenopausal women in Calgary and Edmonton, Canada to an exercise intervention that consisted of an average of 200 min/wk of supervised (123 minutes) and unsupervised (77 minutes) exercise over a 1-year period. Baseline data were collected on demographic, health-related fitness, quality of life, and motivational variables from the theory of planned behavior.Results:Participants completed an average of 95% of their supervised exercise and 79% of their unsupervised exercise. In multivariate analyses, 8.1% (P = .001) of the variance was explained for supervised exercise by being from Edmonton (β = 0.22; P = .004) and older (β = 0.15; P = .050). For unsupervised exercise, 21.1% (P < .001) of the variance was explained by being from Calgary (β = –0.39; P < .001), having a family history of breast cancer (β = 0.21; P = .003), and having higher vitality (β = 0.19; P = .011).Conclusions:Predictors of adherence may differ for supervised and unsupervised exercise, moreover, predicting adherence to supervised exercise may be particularly difficult in well-controlled efficacy trials.

High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women. Cancer Prev Res; 5(4); 583–92. ©2012 AACR.

The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%–100%). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0–1, 1+ drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P

Many estrogen receptor (ER)-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with selective ER modulators (SERMs) such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3ζ, is upregulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen upregulates 14-3-3ζ and may promote the development of endocrine resistance is not known. Our findings herein reveal that the tamoxifen upregulation of 14-3-3ζ results from its ability to rapidly downregulate microRNA (miR)-451 that specifically targets 14-3-3ζ. The levels of 14-3-3ζ and miR-451 were inversely correlated, with 14-3-3ζ being elevated and miR-451 being at a greatly reduced level in tamoxifen-resistant breast cancer cells. Of note, downregulation of miR-451 was selectively elicited by tamoxifen but not by other SERMs, such as raloxifene or ICI182,780 (Fulvestrant). Increasing the level of miR-451 by overexpression, which decreased 14-3-3ζ, suppressed cell proliferation and colony formation, markedly reduced activation of HER2, EGFR and MAPK signaling, increased apoptosis, and, importantly, restored the growth-inhibitory effectiveness of SERMs in endocrine-resistant cells. Opposite effects were elicited by miR-451 knockdown. Thus, we identify tamoxifen downregulation of miR-451, and consequent elevation of the key survival factor 14-3-3ζ, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches to increase expression of this tumor suppressor-like miR should be considered to downregulate 14-3-3ζ and enhance the effectiveness of endocrine therapies. Furthermore, the selective ability of the SERM tamoxifen but not raloxifene to regulate miR-451 and 14-3-3ζ may assist in understanding differences in their activities, as seen in the STAR (Study of Tamoxifen and Raloxifene) breast cancer prevention trial and in other clinical trials.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81-0.93), HOMA-IR (TER=0.86, 95% CI=0.80-0.93), and leptin (TER=0.82, 95% CI=0.78-0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13-1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Purpose The 2000 National Institutes of Health Consensus Conference on Adjuvant Therapy of Breast Cancer recommended chemotherapy for all women with invasive cancer greater than 1 centimeter. Studies of long-term breast cancer survivors have found poorer quality of life (QOL) in women who received adjuvant chemotherapy. The aim of this article is to characterize physical and psychosocial recovery as a function of chemotherapy receipt in the year after medical treatment completion. Patients and Methods Prospective longitudinal survey data (RAND SF-36 and Breast Cancer Prevention Trial [BCPT] Symptom Scales) collected from 558 women with breast cancer enrolled on the Moving Beyond Cancer (MBC) psychoeducational intervention trial were compared according to receipt of chemotherapy. MBC study enrollment occurred within 4 weeks after the end of primary treatment (eg, surgery, chemotherapy, radiation). Self-report questionnaire data collected at enrollment and at 2, 6, and 12 months thereafter were examined, controlling for intervention and with propensity score adjustment for imbalance of covariates. Outcome analyses were carried out by fitting linear mixed models by using SAS PROC MIXED. Results Longitudinal SF-36 scale scores did not differ by chemotherapy treatment exposure, and both groups improved significantly (P < .01) in the year after primary treatment ended. However, adjuvant chemotherapy treatment was associated with significantly more severe physical symptoms, including musculoskeletal pain (P = .01), vaginal problems (P < .01), weight problems (P = .01), and nausea (P = .03). Conclusion Physical and psychosocial functioning improved significantly after breast cancer treatment, independent of receipt of adjuvant chemotherapy. Women who received chemotherapy experienced more severe and persistent physical symptoms that should be more effectively managed as part of survivorship care.