Association between pre-diagnosis recreational physical activity and risk of breast cancer recurrence: the California Teachers Study.

PURPOSE: Studies have reported inverse associations of pre-diagnosis recreational physical activity (RPA) level with all-cause and breast cancer (BCa)-specific mortality among BCa patients. However, the association between pre-diagnosis RPA level and BCa recurrence is unclear. We investigated the association between pre-diagnosis RPA level and risk of BCa recurrence in the California Teachers Study (CTS). METHODS: Stage I-IIIb BCa survivors (n = 6,479) were followed with median of 7.4 years, and 474 BCa recurrence cases were identified. Long-term (from high school to age at baseline questionnaire, or, age 55 years, whichever was younger) and baseline (past 3 years reported at baseline questionnaire) pre-diagnosis RPA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of BCa recurrence overall and by estrogen receptor (ER)/progesterone receptor (PR) status. RESULTS: Long-term RPA was not associated with BCa recurrence risk (ptrend = 0.99). The inverse association between baseline pre-diagnosis RPA level and BCa recurrence risk was marginally significant (≥26.0 vs. <3.4 MET-hrs/wk: HR = 0.79, 95% CI = 0.60-1.03; ptrend = 0.07). However, the association became non-significant after adjusting for post-diagnosis RPA (ptrend = 0.65). An inverse association between baseline pre-diagnosis RPA level and BCa recurrence risk was observed in ER-PR- cases (≥26.0 vs. <3.4 MET-hrs/wk: HR = 0.31, 95% CI = 0.13-0.72; ptrend = 0.04), but not in ER+ or PR+ cases (ptrend = 0.97). CONCLUSIONS: Our data indicates that the benefit of baseline RPA on BCa recurrence may differ by tumor characteristics. This information may be particularly important for populations at higher risk of ER-PR- BCa.

Exercise oncology clinical trials during treatments: a commentary to address the safety concerns of human subjects regulatory reviewers and committees.

Exercise oncology clinical trials contribute to the advancement of our scientific knowledge and to the safety and care of patients diagnosed with cancer. Nevertheless, regulatory reviewers and committees may not be familiar with the well-documented long-term health benefits and safety of the regular practice of physical activity. Moreover, they may not see how the benefits outweigh the risks in the context where patients diagnosed with cancer are typically seen as vulnerable. Therefore, we would like to provide a purpose-built overview of exercise oncology clinical trials for members involved in institutional review committees, including the Scientific Review Committee (SRC), the Institutional Review Board (IRB), and the Data Safety Monitoring Committee (DSMC) to facilitate a greater understanding of the safety and benefits of physical activity during cancer treatments. Communication is key to improve the success of exercise oncology clinical trials, which are vital for patients diagnosed with cancer.

Associations of pre-diagnosis physical activity with treatment tolerance and treatment efficacy in breast cancer patients with neoadjuvant chemotherapy.

PURPOSE: Higher pre-diagnosis physical activity (PA) is associated with lower all-cause mortality in breast cancer (BCa) patients. However, the association with pathological complete response (pCR) is unclear. We investigated the association between pre-diagnosis PA level and chemotherapy completion, dose delay, and pCR in BCa patients receiving neoadjuvant chemotherapy (NACT). METHODS: 180 stage I-III BCa patients receiving NACT (mean [SD] age of diagnosis: 60.8 [8.8] years) in the Sister Study were included. Self-reported recreational and total PA levels were converted to metabolic equivalent of task-hours per week (MET-hrs/wk). The pCR was defined as no invasive or in situ residual in breast or lymph node (ypT0 ypN0). Multivariable logistic regression analyses estimated odds ratios (ORs) and 95% confidence intervals (CIs) for treatment outcomes. RESULTS: In this sample, 45 (25.0%) BCa patients achieved pCR. Higher pre-diagnosis recreational PA was not associated with lower likelihood of chemotherapy completion (highest vs. lowest tertile: OR = 0.87, 95% CI = 0.30-2.56; Ptrend = 0.84), greater dose delay (OR = 1.45, 95% CI = 0.54-3.92; Ptrend = 0.46), or greater odds of pCR (OR = 1.28, 95% CI = 0.49-3.34; Ptrend = 0.44). Associations were similar for pre-diagnosis total PA. Meeting the recommended level of recreational PA was not associated with pCR overall (≥ 7.5 vs. < 7.5 MET-hrs/wk: OR = 1.33, 95% CI = 0.59-3.01). CONCLUSIONS: Although small sample size and limited information on exercise closer to time of diagnosis limit interpretation, pre-diagnosis PA was not convincingly associated with treatment tolerance or treatment efficacy in BCa patients receiving NACT. Future investigations are needed to better understand the impact of pre-diagnosis PA on BCa treatment.

Design and methods of the mobile assessment of cognition, environment, and sleep (MACES) feasibility study in newly diagnosed breast cancer patients.

Endocrine therapy (ET) for breast cancer treatment is associated with cognitive complaints, but their etiology is poorly understood. To address this, we developed and implemented an ambulatory assessment protocol consisting of wearable activity monitors, brief surveys of affect, context, and perceived impairments, and ultra-brief performance-based measures of cognition. Newly diagnosed, ER/PR+, stage 0-III, female breast cancer patients, were recruited. Ambulatory assessments were conducted on smart phones and wearable activity monitors were used to monitor sleep and physical activity. Participants were asked to complete five 7-day measurement bursts (one before starting ET and one each month for 4 consecutive months while on ET). We observed a consent rate of 36%, 27 women completed the study. Of the women that withdrew, 91% dropped prior to the midpoint of follow up. There were no significant differences in demographics, clinical breast cancer characteristics, sleep or physical activity patterns, or measures of cognition between women who completed versus withdrew. Women who did not complete the study provided fewer valid days of baseline data. In conclusion, while some women may be overwhelmed with their cancer diagnosis, we did not identify any predictive characteristics of women whom did not complete the study. This novel method enables the prospective study of psychological changes associated with cancer treatment, capturing a wide array of information about behavior, experience, and cognition, thus providing a picture of the lived experiences of cancer patients before and during exposure to ET.

Updated systematic review of the effects of exercise on understudied health outcomes in cancer survivors.

INTRODUCTION: The American College of Sports Medicine provided guidelines for exercise prescriptions in cancer survivors for specific cancer- and treatment-related health outcomes. However, there was insufficient evidence to generate exercise prescriptions for 10 health outcomes of cancer treatment. We sought to update the state of evidence. METHODS: We conducted a systematic review of these 10 understudied health outcomes (bone health, sleep, cardiovascular function, chemotherapy-induced peripheral neuropathy (CIPN), cognitive function, falls and balance, nausea, pain, sexual function, and treatment tolerance) and provided an update of evidence. RESULTS: While the evidence base for each outcome has increased, there remains insufficient evidence to generate exercise prescriptions. Common limitations observed across outcomes included: variability in type and quality of outcome measurement tools, variability in definitions of the health outcomes, a lack of phase III trials, and a majority of trials investigating breast or prostate cancer survivors only. CONCLUSION: We identified progress in the field of exercise oncology for several understudied cancer- and treatment-related health outcomes. However, we were not able to generate exercise prescriptions due to continued insufficient evidence base. More work is needed to prescribe exercise as medicine for these understudied health outcomes, and our review highlights several strategies to aid in research acceleration within these areas of exercise oncology.

Associations Between Leisure-Time Physical Activity Level and Peripheral Immune Cell Populations in the US General Population, Analysis of the National Health and Nutrition Examination Survey Data, 1999-2018.

BACKGROUND: Chronic levels of inflammation are associated with higher risk of many chronic diseases. Physical activity (PA) lowers the risk of cancer, cardiovascular disease (CVD), diabetes and others. One mechanism for PA-induced protection may be through the immune system. We investigated the association between leisure-time PA and peripheral immune cell populations in a large nationally representative sample of the US general population. METHODS: A total of 17,093 participants [mean (SE) age of 41.6 (0.3) years] of the National Health and Nutrition Examination Survey 1999-2018 were included. Self-reported leisure-time PA was converted to metabolic equivalent of task hours per week (MET-hrs/wk). White blood cell (WBC) count, WBC ratios, and platelet count were derived. Multivariable linear regression analyses were used to estimate associations between leisure-time PA level and peripheral immune cell populations. Multivariable logistic regression analyses were used to estimate associations between leisure-time PA and metrics of WBC count and neutrophil-to-lymphocyte ratio (NLR) which may predict mortality. RESULTS: A higher leisure-time PA level was associated with a lower WBC count (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% confidence interval [CI]): 7.12 (6.86, 7.38) vs. 7.38 (7.12, 7.64) 1000 cells/µL, Ptrend < 0.001) and a lower NLR (> 14.0 vs. < 1.2 MET-hrs/wk adjusted mean (95% CI) 2.04 (1.90, 2.18) vs. 2.13 (1.99, 2.28), Ptrend = 0.007). Leisure-time PA level was not associated with lymphocyte-to-monocyte ratio (LMR; Ptrend = 0.25) or platelet-to-lymphocyte ratio (PLR; Ptrend = 0.69). Compared to the lowest leisure-time PA level (< 1.2 MET-hrs/wk), the highest leisure-time PA level (≥ 14.0 MET-hrs/wk) was associated with a lower probability of a high WBC count (> 8.1 × 109 cells/L; odds ratio [OR] = 0.76, 95% CI = 0.66-0.88) and high NLR (> 2.68; OR = 0.84, 95% CI = 0.72-0.99), which may predict CVD and all-cause mortality. The highest leisure-time PA level also linked to a lower probability of a high WBC count (≥ 8.3 × 109 cells/L; OR = 0.76, 95% CI = 0.66-0.88), which may predict cancer mortality. CONCLUSIONS: We observed an inverse association between leisure-time PA level, WBC count, and NLR, particularly for neutrophil levels. These results suggest that participants at higher levels of leisure-time PA may have lower levels of inflammation, which may be important for future chronic disease outcomes.

WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity.

Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors (n = 339) with overweight or obesity. Compared with Control, the Combination of Exercise and Weight Loss decreased leptin levels (-35.9%; 95% CI: -46.8%, -25.0%) and increased A:L ratio (11.6%; 95% CI: 5.6%, 17.6%) but did not change adiponectin levels (4.1%; 95% CI: -3.1%, 11.2%). Compared with Control, Weight Loss Alone decreased leptin levels (-35.6%; 95% CI: -46.6%, -24.5%) and increased A:L ratio (10.6%; 95% CI: 4.7%, 16.5%) but did not change adiponectin levels (0.9%; 95% CI: -6.0%, 7.9%). Compared with Control, Exercise Alone did not change leptin levels, adiponectin levels, or A:L ratio. In analyses that consolidated intervention groups, compared with Control, weight loss of ≥5% decreased leptin levels (p trend < 0.01) and increased A:L ratio (p trend < 0.01) but did not alter adiponectin levels (p trend = 0.53). Weight loss, with or without exercise, was associated with decreased leptin levels in breast cancer survivors with overweight or obesity. Improvements in the adipokine secretion profile (A:L ratio) were primarily driven by a weight loss-induced change in leptin levels.

Exercise during chemotherapy: Friend or foe?

BACKGROUND: A higher chemotherapy completion rate is associated with better outcomes including treatment efficacy and overall survival. Exercise may have the potential to improve relative dose intensity (RDI) by reducing the frequency and severity of chemotherapy-related toxicities. We examined the association between exercise adherence and RDI and possible clinical- and health-related fitness predictors of RDI. METHODS: Chemotherapy records were extracted from the electronic medical record for patients enrolled in the ENACT trial (n = 105). Chemotherapy completion was assessed using average RDI. A threshold of 85% was established for "high" versus "low" RDI. Logistic regression analyses were used to estimate the associations between the clinical- and health-related fitness predictors of RDI. RESULTS: Patients with breast cancer (BC) had a significantly higher average RDI (89.8% ± 17.6%) compared with gastrointestinal cancer (GI) (76.8% ± 20.9%, p = 0.004) and pancreatic cancer (PC) (65.2% ± 20.1%, p < 0.001). Only 25% of BC patents required a dose reduction compared to 56.3% of GI and 86.4% of PC patients. Cancer site was significantly associated with RDI. Compared with BC, patients with GI (ß = -0.12, p = 0.03) and PC (ß = -0.22, p = 0.006) achieved significantly lower RDI. Every 2.72 unit increase in overall exercise adherence led to a significant 7% decrease in RDI (p = 0.001) in GI patients. Metastatic GI patients had a 15% RDI increase for every 2.72 unit increase in exercise adherence (p = 0.04). CONCLUSION: Exercise is a supportive therapy that has potential to enhance chemotherapy tolerance and completion. The relationship between exercise adherence and RDI is influenced by factor such as cancer site and treatment type. Special attention must be paid to how exercise is prescribed to ensure that exercise adherence does not negatively affect RDI. Cancer site, exercise dosage, and multimodal interventions to address toxicities are key areas identified for future research.

The effects of exercise and diet on oxidative stress and telomere length in breast cancer survivors.

PURPOSE: Cancer and its treatments accelerate biological aging. This analysis tested the hypothesis that exercise and diet reduce oxidative stress and prevent telomere shortening in breast cancer survivors. METHODS: In a 2 × 2 factorial design, 342 breast cancer survivors who were insufficiently physically active and had overweight or obesity at enrollment were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. The endpoints of this analysis were the change from baseline to week 52 in 8-iso-prostaglandin F2α (8-iso-PGF2α) and lymphocyte telomere length. RESULTS: Baseline telomere length was shorter than age-adjusted normative values (median difference: - 1.8 kilobases; 95% CI - 2.4, - 1.1); equivalent to 21 years (95% CI 17, 25) of accelerated chronological aging. Compared to control, exercise alone did not change 8-iso-PGF2α [9.9%; 95% confidence interval (CI) - 1.0, 20.8] or telomere length (13.8%; 95% CI - 15.6, 43.3). Compared to control, diet alone was associated with reduced 8-iso-PGF2α (- 10.5%; 95% CI - 19.5, - 1.5) but did not change telomere length (12.1%; 95% CI - 17.2, 41.3). Compared to control, exercise plus diet was associated with reduced 8-iso-PGF2α (- 9.8%; 95% CI - 18.7, - 0.9) but did not change telomere length (- 8.5%; 95% CI - 32.1, 15.2). Change in 8-iso-PGF2α did not correlate with change in telomere length (r = 0.07; 95% CI - 0.07, 0.20). CONCLUSION: In breast cancer survivors, diet alone or exercise plus diet were associated with reduced oxidative stress but did not change telomere length. This analysis may inform future trials that aim to optimize healthy aging in cancer survivors.

WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Inflammation in Breast Cancer Survivors.

PURPOSE: Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations. METHODS: In a four-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to exercise alone, weight loss alone, exercise plus weight loss, or control for 12 months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). RESULTS: Compared with control, exercise alone increased ICAM-1 (9.3%; 95% confidence interval [CI] = 1.6-16.9) and VCAM-1 (8.6%; 95% CI = 2.6-14.5) but did not change CRP or SAA. Compared with control, weight loss alone reduced CRP (-35.2%; 95% CI = -49.9 to -20.7), and SAA (-25.6%; 95% CI = -39.8 to -11.9) but did not change ICAM-1 or VCAM-1. Compared with control, exercise plus weight loss reduced CRP (-44.1%; 95% CI = -57.1 to -31.1) and SAA (-26.6%; 95% CI = -40.5 to -12.6) but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (e.g., >3 mg·L -1 ), compared with control, weight loss alone (0.17; 95% CI = 0.04-0.30) and exercise plus weight loss (0.31; 95% CI = 0.16-0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels. CONCLUSIONS: In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death.

Physical activity from menarche-to-first pregnancy and risk of breast cancer: the California teachers study.

PURPOSE: A longer menarche-to-first pregnancy window of susceptibility (WOS) is associated with increased breast cancer risk. Whether physical activity, an established preventive risk factor, during the menarche-to-first pregnancy WOS offsets breast cancer risk overall or for specific molecular subtypes is unclear. METHODS: We examined the prospective association between physical activity during the menarche-to-first pregnancy WOS and breast cancer risk in the California Teachers Study (N = 78,940). Recreational physical activity at multiple timepoints were recalled at cohort entry, and converted to metabolic equivalent of task hours per week (MET-hrs/wk). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We observed 5,157 invasive breast cancer cases over 21.6 years of follow-up. Longer menarche-to-first pregnancy WOS (≥ 20 vs. < 15 years) was associated with higher breast cancer risk (HR = 1.23, 95% CI = 1.13-1.34). Women with higher physical activity level during menarche-to-first pregnancy had lower risk of invasive breast cancer (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.89, 95% CI = 0.83-0.97) and triple-negative subtype (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.53, 95% CI = 0.32-0.87). No association was observed for luminal A-like and luminal B-like subtypes. Higher physical activity level was associated with lower breast cancer risk among women with moderate (15-19 years) menarche-to-first pregnancy intervals (≥ 40 vs. < 9 MET-hrs/wk: HR = 0.80, 95% CI = 0.69-0.92), but not with short (< 15 years) or long (≥ 20 years) intervals. CONCLUSION: Physical activity during a WOS was associated with lower breast cancer risk in our cohort. Understanding timing of physical activity throughout the life course in relationship with breast cancer risk maybe important for cancer prevention strategies.

Pre-Diagnosis Diet and Physical Activity and Risk of Cardiovascular Disease Mortality among Female Cancer Survivors.

Sub-optimal diet and physical activity (PA) levels have been associated with increased risk of cardiovascular disease (CVD) mortality. The relationship between pre-cancer diagnosis diet quality and PA level on CVD mortality risk in cancer survivors is unclear. We examined the association between pre-cancer diagnosis diet quality and leisure-time PA and their interaction on CVD mortality in cancer survivors. Diet quality was characterized by the Alternative Mediterranean Diet Index (aMED). Leisure-time PA was converted to a metabolic equivalent of task hours per week (MET-h/wk). During a median of 6.3 years of follow-up of 18,533 female cancer survivors, we identified 915 CVD deaths. aMED score was not associated with CVD mortality. PA level was inversely associated with CVD mortality (HRQ1-Q4 = 0.74; 95% CI: 0.61-0.88; Ptrend = 0.0014). Compared to cancer survivors with the lowest pre-diagnosis aMED score and PA level, cancer survivors with higher aMED scores and higher MET-hrs/wk were at a 33% lower risk of CVD mortality (HR = 0.67; 95% CI: 0.52-0.87). Overall, this study shows PA to be a strong predictor of CVD mortality in female cancer survivors. Our observations support the importance of PA throughout the lifecycle in lowering CVD mortality risk.

Light-intensity and moderate-to-vigorous intensity physical activity among older adult breast cancer survivors with obesity: A narrative review.

BACKGROUND: With an aging population, rising incidence of breast cancer, improved survival rates, and obesity epidemic, there will be a growing population of older adult breast cancer survivors with obesity. This complex population, often with multimorbidity, is at risk for several poor health outcomes, including recurrence, cardiovascular disease, dementia, and diabetes, and a number of deleterious symptoms, including a worsened inflammatory profile, breast cancer- related lymphedema, mobility disability, cognitive impairment, anxiety, and depressive symptoms. A wealth of meta-analytic and randomized controlled trial evidence show that adherence to World Health Organization and 2018 United States Physical Activity guidelines-based levels of moderate-to-vigorous physical activity (MVPA) reduces risk of all-cause mortality, and improves symptoms. However, few survivors engage in recommended levels of MVPA, and symptoms related to their multimorbidity may preclude engaging in sufficient levels of MVPA. Additional research of MVPA in this population is warranted; however, understudied light-intensity physical activity (LIPA) may be a more pragmatic target than MVPA among this complex population facing extensive challenges meeting MVPA recommendations. Large benefits are likely to occur from increasing these survivors' total activity, and LIPA prescriptions may be a more pragmatic approach than MVPA to aid this transition. METHODS: We present a broad, narrative review of the evidence for MVPA and LIPA in this population on an array of health outcomes across the translational science spectrum (clinical, implementation, and public health), and identify a number of directions for future research focused on understanding the potential diverse health effects of LIPA. CONCLUSION: Additional LIPA research is warranted, as LIPA prescriptions may be a pragmatic strategy to effectively promote physical activity to this complex population.

The effects of exercise and diet on sex steroids in breast cancer survivors.

Insufficient physical activity and obesity are associated with an increased risk of cancer recurrence and death in breast cancer survivors. Sex steroid hormones may mediate these associations. This study tested the hypothesis that exercise and diet, as compared to control, favorably change sex steroid hormones. This analysis of data from a subset of participants in a 2 × 2 factorial trial compares 269 postmenopausal breast cancer survivors who were insufficiently physically active and had overweight or obesity and were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. Secondary sex steroid hormone endpoints included estradiol, sex hormone-binding globulin (SHBG), and testosterone. Treatment effects were quantified using a mixed model for repeated measures. Compared to control, exercise alone did not significantly change estradiol (-1.9%; 95% CI: -12.6, 8.8), SHBG (2.4%; 95% CI: -9.9, 14.6), or testosterone (1.2%; 95% CI: -12.2, 14.5). Compared to control, diet alone did not significantly change estradiol (-7.8%; 95% CI: -17.6, 1.9), SHBG (8.2%; 95% CI: -4.2, 20.6), or testosterone (-0.8%; 95% CI: -13.6, 12.0). Compared to control, exercise plus diet did not significantly change estradiol (-6.3%; 95% CI: -16.3, 3.6), SHBG (8.8%; 95% CI: -4.0, 21.7), or testosterone (-5.3%; 95% CI: -18.0, 7.4). In postmenopausal breast cancer survivors who were insufficiently physically active and had overweight or obesity, randomization to exercise alone, diet alone, or exercise plus diet did not statistically significantly change sex steroid hormone concentrations at week 52.

BRCA1/2 Mutations and Cardiovascular Function in Breast Cancer Survivors.

OBJECTIVE: Animal models suggest that BRCA1/2 mutations increase doxorubicin-induced cardiotoxicity risk but data in humans are limited. We aimed to determine whether germline BRCA1/2 mutations are associated with cardiac dysfunction in breast cancer survivors. METHODS: In a single-center cross-sectional study, stage I-III breast cancer survivors were enrolled according to three groups: (1) BRCA1/2 mutation carriers treated with doxorubicin; (2) BRCA1/2 mutation non-carriers treated with doxorubicin; and (3) BRCA1/2 mutation carriers treated with non-doxorubicin cancer therapy. In age-adjusted analysis, core-lab quantitated measures of echocardiography-derived cardiac function and cardiopulmonary exercise testing (CPET) were compared across the groups. A complementary in vitro study was performed to assess the impact of BRCA1 loss of function on human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) survival following doxorubicin exposure. RESULTS: Sixty-seven women with mean (standard deviation) age of 50 (11) years were included. Age-adjusted left ventricular ejection fraction (LVEF) was lower in participants receiving doxorubicin regardless of BRCA1/2 mutation status (p = 0.03). In doxorubicin-treated BRCA1/2 mutation carriers and non-carriers, LVEF was lower by 5.4% (95% CI; -9.3, -1.5) and 4.8% (95% CI; -9.1, -0.5), respectively compared to carriers without doxorubicin exposure. No significant differences in VO2max were observed across the three groups (poverall = 0.07). Doxorubicin caused a dose-dependent reduction in viability of iPSC-CMs in vitro without differences between BRCA1 mutant and wild type controls (p > 0.05). CONCLUSIONS: BRCA1/2 mutation status was not associated with differences in measures of cardiovascular function or fitness. Our findings do not support a role for increased cardiotoxicity risk with BRCA1/2 mutations in women with breast cancer.

Feasibility of a tailored home-based exercise intervention during neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: To evaluate the feasibility of a home-based moderate-to-vigorous intensity, phased (introduction, intermediate, maintenance), exercise prescription in breast cancer patients receiving cardiotoxic neoadjuvant chemotherapy. METHODS: Nineteen breast cancer patients were randomized to intervention or control for the duration of chemotherapy (16-24 weeks). The intervention was one aerobic exercise session at 80-90% VO2max for 25 min/week and 65%-75% VO2max for ≥ 50 min/week. Adherence to the tailored home-based program was assessed by heart rate monitors. Acceptability, tolerability, feasibility, efficacy, change in VO2max, and patient reported outcomes, safety, and clinical events were assessed. RESULTS: 25.7% of eligible women consented (acceptability). Adherence was 87.6%. Women were not able to maintain exercise intensity as chemotherapy progressed (23.7% of exercise minutes were completed at prescribed heart rate during maintenance). Efficacy of the intervention was demonstrated by maintenance of VO2max (-1.0 ± 13.2%) compared to (-27.5 ± 7.4%) the control group. Further, during and after therapy, patients in the intervention arm reported less fatigue (control-baseline: 14.4 ± 15.9; midpoint: 19.0 ± 11.4; follow-up: 29.4 ± 20.0; intervention-baseline: 29.2 ± 24.6; midpoint: 24.6 ± 14.4; follow-up: 23.6 ± 11.9), impairment in activities (control-baseline: 13.7 ± 16.0; midpoint: 32.8 ± 17.0; follow-up: 58.6 ± 27.9; intervention-baseline: 38.7 ± 31.8; midpoint: 47.1 ± 27.5; follow-up: 47.5 ± 31.0), and pain (control-baseline: 80.8 ± 17.1; midpoint: 73.9 ± 20.7; follow-up: 50.7 ± 25.7; intervention-baseline: 68.7 ± 28.4; midpoint: 61.4 ± 22.5; follow-up: 65.3 ± 22.4). There were no differences in adverse events, treatment delays, or pathological complete response. CONCLUSIONS: Neoadjuvant breast cancer patients maintained approximately one hour/week of moderate-intensity exercise over the course of their treatment. Further, this volume of exercise was sufficient to maintain fitness capacity and quality of life compared to the control group. TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT03280836, prospectively registered 9/13/2017, https://clinicaltrials.gov/ct2/show/NCT03280836 .

Dose-dependent effects of aerobic exercise on clinically relevant biomarkers among healthy women at high genetic risk for breast cancer: A secondary analysis of a randomized controlled study.

BACKGROUND: Excess adiposity and dysregulated metabolism are associated with increased cancer risk. Triglycerides, cholesterol, glucose, insulin, HOMA-IR, and VO2 max are robust clinical-metabolic biomarkers of overall health. AIMS: Aerobic exercise may improve clinical-metabolic biomarkers and decrease cancer risk. This secondary analysis of the WISER Sister randomized controlled trial investigated dose-dependent effects of aerobic exercise on clinical biomarker levels in women at high genetic risk for breast cancer. METHODS AND RESULTS: One hundred thirty-nine participants were randomized to: control (<75 min/week), low-dose (150 min/week), and high-dose (300 min/week) aerobic exercise intervention groups. Intervention adherence was assessed via heart monitor. Fasting blood draws, cardio-pulmonary tests, and demographical surveys were taken at baseline and 5 months. Triglyceride, cholesterol, glucose, insulin, and VO2 max changes were assessed for 80 of the 122 study completers. Ninety-six percent of assayed-completers adhered to >80% of their exercise dose. A significant dose-dependent increase in VO2 max was observed for the low-dose and high-dose groups compared to control. No intervention effects were observed for plasma biomarkers. Overweight women (BMI > 25) showed a significant decrease in insulin levels and a trend for decreased triglycerides following exercise intervention. Significant increases in VO2 max were independent of BMI stratification. CONCLUSION: Women at high genetic risk for breast cancer should maintain healthy weights and aerobic capacities through aerobic exercise to achieve measurable benefits on overall health. For overweight women, exercise appears to improve subclinical metabolic dysregulation. However, normal weight women were unaffected by aerobic exercise as their biomarker levels may be below the threshold for improvement. VO2 max increases solely quantified the benefits of exercise in already healthy women at high-risk for breast cancer.

Association of Inflammatory Diets with Inflammatory Biomarkers in Women at High Genetic Risk for Breast Cancer.

Chronically elevated levels of inflammatory biomarkers may contribute to the development of cancer and diet may be an important factor in the interplay between inflammation and cancer. We examined associations between glycemic load (GL), glycemic index (GI), and adapted dietary inflammatory index (ADII) and markers of inflammation and adipokines in 135 premenopausal women at high genetic risk for breast cancer (NCT00892515). We assessed body mass index (BMI), 3-day food records, and blood biomarkers TNF-α, IL-12, CCL2, IL-10, leptin, and adiponectin. Regression models assessed associations between dietary variables and biomarkers, adjusted for caloric intake and BMI. Participants were on average 34.2 years old with mean BMI of 26.8 kg/m2. Significantly higher levels of IL-10 and leptin were observed in participants with higher GI. Leptin and adiponectin were significantly associated with ADII. Leptin remained associated with ADII after adjustment for caloric intake and BMI. There were no associations between inflammatory biomarkers of interest and GL, GI, and ADII, after adjusting for caloric intake and BMI. Elevated leptin levels were observed with higher ADII independent of caloric intake and BMI. The relationship between carbohydrate quality and inflammatory potential of the diet and markers of inflammation may be modulated by leptin.

WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Insulin and Insulin Resistance in Breast Cancer Survivors.

Obesity-associated breast cancer recurrence is mechanistically linked with elevated insulin levels and insulin resistance. Exercise and weight loss are associated with decreased breast cancer recurrence, which may be mediated through reduced insulin levels and improved insulin sensitivity. This is a secondary analysis of the WISER Survivor clinical trial examining the relative effect of exercise, weight loss and combined exercise and weight loss interventions on insulin and insulin resistance. The weight loss and combined intervention groups showed significant reductions in levels of: insulin, C-peptide, homeostatic model assessment 2 (HOMA2) insulin resistance (IR), and HOMA2 beta-cell function (ß) compared to the control group. Independent of intervention group, weight loss of ≥10% was associated with decreased levels of insulin, C-peptide, and HOMA2-IR compared to 0-5% weight loss. Further, the combination of exercise and weight loss was particularly important for breast cancer survivors with clinically abnormal levels of C-peptide.

A randomized trial of exercise and diet on health-related quality of life in survivors of breast cancer with overweight or obesity.

BACKGROUND: Obesity is a chronic, relapsing, and progressive disease; it is associated with poor health-related quality of life (HRQOL) in survivors of breast cancer. METHODS: In this 2 × 2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to 1 of 4 treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. HRQOL end points were measured at baseline and at week 52 using the 36-Item Medical Outcomes Survey-Short Form (SF-36). Repeated measures analysis of covariance quantified the estimated treatment difference (ETD). RESULTS: At baseline, participants had a mean (SD) age of 59.4 years (8.7), body mass index of 34.0 kg/m2 (5.9), and 71 participants (20.2%) self-reported fair or poor general health. After 52 weeks, compared with control, the exercise plus diet improved the physical health summary score (ETD: 5.39; 95% CI, 0.55-10.22); exercise alone (ETD: -1.91; 95% CI, -6.60 to 2.79) and diet alone (ETD: 3.16; 95% CI, -1.52 to 7.83) did not change the physical health summary score. Compared with control, exercise alone (ETD: -0.27; 95% CI, -6.60 to 2.79), diet alone (ETD: 3.25; 95% CI, -1.41 to 7.91), and the exercise plus diet (ETD: 1.75; 95% CI, -2.90 to 6.39) did not change the mental health summary score. Exercise alone did not impact any HRQOL subscale; diet alone improved the vitality subscale; exercise plus diet improved the physical functioning, role-physical and vitality subscales. CONCLUSION: In survivors of breast cancer with overweight or obesity, exercise plus diet improved select HRQOL end points at week 52.