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.

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.

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.

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.

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.

A randomized trial of exercise and diet on body composition in survivors of breast cancer with overweight or obesity.

PURPOSE: Obesity increases the risk of cancer recurrence and death in survivors of breast cancer. This study tested the hypothesis that exercise alone, diet alone, and the combination of exercise plus diet reduce body weight and improve body composition in survivors of breast cancer. METHODS: In this 2 × 2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. Endpoints included body weight and body composition measured by dual-energy x-ray absorptiometry. RESULTS: After 52 weeks, compared with control, diet alone [- 5.39 kg (95% CI - 7.24, - 3.55);- 6.0% (95% CI - 8.0, - 3.9)] and exercise plus diet [- 6.68 kg (95% CI - 8.46, - 4.90);- 7.4% (95% CI - 9.4, - 5.4)] reduced body weight; exercise alone did not change body weight. Compared with control, diet alone [- 3.59 kg (95% CI - 5.00, - 2.17)] and exercise plus diet [- 4.28 kg (95% CI - 5.71, - 2.84)] reduced fat mass; exercise alone did not change fat mass. Compared with control, diet alone [- 0.82 kg (95% CI - 1.50, - 0.15)] and exercise plus diet [- 1.24 kg (95% CI - 1.92, - 0.56)] reduced lean mass; exercise alone did not change lean mass. Compared with control, exercise alone, diet alone, and exercise plus diet did not change bone mineral density. CONCLUSION: In survivors of breast cancer with overweight or obesity, diet alone or diet plus exercise produced clinically meaningful weight loss at week 52. The majority of weight loss was fat mass.

Dose-dependent effect of aerobic exercise on inflammatory biomarkers in a randomized controlled trial of women at high risk of breast cancer.

BACKGROUND: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer. METHODS: Participants were randomized to control (<75 minutes per week; 41 patients), low-dose exercise (150 minutes per week; 38 patients), or high-dose exercise (300 minutes per week; 37 patients) groups. The 5-menstrual cycles-long, home-based treadmill exercise intervention gradually increased in minutes per week and intensity up to a maximum of 80% of the age-predicted maximum heart rate. Blood was collected at baseline and at follow-up and assayed for chemokine (C-C motif) ligand 2 (CCL2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α). RESULTS: A linear dose-response relationship was observed for the proinflammatory biomarkers CCL2 (%Δ of -5.44% in the control group, -0.03% in the low-dose exercise group, and 1.54% in the high-dose exercise group), IL-12 (%Δ of -21.5% in the control group, 38.2% in the low-dose exercise group, and 25.8% in the high-dose exercise group,) and TNF-α (%Δ of -4.69% in the control group, 9.51% in the low-dose exercise group, and 15.7% in the high-dose exercise group) but not for the anti-inflammatory biomarker IL-10 (%Δ of 5.05% in the control group, 6.05% in the low-dose exercise group, and 10.6% in the high-dose exercise group). For IL-12 and TNF-α, the percentage change was significantly higher in the low-dose (IL-12: P < .001; and TNF-α: P = .01) and high-dose (IL-12: P < .001; and TNF-α: P < .001) exercise groups compared with the control group. CONCLUSIONS: Moderate to vigorous aerobic exercise appeared to increase levels of proinflammatory biomarkers in a dose-dependent manner in a population of healthy women at high risk of developing breast cancer. The results of the current study suggest that for healthy premenopausal women, the mechanism of reduced breast cancer risk observed in physically active individuals may not be a result of reduced levels of inflammation.

The influence of mastectomy and reconstruction on residual upper limb function in breast cancer survivors.

PURPOSE: Breast cancer survivorship is common (90% of women survive 5 or more years), but many women are not able to return to full function and well-being after treatment due to functional limitations, persistent pain, and inability to perform daily activities. Since each surgical reconstructive option (e.g., autologous tissue flaps versus implants) can impact shoulder and arm function differently, it is important to understand how shoulder and upper limb strength, mobility, and function are influenced by the type of surgical intervention. Efforts can then focus on prehabiliation strategies to prevent the onset of limitations and on developing rehabilitation protocols that directly target shortcomings. METHODS: The current paper presents a review summarizing how shoulder and upper limb function may be affected by surgical mastectomy and breast reconstruction. RESULTS: Mastectomy and breast reconstruction with implants or autologous tissues present different functional outcomes for patients. Each surgical procedure is associated with unique sequelae derived from the tissues and procedures associated with each surgery. Characterizing the specific functional outcomes associated with each surgical approach will promote the development of targeted rehabilitation strategies that can be implemented into a multidisciplinary treatment planning pathway for breast cancer patients. CONCLUSIONS: Surgical treatments for breast cancer, including mastectomy and breast reconstruction, can have negative effects. Focused efforts are needed to better understand treatment-specific effects so that targeted rehabilitation can be developed to improve patient function, QoL, and ability to return to work and life activities post-breast cancer.

A population-based study of cardiovascular disease mortality risk in US cancer patients.

AIMS: This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. METHODS AND RESULTS: The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973-2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at <35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89-3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. CONCLUSION: The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.

Intra- and Interrater Reliability and Concurrent Validity of a New Tool for Assessment of Breast Cancer-Related Lymphedema of the Upper Extremity.

OBJECTIVE: The goal of this study was to develop and assess intra- and interrater reliability and validity of a clinical evaluation tool for breast cancer-related lymphedema, for use in the context of outcome evaluation in clinical trials. DESIGN: Blinded repeated measures observational study. SETTING: Outpatient research laboratory. PARTICIPANTS: Breast cancer survivors with and without lymphedema (N=71). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The assessment of intraclass correlation coefficients (ICCs) for the Breast Cancer-Related Lymphedema of the Upper Extremity (CLUE) standardized clinical evaluation tool. RESULTS: Intrarater reliability for the CLUE tool was ICC: 0.88 (95% confidence interval [95% CI], 0.71-0.96). Interrater reliability for the CLUE tool was ICC: 0.90 (95% CI, 0.79-0.95). Concurrent validity of the CLUE score (Pearson r) was 0.79 with perometric interlimb difference and 0.53 with the Norman lymphedema overall score. CONCLUSIONS: The CLUE tool shows excellent inter- and intrarater reliability. The overall CLUE score for the upper extremity also shows moderately strong concurrent validity with objective and subjective measures. This newly developed clinical, physical assessment of upper extremity lymphedema provides standardization and a single score that accounts for multiple constructs. Next steps include evaluation of sensitivity to change, which would establish usefulness to evaluate intervention efficacy.

Strategic recruitment of an ethnically diverse cohort of overweight survivors of breast cancer with lymphedema.

BACKGROUND: Black women are more likely to experience adverse effects from cancer treatment such as lymphedema. Thus, black women may particularly benefit from research regarding interventions to improve lymphedema. Herein, the authors report the challenges and strategies related to the recruitment of minority survivors of breast cancer and to the recruitment of survivors of breast cancer with lymphedema into the Women In Steady Exercise Research (WISER) Survivor Clinical Trial. METHODS: Subjects for this community-based trial were recruited from the Philadelphia area through active (mailings) and passive (printed materials and Web site) recruitment strategies. In addition, education sessions coordinated through partner hospitals in communities with a predominantly minority population were conducted to increase awareness of lymphedema in survivors of breast cancer. Women who were interested in the study were screened for lymphedema via telephone questionnaire and invited to see a study-related certified lymphedema therapist to confirm the presence of lymphedema. RESULTS: Screening was conducted among 2295 women: 628 were eligible, 450 consented, and 351 were randomized. Minority women comprised 38% of the study population. Letters to women on state and hospital registries resulted in a 0.4% randomization rate; education sessions yielded a 10% randomization rate. The authors observed that approximately 23.6% of the study sample had no previous diagnosis of lymphedema. CONCLUSIONS: The WISER Survivor Clinical Trial faced multiple recruitment challenges and used unique strategies to successfully enroll minority survivors of breast cancer into a lifestyle intervention. Cancer 2018;124:95-104. © 2017 American Cancer Society.

Patient preference and timing for exercise in breast cancer care.

Exercise is recommended following cancer diagnosis and may be particularly valuable for women receiving cardiotoxic chemotherapy treatments. We investigated breast cancer patient preference on exercise programming in a prospective manner and retrospectively assessed length of time between diagnosis and chemotherapy initiation. Sixty-seven newly diagnosed breast cancer patients responded to questions regarding exercise programming related to cancer treatment and surveys on current activity level. Additionally, a retrospective chart review was conducted on 500 random breast cancer patients. Age, cancer stage, treatment, and treatment dates were extracted. Women were interested in, or, absolutely wanted to, participate in an exercise program before treatment (76.2%). There was uncertainty regarding willingness to delay treatment; 49.2% were willing to delay their treatment if the program was recommended by their doctors, 41.8% would not, and 9.0% were too unsure to respond. However, women would like to hear information about an exercise program for cancer patients when they are first diagnosed (61.9%). We observed that 64.6% of women were below recommended levels of physical activity; yet, current activity was not associated with an interest in an exercise program or willingness to delay treatment. Retrospectively, we observed an average interval of 72.6 ± 34.6 days between cancer diagnosis and initiation of anthracycline-based chemotherapy treatment, with younger women with more advanced cancer receiving anthracycline-based chemotherapy. Based on patient preference and length of time to chemotherapy initiation, a reasonable next step to promote the current recommendations for exercise could be to integrate exercise into breast cancer care earlier in treatment.

Differential Response to Exercise in African Americans with High Levels of Inflammation.

PURPOSE: Systemic inflammation, measured by C-reactive protein (CRP), is an important risk factor for cardiovascular disease (CVD) and mortality. We investigated whether aerobic exercise training (AEXT) affects African Americans with high inflammation (HI) the same way it does African Americans with low inflammation (LI) in terms of CVD risk factors. METHODS: 23 African Americans with CRP levels <3 mg/L (LI) and 14 African Americans with CRP ≥3 mg/L (HI) underwent six months of AEXT. Participants were sedentary, non-diabetic, non-smoking, with clinical blood pressure <160/100 mm Hg, were non-hyperlipidemic, had no signs of cardiovascular, renal, or pulmonary disease, and were not on medication. Measures included CD62E+ endothelial microparticles (EMPs), a measure of early stage endothelial dysfunction, as well as lipid and glucose profile, aerobic fitness, body composition, and blood pressure. RESULTS: The LI group improved aerobic fitness by 10%, body mass index by 3%, and plasma triglycerides by 20%, with no change being observed in HI group for these variables. The HI group improved fasting plasma glucose levels by 10%, with no change occurring in the LI group. Both groups improved CD62E+ EMPs by 38% and 59% for the LI and HI group, respectively. CONCLUSIONS: A standard AEXT intervention differentially affected CVD risk factors among African Americans with high and low inflammation. This may indicate that, in African Americans with high inflammation, AEXT alone may not be enough to reap the same benefits as their low-inflammation peers in terms of CVD risk modification.

Physical activity from menarche to first pregnancy and risk of breast cancer.

Breast tissue is particularly susceptible to exposures between menarche and first pregnancy, and a longer interval between these reproductive events is associated with elevated breast cancer risk. Physical activity during this time period may offset breast cancer risk, particularly for those at highest risk with longer menarche-to-first-pregnancy intervals. We used data from 65,576 parous women in the Nurses' Health Study II free of cancer in 1989 (baseline) and recalled their leisure-time physical activity at ages 12-34 in 1997. Current activity was collected at baseline and over follow-up. Relative risks (RRs) were estimated using multivariable Cox proportional hazards regression models. Between 1989 and 2011, 2,069 invasive breast cancer cases were identified. Total recreational activity between menarche and first pregnancy was not significantly associated with the risk of breast cancer. However, physical activity between menarche and first pregnancy was associated with significantly lower breast cancer risk among women in the highest category of a menarche-to first-pregnancy interval (≥20 years; RR for the highest versus the lowest quartile = 0.73, 95% confidence interval = 0.55-0.97; Ptrend = 0.045; Pinteraction = 0.048). This was not observed in women with a shorter interval. Physical activity between menarche and first pregnancy was associated with a lower risk of breast cancer among women with at least 20 years between these reproductive events. This may provide a modifiable factor that women can intervene on to mitigate their breast cancer risk associated with a longer interval.

The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer.

Asymptomatic cardiotoxicity following breast cancer treatment is a significant issue for many patients, as these patients typically face an increased risk of cardiovascular disease (CVD). Exercise has well established benefits to improve and maintain cardiovascular function across patients with and without CVD. However, there is a dearth of information on the effects of exercise on cardiovascular outcomes in breast cancer patients. While pre-clinical studies support the use of exercise in mitigating cardiotoxicity, only one human study has specifically investigated cardiac function following an exercise intervention during chemotherapy treatment. No significant differences were observed between groups, which highlights the unidentified role of exercise in altering the risk of cardiotoxicity in breast cancer patients. Issues such as establishing the optimal timing, type, and intensity of an exercise program before, during, or after oncologic treatment for breast cancer are unclear. CVD risk and incidence increase in breast cancer survivors post therapy, and CVD is the number one killer of women in the United States. Thus, there is an increasing need to define the efficacy of exercise as a non-pharmacologic intervention in this growing population.

Concomitant low-dose doxorubicin treatment and exercise.

Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 × 10(5)) were injected subcutaneously into the scruff of 6- to 8-wk-old male C57BL/6 mice (n = 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) + vehicle, 2) SED + DOX, 3) EX + vehicle, and 4) EX + DOX. Tumor volume was attenuated in DOX and lowest in EX + DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ß-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOX-induced cardiotoxicity in a murine model of melanoma.

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.

Role of Oncostatin M in Exercise-Induced Breast Cancer Prevention.

Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise.

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.