Abstract
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.
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.
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 (
= 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 (
trend < 0.01) and increased A:L ratio (
trend < 0.01) but did not alter adiponectin levels (
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.
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.
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 (
p
trend
= 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;
p
trend
= 0.07). However, the association became non-significant after adjusting for post-diagnosis RPA (
p
trend
= 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;
p
trend
= 0.04), but not in ER+ or PR+ cases (
p
trend
= 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 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.
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 results of the current randomized controlled trial demonstrate that women at high risk of developing breast cancer experience exercise dose–dependent increases in concentrations of the proinflammatory biomarkers chemokine (C‐C motif) ligand 2, interleukin 12, and tumor necrosis factor α. These data suggest that the mechanism by which physical activity is able to lower breast cancer risk in healthy premenopausal women at high risk of breast cancer may not be through a reduction in levels of inflammation.
Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations.
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).
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.
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.
Adiponectin, leptin, and pro- and anti-inflammatory cytokines are implicated in breast cancer risk and recurrence. Weight loss, via the dynamic interplay of energy balance through exercise and/or ...caloric restriction, decreases risk of breast cancer recurrence.
We investigated the effects of lifestyle modifications (exercise only, or combined caloric restriction and exercise) on adipokines, IL2, IL6, IL8, IL10, C-reactive protein (CRP), and TNFα biomarkers in breast cancer survivors. Searches were completed in June and July of 2019 to identify randomized controlled trials that met inclusion criteria. Weighted mean difference was calculated using random- or fixed-effects models based on the heterogeneity of the studies.
2501 records were identified, with 30 ultimately meeting inclusion criteria of the systematic review; 21 studies provided data suitable for meta-analysis. We observed leptin levels were significantly reduced in the exercise-only group compared with sedentary control WMD -5.66; 95% confidence interval (CI), -11.0 to -0.33;
= 0.04.
Leptin may be a primary mediator of exercise-induced improvements in breast cancer recurrence.
This is the first review and meta-analysis to examine combined exercise and caloric restriction programs in breast cancer survivors. Future studies should further examine combined programs and their efficacy for altering leptin.
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.
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