Long-term effects of aromatase inhibitor withdrawal on bone mineral density in early breast cancer patients: 10-year follow-up results of the BREX study.

PURPOSE: We aimed to provide long-term bone mineral density (BMD) data on early breast cancer patients of the BREX (Breast Cancer and Exercise) study. The effects of exercise and adjuvant endocrine treatment 10 years after randomization were analyzed, with special emphasis on aromatase inhibitor (AI) therapy discontinuation at 5 years. METHODS: The BREX study randomized 573 pre- and postmenopausal breast cancer patients into a 1-year supervised exercise program or a control group. 372 patients were included into the current follow-up analysis. BMD (g/cm2) was measured by dual-energy X-ray absorptiometry at lumbar spine (LS), left femoral neck (FN), and the total hip. Separate groups were displayed according to baseline menopausal status, and whether the patient had discontinued AI therapy at 5 years or not. RESULTS: The BMD change from 5 to 10 years did not significantly differ between the two randomized arms. AI discontinuation at 5 years had statistically significant BMD effects. The FN BMD continued to decrease in patients who discontinued AI therapy during the first 5-year off-treatment, but the decrease was three-fold less than in patients without AI withdrawal (- 1.4% v. - 3.8%). The LS BMD increased (+ 2.6%) in patients with AI withdrawal during the first 5 years following treatment discontinuation, while a BMD decrease (-1.3%) was seen in patients without AI withdrawal. CONCLUSION: This study is to our knowledge the first to quantify the long-term impact of AI withdrawal on BMD. Bone loss associated with AI therapy seems partially reversible after stopping treatment. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov/ (Identifier Number NCT00639210).

Mindfulness is associated with improved psychological well-being but no change in stress biomarkers in breast cancer survivors with depression: a single group clinical pilot study.

BACKGROUND: The aim of this clinical single group pilot study was to assess mental well-being, psychological symptoms, and a set of stress biomarkers among breast cancer survivors with high depressive symptoms undergoing the Mindfulness-Based Stress Reduction (MBSR) program. METHODS: Participants included 23 curatively treated breast cancer survivors from the Helsinki University Central Hospital with clinically significant symptoms of depression (Beck Depression Inventory > 13, and assessed by a psychiatrist), at 1-year post-operative follow-up. Mental wellbeing and psychological symptoms were assessed with self-reported questionnaires (Resilience Scale, Self-Compassion Scale, Five Facet Mindfulness Questionnaire, World Health Organization Quality of Life-questionnaire, Perceived Stress Scale, Beck Depression Inventory, Beck Anxiety Inventory, Insomnia Severity Index); in addition, stress response was assessed with biomarkers (cortisol, adrenocorticotropine, and high-sensitivity-CRP from blood; 24 h-cortisol from urine). All measures were addressed at baseline, mid-program (4 weeks after baseline) and at the completion of the 8-week MBSR program. Engagement to the independent mindfulness home practice was collected with a diary. RESULTS: From baseline to the completion of the 8-week MBSR program, we observed significant increases in resilience (d = 0.60, p = 0.005), and quality of life (d = 0.92, p = 0.002), and significant reductions in symptoms of depression (d = - 1.17, p < 0.0001), anxiety (d = - 0.87, p < 0.0001), insomnia (d = - 0.58, p = 0.006), and marginally significant reduction in perceived stress (d = - 0.40, p = 0.09). We found no changes in self-compassion or mindfulness skills, nor in the stress biomarkers during or at the completion of the program. There was no association between the engagement time to the independent mindfulness practice and any of the outcomes. CONCLUSIONS: Attending the MBSR program was associated with increased wellbeing and reduced psychological symptoms in breast cancer survivors with clinically significant symptoms of depression. However, these favorably experienced changes did not transfer to the level of stress biomarkers during the 8-week program. Lack of association between the engagement in the mindfulness home practice and change in outcomes suggests that in the studied range of practice time, other qualities of MBSR despite the amount of independent practice may have a more important role for the improved wellbeing. Trial registration ISRCTN12326308 at 16/02/2021, retrospectively registered.

Factors predicting long-term physical activity of breast cancer survivors. 5-year-follow-up of the BREX exercise intervention study.

BACKGROUND: The benefits of exercise training are well documented among breast cancer (BC) survivors. Patients decrease their physical activity during treatment, and many fail to regain their previous exercise levels. There is therefore a need to define factors supporting long-term physical activity behavior in this patient group, to target supporting interventions aimed at preventing the decline in physical activity (PA). AIM: The aim of this study was to determine physical and psychosocial factors explaining long-term physical activity after the adjuvant treatments in BC survivors. METHODS: Four-hundred forty-six BC survivors followed for 5-years within a randomized exercise trial participated. Factors explaining (1) physical activity after the adjuvant treatments and (2) changes in physical activity in long-term were analyzed using linear regression models and general estimating equation models. Pretreatment leisure-time physical activity (LTPA), demographic, and treatment factors, physical fitness, and quality of life (Qol) at baseline were independent factors. RESULTS: Exercise levels increased during the first year, and thereafter remained mostly stable. Higher LTPA, higher fitness level, better Qol and older age at baseline were associated with higher physical activity level after adjuvant treatments (p < .001) in multivariate analysis. Higher levels of fatigue (p < .008) and better emotional functioning (p = .017) at baseline were the main factors associated with increased physical activity during the follow-up. CONCLUSION: Previous exercise habits and Qol after adjuvant chemo-, and radiotherapy were the strongest determinants of long-term physical activity levels in breast cancer survivors. Patients with better emotional functioning increased their exercise activity most as did those patients with higher fatigue levels at baseline. Patients suffering from fatigue after adjuvant treatment managed to increase their exercise levels, in contrast to patients with low emotional functioning, and may benefit from physical exercise interventions. Emotionally deprived patients may benefit from psychosocial support to regain their previous exercise levels.

Long-term health-related quality of life of breast cancer survivors remains impaired compared to the age-matched general population especially in young women. Results from the prospective controlled BREX exercise study.

OBJECTIVE: To investigate long-term health-related quality of life (HRQoL) changes over time in younger compared to older disease-free breast cancer survivors who participated in a prospective randomized exercise trial. METHODS: Survivors (aged 35-68 years) were randomized to a 12-month exercise trial after adjuvant treatment and followed up for ten years. HRQoL was assessed with the generic 15D instrument during follow-up and the younger (baseline age ≤ 50) and older (age >50) survivors' HRQoL was compared to that of the age-matched general female population (n = 892). The analysis included 342 survivors. RESULTS: The decline of HRQoL compared to the population was steeper and recovery slower in the younger survivors (p for interaction < 0.001). The impairment was also larger among the younger survivors (p = 0.027) whose mean HRQoL deteriorated for three years after treatment and started to slowly improve thereafter but still remained below the population level after ten years (difference -0.017, 95% CI: -0.031 to -0.004). The older survivors' mean HRQoL gradually approached the population level during the first five years but also remained below it at ten years (difference -0.019, 95% CI: -0.031 to -0.007). The largest differences were on the dimensions of sleeping and sexual activity, on which both age groups remained below the population level throughout the follow-up. CONCLUSIONS: HRQoL developed differently in younger and older survivors both regarding the most affected dimensions of HRQoL and the timing of the changes during follow-up. HRQoL of both age groups remained below the population level even ten years after treatment.

Health-related Quality of Life of Breast Cancer Survivors Attending an Exercise Intervention Study: A Five-year Follow-up.

BACKGROUND/AIM: As the number of breast cancer survivors is increasing, their long-term health-related quality of life (HRQoL) has become an important issue. The aim of the study is to follow up the HRQoL of breast cancer survivors (BCS) in a prospective randomized exercise intervention study and to compare HRQoL to that of the age-matched general female population. PATIENTS AND METHODS: Following adjuvant treatment, 537 patients aged 35-68 and capable of exercise training were randomized to a 12-month exercise trial. In 182 of those patients, HRQoL was measured by the generic 15D at baseline and followed up for five years. Furthermore, the HRQoL of all BCS answering the 15D at five-year follow-up (n=390) was compared to that of a representative sample of the general population. RESULTS: After five years, the BCS' mean HRQoL demonstrated a statistically and clinically significant impairment compared to that of the general population (difference -0.023, p<0.001). The mean HRQoL of BCS followed up from baseline until five years did not improve significantly (change=0.007, p=0.27), whereas the dimensions of usual activities (0.043, p=0.004), depression (0.038, p=0.007), distress (0.030, p=0.036), and sexual activity (0.057, p=0.009) did. CONCLUSION: The HRQoL of BCS was still impaired five years following treatment.

Effectiveness of a 12-month Exercise Intervention on Physical Activity and Quality of Life of Breast Cancer Survivors; Five-year Results of the BREX-study.

BACKGROUND/AIM: This is a report of the 5-year quality of life (QoL) findings of the BREX-study (n=444). PATIENTS AND METHODS: A 12-month exercise intervention was arranged shortly after adjuvant treatments. Physical activity (PA) was assessed by PA diary, physical performance by a 2- km walking test, QoL by the EORTC QLQC30 and BR-23 questionnaires, fatigue by the FACIT-Fatigue scale and depression by the Beck's 13-item depression scale (BDI). RESULTS: Participants who improved their PA from baseline to 5-year follow-up were more likely to improve their global health score (RRR=1.02, p=0.016), physical (RRR=1.02, p=0.009), social (RRR=1.03, p=0.013), role functioning (RRR=1.03, p=0.005), and fatigue (RRR=1.02, p=0.002). An improved 2-km walking test was associated to improved global health, physical and role functioning, body image, future perspectives, and fatigue (p=0.011, p<0.001, p=0.001, p=0.021, p=0.012 and p=0.003). No significant difference between the groups was found. CONCLUSION: Improvement in PA or physical performance yields a positive change in QoL of breast cancer patients.

Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.

BACKGROUND: ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. RESULTS AND LIMITATIONS: The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). CONCLUSIONS: The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. PATIENT SUMMARY: The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing.

Quality of life of recently treated patients with breast cancer.

AIM: To investigate whether the negative quality of life result of a large randomized exercise intervention study (BREX) was due to considerable spontaneous recovery after adjuvant treatments. PATIENTS AND METHODS: The change in QoL was studied in the control patients of the BREX study (Group 1) and a group of similar follow-up patients that did not participate in any intervention study (Group 2). QoL was measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 with the breast cancer module supplement 6 and 12 months after surgery. RESULTS: QoL improved in both groups between 6 and 12 months after surgery. The improvement was similar in both groups for global QoL and for most of the QoL sub-scales. CONCLUSION: No evidence was found to support the hypothesis that participation in an exercise intervention per se significantly improves QoL. Spontaneous improvement in QoL began during the first six months after the primary treatments, which might have confounded the results of the intervention of the BREX study.

Obesity and physical inactivity are related to impaired physical health of breast cancer survivors.

AIM: The aim of the present study was to examine the impact of obesity and physical activity on the health and wellbeing of patients with breast cancer shortly after the adjuvant treatments. PATIENTS AND METHODS: A total of 537 women aged 35 to 68 years with newly-diagnosed breast cancer were enrolled into the exercise intervention study. The physical activity, physical performance (2-km walking test), cardiovascular risk factors, quality of life (EORTC-QoL-C30), co-morbidities and body-mass index (BMI) were measured after the adjuvant treatments. RESULTS: Overall, 191 (39%) patients were overweight (BMI=25-30) and 85 (17%) obese (BMI ≥ 30). Physical activity and performance (p<0.001 and p<0.001), QoL (p<0.001) and high density lipoprotein (HDL)-cholesterol decreased (p<0.001) whereas age (p=0.009), co-morbidities (p<0.001), hypertension (p=0.011), metabolic syndrome (p<0.001), low density lipoprotein (LDL)-cholesterol (p=0.0043), triglycerides (p<0.001), glucose (p<0.001) and insulin (p<0.001) increased linearly with BMI. Higher waist circumference (p=0.0011), triglyceride (p=0.020), insulin (p=0.0098), rate of metabolic syndrome (p=0.028), and lower HDL-cholesterol (p=0.012) and QoL (p<0.001) were associated with low physical activity. Physical activity and BMI were the most important determinants of physical performance (p<0.001 and p<0.001, respectively). CONCLUSION: Obesity and a sedentary lifestyle are related to poor physical performance, increased risk of cardiovascular diseases and impaired QoL, leading to a vicious circle, which impairs patients' physical health and QoL.

Effectiveness of a 12-month exercise program on physical performance and quality of life of breast cancer survivors.

AIM: The study aimed at determining whether physical exercise training improves the quality of life (QoL) and physical fitness of breast cancer survivors. PATIENTS AND METHODS: A total of 573 breast cancer survivors were randomized into an exercise or a control group, 12-months after adjuvant treatments. EORTC QLQ-C30 and BR-23 questionnaires were used for evaluation of QoL, FACIT-F for fatigue and the Finnish modified version of Beck's 13-item depression scale (RBDI) for depression. Physical fitness was assessed by a 2-km walking test, and a figure-8 running test and physical activity (PA) by metabolic equivalent (MET) hours per week (MET-h/wk). RESULTS: Figure-8 running time improved significantly among the patients of the intervention group compared with the controls (p<0.001). No significant between-group differences were observed in 2-km walking time, in PA, EORTC-QLQ-C30, BR-23, FACIT-F or BDI. However, there was a linear relationship between increased PA and improved QoL (p=0.006), irrespective of the intervention. CONCLUSION: Increase in physical activity was associated with improved QoL, but no effect of the exercise intervention was observed.

Recruitment of breast cancer survivors into a 12-month supervised exercise intervention is feasible.

BACKGROUND: The BREX study is one of the largest randomised prospective exercise interventions of breast cancer survivors which aims at investigate whether regular exercise could reduce the long-term side effects of the adjuvant treatments and improve quality of life. MATERIAL AND METHODS: The study was limited to consider patients aged 35-68 years, who had recently completed adjuvant chemotherapy or started endocrine therapy. In this paper, we describe the recruitment process of the 413 randomised patients from the Helsinki University Hospital between September 2005 and September 2007. RESULTS: 768 potentially eligible patients out of the 1321 screened (via medical records) were contacted by phone. After the phone call 240 patients were excluded due to health problems that contraindicated exercise training. The most common health problems were musculoskeletal disorders. A total of 528 patients were considered as eligible for the intervention. Ultimately 413 of them agreed to participate resulting in a 53.8% recruitment rate of the potentially eligible patients. The most important reasons for declining were social, not health related. Eligible patients who did not want to participate did not differ significantly from those who participated according to age, health status, breast cancer treatment and tumour type. DISCUSSION: The high recruitment rate demonstrates breast cancer patient's willingness to participate even in long-lasting supervised exercise programs shortly after adjuvant treatments. After taking into account the selection of the population by age and musculoskeletal health, the results of the present intervention can be generalized to represent urban breast cancer patient population in Finland.