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).

Characterization of clinicopathological features, treatment practices, and outcomes among Finnish advanced breast cancer patients in real-life clinical practice.

PURPOSE: In recent years, several new targeted therapies have emerged for advanced breast cancer (aBC). However, real-life data specific to aBC and different breast cancer subtypes are scarce. This retrospective cohort study was designed to describe the distribution of aBC subtypes, incidence, treatment patterns, survival, and PIK3CA hotspot mutation frequency. METHODS: The study included all patients in the Hospital District of Southwest Finland diagnosed with aBC between 2004 and 2013 and with a sample available in Auria Biobank. In addition to registry-based data collection, 161 HR+/HER2- aBCs were screened for PIK3CA mutations. RESULTS: Altogether, 54.7% of the 444 patients included in the study had luminal B subtype. The smallest representations were in HR-/HER2+ (4.5%) and triple-negative (5.6%) subgroups. The percentage of aBC among all diagnosed breast cancers increased until 2010, after which it remained stable. The triple-negative cancers were associated with shorter median overall survival (5.5 months) compared to other subgroups (16.5-24.6 months). Most (84%) triple-negative cancers also metastasized during the first two years, whereas this was more evenly distributed over time in other subgroups. Of the HR+/HER2- tumors, 32.3% harbored a PIK3CA hotspot mutation. These patients, however, did not have inferior survival compared to patients with PIK3CA wild-type cancers. CONCLUSION: This study described real-world aBC subgroups and indicated that the clinical outcomes of subgroups vary. Although PIK3CA hotspot mutations did not lead to inferior survival, they are relevant as possible treatment targets. Overall, these data could be utilized to further evaluate the subgroup-specific medical needs in breast cancer.

Predicting Effective Adaptation to Breast Cancer to Help Women BOUNCE Back: Protocol for a Multicenter Clinical Pilot Study.

BACKGROUND: Despite the continued progress of medicine, dealing with breast cancer is becoming a major socioeconomic challenge, particularly due to its increasing incidence. The ability to better manage and adapt to the entire care process depends not only on the type of cancer but also on the patient's sociodemographic and psychological characteristics as well as on the social environment in which a person lives and interacts. Therefore, it is important to understand which factors may contribute to successful adaptation to breast cancer. To our knowledge, no studies have been performed on the combination effect of multiple psychological, biological, and functional variables in predicting the patient's ability to bounce back from a stressful life event, such as a breast cancer diagnosis. Here we describe the study protocol of a multicenter clinical study entitled "Predicting Effective Adaptation to Breast Cancer to Help Women to BOUNCE Back" or, in short, BOUNCE. OBJECTIVE: The aim of the study is to build a quantitative mathematical model of factors associated with the capacity for optimal adjustment to cancer and to study resilience through the cancer continuum in a population of patients with breast cancer. METHODS: A total of 660 women with breast cancer will be recruited from five European cancer centers in Italy, Finland, Israel, and Portugal. Biomedical and psychosocial variables will be collected using the Noona Healthcare platform. Psychosocial, sociodemographic, lifestyle, and clinical variables will be measured every 3 months, starting from presurgery assessment (ie, baseline) to 18 months after surgery. Temporal data mining, time-series prediction, sequence classification methods, clustering time-series data, and temporal association rules will be used to develop the predictive model. RESULTS: The recruitment process stared in January 2019 and ended in November 2021. Preliminary results have been published in a scientific journal and are available for consultation on the BOUNCE project website. Data analysis and dissemination of the study results will be performed in 2022. CONCLUSIONS: This study will develop a predictive model that is able to describe individual resilience and identify different resilience trajectories along the care process. The results will allow the implementation of tailored interventions according to patients' needs, supported by eHealth technologies. TRIAL REGISTRATION: ClinicalTrials.gov NCT05095675; https://clinicaltrials.gov/ct2/show/NCT05095675. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34564.

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.

Effect of Adjuvant Trastuzumab for a Duration of 9 Weeks vs 1 Year With Concomitant Chemotherapy for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: The SOLD Randomized Clinical Trial.

Importance: Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. Objective: To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. Design, Setting, and Participants: Open-label, randomized (1:1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m2) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. Intervention: Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. Main Outcomes and Measures: The primary objective was DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. Results: In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m2 had inferior and those treated with 100 mg/m2 had similar DFS as patients in the 1-year group. Conclusions and Relevance: Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT00593697.

[Immuno-oncology--silver bullets or mass destruction weapons?]. / Immuno-onkologia--hopealuoteja vai joukkotuhoaseita?

Modes of treatment affecting the regulatory mechanisms of cell-mediated immunity are changing the treatment practices of various types of cancer. Antibodies inhibiting regulatory molecules of the immune response, i.e. checkpoint inhibitors, are of particular interest. The mechanism of action is enhancement of the body's intrinsic responses to cancer cells through inhibition of negative regulation of the immune defense. Cell-mediated immunity directed to cancerous tissue can be enhanced by removing the brake associated with T-cell activation (CTLA-4 inhibitors). A more physiological mode of action is to abolish the attenuation mechanism of already activated T cells (PD-1 inhibitors). The physiological purpose of both mechanisms is to prevent an excessively strong immune reaction and thus autoimmunity.

Effects of α-tocopherol and ß-carotene supplementation on cancer incidence and mortality: 18-year postintervention follow-up of the Alpha-tocopherol, Beta-carotene Cancer Prevention Study.

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study among 29,133 Finnish male smokers aged 50-69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas ß-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the postintervention effects of α-tocopherol and ß-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n = 2,881) was 1.04 (95% confidence interval [CI], 0.96-1.11) among ß-carotene recipients compared with nonrecipients. For prostate cancer (n = 2,321), RR was 0.97 (95% CI, 0.89-1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing ∼8 years postintervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (p for interaction = 0.01) RR 1.00 (95% CI, 0.88-1.14) in normal-weight men, 0.87 (95% CI, 0.77-0.98) in overweight men, and 1.25 (95% CI, 1.01-1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98-1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99-1.05) for ß-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70-0.99), whereas ß-carotene increased it (RR, 1.20; 95% CI, 1.01-1.42). In conclusion, supplementation with α-tocopherol and ß-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.

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.

[Long-term morbidity caused by breast cancer therapy]. / Rintasyövän hoidon aiheuttama pitkäaikainen sairastavuus.

All forms of breast cancer therapies are associated with both acute adverse effects and manifold long-term morbidity. Due to the common occurrence and favorable prognosis of breast cancer, the number of those suffering from complications worsening the quality of life is considerable. In a significant proportion, the long-term adverse effects caused by the therapy can be alleviated. The importance of follow-up visits of a breast cancer patient is not limited to diagnosing or excluding of relapses. During these visits, the elucidation of long-term adverse effects and their treatment alternatives and even discussing the symptoms and supporting the patient are important with respect to the quality of life.

Metabolic characterization of childhood brain tumors: comparison of 18F-fluorodeoxyglucose and 11C-methionine positron emission tomography.

BACKGROUND: Positron emission tomography (PET) scans of primary brain tumors were performed in pediatric patients to examine whether metabolic characteristics could be used as an index of clinical aggressiveness. METHODS: Twenty-seven pediatric patients with untreated primary central nervous system neoplasms were studied with PET scans using 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) and/or L-[methyl-(11)C] methionine (MET). Metabolic characteristics as assessed with FDG and MET standardized uptake values (SUV) and SUV-to-normal brain ratios were compared with histopathology and selected histochemical features such as proliferation activity (Ki-67(MIB-1)) and apoptotic, vascular, and cell density indices. The median followup time was 43 months. RESULTS: The accumulation of both FDG and MET was significantly higher in high-grade than in low-grade tumors, but a considerable overlap was found. The accumulation of both tracers was associated positively with age. High-grade tumors showed higher proliferative activity and vascularity than the low-grade tumors. In univariate analysis, FDG-PET, MET-PET, and apoptotic index were independent predictors of event-free survival. CONCLUSION: We found that both FDG and MET uptake in pediatric brain tumors are associated with malignancy grade. However, no clear limits of SUVs and SUV-to-normal brain ratios can be set between low-grade and high-grade tumors, which makes the assessment of malignancy grade using metabolic imaging with PET scan difficult in individual cases. Although FDG-PET and MET-PET do not compensate for histopathologic evaluation, they may give valuable additional information especially if invasive procedures to obtain histopathologic samples are not feasible.