Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial.

PURPOSE: The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. METHODS: UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12-18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. RESULTS: Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = - 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: - 1.1, 95% CI = - 1.8; - 0.3; IV: - 1.9, 95% CI = - 3.3; - 0.5, PS: - 1.2, 95% CI = - 2.3; - 0.2). CONCLUSION: TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. TRIAL REGISTRATION: Netherlands Trial Register (NTR5482/NL.52062.041.15), date of registration: December 07, 2015.

Socio-ecological correlates of physical activity in breast and colon cancer survivors 4 years after participation in a randomized controlled exercise trial (PACT study).

BACKGROUND: Having a physically active lifestyle after cancer diagnosis is beneficial for health, and this needs to be continued into survivorship to optimize long-term benefits. We found that patients, who participated in an 18-week exercise intervention, reported significant higher physical activity (PA) levels 4 years after participation in a randomized controlled trial of supervised exercise delivered during chemotherapy (PACT study). This study aimed to identify social-ecological correlates of PA levels in breast and colon cancer survivors 4 years after participation in the PACT study. METHODS: Self-reported PA levels and potential correlates (e.g. physical fitness, fatigue, exercise history, and built environment) were assessed in 127 breast and colon cancer survivors shortly after diagnosis (baseline), post-intervention and 4 years later. Multivariable linear regression analyses were performed to identify social-ecological correlates of PA 4 years post-baseline. RESULTS: The final model revealed that lower baseline physical fatigue (ß = -0.25, 95% CI -0.26; -0.24) and higher baseline total PA (0.06, 95% CI, 0.03; 0.10) were correlated with higher total PA levels 4 years post-baseline. Higher baseline leisure and sport PA (0.02, 95% CI 0.01; 0.03), more recreational facilities within a buffer of 1 km (4.05, 95% CI = 1.28; 6.83), lower physical fatigue at 4-year follow-up (-8.07, 95% CI -14.00; -2.13), and having a positive change in physical fatigue during the intervention period (0.04, 95% CI 0.001; 0.07) were correlates of sport and leisure PA levels 4 years post-baseline. CONCLUSIONS: This study suggests that baseline and 4-year post-baseline physical fatigue, and past exercise behaviour, were significant correlates of PA 4 years after participation in an exercise trial. Additionally, this study suggests that the built environment should be taken into account when promoting PA. Understanding of socio-ecological correlates of PA can provide insights into how future exercise interventions should be designed to promote long-term exercise behaviour. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on 9 December 2009, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2138.

The association between changes in muscle mass and quality of life in patients with metastatic colorectal cancer.

BACKGROUND: Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment-related toxicities and reduced survival. Muscle loss may contribute to reduced health-related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient-reported HRQoL. METHODS: This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were-after initial treatment-randomized between maintenance treatment with capecitabine plus bevacizumab (CAP-B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales. RESULTS: Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP-B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (-10.0 and -15.0, respectively) and pain (-16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (-28.5 and -30.7, respectively). CONCLUSIONS: In mCRC, SMM preservation during CAP-B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning.

Moderators of Exercise Effects on Cancer-related Fatigue: A Meta-analysis of Individual Patient Data.

PURPOSE: Fatigue is a common and potentially disabling symptom in patients with cancer. It can often be effectively reduced by exercise. Yet, effects of exercise interventions might differ across subgroups. We conducted a meta-analysis using individual patient data of randomized controlled trials (RCT) to investigate moderators of exercise intervention effects on cancer-related fatigue. METHODS: We used individual patient data from 31 exercise RCT worldwide, representing 4366 patients, of whom 3846 had complete fatigue data. We performed a one-step individual patient data meta-analysis, using linear mixed-effect models to analyze the effects of exercise interventions on fatigue (z score) and to identify demographic, clinical, intervention- and exercise-related moderators. Models were adjusted for baseline fatigue and included a random intercept on study level to account for clustering of patients within studies. We identified potential moderators by testing their interaction with group allocation, using a likelihood ratio test. RESULTS: Exercise interventions had statistically significant beneficial effects on fatigue (ß = -0.17; 95% confidence interval [CI], -0.22 to -0.12). There was no evidence of moderation by demographic or clinical characteristics. Supervised exercise interventions had significantly larger effects on fatigue than unsupervised exercise interventions (ßdifference = -0.18; 95% CI -0.28 to -0.08). Supervised interventions with a duration ≤12 wk showed larger effects on fatigue (ß = -0.29; 95% CI, -0.39 to -0.20) than supervised interventions with a longer duration. CONCLUSIONS: In this individual patient data meta-analysis, we found statistically significant beneficial effects of exercise interventions on fatigue, irrespective of demographic and clinical characteristics. These findings support a role for exercise, preferably supervised exercise interventions, in clinical practice. Reasons for differential effects in duration require further exploration.

Loss of skeletal muscle index and survival in patients with metastatic colorectal cancer: Secondary analysis of the phase 3 CAIRO3 trial.

BACKGROUND: Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. METHODS: This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP-B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX-B). Upon first disease progression (PD1), CAPOX-B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time-periods; p1: during initial CAPOX-B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1-p3, with PD1, PD2, and survival was studied by Cox regression models. RESULTS: This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean -0.6 SMI units [95% CI -1.07;-0.26] and p3: -2.2 units [-2.7;-1.8], whereas during p2, SMI increased + 1.2 units [0.8-1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09-1.35]; 1.54 [1.31-1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10-1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14-1.63]). CONCLUSIONS: In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

Supplemental MRI Screening for Women with Extremely Dense Breast Tissue.

BACKGROUND: Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to improve early detection and reduce interval breast cancers in such patients. METHODS: In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period. RESULTS: The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval [CI], 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening. CONCLUSIONS: The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).

Trajectory of body mass and skeletal muscle indices and disease progression in metastatic colorectal cancer patients.

BACKGROUND: Knowledge of the evolution of BMI and skeletal muscle index (SMI) measurements during advanced cancer and their relationships with disease progression (PD) is relevant to improve the timing of interventions that may improve cachexia-associated outcomes. OBJECTIVES: We investigated BMI and SMI trajectories and their associations with PD in metastatic colorectal cancer (mCRC) patients during consecutive palliative systemic regimens. METHODS: In a secondary analysis of the primary CAIRO3 trial, we included 533 mCRC patients with BMI measurements repeated every 3 wk and 95 randomly selected patients with SMI measurements repeated every 9 wk. We studied 2 periods: p1, during first-line maintenance capecitabine + bevacizumab or observation until the first progression of disease (PD1); and p2, during capecitabine + oxaliplatin + bevacizumab or another reintroduction treatment from PD1 until the second progression of disease (PD2). BMI and SMI trajectories were modeled separately throughout both periods, and joint longitudinal-survival modeling was used to investigate the relationships between slopes in BMI and SMI with PD at 9 and 3 wk pre-PD. A multivariate longitudinal joint model was used to investigate the association between the BMI trajectory and PD at time of PD, independent of SMI. RESULTS: During p1, the slopes in BMI and SMI were associated with early PD1 [HRs for 9-wk BMI: 1.54 (95% CI: 1.33, 1.76); 9-wk SMI: 1.38 (95% CI: 0.87, 1.89), NS; 3-wk BMI: 1.74 (95% CI: 1.48, 1.99); 3-wk SMI: 2.65 (95% CI: 1.97, 3.32)]. During p2, only the slope in SMI was related to PD2 [9-wk BMI: 1.09 (95%: CI: 0.73, 1.45), NS; 9-wk SMI: 1.64 (95% CI: 1.25, 2.04); 3-wk BMI: 1.17 (95% CI: 0.77, 1.57); 3-wk SMI: 1.11 (95% CI: 0.70, 1.53)]. In models mutually adjusting for BMI and SMI, SMI was associated with PD in p1 [p1 ( n = 95), HR BMI: 1.32 (95% CI: 0.74, 2.39), NS; p1, HR SMI: 1.50 (95% CI: 1.04, 2.14); p2 ( n = 50), BMI: 0.98 (95% CI: 0.55, 1.75), NS; p2, HR SMI: 1.11 (95% CI: 0.61, 2.05), NS]. CONCLUSIONS: In mCRC patients during palliative systemic treatment, SMI losses, irrespective of BMI losses, may be a marker for the early initiation of cachexia interventions.

Potential for Reducing Time to Referral for Colorectal Cancer Patients in Primary Care.

PURPOSE: An optimal diagnostic process in primary care is pivotal for reducing cancer-related disease burden. This study aims to explore reasons for long times to referral for Dutch colorectal cancer (CRC) patients in primary care. METHODS: A retrospective cohort study of anonymized free-text primary care records from the Julius General Practitioners' Network database, linked to the Netherlands Cancer Registry. Patients with a confirmed CRC diagnosis from 2007 through 2011 that symptomatically presented in primary care were included. Median time and interquartile ranges from presentation in primary care to referral were calculated for multiple patient and presentation characteristics. Associations of these characteristics with long time to referral (75th percentile was ≥59 days) were examined with log-binomial regression analyses. Routes to referral of patients with the longest times to referral were explored using thematic free-text analyses (90th percentile at ≥219 days). RESULTS: Among the 309 people with CRC, patients who were female, did not have a registered family history, had a history of malignancy, lacked alarm symptoms at presentation, or had hemorrhoids at physical examination were at risk for longer time to referral in univariable analyses (longer median durations and/or univariable association with the 75th percentile). Only presentation without alarm symptoms showed a statistically significant association with long duration (75th percentile) in multivariable analysis (relative risk = 1.7; 95% CI, 1.1-2.6). Thematic exploration of the diagnostic routes to referral of patients with the longest durations (90th percentile) showed 2 dominating themes: "alternative working diagnosis" and "suboptimal diagnostic strategies," and included the sub-themes "omitting to reconsider an initial diagnosis" and "lacking follow-up." CONCLUSIONS: Long time to referral for CRC in primary care is mainly related to low cancer suspicion. There is potential for reducing the longest times to referral for patients with CRC in primary care, with earlier reconsideration of the initial hypothesis and implementation of strict follow-up consultations.

Factors Contributing to Cancer-Related Muscle Wasting During First-Line Systemic Treatment for Metastatic Colorectal Cancer.

BACKGROUND: Increasing evidence indicates that loss of muscle mass is associated with adverse outcomes in metastatic colorectal cancer. Here, we investigate which demographic, lifestyle- (smoking), tumor-, and treatment-related factors are associated with muscle loss in patients with metastatic colorectal cancer during first-line palliative systemic treatment. METHODS: Data from 300 patients with computed tomography scans both at start and after six initial cycles of capecitabine plus oxaliplatin and bevacizumab was used (CAIRO3). From computed tomography, muscle mass normalized for stature (skeletal muscle index [SMI]) was calculated. A priori-selected variables were tested using multivariable linear regression models (P values ≤.05). Two models were developed: Model 1 contained variables measured at start and Model 2 contained variables assessed after initial therapy. RESULTS: In Model 1, loss of SMI was statistically significantly associated with a higher initial SMI (-0.32%, 95% confidence interval [CI] = -0.45% to -0.19% per unit increase in initial SMI), smoking status (-2.74%, 95% CI = -5.29% to -0.19% for smokers), and interval of metastases (-3.02%, 95% CI = -5.50% to -0.53%) for metachronous vs synchronous metastases), and primary tumor resection was statistically significantly associated with a gain in SMI (2.17%, 95% CI = 0.13% to 4.21% for resection vs no resection). In Model 2, loss of SMI was statistically significantly associated with response to capecitabine plus oxaliplatin and bevacizumab (-2.48%, 95% CI = -4.33% to -0.62% for stable disease vs partial/complete response). CONCLUSIONS: Our results highlight, given the association of sarcopenia and survival, that patients with higher SMI should not be ignored. In addition, smoking is a potentially modifiable factor associated with muscle loss. The association between smoking and muscle loss might relate to worse clinical outcomes in smokers with metastatic colorectal cancer.

Effect of physical exercise on cognitive function and brain measures after chemotherapy in patients with breast cancer (PAM study): protocol of a randomised controlled trial.

INTRODUCTION: After treatment with chemotherapy, many patients with breast cancer experience cognitive problems. While limited interventions are available to improve cognitive functioning, physical exercise showed positive effects in healthy older adults and people with mild cognitive impairment. The Physical Activity and Memory study aims to investigate the effect of physical exercise on cognitive functioning and brain measures in chemotherapy-exposed patients with breast cancer with cognitive problems. METHODS AND ANALYTICS: One hundred and eighty patients with breast cancer with cognitive problems 2-4 years after diagnosis are randomised (1:1) into an exercise intervention or a control group. The 6-month exercise intervention consists of twice a week 1-hour aerobic and strength exercises supervised by a physiotherapist and twice a week 1-hour Nordic or power walking. The control group is asked to maintain their habitual activity pattern during 6 months. The primary outcome (verbal learning) is measured at baseline and 6 months. Further measurements include online neuropsychological tests, self-reported cognitive complaints, a 3-tesla brain MRI, patient-reported outcomes (quality of life, fatigue, depression, anxiety, work performance), blood sampling and physical fitness. The MRI scans and blood sampling will be used to gain insight into underlying mechanisms. At 18 months online neuropsychological tests, self-reported cognitive complaints and patient-reported outcomes will be repeated. ETHICS AND DISSEMINATION: Study results may impact usual care if physical exercise improves cognitive functioning for breast cancer survivors. TRIAL REGISTRATION NUMBER: NTR6104.

Attendance and compliance with an exercise program during localized breast cancer treatment in a randomized controlled trial: The PACT study.

PURPOSE: Maintaining high adherence rates (session attendance and compliance) in exercise programs during breast cancer treatment can be challenging. We aimed to identify adherence rates and predictors to an exercise program during adjuvant breast cancer treatment. METHODS: Ninety-two patients with localized breast cancer undergoing chemotherapy were randomly assigned to an 18-week supervised moderate-to-high intensity aerobic and resistance exercise program, including two 1-hour sessions/week. Additionally, participants were asked to be physically active for at least 30 minutes/day on at least three other days. We report median percentages for attendance, compliance with the prescribed duration and intensity of aerobic and muscle strength exercises, and the exercise advice given. Predictors included in univariate and multivariable linear regression models were demographical, tumor- and treatment-related factors, constructs of the theory of planned behavior, psychological and physical factors. RESULTS: Patients attended 83% (interquartile range: 69-91%) of the supervised sessions. Compliance with the duration of aerobic exercise, high-intensity aerobic exercise (cycling at the ventilatory threshold), muscle strength exercises and the exercise advice were 88%(64-97%), 50%(22-82%), 84%(65-94%) and 61%(33%-79%), respectively. Education, radiotherapy, BMI and physical fatigue were important predictors of adherence to supervised exercise. Beliefs about planned behaviors were important predictors, especially for compliance with the exercise advice. CONCLUSIONS: Attendance to and compliance with an 18-week aerobic and strength exercise program were high. The lowest compliance was found for high-intensity supervised aerobic exercise. The identified predictors should be considered when designing or adapting exercise programs for patients with localized breast cancer to increase adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 Dutch Trial Register NTR2138.

The Trials within Cohorts design faced methodological advantages and disadvantages in the exercise oncology setting.

OBJECTIVES: The Trials within Cohorts (TwiCs) design is an alternative for pragmatic randomized controlled trials (RCTs) and might overcome disadvantages such as difficult recruitment, dropout after randomization to control, and contamination. We investigated the applicability of the TwiCs design in an exercise oncology study regarding the recruitment process, representativeness of the study sample, contamination, participation, and dropout. METHODS: The Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA) Fit TwiCs evaluates an exercise intervention in inactive breast cancer patients. Eligible patients participating in the prospective UMBRELLA were identified and randomized. Patients randomized to the intervention (n = 130) were offered the intervention, whereas controls (n = 130) were not informed. RESULTS: Fifty-two percent (n = 68) accepted the intervention. Because this rate was lower than expected, a larger sample size was required than initially estimated (n = 166). However, recruitment of 260 patients was still completed by one researcher within 30 months. Unselective eligibility screening and randomization before invitation improved representativeness. Disadvantage of the design might be inclusion of ineligible patients when cohort information is limited. Furthermore, the design faced higher noncompliance in the intervention group, but prevention of contamination. CONCLUSION: The TwiCs design improved logistics in recruitment and prevented contamination, but noncompliance due to refusal of the intervention was higher compared with conventional pragmatic exercise oncology RCTs, which may dilute the estimated intervention effect.

Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies.

OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Receptor activator of nuclear factor kB ligand, osteoprotegerin, and risk of death following a breast cancer diagnosis: results from the EPIC cohort.

BACKGROUND: Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. METHODS: Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. RESULTS: Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. CONCLUSIONS: High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.

Caloric restriction reduces age at menopause: the effect of the 1944-1945 Dutch famine.

OBJECTIVE: To assess the effect of caloric restriction, as endured during the 1944-1945 Dutch famine, on the age at which natural menopause occurs and to identify specific vulnerable age periods in which caloric restriction has the largest effect. DESIGN: This was a population-based cohort study conducted in Utrecht, the Netherlands. Between 1983 and 1986, 9,471 women aged 40 to 73 years at the time of interview were classified regarding their exposure to the famine. Age at natural menopause was obtained from all available data, retrospectively as well as prospectively. We estimated differences in mean age at natural menopause between famine exposure categories (not, moderately, and severely exposed), with adjustment for smoking, parity, socioeconomic status, body mass index, age at menarche, and year of birth. RESULTS: Women experienced natural menopause on average 0.36 years earlier (95% CI: -0.60, -0.11) when severely exposed to the famine and 0.06 years earlier (95% CI: -0.22, 0.09) when moderately exposed compared with the unexposed women. This effect was particularly pronounced in those severely exposed from 2 to 6 years of age: -1.83 years (95% CI: -3.03, -0.63). CONCLUSIONS: Our findings suggest that caloric restriction decreases age at natural menopause. Early childhood seems to be a particularly sensitive age period for this effect.

Impact of different palliative systemic treatments on skeletal muscle mass in metastatic colorectal cancer patients.

BACKGROUND: Observational studies suggest that loss of skeletal muscle mass (SMM) is associated with chemotherapy-related toxicity, poor quality of life, and poor survival in metastatic colorectal cancer (mCRC) patients. Little is known about the evolution of SMM during palliative systemic therapy. We investigated changes in SMM during various consecutive palliative systemic treatment regimens using repeated abdominal computed tomography scans of mCRC patients who participated in the randomized phase 3 CAIRO3 study. METHODS: In the CAIRO3 study, mCRC patients with stable disease or better after 6 cycles of first-line treatment with capecitabine + oxaliplatin + bevacizumab (CAPOX-B) were randomized between maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation. Upon first disease progression, in both groups, CAPOX-B or other treatment was reintroduced until the second disease progression, which was the primary study endpoint. We analysed 1355 computed tomography scans of 450 (81%) CAIRO3 patients (64 ± 9.0 years, CAP-B n = 223; observation n = 227) for SMM at four time points (i.e. prior to the start of pre-randomization initial treatment, at randomization, and at first and at second disease progression) using the Slice-o-matic software and single slice evaluation at the lumbar 3 level. By using accepted and widely used formulas, whole body SMM was calculated. A linear mixed effects model, adjusted for relevant confounders, was used to assess SMM changes for the total group and within and between study arms. RESULTS: During 6 cycles of initial treatment with CAPOX-B prior to randomization, SMM decreased significantly in all patients [CAP-B arm: -0.53 kg (95% CI -1.12; -0.07) and observation arm: -0.85 kg (-1.45; -0.25)]. After randomization, SMM recovered during CAP-B treatment by 1.32 kg (0.73; 1.90) and observation by 1.20 kg (0.63; 1.78) (median time from randomization to first disease progression 8.6 and 4.1 months for CAP-B arm and observation arm, respectively). After first progression and during reintroduction treatment with CAPOX-B or other treatment, SMM again decreased significantly and comparable in both arms, CAP-B: -2.71 kg (-3.37; -2.03), and observation: -2.01 kg (-2.64; -1.41) (median time from first progression until second progression CAP-B arm: 4.7 months and observation arm: 6.6 months). CONCLUSIONS: This longitudinal study provides a unique insight in SMM changes in mCRC patients during palliative systemic treatment regimens, including observation. Our data show that muscle loss is reversible and may be influenced by the intensity of systemic regimens. Although studies have shown prognostic capacity for SMM, the effects of subsequent changes in SMM are unknown and may be clues for new future therapeutic interventions.

Effect of exercise and/or reduced calorie dietary interventions on breast cancer-related endogenous sex hormones in healthy postmenopausal women.

BACKGROUND: Physical inactivity and being overweight are modifiable lifestyle risk factors that consistently have been associated with a higher risk of postmenopausal breast cancer in observational studies. One biologic hypothesis underlying this relationship may be via endogenous sex hormone levels. It is unclear if changes in dietary intake, physical activity, or both, are most effective in changing these hormone levels. OBJECTIVE: This systematic review and meta-analysis examines the effect of reduced caloric dietary intake and/or increased exercise levels on breast cancer-related endogenous sex hormones. METHODS: We conducted a systematic literature search in MEDLINE, Embase, and Cochrane's Central Register of Controlled Trials (CENTRAL) up to March 2017. Main outcome measures were breast cancer-related endogenous sex hormones. Randomized controlled trials (RCTs) reporting effects of reduced caloric intake and/or exercise interventions on endogenous sex hormones in healthy, physically inactive postmenopausal women were included. Studies including women using hormone therapy were excluded. The methodological quality of each study was assessed by the Cochrane's risk of bias tool. RESULTS: From the 2599 articles retrieved, seven articles from six RCTs were included in this meta-analysis. These trials investigated 1588 healthy postmenopausal women with a mean age ranging from 58 to 61 years. A combined intervention of reduced caloric intake and exercise, with durations ranging from 16 to 52 weeks, compared with a control group (without an intervention to achieve weight loss) resulted in the largest beneficial effects on estrone treatment effect ratio (TER) = 0.90 (95% confidence interval (CI) = 0.83-0.97), total estradiol TER = 0.82 (0.75-0.90), free estradiol TER = 0.73 (0.66-0.81), free testosterone TER = 0.86 (0.79-0.93), and sex hormone biding globulin (SHBG) TER = 1.23 (1.15-1.31). A reduced caloric intake without an exercise intervention resulted in significant effects compared with control on total estradiol TER = 0.86 (0.77-0.95), free estradiol TER = 0.77 (0.69-0.84), free testosterone TER = 0.91 (0.84-0.98), and SHBG TER = 1.20 (1.06-1.36). Exercise without dietary change, versus control, resulted in borderline significant effects on androstenedione TER = 0.97 (0.94-1.00), total estradiol TER = 0. 97 (0.94-1.00), and free testosterone TER = 0. 0.97 (0.95-1.00). CONCLUSIONS AND RELEVANCE: This meta-analysis of six RCTs demonstrated that there are beneficial effects of exercise, reduced caloric dietary intake or, preferably, a combination of exercise and diet on breast cancer-related endogenous sex hormones in physically inactive postmenopausal women.

KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case-Control Study.

Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.Experimental Design: KIM-1 concentrations were measured in prediagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to 5 years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival.Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 [95% confidence interval (CI), 1.44-2.03, P = 4.1 × 10-23], corresponding to an IRR of 63.3 (95% CI, 16.2-246.9) comparing the 80th to the 20th percentiles of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver-operating characteristic curve of 0.8 compared with 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (P = 0.0053).Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival. Clin Cancer Res; 24(22); 5594-601. ©2018 AACR.

Four-year effects of exercise on fatigue and physical activity in patients with cancer.

BACKGROUND: In the earlier randomized controlled Physical Activity during Cancer Treatment (PACT) study, we found beneficial effects of an 18-week supervised exercise program on fatigue in patients with newly diagnosed breast or colon cancer undergoing adjuvant treatment. The present study assessed long-term effects of the exercise program on levels of fatigue and physical activity 4 years after participation in the PACT study. METHODS: The original study was a two-armed, multicenter randomized controlled trial comparing an 18-week supervised exercise program to usual care among 204 breast cancer patients and 33 colon cancer patients undergoing adjuvant treatment. Of the 237 PACT participants, 197 participants were eligible and approached to participate in the 4-year post-baseline measurements, and 128 patients responded. We assessed fatigue and physical activity levels at 4 years post-baseline and compared this to levels at baseline, post-intervention (18 weeks post-baseline), and at 36 weeks post-baseline. RESULTS: Intention-to-treat mixed linear effects model analyses showed that cancer patients in the intervention group reported significantly higher moderate-to-vigorous total physical activity levels (141.46 min/week (95% confidence interval (CI) 1.31, 281.61, effect size (ES) = 0.22) after 4 years compared to the usual care group. Furthermore, cancer patients in the intervention group tended to experience less physical fatigue at 4 years post-baseline compared to the usual care group (- 1.13, 95% CI -2.45, 0.20, ES = 0.22), although the result was not statistically significant. CONCLUSION: Patients with breast or colon cancer who participated in the 18-week exercise intervention showed significant higher levels of moderate-to-vigorous total physical activity levels and a tendency towards lower physical fatigue levels 4 years post-baseline. Our result indicate that exercising during chemotherapy is a promising strategy for minimizing treatment-related side effects, both short and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571 , Dutch Trial Register NTR2138 . Trial registered on 9 December 2009.

The combined effect of mammographic texture and density on breast cancer risk: a cohort study.

BACKGROUND: Texture patterns have been shown to improve breast cancer risk segregation in addition to area-based mammographic density. The additional value of texture pattern scores on top of volumetric mammographic density measures in a large screening cohort has never been studied. METHODS: Volumetric mammographic density and texture pattern scores were assessed automatically for the first available digital mammography (DM) screening examination of 51,400 women (50-75 years of age) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. The texture assessment method was developed in a previous study and validated in the current study. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. All screen-detected breast cancers diagnosed at the first available digital screening examination were excluded. During a median follow-up period of 4.2 (interquartile range (IQR) 2.0-6.2) years, 301 women were diagnosed with breast cancer. The associations between texture pattern scores, volumetric breast density measures and breast cancer risk were determined using Cox proportional hazard analyses. Discriminatory performance was assessed using c-indices. RESULTS: The median age of the women at the time of the first available digital mammography examination was 56 years (IQR 51-63). Texture pattern scores were positively associated with breast cancer risk (hazard ratio (HR) 3.16 (95% CI 2.16-4.62) (p value for trend <0.001), for quartile (Q) 4 compared to Q1). The c-index of texture was 0.61 (95% CI 0.57-0.64). Dense volume and percentage dense volume showed positive associations with breast cancer risk (HR 1.85 (95% CI 1.32-2.59) (p value for trend <0.001) and HR 2.17 (95% CI 1.51-3.12) (p value for trend <0.001), respectively, for Q4 compared to Q1). When adding texture measures to models with dense volume or percentage dense volume, c-indices increased from 0.56 (95% CI 0.53-0.59) to 0.62 (95% CI 0.58-0.65) (p < 0.001) and from 0.58 (95% CI 0.54-0.61) to 0.60 (95% CI 0.57-0.63) (p = 0.054), respectively. CONCLUSIONS: Deep-learning-based texture pattern scores, measured automatically on digital mammograms, are associated with breast cancer risk, independently of volumetric mammographic density, and augment the capacity to discriminate between future breast cancer and non-breast cancer cases.