Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: results of the lifestyle intervention pilot study LIBRE-1.

PURPOSE: Emerging evidence suggests that the progesterone-mediated receptor activator of nuclear factor κB (RANK)/soluble RANK ligand (sRANKL)/osteoprotegerin (OPG) pathway plays an important role in mammary carcinogenesis and is hyperactivated in germline (g)BRCA1/2 mutation carriers. We analyzed the effects of a 3-month intensive lifestyle intervention within the LIBRE-1 study on the serum levels of OPG and sRANKL and hypothesized that the intervention program provides a beneficial impact on the biomarkers by increasing OPG and reducing sRANKL serum concentrations. METHODS: Serum levels of OPG and sRANKL of 49 gBRCA1/2 mutation carriers were quantified using enzyme-linked immunosorbent assays. We used previously collected blood samples from participants of the prospective LIBRE-1 study, who were randomized into an intervention group (IG), increasing physical activity and adherence to the Mediterranean diet (MedD) through supervised sessions from study entry to the first study visit after 3 months and a usual-care control group (CG). Differences in biomarker levels before and after the 3-month intervention were tested within and between study groups. RESULTS: The lifestyle intervention resulted in a significant increase in OPG for participants in both the IG (q = 0.022) and CG (q = 0.002). sRANKL decreased significantly in the IG (q = 0.0464) and seemed to decrease in the CG (q = 0.5584). An increase in the intake of Omega-3 polyunsaturated fatty acids was significantly associated with an increase in OPG (r = 0.579, q = 0.045). Baseline serum levels of sRANKL were a strong predictor for the change of sRANKL in the course of the intervention (ß-estimate = - 0.70; q = 0.0018). Baseline physical fitness (assessed as VO2peak) might predict the change of OPG in the course of the intervention program (ß-estimate = 0.133 pg/ml/ml/min/kg; p = 0.0319; q = 0.2871). CONCLUSION: Findings from this pilot study seem to confirm our hypothesis by showing an increase in OPG and decrease in sRANKL over a 3-month lifestyle intervention and suggest that increased physical activity and adherence to the MedD are potent modulators of the biomarkers OPG and potentially sRANKL.

Precursor fractions of neurotensin and enkephalin might point to molecular mechanisms of cancer risk modulation during a lifestyle-intervention in germline BRCA1/2 gene mutation carriers.

BACKGROUND: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC. METHODS: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors. RESULTS: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis. CONCLUSION: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

Exercise Therapy in Oncology.

BACKGROUND: The diagnosis and treatment of cancer are highly stressful. Exercise therapy is often used to mitigate the adverse effects of treatment. But how good is the evidence base, and what has changed in recent years? In this narrative review, we present the current data and what it implies for the care of adults with cancer. METHODS: This review is based on data from meta-analyses and systematic reviews concerning 16 relevant clinical endpoints (outcomes) of exercise therapy for cancer patients. RESULTS: The literature evaluated for this paper reveals that targeted exercise therapy is feasible and safe under appropriate supervision. It is highly effective for improving eight endpoints (anxiety, depression, fatigue, quality of life, physical function, secondary lymphedema after breast cancer, urinary incontinence, post-mastectomy pain syndrome in breast cancer) and may also have a beneficial effect on sleep quality, cardiotoxicity, and cognitive function. Less conclusive studies are currently available with respect to chemotherapy-induced polyneuropathy, nausea/vomiting, and bone health. There is currently insufficient data to suggest any benefit with respect to sexual function and risk factors for falling. CONCLUSION: The data shows that exercise therapy for cancer patients is safe and has manifold effects on selected clinically relevant parameters. Further studies should be performed regarding the possible utility of exercise therapy against treatment-related side effects for which the evidence is currently insufficient. On the basis of the currently available and already existing recommendations, quality-assured exercise therapy can be recommended to cancer patients suffering from a wide range of neoplastic conditions.

Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers.

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors. Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors. Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 - 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness (OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a previous diagnosis of breast cancer (p = 0.28). Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

[Physical Activity and Cancer]. / Sporttherapie bei Krebs.

The value of physical activity in cancer prevention and therapy has been increasingly recognised during the last twenty years. Many patients suffer from a loss of physical performance and a decline in quality of life - with fatigue, anxiety and depression as a direct result of their disease and therapy. Since the 1990 s, there has been a substantial increase in scientific evidence demonstrating the positive effects of physical activity in cancer patients. This article presents an overview of the most important studies investigating the effects of physical activity for breast, colon, and prostate cancer.