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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 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.

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.

Background: The Mediterranean diet (MD) is an anti-inflammatory diet linked to improved health-related quality of life (HRQoL). Germline (g)BRCA1/2 mutation carriers have an increased risk of developing breast cancer and are often exposed to severe cancer treatments, thus the improvement of HRQoL is important. Little is known about the associations between dietary intake and HRQoL in this population. Methods: We included 312 gBRCA1/2 mutation carriers from an ongoing prospective randomized controlled lifestyle intervention trial. Baseline data from the EPIC food frequency questionnaire was used to calculate the dietary inflammatory index (DII), and adherence to MD was captured by the 14-item PREDIMED questionnaire. HRQoL was measured by the EORTC QLQ-C30 and LOT-R questionnaires. The presence of metabolic syndrome (MetS) was determined using anthropometric measurements, blood samples and vital parameters. Linear and logistic regression models were performed to assess the possible impact of diet and metabolic syndrome on HRQoL. Results: Women with a prior history of cancer (59.6%) reported lower DIIs than women without it (p = 0.011). A greater adherence to MD was associated with lower DII scores (p < 0.001) and reduced odds for metabolic syndrome (MetS) (p = 0.024). Women with a more optimistic outlook on life reported greater adherence to MD (p < 0.001), whereas a more pessimistic outlook on life increased the odds for MetS (OR = 1.15; p = 0.023). Conclusions: This is the first study in gBRCA1/2 mutation carriers that has linked MD, DII, and MetS to HRQoL. The long-term clinical implications of these findings are yet to be determined.

BackgroundGermlineBRCA1/2mutation 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.MethodsThe 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.ResultsAt 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.ConclusionOur results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.

BACKGROUND: Risk factors for cardiovascular disease (CVD) and breast cancer overlap substantially. Identification of the underlying mechanisms associated with this co-occurrence is of great public health importance. Adrenomedullin (AM) is an almost ubiquitously expressed peptide with vasodilator and natriuretic properties. Previous studies have observed a link between high AM levels and worse prognosis in patients with myocardial infarction and heart failure, indicating a crucial role in the pathophysiology of CVD. Moreover, AM is expressed in 80% of sporadic breast cancers, and the degree of expression is associated with tumour growth, local tumour progression and bone metastases. High plasma AM levels are linked to arterial hypertension, diabetes, obesity and smoking. Preliminary evidence suggests that AM influences the osteoclast differentiation mediated by Receptor Activator of NF-κB Ligand (RANKL), an important signalling pathway in BRCA1-associated breast tumorigenesis. OBJECTIVE: Besides an elevated risk of breast cancer, recent studies revealed that BRCA mutation carriers are potentially at higher cardiovascular risk. The value of AM in BRCA mutation carriers is unknown. The aim of this study was to examine circulating plasma AM levels in BRCA mutation carriers and assess their association with modifiable risk factors. METHODS: AM concentrations were measured in 290 BRCA1/2 mutation carriers without overt CVD, participating in the randomized controlled LIBRE study (NCT numbers: NCT02087592, NCT02516540), by an immunoassay (sphingotest® bio-ADM®). Subjects were classified into high versus low AM levels based on the median plasma AM level in the entire cohort (13.9 pg/mL). Univariate logistic regression models were used to estimate the odds ratio (OR) of having high circulating AM levels by metabolic syndrome (MetS), cardiorespiratory fitness (CRF), body mass index (BMI), circulating insulin, smoking, current age, BRCA mutation status (BRCA1 or BRCA2) and previous diagnosis of breast cancer. MetS was defined in accordance with the criteria of the Third Adult Treatment Panel (ATP III). CRF was measured by peak oxygen uptake (VO2peak) assessed on a cycle ergometer via standardized cardiopulmonary exercise testing. RESULTS: Of all women (median age: 43 years), 57.9% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was 3 years (range: 0-32 years). Women fulfilling the criteria of metabolic syndrome had over 17 times higher odds of having increased AM levels compared to those who did not meet the criteria (OR = 17.49, p < 0.001). Moreover, high AM levels were associated with lower VO2peak (OR = 0.91, p < 0.001), higher BMI (OR = 1.24, p < 0.001) and higher circulating insulin levels (OR = 1.1, p < 0.001). AM levels were higher in women who have ever smoked (OR = 1.73, p = 0.022), and AM levels increased with the number of pack-years smoked (OR = 1.03, p = 0.06). AM levels were not associated with age (p = 0.143), BRCA mutation status (p = 0.51) or previous diagnosis of breast cancer (p = 0.48). After adjustment for confounding variables, we observed that MetS (OR = 10.78, p = 0.002) and VO2peak (OR = 0.92, p = 0.001) were independent determinants of circulating AM. CONCLUSIONS: This is the first study in BRCA mutation carriers that has linked circulating AM levels to MetS and CRF. The long-term clinical implications of these findings are yet to be determined. Conflict of interest: The study is funded by the German Cancer Aid (Deutsche Krebshilfe) within the Priority Program “Primary Prevention of Cancer” (Grant no. 110013). JS and OH are employed by Sphingotec GmbH, a company having patent rights in and commercializing the bio-ADM assay. SG and MK received grants from Sphingotec GmbH. JL, MYD, MB and MH have nothing to disclose. Citation Format: Jacqueline Lammert, Sabine Grill, Maryam Yahiaoui-Doktor, Maryam Basrai, Joachim Struck, Oliver Hartmann, Martin Halle, Marion Kiechle. High circulating levels of adrenomedullin are associated with metabolic syndrome and low cardiorespiratory fitness in BRCA1 and BRCA2 mutation carriers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-16.

OBJECTIVES The value of a high-risk surveillance program for mutation carriers and women at high familial breast cancer risk has not been extensively studied. A Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established at the Royal Melbourne Hospital in 2010 to provide multimodality screening and risk management strategies for this group of women. The aims of this study were to evaluate the program and describe breast cancer diagnoses for BRCA1, BRCA2, and other germline mutation carriers as well as high-risk noncarriers attending the BOCRMC. METHODS Clinical data from mutation carriers and noncarriers with a ≥25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of cancer were determined. RESULTS A total of 206 mutation carriers and 305 noncarriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow-up of 34 months, 15 (seven invasive) breast cancers were identified in mutation carriers, with seven (six invasive) breast cancers identified in noncarriers. Of these, 20 (90.9%) were detected by annual screening, whereas two (9.1%) were detected as interval cancers (both in BRCA1 mutation carriers). Median size of the invasive breast cancers was 11 mm (range: 1.5-30 mm). The majority (76.9%) were axillary node negative. In women aged 25-49 years, the annualized cancer incidence was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers, and 0.5% in noncarriers. This compares to 0.06% annualized cancer incidence in the general Australian population. CONCLUSIONS Screening was effective at detecting early-stage cancers. The incidence of events in young noncarriers was substantially higher than in the general population. This potentially justifies ongoing management through a specialty clinic, although further research to better personalize risk assessment in noncarriers is required.

Increasing rates of obesity, lack of physical activity, sedentary behavior, and frequent alcohol consumption are major lifestyle-related risk factors for breast cancer. In fact, it has been estimated that about one-third of breast cancer cases are attributable to factors women can change. Most research has focused on examining the impact of one single exposure on breast cancer risk while adjusting for other risk modifiers. Capitalizing on big data, major efforts have been made to evaluate the combined impact of well-established lifestyle factors on overall breast cancer risk. At the individual level, data indicate that even simple behavior modifications could have a considerable impact on breast cancer prevention. Moreover, there is emerging new evidence that adopting a healthy lifestyle may be particularly relevant for women with hereditary susceptibility to breast cancer. On the absolute risk scale, studies suggest that the presence of certain risk factors, such as excessive body weight, had a substantially higher impact on breast cancer risk if women had a hereditary predisposition to cancer. The existing body of knowledge gives the medical professionals guidance as to which factors to focus on when counseling patients. However, well-designed randomized controlled trials utilizing objective methods are crucial to providing concrete recommendations.

Physical activity is inversely associated with the risk of breast cancer among women in the general population. It is not clear whether or not physical activity is associated with the risk of BRCA-associated breast cancer. We conducted a case–control study of 443 matched pairs of BRCA mutation carriers to evaluate the association between physical activity and breast cancer risk. Moderate and vigorous physical activities at ages 12–13, ages 14–17, ages 18–22, ages 23–29 and ages 30–34 were determined using the Nurses’ Health Study II Physical Activity Questionnaire. We estimated mean metabolic equivalent task hours/week for moderate, vigorous and total physical activities overall (ages 12–34), during adolescence (ages 12–17) and during early adulthood (ages 18–34). Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for total, moderate and strenuous recreational physical activities and breast cancer risk, by menopausal status. Overall, there was no significant association between total physical activity and subsequent breast cancer risk (ORQ4 vs. Q1 = 1.01, 95% CI 0.69–1.47; P-trend = 0.72). Moderate physical activity between ages 12–17 was associated with a 38% decreased risk of premenopausal breast cancer (ORQ4 vs. Q1 = 0.62; 95% CI 0.40–0.96; P-trend = 0.01). We found no association between exercise and breast cancer diagnosed after menopause. These findings suggest that early-life physical activity is associated with a reduced risk of premenopausal breast cancer among BRCA mutation carriers. Future prospective analyses, complemented by mechanistic evidence, are warranted in this high-risk population.

The aim of this analysis in a pilot study population was to investigate whether we can verify seemingly harmful lifestyle factors such as nicotine and alcohol indulgence, obesity, and physical inactivity, as well as a low socioeconomic status for increased cancer prevalence in a cohort of BRCA 1 and 2 mutation carriers. The analysis data are derived from 68 participants of the lifestyle intervention study LIBRE-1, a randomized, prospective trial that aimed to test the feasibility of a lifestyle modification in BRCA 1 and 2 mutation carriers. At study entry, factors such as medical history, lifestyle behavior, and socioeconomic status were retrospectively documented by interview and the current BMI was determined by clinical examination. The baseline measurements were compared within the cohort, and presented alongside reference values for the German population. Study participants indicating a higher physical activity during their adolescence showed a significantly lower cancer prevalence (p = 0.019). A significant difference in cancer occurrence was observed in those who smoked prior to the disease, and those who did not smoke (p