Effects of lifestyle intervention in BRCA1/2 mutation carriers on nutrition, BMI, and physical fitness (LIBRE study): study protocol for a randomized controlled trial

The LIBRE training program is primarily endurance-oriented training, which is completed during the course of one year. After a mandatory introductory lecture on the theory behind the intervention training, the goal is to increase physical activity to ≥18 MET-h/week (MET = Metabolic Equivalent of Task). This activity level has been correlated consistently with a reduction of morbidity and mortality in patients with breast cancer [8, 19]. This goal should be achieved within the first 12 weeks and maintained throughout the whole study period. Each subject receives an individual training plan, which is continuously adapted according to her fitness status to support this goal. The training is divided into two phases: the intensity of the first phase should be at least 50–60 % of peak oxygen consumption (VO₂ peak) (initial phase, weeks 1–6), and that of the second phase should be 60–75 % of the VO₂ peak (optimization phase, weeks 7–12). In the first 12 weeks of the intervention program, training takes place 2 times per week as supervised training and once per week as home-based training (HBT). Afterwards supervised training units are only carried out monthly so that training in phase II (months 4–12) is mainly HBT. Training continues to take place with an intensity of at least 60–75 % of the VO₂ peak in accordance with the individual training plan.

A record of compliance with the training intervention program as well as with the achieved MET-hours/week is kept in the training diaries (questionnaire on physical activity, V0–V2). Participants are asked to record their daily activities as well as intentional physical activity including intensity and duration of training. The training intensity levels are assessed from spiroergometry and are outlined in the diary, which facilitates training control. Monthly supervised training units (as of V1) offer the opportunity to realign training intensity and discuss any problems with adherence to training. In addition, physical activity is recorded by questionnaires (International Physical Activity Questionnaire, IPAQ) [21, 22] from SE–V4, and physical fitness is assessed by cardiopulmonary exercise testing by spiroergometry (VO₂ peak) [23] at time points SE, V1, and V2.

Within the framework of the LIBRE study, the nutrition intervention is based on the principles of a Mediterranean dietary pattern (MD). Furthermore, obese patients (BMI ≥30 kg/m²) are instructed to limit their energy (kilocalorie) intake. Nutrition intervention in the intervention group begins with an intensive 3-month nutrition program during which biweekly nutrition courses led by dietitians take place in groups. The group course includes a cooking class and a guided tour of a supermarket. At the end of the first 3 months, the nutrition courses take place at monthly intervals for the remaining course of the first study year. The main objective of the nutrition intervention is to provide practical nutritional training, which should enable the subjects to achieve a long-term change in their eating habits, replacing former eating habits with the MD. Eating habits are recorded using validated questionnaires (the European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire [EPIC-FFQ] and Mediterranean Diet Adherence Screener [MEDAS]) at the time points SE, V1, V2, V3, and V4. Participants of the intervention group additionally received the MEDAS questionnaire at time points V1-6 and V1-9.

Psychological support of the intervention group comprises solely an explanation of the psychological data survey questionnaires given to the study participants. Explicit psychological support is not planned. The participants are informed that the objective of the lifestyle study is, among other things, that the lifestyle change including regular physical activity and healthy eating should lead to an improvement in general quality of life, stress reduction, a more optimistic outlook on life, and a better attitude towards endurance training and MD. In order to verify this, the participants receive the questionnaires Trier Inventory for Chronic Stress (TICS), Life Orientation Test-Revised (LOT-R), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires-Core 30 and BR23 (EORTC QLQ-C30/-BR23), and Evaluation of Physical Activity and Nutrition (“Bewertung koerperlicher Aktivitaet und Ernaehrung” [BKAE]) at different time points (SE, V1, V2, V3, and V4). Advice on psycho-oncological aspects of the LIBRE study is given during the introductory lecture at the beginning of the study. Particular importance is attached to participants giving as detailed information as possible in the survey questionnaires.

Psychological advice given to the study participants should serve to inform the subjects of the significance and improvement of psycho-social lifestyles for the prevention of breast and ovarian cancer, as well as to promote compliance and recognize possible psychological impediments for participation in the study.

Data will be gathered by means of an interview at study enrollment (SE). In addition to a basic clinical assessment, pre-existing internal and gynecological illnesses, and general risk and protective factors such as body weight, alcohol consumption, nutritional behavior, level of activity, and number of pregnancies will be assessed.

This will also be collected at SE. The psychosocial and socioeconomic risk and protective factors such as living conditions, job situation, and income level will be assessed.

Data will be gathered by means of an interview at SE. The previous diagnostic and therapeutic radiation exposure will be documented.

This will be handed out at V1, V2, V3, and V4. Questions will capture the subject’s acceptance of the study, their satisfaction with the supervision, an evaluation of the physical activity and nutrition program, and their assessment of the everyday practicality of the intervention program.

Within this examination at time points SE and V1–V4, the patient’s medical history is taken and a clinical examination with focus on the cardiovascular system will be performed. A resting electrocardiogram (ECG), pulmonary function testing, and blood pressure measurements are obligatory. Resting heart rate and blood pressure are recorded as measuring parameters.

Spiroergometry is an objective and well-known examination for assessment of the cardiopulmonary system, as it measures the respiratory gases under exercise stress. As the maximal oxygen uptake and the aerobic and anaerobic respiratory capacity are measured, the results enable a precise statement about the maximum cardiopulmonary capacity as well as aerobic and anaerobic capacity. The target parameters VO₂ peak as well as VO₂ at ventilatory aerobic and anaerobic thresholds (VT1 and VT2) [23] provide information on the fitness level at visits SE, V1, and V2.

The International Physical Activity Questionnaire (IPAQ) comprises five areas of activity, which are examined independently of each other [24]. The questionnaire is a simple instrument which can be used to collect internationally comparable data for health-promoting physical activity. The aim is to assess different modes of physical activity performed in daily life. The questionnaire relates to the time which has been spent on physical activity during the last seven days. Activities within the scope of occupational, household, and garden tasks and moving between destinations are included as well. The IPAQ is assessed at all study time points (SE, V1–V4).

The examination of physical constitution comprises the documentation of anthropometric parameters such as height, body weight, waist, hip, and upper arm measurements, skinfold tests, and the bioelectric impedance analysis (BIA) measurement at visits SE, V1, V2, V3, and V4. These measurements serve to record the percentage of body fat, BMI, and level of muscle mass and body water.

Within the context of the study, various blood values are determined (Table 2). Blood values are measured in the intervention group as well as in the control group at the time points (SE, V1–V4).

The subjects in the intervention group as well as in the control group take stool samples at home at the five time points (SE, V1–V4). A collective microbiome and metabolome analysis is carried out at a later date.

The EPIC Food Frequency Questionnaire (EPIC-FFQ) [25‐27] refers to food consumption during the past year and covers 148 food items. For each item questions are asked concerning the average quantity consumed (predefined servings) and the frequency of consumption (one to six times per day, week, month, or year). Color photos simplify the definition of serving sizes for food items which are not consumed in normal household quantities. Furthermore, the participants are specifically asked about their use of cooking fats/oils, the frequency of consumption of sauces with meat and fish, the fat content of the milk they consume, the use of sugar and milk in coffee and tea, and the seasonal consumption of fresh fruit and vegetables. The data input and questionnaires are evaluated via the study management system (SMS) for health research, which has been developed and supervised by the Department of Epidemiology of the German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE). The EPIC-FFQ is conducted at all five time points (SE, V1–V4) in both the intervention group and the control group.

The Mediterranean Diet Adherence Screener (MEDAS) [28] was developed within the scope of the PREDIMED study and is an instrument used to determine the extent to which the Mediterranean dietary pattern is adhered. It comprises 14 questions. The evaluated Spanish version was translated into German for the LIBRE study and complemented by pictures of serving sizes. The German version of the MEDAS will be validated within the scope of the pilot study. The MEDAS questionnaire is conducted at all five time points (SE, V1–V4) in both the intervention and the control group and at time points V1-6 and V1-9 in the intervention group.

In order to acquire information on health-related quality of life (HRQOL), a composed questionnaire from the European Organisation for Research and Treatment of Cancer (EORTC), comprising a 30-item core questionnaire (QLQ-C30) and a 23-item breast cancer module (QLQ-BR23), is used before and after the intervention [29, 30]. Accordingly there are reference values by Scott et al. [31] which are of great importance for comparing our data. The advantage of the QLQ-C30/-BR23 is on one hand its present-day relevance and on the other hand its validation for breast cancer (QLQ-BR23). We formulate the hypothesis that regular physical activity and the implementation of healthy nutrition (intervention group) can lead to a general and specific improvement in HRQOL. The 53 questions focus on cognitive, social, emotional, and physical functioning, and one scale evaluates the global health status in general. Three other scales estimate fatigue, pain, as well as nausea and vomiting, and six single items measure dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties. The breast cancer-specific module QLQ-BR23 comprises 23 multiple and single items assessing disease symptoms (breast and arm symptoms, upset caused by hair loss and systemic therapy side effects) as well as addressing body image, sexual functioning, and future perspectives. Validation studies in European countries and the USA have been conducted within a cross-cultural context [32].

The Life Orientation Test-Revised (LOT-R) [33] is developed to collect individual differences of generalized optimism versus pessimism in the form of a personality variable. It has been applied in various intervention studies which, among other things, look at the consequences of dispositional optimism on behavior, emotion, and physical health. We also formulate the hypothesis that regular physical activity and the implementation of healthy nutrition (intervention group) can lead to a more optimistic attitude to life.

The Screening Scale for Chronic Stress (SSCS) included in the Trier Inventory for Chronic Stress is a 12-item (short version) questionnaire which measures five different aspects of chronic stress: lack of social recognition, business pressures, social stress, chronic anxiety, and overburdening [34]. One can hypothesize that regular physical activity and the implementation of healthy nutrition (intervention group) can lead to a reduction in the individual perception of stress and to better stress management. The SSCS questionnaire has been well examined on a test statistical basis and shows good variables for quality criteria.

It is established in social-psychological attitude research that a person’s positive attitude towards lifestyle (here regular exercise and healthy eating) does not in itself correspond to an equivalent everyday behavior (i.e., to really eat healthfully and practice regular sports or exercise). Most people take a positive view of prevention such as cancer screening, but de facto only a small number of people actively make use of cancer prevention measures. Therefore, for the present LIBRE study, above all due to the question of the practicability of the intervention program in the sense of good compliance, it is important to ask about the attitudes towards lifestyle changes. In particular, we are interested in two questions. (1) What are the predictors of regular participation in preventive measures (sport, nutrition)? (2) Are attitudes, subjective norms, or perceived behavior control towards a behavior relevant for the intention of behavior (i.e., to train regularly and to eat healthfully) and for the de facto behavior shown? To answer these questions, we developed a new questionnaire based on the theory of planned behavior according to Fishbein and Ajzen [35]. This theory maintains that the best predictors for planned and deliberate behavior are the intentions related to behavior. Behavioral intentions are defined by attitudes towards a behavior, subjective norms, and perceived behavior control. The theory of planned behavior has been examined in many studies dealing with health psychology (e.g., surgery intentions, food adherence, and physical activity behavior among others) [36‐40].

The questionnaire Evaluation of Physical Activity and Nutrition (Bewertung koerperlicher Aktivitaet und Ernaehrung, BKAE) contains questions which are divided into two sections: physical activity and regular healthy nutrition. Each section has four scales (two attitudes, subjective norms, and perceived behavior control) and two innovative single items (past behavior and factor time and guidance). All questions are measured on seven-point Likert scales and, to avoid conformational bias, several statements are reverse scaled.