Lifestyle intervention in BRCA1/2 mutation carriers: study protocol for a prospective, randomized, controlled clinical feasibility trial (LIBRE-1 study)
To the best of our knowledge, the LIBRE-1 study is the first prospective randomized lifestyle intervention trial in BRCA mutation carriers worldwide. Since the patients in the intervention arm will be given a strict and intensely structured intervention program, the purpose first is to assess the feasibility of the study design in a multicenter setting including 60 female mutation carriers. We are aware that the study protocol is time-consuming and demanding for the patients including regular exercise and changes in nutritional habits but believe it necessary to cover/investigate all relevant factors. Especially, during the first study visit, the questionnaires amount to a large contribution for the participants. However, the questionnaires can be answered during the waiting time between the examinations, e.g., spiroergometry, ECG, and body composition, lasting approximately half a day. In order to meet a high compliance rate, all participants will be informed beforehand about the time necessary for study examinations. For the time spent for examinations, patients will also receive a small financial reimbursement.
The Mediterranean diet though is widely accepted as a healthy diet in Germany. In addition, randomized controlled intervention studies have revealed that it is effective in the primary prevention of cardiovascular diseases [45], in improving diabetes [46] and cognitive function [47], and recently also in the primary prevention of invasive breast cancer [48].
Once compliance and acceptance of the study protocol have been proven (LIBRE-1), we will proceed with a larger cohort of mutation carriers with the intention to investigate whether the improvement of physical fitness, body weight, quality of life, and stress coping capacity leads to a reduction of breast cancer risk, progression of disease, and even mortality. On the basis of the LIBRE-1 results, it will be possible to outline a lifestyle program with high adherence even over 12 months of intervention (LIBRE trial). The current feasibility study will also reveal barriers to and constraints of the intervention, which will then have to be modified for the larger clinical trial.
One of the foreseen limitations of the trial will be selection bias for those patients being interested in lifestyle intervention and for those who will be randomized to usual care, especially for highly motivated participants. The latter patients may be disappointed on being assigned to the control arm and might either withdraw from the study or follow exercise instructions from the IG. These biases cannot be excluded in any lifestyle intervention trial. However, physical activity will be assessed using questionnaires and an accelerometer in both arms, and any cross-over of patients can be monitored. In addition, physical fitness will be objectively assessed by spiroergometry in both arms, which will also yield information on the long-term involvement of physical activity.
On the other hand, restraints for less motivated patients, e.g., due to professional obligations or as cares for children or other family members, may have an impact on adherence to supervised exercise sessions and everyday physical activities. In addition, a cross-over from CG to IG group for the Mediterranean dietary pattern cannot be excluded as previously outlined for physical activity. However, nutritional habits will also be assessed by questionnaire and BMI and body composition measured in both groups. Because of these problems in lifestyle intervention trials, it is a clear aim to avoid cross-over or bias of investigations by assuring that patients be treated identically regardless of the group assignment.
This LIBRE initiative (pilot and clinical study) will have the potential to reveal whether a structured lifestyle intervention program may prevent tumor incidence in BRCA mutation carriers. This will have to be compared with current risk-reducing strategies for women at risk, including prophylactic mastectomy, and could then be added to early detection programs. Furthermore, by following a structured exercise program and dietary changes, mutation carriers will attain an independent and self-governed role in cancer prevention and successfully reduce their stress levels [39]. By improving and optimizing the latter, we expect a preventive health effect not only on a somatic but also on the mental status of these patients.