The evaluated intervention is a home-based, personalized physical activity program. The frequency, duration, and intensity of physical activity sessions are modulated depending on patients’ capacities.

Patients are encouraged to accumulate at least 150 minutes per week of moderate-to-vigorous intensity physical activity to maintain and improve health benefits. In addition, patients are asked to walk at least 30 minutes per day, increase their activities in their daily routine, and reduce their sedentary time. Several individual strategies are established with patients to attain their objectives (eg, using stairs whenever possible and walking for groceries or shopping). Moreover, meetings at the center with physical activity instructors are proposed depending on patients’ needs. Patients receive feedback at least monthly from their instructor. For patients undergoing chemotherapy, meetings take place during their day care visits at the cancer center. For patients with hormonal therapy treatment, meetings occur by phone or during a consultation with a physician in the center.

Activity trackers (Nokia Go wristband, Nokia France, Issy-les-Moulineaux, France) are given to all study participants. Patients are instructed to wear the device every day for the duration of the 6-month intervention. In addition, patients receive real-time feedback on their number of steps per day. Recommendations are to achieve 5000-10,000 steps a day depending on patients’ ability and comorbidities. For a patient who reaches 10,000 steps per day, we will advise her to maintain her goal. For a patient who is not able to achieve 5000 steps a day, we will gradually increase her objective. The goal is adjusted regularly throughout the 6-month intervention period. The instructor has access to the data pertaining to the number of steps per day and can modify the daily steps goal directly in the app or by a phone call to the patients during meetings.

Data are collected by regular transfer to the wearable activity tracker mobile phone app (Nokia Health Mate) available on a mobile phone or Tablet PC. Patients can use the mobile phone app to follow their number of steps per day represented by a graph. After receiving the wearable activity tracker, patients are called on days 7 and 14 to ensure the proper use of the device and answer any questions. Personalized objectives might be redefined to increase their daily physical activity. For patients without a mobile phone, data are collected during the 6-month intervention when visiting the hospital for a consultation every week or 2 weeks. Instructors might use the activity tracker interface to monitor change over time and to adapt to physical activity recommendations. At the end of the 6-month intervention, patients can keep the activity tracker to continue their efforts.

Demographic and clinical data, including date of birth, age at diagnosis, living situation, employment status, hormonal status, tumor histology, personal history of breast cancer, sites of metastases, and current treatment, are collected at the baseline. The Response Evaluation Criteria In Solid Tumors (RECIST) is used to assess the tumor progression between the diagnosis and the end of the physical activity program [36]. All clinical data are extracted from patients’ electronic medical records.

The standing height (cm), body weight (kg), waist (cm), and hip (cm) circumferences are measured using standardized procedures. The waist circumference is measured midway between the last floating rib and the iliac crest. The hip circumference is measured at the tip of the pubis. The body mass index is calculated as the body weight in kilograms divided by the square of the height in meters.

Cardiorespiratory fitness is measured by evaluating the peak oxygen consumption during the 6-minute walk test (6MWT) [37,38]. Patients are asked to perform the maximum walk shuttle distance on 30-meter-long flat corridors in 6 minutes. During this test, the oxygen consumption, carbon dioxide production, heart rate, and oxygen arterial saturation are continuously recorded using a portable respiratory gas analyzer (MetaMax 3b; Cortex Biophysik, Leipzig, Germany). In addition, the perception of the difficulty during 6MWT is evaluated at the end of the test using the Borg Rating of Perceived Exertion questionnaire [39].

Then, prehensile and grip strength is measured using a hand dynamometry (Jamar Plus Digital Hand Dynamometer; Patterson Medical, Huthwaite, United Kingdom), which is a validated index of the elbow extension strength [40]. Moreover, patients are asked to squeeze the handgrip as strongly as possible for 5 seconds to obtain the maximal force. Of note, two measures are performed on each hand, and the best performance is registered.

The maximum isometric strength of quadriceps extension is measured using a back-leg dynamometer (DFS II Series Digital; Force Gauges Chatillon, Largo, FL, USA). Patients are asked to sit on a chair with the knee articulation at 90°, arms crossed on the chest, and the dynamometer attached to the ankle. At the signal of the instructor, patients must try to extend the leg as strongly as possible in 3 seconds. Only the dominant leg is tested twice, and the best performance is obtained.

The International Physical Activity Questionnaire (IPAQ) [41] is used to measure the self-reported physical activity. IPAQ (long form) is a validated self-administered physical activity questionnaire with 31 items and covers 4 activity domains, work-related physical activity, transportation physical activity, domestic physical activity, and recreational physical activity [41]. IPAQ gives specific scores in the metabolic equivalent of task (MET)-minutes/week for walking, moderate-intensity, and vigorous-intensity activity within each of the work, transportation, domestic chores and gardening (yard), and leisure-time domains. Questions are coded and converted in MET per minute and per week according to the Compendium of Physical Activities [42] by multiplying the number of METs by the duration and frequency of the activity. Then, the total physical activity score for each intensity is obtained by adding the score for this intensity in each domain and by adding the number of MET-minutes per week at each intensity.

Next, the global score of physical activity is divided into 3 categories commonly used by physical activity guidelines (<600 MET-minutes/week is equivalent to low physical activity; between 600 and 3000 MET-minutes/week is equivalent to moderate physical activity; and >3000 corresponds to high physical activity [43]). Furthermore, the sedentary time in minutes per week is obtained by adding the weekday sitting time in minutes for 5 weekdays, and the weekend sitting time in minutes for 2 days.

The quality of life is measured with the European Organization for Research and Treatment of Cancer Quality Of Life Questionnaire (QLQ-C30) and its specific module for breast cancer (BR-23) [44]. QLQ-C30 is a 30-item self-administered questionnaire that evaluates 5 functioning domains (physical, role, emotional, cognitive, and social), a global quality of life domain, 3 symptom domains (pain, fatigue, and nausea), and 6 single items (dyspnea, insomnia, anorexia, diarrhea, constipation, and financial impact). Each item is associated with a score ranging from 0 to 100. For the functioning and global scales, a higher score corresponds to a better functioning level. The specific module for breast cancer (BR-23) gathers data about perceived body image, sexual functioning, sex enjoyment, arm symptoms, breast symptoms, and systemic therapy side effects.

Fatigue is assessed with the revised Piper Fatigue Scale [45,46], which is a 22-item self-reported questionnaire with 4 subscales, behavioral and severity, affective, sensory, and cognitive and mood. All these items together produce a score for total fatigue defining categories as follows: no fatigue (score=0), mild fatigue (score 1-3), moderate fatigue (score 4-6), and severe fatigue (score 7-10).

The social deprivation is assessed using the EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centres) score [47,48]. The score is computed by adding each question coefficient to intercept whenever the answer is “yes.” The score ranges from 0 to 100 with the threshold for deprivation at 30, and higher scores indicate greater deprivation levels.

Preferences, facilitators, and barriers are evaluated with the translated version of a specific questionnaire developed by Vallance et al [49]; this questionnaire includes questions regarding the interest and willingness of patients with metastatic breast cancer to participate in a physical activity program designed for patients with metastatic breast cancer. In addition, it includes questions on their interest and preferences for physical activity counseling and specific aspects of these programs, including how, where, and when they would be interested in these physical activity programs as well as the type of intervention that would be most amenable for them.

A 7-mL blood sample is collected at the baseline (D1) and at the end of the study after 6 months (M6). The sample is centrifuged within half an hour after drawing and kept at 4°C before and during centrifugation. The plasma is distributed into cryotube aliquots of 1 mL and buffy coat in a single 1-mL cryotube; these cryotubes are frozen and stored at −80°C at the center and used for the analyses of oxidative stress and antioxidant biomarkers. Superoxide dismutase, catalase, glutathione peroxidase enzymatic activities, and markers of DNA oxidation (8-hydroxy-2'-deoxyguanosine), prostaglandins oxidation (8-Iso Prostaglandin F_2α) are measured in the plasma [50]. Furthermore, levels of circulating growth factors, cytokines, neutrophils, monocytes, and natural killer cells are assessed as previously described [51].

The sample size was defined empirically to explore the feasibility of the program according to the enrollment potential in the study center. Because the main objective of the ABLE Trial was to assess the feasibility of a physical activity intervention in women with metastatic breast cancer, without major regard for the efficiency, no formal calculation was performed. Given that 200 patients are treated annually for metastatic breast cancer in the Center Léon Bérard and that 60% of patients are expected to survive for at least 6 months, with a projected acceptance rate of 50%, the pilot study will aim to recruit 60 patients within 9 months.

Patients’ characteristics will be described at D1 and M6 using the mean and SD for quantitative data, frequency, and percentage for qualitative data.

The primary outcome to assess the feasibility of the study will be the proportion of patients achieving the physical activity recommendations corresponding to 150 minutes per week of moderate physical activity evaluated by the IPAQ score during the last week of the study. In addition, we will estimate the proportion of patients who agreed to participate in the ABLE Trial among eligible patients. The reasons for refusal will be documented and described as well.

The secondary outcomes to assess will be the evolution of physical activity, anthropometric, physical fitness, psychological, and biological variables between the initiation (D1) and the completion (M6) of the physical activity intervention using Wilcoxon signed-rank tests. In addition, the level of physical activity according to biological, psychological, and clinical outcomes adjusted on potential confounders, including age, treatment, and number of visits, will be explored using multiple linear regressions. Moreover, the level of oxidative stress will be correlated to the RECIST criteria. Data on barriers and facilitators of the adherence to a physical activity program from D1 to M6 will be compared by Mac Nemar tests. All statistical analyses will be performed using SAS software (version 9.4. SAS Institute Inc, Cary, NC, USA).