The FASTEX trial: Fasting mimicking diet and exercise medicine as adjuvant therapies in the treatment of patients with breast cancer.

Patients will choose what group they want to be allocated at. Arm 1: Fasting mimicking diet (FMD) group. Patients will follow a FMD (plant-based, low calories, low sugar, low protein diet), for 5 days, on chemotherapy weeks or every two weeks if chemotherapy regimen is weekly, for 12 weeks. The diet will start 2 days before the chemotherapy infusion to induce a differential stress response between normal and tumour cells and end two days after, as refeeding during this period may increase the susceptibility of healthy cells to the cytotoxic damage from chemotherapy by promoting DNA synthesis . On day 1 and day 5 the diet consists of ~900-1100 kcal with 9-15% protein, and on days 2–4 it consists of ~500-600 kcal, with 9-12% of protein. The experimental dietary regimen will be prescribed as a list of foods (e.g., cereals such as quinoa and rice, legumes, vegetables, seeds and nuts, olive or coconut oil) and drinks (water, coffee, tea, tisanes), with their allowed amount specified . Participants will also be asked to complete a food diary during each FMD cycle. Between FMD cycles, patients will be asked to follow their usual diet, encouraging them to have adequate caloric (30–40 kcal/kg weight/day) and protein intake (1.5 g protein/kg weight/day). Weight will be measured between FMD cycles; if there is a 5% or greater weight lost, calculated as (weight loss in kg / baseline weight) *100 , the diet between cycles will be reviewed and adjusted by a dietitian affiliated with the study. Compliance to the FMD will be measured for the intervention group by assessing the number of FMD cycles each patient follows (recorded in their food diaries). Arm 2: Exercise program group. Exercise program sessions will be supervised and they will be performed at the Exercise Medicine Research Institute (EMRI) associated exercise facilities (ECU Joondalup, ECU Mount Lawley, UWA, Fiona Stanley Hospital, West Coast Health and High-Performance Lathlain). The duration will be 12 weeks. Participants will be supervised by a trained person overseen by an accredited exercise physiologist (AEP) for each exercise session over their chemotherapy treatment. Supervised sessions will be be conducted one-on-one or in small groups (up to 6 participants). The exercise intervention will consist of 100-180 min of moderate to vigorous exercise per week, comprising supervised resistance and aerobic exercise. During the weeks of chemotherapy, patients will exercise 2 days/week for 50-60 min per session (15-20 min of aerobic and 20-25 min of resistance training). During the weeks without chemotherapy treatment, patients will exercise 3 days/week for 50-60 min per session (15-20 min of aerobic and 20-25 min of resistance training). Each session will start with 5 minutes of warm-up (low-intensity aerobic exercise such as treadmill walking) and will end with a 10-minute cool-down (stretching and breathing relaxation). As participants will be exercising during chemotherapy, the prescription will enable patients to autoregulate sessions, weekly and monthly exercise dosage through modifications to mode, intensity, frequency, duration and/or total volume, depending on the participant’s perceived preparedness for training at the start of each exercise session. Tolerance will be determined at the end of each exercise training session using Borg’s Rating of Perceived Exertion (RPE) 6–20 scale, with <7 corresponding to “very, very light”;7–9,“very light”;9–11,“fairly light,”11–13,“somewhat hard,”13–15,“hard,”15–17,“very hard”; and 17–20,“very, very hard”. Resistance training Resistance training will comprise 2 sets of 8-12 repetitions for 6-8 different strength exercises at moderate to vigorous intensity (RPE set at 11-15 on the 6-20 Borg scale) targeting the major upper and lower body muscle groups performed using body weight and equipment such as exercise machines and dumbbells. Load will be gradually increased by 5-10 % if the patient can complete more than prescribed repetitions with the correct technique. Exercises will include knee push-ups, squats, lunges, planks, leg press, leg extension, leg curl, seated calf raise, chest press, seated row, biceps curl, and triceps extension. Aerobic training Aerobic training will involve cardiorespiratory exercise using a variety of modes such as walking and jogging on a treadmill or cycling on a stationary ergometer. Intensity will be progressed over the 16-week period by increasing resistance or speed to elicit a target RPE of 11-15 on the 6-20 Borg scale. Compliance to the exercise sessions will be assessed by attendance rate, determinised by the total and weekly number of exercise sessions attended versus the number of sessions prescribed, and by the adherence rate, determined by the number of sessions where the prescribed exercise are successfully completed (including volume and intensity) versus the number of sessions attended.

Patients will choose what group they want to be allocated at. No direct comparison will be performed between the exercise and FMD groups. Both intervention groups will be compared only with the control group. Arm 1: Fasting mimicking diet (FMD) group. Patients will follow a FMD (plant-based, low calories, low sugar, low protein diet), for 5 days, on chemotherapy weeks or every two weeks if chemotherapy regimen is weekly, for 12 weeks. The diet will start 2 days before the chemotherapy infusion to induce a differential stress response between normal and tumour cells and end two days after, as refeeding during this period may increase the susceptibility of healthy cells to the cytotoxic damage from chemotherapy by promoting DNA synthesis . On day 1 and day 5 the diet consists of ~900-1100 kcal with 9-15% protein, and on days 2–4 it consists of ~500-600 kcal, with 9-12% of protein. The experimental dietary regimen will be prescribed as a list of foods (e.g., cereals such as quinoa and rice, legumes, vegetables, seeds and nuts, olive or coconut oil) and drinks (water, coffee, tea, tisanes), with their allowed amount specified . Participants will also be asked to complete a food diary during each FMD cycle. Between FMD cycles, patients will be asked to follow their usual diet, encouraging them to have adequate caloric (30–40 kcal/kg weight/day) and protein intake (1.5 g protein/kg weight/day). Weight will be measured between FMD cycles; if there is a 5% or greater weight lost, calculated as (weight loss in kg / baseline weight) *100 , the diet between cycles will be reviewed and adjusted by a dietitian affiliated with the study. Compliance to the FMD will be measured for the intervention group by assessing the number of FMD cycles each patient follows (recorded in their food diaries). Arm 2: Exercise program group. Exercise program sessions will be supervised and they will be performed at the Exercise Medicine Research Institute (EMRI) associated exercise facilities (ECU Joondalup, ECU Mount Lawley, UWA, Fiona Stanley Hospital, West Coast Health and High-Performance Lathlain). The duration will be 12 weeks. Participants will be supervised by a trained person overseen by an accredited exercise physiologist (AEP) for each exercise session over their chemotherapy treatment. Supervised sessions will be be conducted one-on-one or in small groups (up to 6 participants). The exercise intervention will consist of 100-180 min of moderate to vigorous exercise per week, comprising supervised resistance and aerobic exercise. During the weeks of chemotherapy, patients will exercise 2 days/week for 50-60 min per session (15-20 min of aerobic and 20-25 min of resistance training). During the weeks without chemotherapy treatment, patients will exercise 3 days/week for 50-60 min per session (15-20 min of aerobic and 20-25 min of resistance training). Each session will start with 5 minutes of warm-up (low-intensity aerobic exercise such as treadmill walking) and will end with a 10-minute cool-down (stretching and breathing relaxation). As participants will be exercising during chemotherapy, the prescription will enable patients to autoregulate sessions, weekly and monthly exercise dosage through modifications to mode, intensity, frequency, duration and/or total volume, depending on the participant’s perceived preparedness for training at the start of each exercise session. Tolerance will be determined at the end of each exercise training session using Borg’s Rating of Perceived Exertion (RPE) 6–20 scale, with <7 corresponding to “very, very light”;7–9,“very light”;9–11,“fairly light,”11–13,“somewhat hard,”13–15,“hard,”15–17,“very hard”; and 17–20,“very, very hard”. Resistance training Resistance training will comprise 2 sets of 8-12 repetitions for 6-8 different strength exercises at moderate to vigorous intensity (RPE set at 11-15 on the 6-20 Borg scale) targeting the major upper and lower body muscle groups performed using body weight and equipment such as exercise machines and dumbbells. Load will be gradually increased by 5-10 % if the patient can complete more than prescribed repetitions with the correct technique. Exercises will include knee push-ups, squats, lunges, planks, leg press, leg extension, leg curl, seated calf raise, chest press, seated row, biceps curl, and triceps extension. Aerobic training Aerobic training will involve cardiorespiratory exercise using a variety of modes such as walking and jogging on a treadmill or cycling on a stationary ergometer. Intensity will be progressed over the 16-week period by increasing resistance or speed to elicit a target RPE of 11-15 on the 6-20 Borg scale. Compliance to the exercise sessions will be assessed by attendance rate, determinised by the total and weekly number of exercise sessions attended versus the number of sessions prescribed, and by the adherence rate, determined by the number of sessions where the prescribed exercise are successfully completed (including volume and intensity) versus the number of sessions attended.