REstoring Metabolic FLEXibility Through Combined Exercise in Breast Cancer Survivors: A Randomized Controlled Trial.

The REFLEX study is a randomized, controlled clinical trial designed to evaluate the impact of a 16-week supervised, combined exercise program on metabolic flexibility and cardiorespiratory fitness in breast cancer survivors. While cancer treatments have significantly improved survival rates, the disease and its therapies often cause systemic mitochondrial dysfunction and muscle loss. This leads to persistent "metabolic inflexibility"-a reduced ability to efficiently switch between burning carbohydrates and fats for energy. This inflexibility, exacerbated by sedentary behavior and cancer-related fatigue, can severely diminish a patient's functional autonomy and overall quality of life. The trial focuses on assessing whether exercise can restore this metabolic adaptability in women aged 18 to 70 with stage I-III breast cancer who are currently on hormonal treatment and completed neo/adjuvant chemotherapy within the past 6 months. The study operates on the primary hypothesis that an individualized exercise intervention will significantly improve the participants' metabolic flexibility-measured via the metabolic crossover point-and overall aerobic capacity (VO2max) when compared to a control group. Additionally, the trial will analyze secondary outcomes, including changes in cardiovascular and metabolic risk factors, muscle strength, body composition (such as bone mineral density), and patient-reported outcomes assessing quality of life, fatigue, joint pain, anxiety, and depression. A total of 44 participants will be randomly assigned to either the intervention or control group. Participants in the intervention group will complete a 16-week program consisting of two weekly supervised sessions. Each session lasts between 55 and 85 minutes and includes a tailored combination of aerobic and strength training based on the individual's baseline fitness and metabolic thresholds. Participants in the control group. will receive standard educational materials via email, featu