Breast cancer stands as the foremost cause of cancer-related deaths among women worldwide, with the highest incidence of any cancer type. The choice of therapeutic interventions hinges upon factors like cancer stage, cell subtype, and tumor size. Consequently, individuals with more aggressive tumors, such as HER+2 and Triple Negative, or larger tumors often undergo neoadjuvant chemotherapy before breast surgery. However, these anticancer treatments come with side effects like cancer-related fatigue, reduced functional capacity, and changes in body composition, notably skeletal muscle atrophy. Skeletal muscle loss correlates with heightened mortality rates, cardiotoxicity, and diminished quality of life, underscoring the need for early therapeutic interventions. One such promising strategy is prehabilitation, which involves resistance-exercise training aimed at bolstering skeletal muscle mass from the outset of the disease, even preceding breast surgery. Resistance-exercise training has shown favorable effects on women undergoing adjuvant therapy or survivors of breast cancer, however, its molecular and clinical effects in women with breast cancer undergoing neoadjuvant therapy are unknown.

Hypothesis: Prehabilitation based on resistance-exercise training before surgery in women with breast cancer undergoing neoadjuvant therapy increases skeletal muscle mass compared with usual care.

Secondary, prehabilitation based on resistance-exercise training before surgery in women with breast cancer undergoing neoadjuvant therapy generates better results in body composition, physical performance, clinical parameters (serious adverse events, hospital readmission, infection, complications), physiological parameters and quality of life at one-month hospital discharge compared to usual care.

Objective: To determine the effects of prehabilitation based on resistance-exercise training versus usual care, before and after breast surgery, on skeletal muscle mass in women with breast cancer undergoing neoadjuvant chemotherapy.

Methodology: A single-blind, randomized controlled clinical trial will be developed. Sixty-eight postmenopausal women with stage I, II and III breast cancer with HER2+ type breast tumor and Triple negative breast cancer undergoing neoadjuvant therapy and with an indication for breast surgery will be divided into two groups: usual care (CONTROL, n=34) versus Prehabilitation (P-REHAB, n=34). All participants will receive an education session 20 weeks before surgery + neoadjuvant chemotherapy for 16-20 weeks as is normally done for this type of patien. Only participants in the P-REHAB group will undergo 16-20 weeks of whole-body resistance-exercise training (twice a week). At baseline, after prehabilitation program and 4 weeks after surgery, the cross-sectional area of the quadriceps muscle and of the muscle region at lumbar level 3 will be determined by CT-Scan. Also, fasting blood samples will be obtained to measure biochemical and molecular markers (e.g. miRNAs). Maximal strength will be determined by 1 repetition maximum (1RM) leg press, leg extension, lat pull down, chest press, horizontal row, and handgrip. In addition, physical performance will be assessed with the short physical performance battery (SPPB), functional capacity with the 6-minute walk test, quality of life with the BR23 questionnaire, and cancer-related fatigue with the Brief Fatigue Inventory scale at the same time points. Finally, samples from tumor breast cancer and pectoralis muscle will be obtained on the day of breast surgery.

Expected results: It is expected that prehabilitation based on resistance-exercise training results in increased muscle mass in women with breast cancer undergoing neoadjuvant chemotherapy compared to participants receiving usual care. Also, it is expected that this intervention before surgery in women with breast cancer undergoing neoadjuvant therapy will generate better results in clinical parameters (serious adverse events, hospital readmission, infection, complications) and quality of life one month after hospital discharge compared to usual care . These results will allow the creation of local, regional, national and international strategies to combat the adverse effects of breast cancer and its antineoplastic treatment, especially in women with more aggressive breast cancer.

Inclusion Criteria:

• Postmenopausal women with breast cancer in stages I, II and III with luminal breast tumor, HER2+ or TNBC
• Indication for neoadjuvant chemotherapy
• Candidates for curative breast surgery
• Body mass index: 18.5 \