PhActHealth is a multicenter randomized controlled trial enrolling women with newly diagnosed luminal B or triple-negative breast cancer (BC) who are candidates for neoadjuvant therapy. The study aims to investigate the effects of a preoperative, unsupervised exercise training program on exercise capacity, as well as on immune response, autonomic nervous system (ANS) regulation, cardiovascular health, and tumor aggressiveness prior to surgical removal.
Participants are randomly assigned to either an intervention group or a control group. All patients receive lifestyle counseling, while those in the intervention group additionally follow a personalized aerobic and resistance exercise program throughout the neoadjuvant treatment period before surgery.
The primary outcome is the improvement in exercise capacity. The secondary outcomes are tumor-specific and systemic responses to the intervention, evaluated by analyzing molecular, metabolic, and inflammatory markers, as well as clinical and functional parameters.
being a patient with first diagnosis of primary BC;
luminal BC tumor subtype B defined as positive for estrogen and/or progesterone receptor expression, HER2 negative and high Ki-67; or triple Negative BC tumor subtype defined as negative for estrogen and/or progesterone receptor expression, HER2 negative, defined by the Pathology and Medical Oncology units as defined by the ESMO Guidelines Committee (referred to the American Society of Clinical Oncology/College of American Pathologists guidelines for assessment of hormone receptor (HR) status (i.e. ER and 4 PgR)25 and HER2 status, and by the International Ki-67 in Breast Cancer Working Group for Ki-67);
candidate for chemotherapy/immunotherapy neoadjuvant treatment;
signed informed consent for study participation;
therapeutic modifications during the intervention period;
presence of chronic conditions (such as autoimmune diseases, neurodegenerative diseases, psychiatric disorders/cognitive disabilities, chronic obstructive pulmonary disease);
presence of any condition that significantly impairs the ability to perform exercise;
pregnancy/lactation/intention to initiate pregnancy;
Parallel
Pre-habilitation exercise program
BehavioralParticipants undertake a 16-week personalized pre-habilitation exercise training program as follows: * Aerobic training: five times per week with an initial session duration set at 45 minutes.The initial target intensity is set at 40% of the Heart Rate Reserve (HRR). Both duration and intensity are progressively increased based on individual exercise tolerance, aiming for an intensity of approximately 60% HRR and a duration of 60 minutes per session. * Resistance training: twice per week, ensuring at least 24-48 hours of recovery between sessions. Patients follow the prescribed number of sets and repetitions demonstrated in in the video tutorials provided by the study staff.
Exercise capacity
Change in metabolic equivalents of task (METs) at peak exercise intensity, measured during a maximal exercise stress test.
Pathologic Complete Response (pCR)
Defined as the absence of residual invasive cancer in the breast and axillary lymph nodes at surgery (ypT0/is ypN0). Results will be reported as the proportion of participants achieving pCR (%)
Residual Cancer Burden (RCB)
Assessed according to the validated RCB index calculated from primary tumor dimensions, tumor cellularity, and nodal involvement at surgery. Results will be reported as both continuous RCB score (unitless index) and categorical RCB class (RCB-0, RCB-I, RCB-II, RCB-III)
Stromal Tumor-Infiltrating Lymphocytes (sTILs)
Assessed on hematoxylin and eosin (H\&E)-stained sections from diagnostic biopsies and surgical specimens according to the recommendations of the International Immuno-Oncology Biomarker Working Group. Results are reported as the percentage (%) the stromal area within the borders of the invasive tumor occupied by mononuclear inflammatory cells (predominantly lymphocytes and plasma cells).
Tumor Angiogenesis
Assessed by immunohistochemical evaluation of tumor-associated microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in tumor tissue. MVD is quantified using an endothelial marker such as CD31 or CD34 and reported as the number of immunostained microvessels per field or per mm². VEGF expression is reported as the percentage (%) of positive tumor cells and staining intensity.
Gut microbiota
Change in microbial diversity (species diversity %) assessed by next-generation sequencing (NGS) of the V3-V4 region of the 16S rDNA gene
Body mass index (BMI)
Calculated as body mass in kilograms (kg) divided by height in meters squared (m²) and is expressed in kilograms per square meter (kg/m²).
Fat Mass (FM)
Assessed by bioimpedance analysis (BIA 101, Akern, Italy, BodyStat Ltd.) and is expressed as a percentage (%).
Fat-free mass (FFM)
Assessed by bioimpedance analysis (BIA 101, Akern, Italy, BodyStat Ltd.) and is expressed as a percentage (%).
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University of Milan
Lead sponsor
University of Urbino "Carlo Bo"
Collaborator
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Collaborator
Istituto Auxologico Italiano
Collaborator
