Physical Activity and Healthy Aging: Promoting Cardio-metabolic Capacity to Fight Chronic Inflammation and Improve Outcomes in Breast Cancer Patients (PhActHealth Study)

University of Milan126 enrolled

Overview

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.

BC is strongly affected by systemic inflammation and immune alterations. Exercise has been demonstrated improving cardiometabolic health and reducing inflammatory markers in patients with oncology diseases. However, its role in the pre-operative setting, during neoadjuvant therapy, still remains poorly defined. The PhActHealth study investigates whether a structured pre-operative exercise program can improve functional capacity and modulate tumor and systemic biological markers in breast cancer patients, before surgery, and improve survival and quality of life, after surgery. The PhActHealth study aims to comprehensively investigate the impact of a pre-operative, remotely monitored exercise training program in patients with BC, with a dual focus: (i) Improving exercise capacity; (ii) Exploring the potential modulation of biomarkers involved in tumor progression, systemic inflammation, and immune response by integrating functional assessments, biological analyses, and patient-reported outcomes. Women with operable BC who are candidates for neoadjuvant therapy are enrolled after confirmation of eligibility criteria, and randomly assigned to either an intervention arm (IA) or a control arm (CA). The intervention begins with the initiation of systemic therapy and continues until the planned date of surgery; then, two follow-ups are performed. At baseline, patients enrolled in both study arms receive lifestyle counseling, with specific recommendations for maintaining an active lifestyle based on the currently available international guidelines. In addition to lifestyle counseling, participants enrolled in the IA receive a personalized pre-habilitation exercise training program - which is undertaken autonomously and remotely monitored - until one week before surgery. Then, all participants undergo the planned surgical treatment, followed according to routine clinical practice, during which two follow-ups are scheduled. The primary outcome is peak exercise capacity while secondary outcomes are tumor response and proliferation, immune and angiogenesis markers in tumor tissue, systemic inflammatory and metabolic biomarkers, body composition, autonomic function, and quality of life, overall and disease-free survival, as well as other functional and psychosocial parameters. At baseline and before surgery, urine, blood, stool, and tumor biopsy samples are collected, and all primary and secondary outcomes are assessed, except overall and disease-free survival, which are assessed at the follow-up time-points, and quality of life which is assessed at all time-points.

Interventions

Pre-habilitation exercise programBEHAVIORAL

Participants 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.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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; * declared being not engaged in any competitive or recreational physical activity. Exclusion Criteria: * 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; * prior chemotherapy or immunotherapy within the past three years; * high baseline physical activity level (i.e. performing exercise at a dose of 600 MET minutes a week or greater, according to the score of the International Physical Activity Questionnaire \[IPAQ\]).

Outcomes

Primary Outcomes

Exercise capacity

Change in metabolic equivalents of task (METs) at peak exercise intensity, measured during a maximal exercise stress test.

Time frame: Baseline and 6 months

Secondary Outcomes

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 (%)

Time frame: At surgery, following completion of neoadjuvant treatment

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)

Time frame: At surgery, following completion of neoadjuvant treatment

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).

Time frame: Baseline diagnostic biopsy and surgery

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.

Time frame: Baseline diagnostic biopsy and surgery

Tumor tissue Insulin-like growth factor 1 (IGF-1) expression

Evaluated by immunohistochemistry (IHC) and expressed as the percentage (%) of positive tumor cells in diagnostic biopsies and surgical specimens. Expression is quantified according to the percentage of positive tumor cells and staining intensity, using an H-score or an equivalent validated scoring system.

Time frame: Baseline diagnostic biopsy and surgery

IGF-1 receptor expression (IGF-1R)

Evaluated by immunohistochemistry (IHC) and measured as the percentage (%) of positive tumor cells staining intensity, and cellular localization, using an H-score or an equivalent validated scoring system.

Time frame: Baseline diagnostic biopsy and surgery

Ki-67 expression

Measured as the percentage (%) of positively stained tumor cells on diagnostic biopsies and surgical specimens. In hormone receptor-positive tumors, the proportion of patients achieving a post-treatment Ki-67 ≤2.7% will also be explored as an indicator of complete cell-cycle arrest. In TNBC, Ki-67 changes will be considered exploratory and interpreted together with pCR and RCB. In a subset of cases, transcript-level changes in proliferation- and immune-related genes will be explored using RNA in situ hybridization with spatial resolution.

Time frame: Baseline diagnostic biopsy and surgery

Lipid Profile

Change in total cholesterol (mg/dL), High-density lipoprotein (HDL) cholesterol (mg/dL), Low-density lipoprotein (LDL) cholesterol (mg/dL), triglycerides (mg/dL), assessed in the blood

Time frame: Baseline and 6 months

Blood glucose

Assessed in blood samples and expressed in milligrams per deciliter (mg/dL).

Time frame: Baseline and 6 months

Glycated hemoglobin (HbA1c)

Assessed in blood samples and expressed in millimoles per mole (mmol/mol)

Time frame: Baseline and 6 months

Insulin

Assessed in blood samples and expressed in milli-international units per liter (mIU/L).

Time frame: Baseline and 6 months

Liver function markers

Change in Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) assessed in the blood (U/L)

Time frame: Baseline and 6 months

C-reactive protein (CRP)

Change in C-reactive protein (CRP) (mg/dL), assessed in the blood

Time frame: Baseline and 6 months

High-sensitivity C-reactive protein (hs-CRP)

Change in High-sensitivity C-reactive protein (hs-CRP) (mg/dL), assessed in the blood

Time frame: Baseline and 6 months

Interleukin-6 (IL-6)

Change in Interleukin-6 (IL-6) (pg/mL), assessed in the blood

Time frame: Baseline and 6 months

Neutrophil-to-lymphocyte ratio (N/L)

Change in Neutrophil-to-lymphocyte ratio (N/L), calculated from blood neutrophil and lymphocyte counts

Time frame: Baseline and 6 months

Platelet-to-lymphocyte ratio (P/L)

Change in platelet-to-lymphocyte ratio (P/L), calculated from blood platelet and lymphocyte counts

Time frame: Baseline and 6 months

Thyroid Function

Change in Thyroid-stimulating hormone (TSH) assessed in the blood (mIU/L)

Time frame: Baseline and 6 months

Epigenetic markers

Changes in DNA methylation and miRNA expression will be assessed using validated molecular techniques. DNA methylation will be evaluated by genome-wide methylation arrays and/or bisulfite pyrosequencing, while miRNA expression will be quantified by reverse transcription quantitative PCR (RT-qPCR).

Time frame: Baseline and post-intervention/pre-surgery

Physical Activity and Healthy Aging: Promoting Cardio-metabolic Capacity to Fight Chronic Inflammation and Improve Outcomes in Breast Cancer Patients (PhActHealth Study)

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts