Breast Cancer
Conditions
Keywords
chronic inflammation, luminal B breast cancer, Triple Negative Breast Cancer (TNBC), lifestyle intervention, exercise, METs
Brief summary
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.
Detailed description
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
BEHAVIORALPre-habilitation exercise program
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.
Sponsors
University of Milan
University of Urbino "Carlo Bo"
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Istituto Auxologico Italiano
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants are randomized into two arms: assessed before and after the intervention with personalized pre-habilitation exercise training program and lifestyle advice.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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 \[IPAQ\]).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exercise capacity | Baseline and 6 months | Change in metabolic equivalents of task (METs) at peak exercise intensity, measured during a maximal exercise stress test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response (pCR) | At surgery, following completion of neoadjuvant treatment | 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) | At surgery, following completion of neoadjuvant treatment | 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) | Baseline diagnostic biopsy and surgery | 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 | Baseline diagnostic biopsy and surgery | 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. |
| Tumor tissue Insulin-like growth factor 1 (IGF-1) expression | Baseline diagnostic biopsy and surgery | 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. |
| IGF-1 receptor expression (IGF-1R) | Baseline diagnostic biopsy and surgery | 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. |
| Ki-67 expression | Baseline diagnostic biopsy and surgery | 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. |
| Lipid Profile | Baseline and 6 months | 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 |
| Blood glucose | Baseline and 6 months | Assessed in blood samples and expressed in milligrams per deciliter (mg/dL). |
| Glycated hemoglobin (HbA1c) | Baseline and 6 months | Assessed in blood samples and expressed in millimoles per mole (mmol/mol) |
| Insulin | Baseline and 6 months | Assessed in blood samples and expressed in milli-international units per liter (mIU/L). |
| Liver function markers | Baseline and 6 months | Change in Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) assessed in the blood (U/L) |
| C-reactive protein (CRP) | Baseline and 6 months | Change in C-reactive protein (CRP) (mg/dL), assessed in the blood |
| High-sensitivity C-reactive protein (hs-CRP) | Baseline and 6 months | Change in High-sensitivity C-reactive protein (hs-CRP) (mg/dL), assessed in the blood |
| Interleukin-6 (IL-6) | Baseline and 6 months | Change in Interleukin-6 (IL-6) (pg/mL), assessed in the blood |
| Neutrophil-to-lymphocyte ratio (N/L) | Baseline and 6 months | Change in Neutrophil-to-lymphocyte ratio (N/L), calculated from blood neutrophil and lymphocyte counts |
| Platelet-to-lymphocyte ratio (P/L) | Baseline and 6 months | Change in platelet-to-lymphocyte ratio (P/L), calculated from blood platelet and lymphocyte counts |
| Thyroid Function | Baseline and 6 months | Change in Thyroid-stimulating hormone (TSH) assessed in the blood (mIU/L) |
| Epigenetic markers | Baseline and post-intervention/pre-surgery | 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). |
Countries
Italy
Contacts
CONTACTElia M Biganzoli, Professor
CONTACTRoberta Biciuffi, MSc
PRINCIPAL_INVESTIGATORFrancesca Bianchi, PhD
University of Milan
PRINCIPAL_INVESTIGATORChristine Desmedt, PhD
Laboratory for Translational Breast Cancer Research, Ku Leuven
PRINCIPAL_INVESTIGATORValentina Bollati, PhD
University of Milan
STUDY_DIRECTORElia M Biganzoli, PhD
University of Milan
PRINCIPAL_INVESTIGATORElena Barbieri, PhD
Università degli Studi di Urbino Carlo Bo'
PRINCIPAL_INVESTIGATORRoberta Biciuffi, MSc
University of Milan
Outcome results
None listed