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NCT Number: NCT07776951

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

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.

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Key information

Conditions

Breast Cancer Behavior Breast Diseases Breast Neoplasms Motor Activity Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases Triple Negative Breast Neoplasms

Age range

18 year and older

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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]).

Treatment and study plan

Pre-habilitation exercise program

Behavioral

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.

Primary outcomes

  1. Exercise capacity

    Time frame: Baseline and 6 months

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

Secondary outcomes

  1. Pathologic Complete Response (pCR)

    Time frame: 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 (%)

  2. Residual Cancer Burden (RCB)

    Time frame: 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)

  3. Stromal Tumor-Infiltrating Lymphocytes (sTILs)

    Time frame: 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).

  4. Tumor Angiogenesis

    Time frame: 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.

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

    Time frame: 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.

  6. IGF-1 receptor expression (IGF-1R)

    Time frame: 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.

  7. Ki-67 expression

    Time frame: 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.

  8. Lipid Profile

    Time frame: 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

  9. Blood glucose

    Time frame: Baseline and 6 months

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

  10. Glycated hemoglobin (HbA1c)

    Time frame: Baseline and 6 months

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

  11. Insulin

    Time frame: Baseline and 6 months

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

  12. Liver function markers

    Time frame: Baseline and 6 months

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

  13. C-reactive protein (CRP)

    Time frame: Baseline and 6 months

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

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

    Time frame: Baseline and 6 months

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

  15. Interleukin-6 (IL-6)

    Time frame: Baseline and 6 months

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

  16. Neutrophil-to-lymphocyte ratio (N/L)

    Time frame: Baseline and 6 months

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

  17. Platelet-to-lymphocyte ratio (P/L)

    Time frame: Baseline and 6 months

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

  18. Thyroid Function

    Time frame: Baseline and 6 months

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

  19. Epigenetic markers

    Time frame: 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).

Other outcomes

  1. Gut microbiota

    Time frame: At follow up (6 and 12 months)

    Change in microbial diversity (species diversity %) assessed by next-generation sequencing (NGS) of the V3-V4 region of the 16S rDNA gene

  2. Body mass index (BMI)

    Time frame: Baseline and 6 months

    Calculated as body mass in kilograms (kg) divided by height in meters squared (m²) and is expressed in kilograms per square meter (kg/m²).

  3. Fat Mass (FM)

    Time frame: Baseline and 6 months

    Assessed by bioimpedance analysis (BIA 101, Akern, Italy, BodyStat Ltd.) and is expressed as a percentage (%).

  4. Fat-free mass (FFM)

    Time frame: Baseline and 6 months

    Assessed by bioimpedance analysis (BIA 101, Akern, Italy, BodyStat Ltd.) and is expressed as a percentage (%).

  5. Total body water (TBW)

    Time frame: Baseline and 6 months

    Assessed by bioimpedance analysis (BIA 101, Akern, Italy, BodyStat Ltd.) and is expressed as a percentage (%).

  6. Heart rate variability (HRV)

    Time frame: Baseline and 6 months

    Change in heart rate variability (HRV), assessed by noninvasive autoregressive spectral analysis of continuously recorded 2-lead electrocardiographic signals using the CubeStress System (configuration package HD+12), at rest and during active orthostatism.

  7. Blood pressure variability (BPV)

    Time frame: Baseline and 6 months

    Change in blood pressure variability (BPV), assessed by noninvasive autoregressive spectral analysis of continuously recorded blood pressure signals using the CubeStress System (configuration package HD+12), at rest and during active orthostatism.

  8. Respiratory Frequency

    Time frame: Baseline and 6 months

    Change in respiratory frequency, assessed from continuously recorded respiratory signals using a piezoelectric respiratory band placed on the chest and connected to the CubeStress System (configuration package HD+12), at rest and during active orthostatism.

  9. Physical Activity

    Time frame: Baseline and 6 months

    Change in physical activity level assessed using the International Physical Activity Questionnaire (IPAQ), administered as part of the lifestyle questionnaire.

  10. Dietary Habits

    Time frame: Baseline and 6 months

    Change in adherence to a healthy dietary pattern assessed using the American Heart Association Healthy Diet Score (AHA score), administered as part of the lifestyle questionnaire.

  11. Final compliance questionnaire

    Time frame: At 6 months

    A custom-made questionnaire evaluating the subjective perception of the effects of exercise

  12. Health-related quality of life

    Time frame: Baseline, 6 months and at follow ups at 6 and 12 months

    Assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The questionnaire includes functional scales (physical, role, cognitive, emotional, and social functioning), symptom scales (fatigue, pain, nausea, and vomiting), and a global health status/quality of life scale. Scores are transformed to a 0-100 scale. Higher scores indicate better quality of life.

  13. Mental health

    Time frame: Baseline and 6 months

    Assessed using Mental Health Continuum Short Form (MHC-SF), composed of 14 items. Each item can be scored between 0 and 5 and the total score on the scale can range from 0 to 70 points. Higher scores indicate a higher level of emotional wellbeing.

  14. Anxiety and depression

    Time frame: Baseline and 6 months

    Assessed using the Hospital Anxiety and Depression Scale (HADS), a 14-item questionnaire comprising two 7-item subscales measuring anxiety (HADS-A) and depression (HADS-D). Each item is scored on a 4-point Likert scale (0-3). Subscale scores range from 0 to 21, with higher scores indicating greater anxiety or depressive symptoms.

  15. Daily sleepiness

    Time frame: Baseline and 6 months

    Assessed using the Epworth Sleepiness Scale (ESS), an 8-item self-administered questionnaire. Each item is rated on a 4-point scale (0-3), and the total score ranges from 0 to 24. Higher scores indicate a greater likelihood of dozing or falling asleep.

  16. Quality of sleep

    Time frame: Baseline and 6 months

    Assessed using the Pittsburgh Sleep Quality Index (PSQI), a 19-item questionnaire comprising seven component scores that are summed to generate a global score ranging from 0 to 21. Higher scores indicate poorer sleep quality.

  17. 6-Minute Walking Test (6MWT)

    Time frame: Baseline and 6 months

    Performed according to international guidelines to assess aerobic capacity. The total distance walked during the 6-minute test is recorded in meters (m).

  18. Handgrip strength (HGS) - Right Hand

    Time frame: Baseline and 6 months

    Assessed using an isometric dynamometer to evaluate upper limb muscle strength. The assessment is performed in a sitting position with the elbow flexed at 90 degrees. Three measurements are performed, with each measurement recorded in kilograms (kg). The mean of the three readings is calculated as the final right-hand handgrip strength value, expressed in kilograms (kg).

  19. Handgrip strength (HGS) - Left Hand

    Time frame: Baseline and 6 months

    Assessed using an isometric dynamometer to evaluate upper limb muscle strength. The assessment is performed in a sitting position with the elbow flexed at 90 degrees. Three measurements are performed, with each measurement recorded in kilograms (kg). The mean of the three readings is calculated as the final left-hand handgrip strength value, expressed in kilograms (kg).

Study contacts

Contact information is provided by the study sponsor or research team.

Elia M Biganzoli, Professor

CONTACT

[email protected]

+39 02503 19652

Roberta Biciuffi, MSc

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

University of Milan

Other

Collaborators

  • Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
  • Istituto Auxologico Italiano
  • University of Urbino "Carlo Bo"

Registry information

Official study title

PhActHealth - Physical Activity and Healthy Aging: Fighting Low Grade Chronic Inflammation to Put Out the Cardio-oncologic Risk

Acronym: PhActHealth

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Aug 20, 2026
Registry last updated
Aug 20, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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