The aim of this clinical trial is to evaluate whether following a multimodal prehabilitation program including physical exercise, nutritional support and psychological intervention during neoadjuvant chemotherapy in breast cancer patients could improve the pathological response to chemotherapy. 214 women with non-metastatic breast cancer with indication of chemotherapy before surgery will be eligible to participate. Patients will be randomly assigned to either the intervention group or the control group. * Patients assigned to the intervention group (107 women) will undergo a directed multimodal prehabilitation program during the chemotherapy (4-6 months), including structured physical exercise, psychological intervention and nutritional guidance. * Patients assigned to the control group (107 women) will undergo standard clinical management for their disease without multimodal prehabilitation. The response to chemotherapy between the two groups will be evaluated and compared. It is expected that multimodal prehabilitation will increase the response to chemotherapy and will improve the postoperative recovery of patients and their quality of life, as well as reducing the number of complications from surgery and chemotherapy treatment. Changes in the tumor microenvironment are also expected after prehabilitation.
Breast cancer (BC) is the most common neoplasm worldwide and the leading cause of death among women. Neoadjuvant chemotherapy (NACT) is currently one of the main therapeutic pillars. The pathological response after NACT has demonstrated prognostic value in BC, being also a determinant factor for posterior treatments. In recent years, research has increasingly focused on the impact of lifestyle changes on BC, such as physical exercise, diet, and psychological interventions. These actions are part of what is known as prehabilitation, defined as the set of strategies applied prior to surgery to optimize the physical and emotional condition of patients before the surgical intervention. The individual application of these strategies in BC patients has shown improved oncological outcomes, with positive effects on quality of life and tolerance to medical treatments. Furthermore, evidence suggests that these interventions may favorably modulate the tumor microenvironment by reducing intratumoral hypoxia, enhancing antitumor immune responses, and modulating systemic pro-inflammatory states. Despite the demonstrated benefits of prehabilitation in multiple medical and surgical fields, there is limited evidence regarding its impact on systemic treatment outcomes in BC patients. There is also a lack of solid evidence evaluating the role of multimodal prehabilitation (combining different prehabilitation strategies) in BC, as well as its effect on treatment response and tolerance. The current study proposes the application of a multimodal prehabilitation program during the NACT window, based on structured physical exercise, psychological therapy (mindfulness or anxiety-control techniques), and nutritional counseling in BC patients, as a strategy to enhance treatment response through changes in the tumor microenvironment. Additionally, it will be assessed whether the intervention improves treatment tolerance and postoperative recovery, among others. The study consists of a randomized, single-blind, controlled clinical trial with two parallel groups that will include 214 women diagnosed with non-metastatic breast cancer, eligible for NACT, and awaiting surgery at our center. Participants will be randomized into two parallel groups in a 1:1 ratio (control and intervention group, including 107 women each). A basal evaluation will be performed in all patients before starting NACT, reporting their physical, nutritional and psychological status, as well as a tumor microenvironment study in the diagnostic biopsy sample. All patients will undergo 4-6 months of NACT, the control group with standard clinical management and the intervention group following the multimodal prehabilitation program. After NACT, the physical, nutritional and psychological status of all patients will be re-evaluated. Patients will undergo surgery according to their disease and the pathological response to the treatment will be assessed. The primary outcome will be the pathological response after NACT in both groups, assessed through the Residual Cancer Burden (RCB) index. Secondary outcomes will include NACT tolerance, quality of life, psychological and nutritional status, postoperative recovery, tumor microenvironment changes and patients' physical condition. The group of BC patients undergoing the multimodal prehabilitation program during NACT is expected to achieve better response rates (RCB 0 and I) than the control group. Furthermore, the multimodal intervention is anticipated to promote quantitative and/or qualitative changes in the tumor microenvironment, improve NACT tolerance, enhance quality of life, and optimize postoperative recovery and the patients' physical, psychological, and nutritional status.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
214
Multimodal prehabilitation program during NACT (4-6 months) that will combine: 1) Physical exercise: cardiovascular and strength exercises designed by specialized physiotherapists, structured in 1-hour sessions twice a week. The characteristics of the activity will be adapted to the treatment phase and the physical condition of each woman. 2) Psychological therapies: standardized mindfullness practice by a specialized psychologist. As an alternative, patients who refuse mindfullness could receive psychological sessions on stress and anxiety management. 3) Nutritional counseling: periodic sessions with a specialized nutritionist providing dietary recommendations and nutritional advice adapted to the disease and condition of the patients.
Hospital Clínic de Barcelona
Barcelona, Spain
RECRUITINGResidual Cancer Burden Index (RCB)
The main variable of the trial is the RCB index score, obtained from the histological specimen of the oncological surgery performed after NAC. The four levels of response of the RCB index (RCB 0, I, II and III) will be divided into a favorable profile of response (fRCB), that will include cathegories RCB 0 and I, and an unfavorable response profile (uRCB), including RCB II and III. It is estimated that the average rate of a favorable RCB (fRCB) score, including RCB 0 and RCB I, will be approximately 40% in the control arm. Parallelly, the expected rates of unfavorable RCB (uRCB) scores, including RCB II and RCB III, are 60%. The objective is to improve the response rates by 20% in the intervention group, with 60% of fRCB scores and 40% of uRCB scores in this group.
Time frame: From enrollment (baseline, day 1) until the end of treatment at 4-6 months (preoperative).
Tumor microenvironment (Gene expression analyses)
Formalin fixed-paraffin embedded tumor tissue blocks will be analyzed by hematoxylin and eosin staining, to check tumor surface area. Samples with ≥20% of tumor cells will be selected for RNA extraction. The High Pure FFPET RNA Isolation Kit (Roche) will purify RNA from FFPE tumor samples. A minimum of ∼100 ng of total RNA will be used to measure the expression of 185 breast cancer-related and immune-related genes including the genes of PAM50 and HER2DX and 7 housekeeping genes using the nCounter platform (Nanostring Technologies, Seattle, USA). The gene expression for each sample will be independently normalized to the geometric mean of housekeeping genes. The 14-gene immunoglobulin (IGG) signature (i.e., CD27, CD79A, HLA-C, IGJ, IGKC, IGL, IGLV3-25, IL2RG, CXCL8, LAX1, NTN3, PIM2, POU2AF1 and TNFRSF17) will be calculated.
Time frame: From enrollment (baseline, day 1) until the end of treatment at 4-6 months (postoperative).
Tumor staging
Registered according to the TNM system by the. American Joint Committee on Cancer (AJCC) 8th edition
Time frame: At diagnosis or day 1 (clinical TNM or cTNM) and after surgery (pathological TNM or pTNM)
Tumor cellularity after NACT
Reported as the percentage (%) of neoplastic cells in the surgical specimen.
Time frame: After the surgery (after NACT, 4-6 months from day 1)
Assessment of vascular density in peritumoral areas
The assessment will involve evaluating microvascular density through immunohistochemical staining for CD31 on tumor or tumor bed sections. This evaluation follows a two-step process: 1. Hotspot Area Selection: Identification of hotspot areas under a light microscope at 4x magnification. 2. Manual Counting: Manual counting of all vascular lumens in the selected field at 20x magnification. This method ensures precise quantification of vascular density in both the peritumoral and tumor bed regions.
Time frame: At enrollment (baseline, day 1) and at the end of treatment at 4-6 months (postoperative).
Adverse effects of neoadjuvant chemotherapy
They will be recorded by the research team and classified according to the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0. Data will be collected at the end of NAC in both groups.
Time frame: After the treatment (4-6 months later, presurgical).
Chemotherapy completion rate
The proportion of patients who received the full course of chemotherapy with the corresponding dose. This will be evaluated before surgery in both groups.
Time frame: At the end of the treatment (4-6 months after day 1, preoperative)
Hospitalization during NACT
Need for hospitalization during neoadjuvant chemotherapy: the number of hospital admissions prior to surgery will be recorded as an absolute count.
Time frame: At the end of the treatment (4-6 months after day 1, preoperative)
Post-surgical hospitalization
Length of hospitalization after oncological surgery: Measured in days.
Time frame: From the surgery (5-7 months after day 1) until 30 days after the operation.
Pain control after oncological surgery
Pain will be assessed using the Visual Analogue Scale (VAS) during the hospital stay. The scale ranges from 0 to 10, with higher scores indicating greater pain severity.
Time frame: Since the surgery is done (5-7 months from day 1) until hospital discharge.
Post-operative complications
These will be classified based on timing as immediate postoperative complications (during the procedure or within 24 hours), early complications (up to 7 days post-surgery), and late postoperative complications (from 7 to 30 days post-surgery). Severity will be recorded using the Clavien-Dindo scale. Emergency visits and readmissions will also be reported: The absolute number, reasons, and length of hospital stay will be recorded up to 30 days post-surgery.
Time frame: From the surgery (5-7 months from day 1) until 30 days after.
Weight
Weight in kilograms will be registered before and after NACT
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 year after surgery.
Body Mass Index
Body mass index (BMI) will be measured before and after chemotherapy (kg/m2)
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 year after surgery.
Physical activity level
The international questionnaire of Physical Activity (IPAQ) will be used to register the level of physical activity of the subjects. Minimum score: 0 MET-min/week. Maximum score: no formal upper limit (normally 20,000 MET-min/week). According to the punctuation, the level of physical activity can be classified into low (\< 600 MET-min/week), moderate (≥ 600 and \< 3,000 MET-min/week) or high (≥ 3,000 MET-min/week).
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical) and 1 year after the surgery.
Strength
Assessed through the hand grip strength test, using a hand-held dynamometer (measured in kilograms).
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical) and 1 year after the surgery.
Estimated maximal oxygen uptake (VO2 max)
To evaluate the general physical status of patients (as an estimate of VO₂), the 30-Second Sit-to-Stand Test will be performed and recorded as an absolute number.
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical) and 1 year after the surgery.
Change in oxygen consumption (VO2) from baseline to post-neoadjuvant therapy
Through a Cardiopulmonary Exercise Testing (CPET), the oxygen consumption will be measured in all patients (ml/kg/min) before and after finishing neoadjuvant chemotherapy.
Time frame: Before the chemotherapy (baseline or day 1) and after the treatment (4-6 months later, presurgical).
Patient-perceived quality of life
Measured using the EORTC QLQ-30 questionnaire (0-100 points: higher scores on functional scales and the global health status scale indicate better functioning and quality of life, while higher scores on symptom scales indicate a higher level of symptoms).
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), 1 month after surgery and 1 year after the surgery.
Anxiety and Depression levels
Assessed using the Hospital Anxiety and Depression Scale (HADS), which score ranges from 0 to 21 points. Higher scores indicate more severe symptoms of anxiety or depression: 0-7: Normal or no significant anxiety/depression, 8-10: Mild anxiety/depression, 11-15: Moderate anxiety/depression, 16-21: Severe anxiety/depression.
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), 1 month after surgery and 1 year after the surgery.
Mindfulness status
Assessed through the Five Facet Mindfulness Questionnaire (FFMQ). Score 39 - 195 points. A higher score indicates a greater level of mindfulness.
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 month after surgery.
Nutritional status
Complete blood analysis: Including liver and renal profile, blood count, ionogram, albumin, prealbumin, glucose, interleukin-6 and IGF-1.
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), and 1 year after the surgery.
Adherence to mediterranean diet
Validated Questionnaire of Mediterranean Diet Adherence (MEDAS-14). Scoring: 0-14 points. Higher scores mean higher adherence to Mediterranean diet, being a score equal or superior to 9 considered a good adherence to such diet.
Time frame: Before the chemotherapy (baseline or day 1), after the treatment (4-6 months later, presurgical), 1 month after surgery and 1 year after the surgery.
Prehabilitation program adherence
Measured by the number of sessions attended relative to the scheduled sessions.
Time frame: After the prehabilitation program (4-6 months from day 1, presurgical).
Body image perception
Assessment of how patients perceive and feel about their physical appearance after the finalization of breast cancer treatments through the validated questionnaire Body Image Scale Questionnaire (BIS).
Time frame: 1 year after the surgery
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