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.
Histologically confirmed diagnosis of non-metastatic breast cancer: stages cT1-T4, cN0-N3, M0, and candidates for neoadjuvant chemotherapy (NAC).
Age ≥ 18 years.
Signed informed consent.
Contraindication or physical inability to perform moderate-to-high intensity physical exercise.
Pregnant or breastfeeding patients.
Presence of other active synchronous neoplasms.
Metastatic breast cancer (stage IV).
Parallel
Multimodal prehabilitation
BehavioralMultimodal 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.
Residual 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.
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.
Tumor staging
Registered according to the TNM system by the. American Joint Committee on Cancer (AJCC) 8th edition
Tumor cellularity after NACT
Reported as the percentage (%) of neoplastic cells in the surgical specimen.
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.
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Hospital Clinic of Barcelona
Lead sponsor
Fundació La Marató de TV3
Collaborator
