Effect of Physical Exercise on Tumor Proliferation of Luminal B Breast Cancer Patients

Study Overview
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Brief Summary
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Observational study to evaluate the effect of physical exercise prior to surgery and adjuvant systemic treatment in women with newly diagnosed operable hormone receptor(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers

Detailed Description
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Effect of exercise on tumor aggressiveness and the impact on patients' quality of life. Exercise is a safe and effective treatment for women diagnosed with breast cancer (BC), that has an integral benefit during and after treatments, however, the effect at the tumour microenvironment it is unknown; previous studies have evaluated the association between exercise and BC, finding a positive influence on it, which suggest that exercise could reduce the aggressiveness of the tumour. This study will explore the exercise impact in tumor microenvironment, as part of the therapy given to the patients prior to surgery and treatment. In addition, different serum biomarkers involved and the tailoring of exercise for these women will be evaluated. The effect of exercise on treatments secondary effects, biomarkers and quality of life will be evaluated after 6 months of BC surgery. This project will open a window of opportunity to explore new translational research as well as new treatment vias to the patients of this breast cancer subgroup.

Official Title
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Effect of Physical Exercise on Ki-67 Levels in Women With Operable Breast Cancer Hormonal Receptor Positive, HER2 Negative

Conditions
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Breast Cancer, Luminal B

Intervention / Treatment
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* Other: Exercise
* Other: Stretching


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, previously untreated clinical stage I-IIIA without previous treatment. ER positive breast cancer according to local results. (RH+ is defined as ≥ 1% assessed by Immunohistochemistry (IHC) to Estrogen Receptor (ER) and/or Progesterone Receptor (P)E). HER2 negative in the primary tumour according to local results. (HER2 confirmation should be done following the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2013 guidelines) Scheduled to undergo surgical resection. Ki67 levels must be over 13%, according to local results. At least 14 days from enrolment to planned surgical resection. Karnofsky performance status of at least 70% at study entry or 0-1 level in Eastern Cooperative Oncology Group (ECOG) Scale. Signed consent prior to initiation of study-related procedures. Exclusion Criteria: Schedule to receive any form of induction/neoadjuvant therapy Significant cardiac disease (ventricular ejection fraction of <50%, unstable angina, placement of cardiac stents and myocardial infarction within precious 6 months) Any pulmonary dysfunction which may affect to the exercise program perform. Any mental disease or condition that compromise the physical, psychological and emotional patients' wellness or affect to the process. Contraindications to a cardiopulmonary exercise test as recommended by the American Thoracic Society.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| High intensity physical exercise<br>Supervised Exercise Group: Customized and supervised exercise high intensity training program during 2-3 weeks previous surgery. | Other: Exercise<br>* Exercise intervention adapted to maximum rate of oxygen consumption measured during incremental exercise (VO2level) of each patient, working between 60% to 100% VO2level. The activity will be walk-run in a treadmill. 10 sessions minimum<br>|
| Control<br>Supervised Stretching Group: a stretching and body balance classes will be developed to control the possible confounders and to control the exercise level of participants. | Other: Stretching<br>* Stretching and relaxing exercise during 30 minutes. Same number of sessions as intervention group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor proliferation (Ki67) | Tumor proliferation (Ki67) will be assessed immunohistochemically at basal biopsies versus post-surgery tumor samples. | Post-surgery, an average of 6 months | 
| Proliferation Score | A 50-gene quantitative polymerase chain reaction (qPCR) assay (PAM50) will be used to identify the intrinsic biological subtypes using RNA isolated from formalin-fixed, paraffin-embedded (FFPE) tissue from baseline biopsies samples and post-surgery tumor samples. | Post-surgery, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline molecular subtypes | A 50-gene qPCR assay (PAM50) will be used to identify the intrinsic biological subtypes using RNA isolated from formalin-fixed, paraffin-embedded (FFPE) tissue from baseline biopsies samples and post-surgery tumor samples. | Post-surgery, an average of 6 months | 
| Changes in tumor microenvironment: levels of Vascular endothelial growth factor (VEGF) | VEGF will be evaluated on tissue from baseline biopsies samples and post-surgery tumor samples by Immunohistochemistry (IHC) | Post-surgery, an average of 6 months | 
| Changes in tumor microenvironment: levels of factor Hypoxia-inducible factor 1 (HIF-1) | HIF-1 will be evaluated on tissue from baseline biopsies samples and post-surgery tumor samples by Immunohistochemistry (IHC) | Post-surgery, an average of 6 months | 
| Change in tumor microenvironment: levels of cleaved caspase 3 | Levels of cleaved caspase 3 will be evaluated on tissue from baseline biopsies samples and post-surgery tumor samples by Immunohistochemistry (IHC) | Post-surgery, an average of 6 months | 
| Oxygen uptake during peak exercise (VO2peak) | VO2peak will be obtained of the Cardiopulmonary exercise testing (CPET) performed at baseline and after the exercise program until surgery. | Post-surgery, an average of 6 months | 
| Change in body composition | Change in body composition will be assessed by bioimpedance parameters. Bioelectrical impedance analysis (BIA) is a commonly used method for estimating body composition, and in particular body fat, and will be performed at baseline and after the exercise program until surgery. | Post-surgery, an average of 6 months | 
| Change in fatigue levels | Change in fatigue levels will be assessed by questionnaire Functional Assessment of Cancer Therapy: Fatigue (FACT-F). The physical well-being domain has 7 items with scores from 0 to 28 points; social/family well-being, 7 items with score from 0 to 28 points; emotional well-being, 6 items with score from 0 to 24 points; functional well-being, 7 items with score from 0 to 28 points; and fatigue subscale, 13 items with score from 0 to 52. Each item has ﬁve likert-type options graduated from 0 to 4: Not at all, A little bit; Somewhat; Quite a bit; Very much'. The ﬁnal score of FACT-F is obtained by adding the scores of the ﬁve domains, and may vary from 0 to 160 points. The higher the number of points, the better the quality of life and the less the fatigue of the patients is. To obtain the score, the negative questions are reverted; then the answers of the domains are added up, and a proportional average is carried out in case of non answered items. | Post-surgery, an average of 6 months | 
| Change in quality of life levels | Change in quality of life levels will be assessed by questionnaire Functional Assessment of Cancer Therapy: Breast Cancer (FACT-B). The FACT-B is a breast cancer-specific HRQoL instrument of the FACIT system. The 37-item are divided into five subscales, namely physical (PWB), social/family (SWB), emotional (EWB), functional well-beings (FWB), and the additional concerns for breast cancer (BCS). Each item is rated on a 5-point Likert scale. Negatively worded items were recoded such that a higher score indicates a better HRQoL. The FACT-B total score is the sum of scores of all five subscales. | Post-surgery, an average of 6 months | 
| Change in depression levels | Change in depression levels will be assessed by questionnaire Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D is a 20-item measure assessing symptoms of depression with items phrased as self-statements (e.g., I felt hopeful about the future). Respondents rate how frequently each item applied to them over the course of the past week. Ratings were based on a 4-point Likert scale ranging from 0 (rarely or none of the time [less than 1 day]) to 3 (most or all of the time [5-7 days]). | Post-surgery, an average of 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Physical exercise, Breast Cancer