Resistance vs. Aerobic Training on Breast Cancer Patients Undergoing Neoadjuvant Treatment

Study Overview
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Brief Summary
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A recent consensus study suggested that understanding the impact of exercise on the tumor microenvironment and therapy effectiveness is paramount and should be considered as a research priority. Therefore, the research team intends to address some of the scientific challenges proposed, which represent clear gaps in the current knowledge. The investigators propose a randomized controlled trial conducted during all neoadjuvant treatment duration that aims to evaluate and compare the effects of two different exercise protocols (aerobic and resistance training) against a relaxation control group on Ki-67% changes as the main outcome in breast cancer patients. Secondary outcomes will be body composition; resting metabolic rate; physical fitness; quality of life, fatigue, depression/anxiety; accelerometry data (physical activity levels, sedentary time); sleep quality; tumor biology (size, hypoxia, and immune profile); glycemic, lipid, and inflammatory profile. This project will help not only researchers with the design of future exercise intervention protocols but will also help exercise physiologists in the decision-making process when defining training programs. Moreover, the investigators expect that this research program will encourage more cancer patients to exercise. The team expects that patients with breast cancer engaging in structured exercise will show a more marked decrease in Ki-67, tumor size, and hypoxia and increase the tumor-infiltrating lymphocytes (TILs) compared to controls. The investigators anticipate a more noticeable decrease in the preoperative endocrine prognostic index (PEPI) score and in the Residual Breast Cancer (RCB) in both training groups (respectively with hormonal and chemotherapy). Also, frequent declines in physical fitness are expected to be mitigated in exercisers. It is hypothesize that aerobic training will ameliorate cardiorespiratory fitness and fat mass, while the effects of resistance training will be more relevant for muscle strength, muscle mass, and bone health. Both exercise groups will show greater improvements in quality of life, fatigue, depression, anxiety, and sleep quality. Regarding glycemic, lipid, and inflammatory profiles, the investigators expect to see more favorable changes in both training groups, with a more evident decrease in fasting glucose and insulin, HbA1c%, total and LDL-cholesterol, and triglycerides, and the increase in HDL-cholesterol. The increase in C-reactive protein (CRP), tumor necrosis factor -α (TNF-α), interleukin-6 (IL-6), IL-8, IL-1β, IL-1ra, and insulin-like growth factor-1 (IGF-1) and the decrease in brain-derived neutrotophic factor (BDNF), IL-12p70, IL-10, oncostatin M will be smaller in exercise groups.

Detailed Description
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Exercise plays a crucial role in breast cancer prevention and more recently it appears as a safe, non-pharmacological, and cost-effective adjuvant therapy for cancer. Indeed exercise improves the quality of life, fatigue, physical fitness, and also has a positive impact on tumor intrinsic characteristics. Most of the studies regarding the effects of exercise in breast cancer patients were performed after surgery or in survivors. Despite being a window of opportunity to study the impact of exercise on biological properties of the tumor, namely on proliferation markers, the investigations conducted during the neoadjuvant period are still scarce and most of the literature derives from animal studies. Although originating from pilot investigations, the initial human-based evidence suggests that exercise interventions are feasible during neoadjuvant therapy and can potentially reduce some proliferation markers such as Ki-67 (i.e. a widely used prognostic marker), induce favorable changes in tumor-related genes, and increase survival. Power and sample calculations (G-Power, Version 3.1.9.2) are based on an effect size of 0.25 for KI-67 while using ANOVA - repeated measures within-between interactions, a power of 0.80, a significance of 0.05, and an expected dropout of 40%. The calculation yielded a total sample size of 120 participants (60 undergoing chemotherapy and 60 undergoing hormone therapy: 20 participants per group per each treatment). The power and sample calculations were performed using a study that reported the effect of medication on KI-67 since no study has evaluated the effects of an exercise intervention on that variable and has obtained significant results. Participants will be recruited to take part in an intervention study for breast cancer patients undergoing neoadjuvant treatment. The recruitment will take place at Champalimaud Clinical Center Breast Unit / Champalimaud Foundation. To improve exercise adherence, the following strategies will be implemented: Thematic sessions about several topics such as physical activity (PA) guidelines, active lifestyle, nutrition, the benefits of exercise for breast cancer patients, etc. Each session will last 1-hour (30 minutes presentation + 30 minutes discussion/questions) and will occur once a month. These thematic sessions are mandatory. Group activities: once a month, a group activity will be promoted (exercise outdoor sessions, group walk, group dinner, etc.). In these group activities, participants may invite family members to participate. The NEO-program website presenting the mission/goals, team members, activities, news and events, contacts, etc. Facebook and Instagram account (share information and photos); before the intervention, written consent for image collection will be requested. The investigator records clinical data, using a paper or electronic case report form (CRF), all data is collected in an online database that is available through the Champalimaud Clinical Center intranet. Participating physicians have a personal account to log in to the registration page and access the electronic CRF. They will have permanent access to their series of patients. The participating physician ensures the confidentiality, accuracy, completeness, legibility, and timeliness of the data recorded. Data handling and statistical analysis will be done anonymously by the investigator, with the subject identification code list only available to the local investigator (and research nurse if applicable) working in the local center. The code will be based on the birth date and center abbreviation (and not patient initials). The Sponsor will be the owner of the data. Data will be kept for 20 years. The Participating Investigator and the Participating Site shall treat all information and data relating to the Study disclosed to Participating Site and/or Investigator in this study as confidential and shall not disclose such information to any third parties or use such information for any purpose other than the performance of the Study. The collection, processing, and disclosure of personal data, such as patient health and medical information are subject to compliance with applicable personal data protection and the processing of personal data legislation (including but not limited to the European Union Directive 95/46/EC). Champalimaud Foundation takes out the appropriate insurance.

Official Title
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Effects of Resistance vs. Aerobic Training on Ki-67 and Other Health-Related Biomarkers: The NEO-Program, a Randomized Controlled Trial on Breast Cancer Patients Undergoing Neoadjuvant Treatment

Conditions
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Breast Cancer

Intervention / Treatment
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* Behavioral: Aerobic Training Group
* Behavioral: Resistance Training Group
* Other: Control group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed hormone-responsive/human epidermal growth factor receptor-2 (HER2) negative breast cancer (stage 0-III); scheduled for neoadjuvant treatment (cohort A - chemotherapy; cohort B - endocrine therapy) Women aged ≥ 18 years; nonpregnant Do not be involved in any structured exercise program in the past 6 months Medical approval to participate in the study Willingness to attend exercise sessions Exclusion Criteria: Treated for any cancer in the past 5 years (except basal cancer) Uncontrolled heart disease (heart failure, uncontrolled coronary heart disease, and uncontrolled hypertension, cardiac disease) Diabetes mellitus Lung condition (chronic obstructive or restrictive pulmonary disease) Psychological disorders (dementia, Alzheimer, and Parkinson Disease) Severe disability, or other medical condition that prevents from exercise training Alcohol or drugs abuse

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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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be followed in a randomized controlled trial conducted during the full duration of neoadjuvant treatment (i.e. 4- to 6-months, depending on patient treatment plan) and two cohorts will be defined: A - breast cancer patients undergoing chemotherapy; B - breast cancer patients undergoing endocrine therapy. Within each cohort, the participants will be divided into three groups: 1) aerobic training; 2): resistance training; 3): control group. The intervention is designed to have equal energy expenditure throughout the exercise sessions in both exercise groups (10 kcal/kg/week). All training groups will complete 3 sessions/week. To ensure that both exercise groups are isoenergetic, a portable gas analyzer will be used and blood lactate will be collected. Mandatory thematic sessions about several topics such as physical activity guidelines, active lifestyle will be implemented.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aerobic Training<br>Three sessions per week during 4-6-months according to each individual treatment plan. Participants allocated in this group will perform moderate-intensity cycling exercise. | Behavioral: Aerobic Training Group<br>* The participants will perform continuous cycling at 30%-35% of their heart rate reserve for one month (phase 1: adaptive phase). Then, the intensity will increase every 4-5 weeks (± 5%) up to a maximum of 64% of heart rate reserve (moderate intensity), depending on the participant's tolerance. An individualized equation establishing the relationship between heart rate, oxygen consumption, and power output will be determined during the cardiorespiratory fitness assessment and used to determine exercise intensity.<br>* Other names: AT, moderate continuous cycling;|
| Experimental: Resistance training<br>Three sessions per week during 4-6-months according to each individual treatment plan. Participants allocated in this group will perform weight-machine strength exercises of the upper and lower body. | Behavioral: Resistance Training Group<br>* Initially, and during the first two weeks of the adaptive phase (1-month), the resistance training group will perform one set of 8-12 repetitions (40%-repetition maximum) of 8 exercises for upper and lower body (squat, leg extension, leg curl, deadlift, plank, dead bug, seated row, shoulder press). Then, in the last two weeks, the participants will perform 2 sets of each exercise (45%-repetition maximum). After the adaptive phase, three sets of each exercise will be performed. The initial load will be 50% -repetition maximum increasing up to a maximum of 70%-repetition maximum at the end of the study. Every 4-5 weeks the load will be reviewed and adjusted according to individual.<br>* Other names: RT, machine-weight training;|
| Active Comparator: Control Group<br>One session per week of relaxation/stretching. | Other: Control group<br>* The control group will perform a weekly stretching/relaxation session for 45 minutes.<br>* Other names: Relaxation/stretching group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline Ki67% at the end of the intervention | Initial tumor biopsy and the post-neoadjuvant surgical specimen will be evaluated. Pathology evaluation will include the Ki67 assessment. The time frame depends on each participant's treatment plan. | 4-6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in body mass index (BMI) from baseline to T1 and T2 | To calculate BMI (kg/m2), Weight and height will be measured on an electronic scale with a stadiometer without shoes wearing minimal clothing to the nearest 0.01 kg/0.1 cm (Seca, Hamburg, Germany). T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Changes in hip and waist circumferences from baseline to T1 and T2 | Waist circumference will be assessed according to the NIH (horizontal plane at the level of the iliac crest) and World Health Organization (WHO) protocol (midpoint between the lower margin of the last palpable rib and the top of the iliac crest). Hip circumference will be taken around the widest portion of the buttocks. Two measurements (to the nearest 0.1 cm) will be performed and a mean value will be calculated. If the two measurements differ by more than 0.5 cm, a third one will be performed and the two closest measurements will be considered.T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Changes in bone mineral density from baseline to T1 and T2 | Dual-energy X-ray absorptiometry (GE Lunar Prodigy Primo Hologic, Wisconsin, USA) will be used to estimate bone mineral content/density. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Changes in lean body mass from baseline to T1 and T2 | Dual-energy X-ray absorptiometry (GE Lunar Prodigy Primo Hologic, Wisconsin, USA) will be used to estimate percentage of lean body mass. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Changes in phase angle from baseline to T1, T2, T3, T4, T5, T6 | The participants will undergo bioelectrical impedance analysis (BIA) (single frequency, 50 kilohertz (kHz) ± 1%, NutriLAB, Akern) to determine the PhA and body water compartments (total, extracellular, and intracellular). The participants will be measured in a lying position, with legs apart from each other and arms apart from the trunk, so that the medial surface of the limbs will not touch the rest of the body. Four electrodes (2 in each limb) will be placed on the hand and foot of the dominant side, with a distance of 5 cm between both. T moments depend on each participant's treatment plan: T1, T2, T3, T4, T5 correspond to 1-, 2-, 3-, 4-, 5-months after the beginning of the intervention, respectively; T6, 6-months (end of the intervention). On those that will undergo a 4-months treatment plan, only T1, T2, T3, and T4 will be performed. | 4-6 months | 
| Changes in resting metabolic rate from baseline to the end of the intervention | Resting metabolic rate will be measured using indirect calorimetry using a gas analyzer (QUARK resting metabolic rate (RMR) w/ Cardio Pulmonary Exercise Test (CPET), version 9.1, Cosmed, Rome, Italy). The participants will be in a lying position for 30-minutes while using a mask. The first 5-minutes of gas measurement will be discarded. A steady-state period of 5-minutes for oxygen and carbon dioxide volumes (coefficient of variation ≤ 5%) will be used for analyses. The time frame depends on each participant's treatment plan. | 4-6 months | 
| Changes in peak oxygen content from baseline to the end of the intervention | Peak oxygen uptake (VO2 peak) will be determined by an incremental supervised CPET performed on a cycle ergometer. The assessment will start at 20 Watts and then the workloads will increase 10 Watts/min. Cadence: 60-70 rpm. All tests will be monitored using a 12-lead electrocardiogram PC-based acquisition module by a certified cardiologist, and heart rate will be recorded using Omnia software. After the calibration, inspired and expired gases will be continuously analyzed through a gas analyzer (QUARK RMR w/CPET, version 9.1, Cosmed, Rome, Italy). Participants will exercise until at least two of the following test termination criteria are reached: (1) volitional fatigue; (2) respiratory exchange ratio reached 1.1 or higher; (3) predicted maximal heart rate; (4) oxygen uptake do not increase despite increasing workload. Peak oxygen will be determined as the highest 20 seconds average of the last minute. The time frame depends on each participant's treatment plan. | 4-6 months | 
| Changes from baseline to T1 and T2 in upper limb strength | The handgrip strength test (hydraulic calibrated hand dynamometer - JAMAR) as defined by the American Society of Hand Therapists will be performed to assess upper limb strength. 3 isometric repetitions (separated by 1-minute recovery) will be performed in a seated position. The shoulder joint should be adducted and neutrally rotated; the elbow flexed at 90º, and the forearm in midprone neutral position. The mean of the three trials will be calculated. Verbal encouragement will be provided. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Changes from baseline to T1 and T2 in lower limb strength | To evaluate lower limb strength, an isometric mid-thigh pull will be performed while using a force sensor (Chronojump). 3 maximal voluntary repetitions will be performed for 4-5 seconds while receiving a verbal stimulus, with 3 minutes recovery between trials. The bar will be positioned near the thigh and the knees should be positioned at 120º. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Change from baseline to T1 and T2 in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores | The EORTC-QLQ-C30 is a 30-item questionnaire composed of 5 multi-item functional subscales (physical, role, emotional, cognitive , and social functioning), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global quality of life (QOL) subscale, and 6 single item symptom scales assessing other cancer-related symptoms . The questionnaire employs 28 4-point Likert scales with responses from not at all to very much and two 7-point Likert scales for global health and overall QOL. Responses to all items are then converted to a 0 to 100 scale. For functional and global QOL scales, higher scores represent a better level of functioning/QOL. For symptom-oriented scales, a higher score represents more severe symptoms. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 
| Change from baseline to T1 and T2 in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores | The EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales (systemic side effects, breast symptoms, arm symptoms, upset by hair loss). QLQ-BR23 questionnaire employs 4-point scales with responses from 'not at all' to 'very much'. All scores are converted to a 0 to 100 scale. For functional scales, higher scores represent a better level of functioning. T1 and T2 depend on each participant's treatment plan: T1, middle of the intervention; T2, end of the intervention. | 4-6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Quality of life, Neoadjuvant treatment, Tumor biology, Physical fitness, Sleep quality