Metabolic Flexibility in Patients With Early Triple-negative Breast Cancer and the Possible Effect of a Physical Exercise Intervention
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Respiratory Exchange Ratio (RER)
研究概览
简要总结
Cancer is considered a major global public health problem. It was estimated that in 2022 approximately 19.9 million new cancer cases were diagnosed worldwide, and this number is expected to increase over the next two decades to 28.0 million (1). Specifically, breast cancer (BC) represents the highest incidence worldwide, with approximately 2.3 million new cases diagnosed in 2022 (1).
A higher incidence of BC is observed in developed countries, which may be due to high rates of obesity, alcohol and tobacco consumption, early onset of puberty, the use of contraceptives and hormonal therapies, low levels of physical activity, and giving birth at later ages (2,3). In addition to the factors mentioned above, hereditary factors and age also represent risk factors for cancer development (2,3). Finally, the presence of family members with breast and/or ovarian cancer carrying mutations in the BRCA1 or BRCA2 genes, among others, which increase the likelihood of tumor proliferation, as well as age over 40 years, also increase the probability of developing BC (2,3).
Specifically, there is a molecular subtype that does not respond to hormonal receptors or HER2 and may be more aggressive and have fewer specific treatment options, known as triple-negative breast cancer (TNBC).
Metabolic flexibility (MF) is described as the ability of the body to adapt to energy demands in different contexts. During chemotherapy and after surgery, significant changes may occur, such as increased body fat, loss of muscle mass, cancer-related fatigue, metabolic alterations, and decreased quality of life. These changes may persist even years after treatment and may affect both well-being and recovery. It could therefore be suggested that metabolic flexibility in muscle fibers in patients with TNBC may be reduced, particularly in patients undergoing systemic treatment, with potential difficulties adapting to different intensities and energy demands in daily life. A decrease in muscle metabolic flexibility would also imply a reduction in muscle strength and physical function, significantly impairing quality of life.
Therefore, the main objective of this study is to analyze muscle metabolic flexibility at different stages of early disease and to evaluate whether different types of exercise training can improve these outcomes.
To achieve this, assessments will be conducted at four time points during the early stages of the disease: at diagnosis, after neoadjuvant treatment, after surgery, and following an exercise intervention. The assessments will include blood analyses, body composition measurements, cycling exercise tests to evaluate oxygen consumption and the utilization of fat and glucose, measurements of muscle strength, and questionnaires assessing fatigue and quality of life.
After surgery, participants will be randomly assigned to one of four groups for 12 weeks: a control group receiving general physical activity recommendations; a moderate-intensity cardiovascular exercise group focused on maximal fat oxidation; a high-intensity interval cardiovascular exercise group; and a progressive resistance training group. The final objective is to determine which type of exercise most effectively improves metabolic flexibility, muscle strength, body composition, and overall well-being.
Participation in the study is voluntary and does not affect standard medical care. All assessments and training sessions will be supervised by qualified exercise professionals to ensure participant safety.
详细描述
Cancer is recognized as a major global socio-health issue. In 2022, it was estimated that approximately 19.9 million new cancer cases were diagnosed worldwide, and this number is projected to rise to 28.0 million over the next two decades (1). Breast cancer (BC) specifically exhibits the highest incidence globally, with around 2.3 million new cases reported in 2022 (1). According to the Spanish Society of Medical Oncology (SEOM), 37,682 new BC cases are expected to be diagnosed in Spain in 2025 (1).
Currently, BC subtypes are classified based on their molecular characteristics (2,3). The triple-negative (TN) molecular subtype is defined by the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for 10-20% of invasive BC cases and is considered more biologically and clinically aggressive than other subtypes (2,3). It also presents a poorer prognosis and more limited treatment options (2,3).
Metabolic flexibility (MF) refers to the body's capacity to adapt to energy demands under varying conditions (4,5). Mitochondria, as the primary cellular organelles responsible for energy production, facilitate substrate oxidation to generate ATP according to required intensity levels (5). In contrast, metabolic inflexibility in muscle fibers is characterized by impaired lactate clearance, reduced lipid oxidation capacity, and rapid switching from fat to carbohydrate (CHO) oxidation (6).
Some studies suggest that cancer induces systemic mitochondrial dysfunction across multiple tissues, influenced both by disease pathophysiology and the toxicity of oncological treatments (7). Additionally, decreased PGC-1α levels have been observed in patients receiving neoadjuvant chemotherapy (NAC). PGC-1α is a key transcriptional coactivator regulating mitochondrial biogenesis, and its reduction may contribute to inefficient energy production, resulting in muscle dysfunction and loss of both mass and function in cancer patients (7,8).
Moreover, women with BC who undergo chemotherapy are more likely to gain fat mass compared to age-matched women without BC (7,9,10,11). Excess adipose tissue is linked to metabolic disease and elevated pro-inflammatory cytokines, further contributing to mitochondrial and metabolic dysfunction. Increased fat mass has also been associated with higher risks of recurrence, disease progression, and mortality in BC studies (7,9,10,11).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 55 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female between 20-55 years of age.
- •Confirmed histological new diagnosis of stage I to III triple-negative breast cancer and a candidate to receive systemic neoadjuvant treatment with chemotherapy +/- immunotherapy.
- •Must not have started systemic treatment for the neoplastic disease.
- •Participating in any external physical exercise program or sports activities during the experimental study phase.
- •Inability to understand and provide written Informed Consent (IC)
排除标准
- •Having neurological or orthopedic disease at the time of recruitment or during the study evaluation and intervention.
- •Inability to understand Spanish language.
- •Presenting absolute contraindications for performing a cardiopulmonary exercise test (CPET) such as heart failure, myocarditis, acute pericarditis, severe aortic stenosis, aortic dissection, vascular toxicity, uncontrolled severe arterial hypertension, uncontrolled severe cardiac arrhythmias, pulmonary thromboembolism, or severe anemia.
- •Have relative contraindications for performing a CPET such as bradyarrhythmias or tachyarrhythmias, moderate valvular stenosis, inability to perform physical or mental exertion, chronic infectious diseases, musculoskeletal disabilities, ventricular aneurysm, second- or third-degree atrioventricular block, or severe arterial hypertension.
结局指标
主要结局
Respiratory Exchange Ratio (RER)
时间窗: 1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.
The respiratory exchange ratio is the ratio of carbon dioxide production (VCO2) to oxygen consumption (VO2) measured during respiration. It is obtained through indirect calorimetry during rest or exercise and reflects substrate utilization (fat or carbohydrate oxidation).
Fat Oxidation (FATox)
时间窗: 1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.
Fat oxidation refers to the rate at which fatty acids are used as an energy substrate by the body during rest or exercise. It is typically estimated from oxygen consumption (VO2) and carbon dioxide production (VCO2) using indirect calorimetry. FATox is commonly expressed in grams per minute (g/min).
Carbohydrate Oxidation (CHOox)
时间窗: 1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.
Carbohydrate oxidation refers to the rate at which carbohydrates are metabolized to produce energy during rest or physical exercise. It is estimated using oxygen consumption (VO2) and carbon dioxide production (VCO2) measured through indirect calorimetry. CHOox is typically expressed in grams per minute (g/min).
Energy Expenditure
时间窗: 1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.
This variable represents the amount of energy derived from fat and CHO oxidation during rest or exercise. It is estimated using oxygen consumption (VO2) and carbon dioxide production (VCO2) obtained through indirect calorimetry. Energy expenditure is typically expressed in kilocalories (kcal).
Lactate Concentration
时间窗: 1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.
Lactate concentration represents the amount of lactate present in the blood during rest or exercise. It is measured using the Lactate Plus device through capillary puncture of the middle or ring finger of the non-dominant hand and is expressed in millimoles per liter (mmol/L). This variable provides information about anaerobic metabolism and exercise intensity.
次要结局
- Resting Energy Expenditure (REE)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Power(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Maximal Oxygen Consumption (VO2máx)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Ventilatory Volume (VE)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Oxygen Consumption (VO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Carbon Dioxide Production (VCO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Partial Pressure of Carbon Dioxide (PETCO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Ventilatory Oxygen Equivalent (VE/VO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Ventilatory Carbon Dioxide Equivalent (VE/VCO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Heart Rate Variability (HRV)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Heart Rate (HR)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Oxygenated Haemoglobin (HbO2)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Deoxygenated Haemoglobin (HHb)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- % Tissue Saturation Index (%TSI)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Body Mass Index (IMC)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Fat Mass(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Muscle Mass(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Bone Mass(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Bone Mineral Density (BMD)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Total Visceral Fat Volume (cm3VAT)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Basal Metabolic Rate (BMR; TMB in Spanish)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Lower Limb Rate of Force Development (RFD_LL)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Phase Angle (PhA)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Glucose(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Lipid Profile(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Glycated Hemoglobin (HbA1c)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- C-Reactive Protein (CRP)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Maximum Strenght(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Maximum Upper Limb Strength Time (TSmaxUL)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Upper Limb Rate of Force Development (RFD_UL)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Lower Limb Asymmetry (AsymLL)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Quality of Life (QLQ-C30)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Quality of life (QLQ-BR45)(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
- Fatigue(1 week after diagnosis (baseline); 1 week after completion of neoadjuvant treatment; 4 weeks after breast surgery or upon surgeon approval; and 1 week after completion of the exercise intervention or control period.)
研究者
Lidia Brea Alejo
Associate Professor
European University of Madrid