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).
Evidence highlights the crucial role physical exercise plays in cellular metabolism. Studies demonstrate that exercise significantly influences glucose levels, insulin resistance, growth factors, fat oxidation rates, and lactate clearance (12,13). Dysregulation of these factors may activate tumor signaling pathways, posing a risk for tumor proliferation (12,13,14). Consequently, modulating metabolism through physical activity could be fundamental in influencing cancer progression (12,13,14).
Exercise is key for activating the AMPK signaling pathway, an enzyme triggered under high-energy demands. Activation of AMPK promotes GLUT4 translocation, enhancing glycolysis, fatty acid (FA) oxidation, and mitochondrial biogenesis, including upregulation of PGC-1α (15,16). Continuous endurance training has been shown to sustain AMPK activation for hours post-exercise, with longer durations producing greater benefits (15,17). Similarly, high-intensity cardiovascular training appears to elevate AMPK levels hours after the activity (15,17).
Alongside increased AMPK and PGC-1α activity, training has been associated with greater mitochondrial content and function in muscle fibers (4,6,16,18). This enhances fatty acid oxidation capacity in mitochondria, thereby improving metabolic flexibility (4,6,18). Altogether, these adaptations increase the ability of muscle fibers-now with more mitochondria-to utilize multiple substrates efficiently, improving MF (4,6,18,19).
Recent research also indicates that increasing muscle strength and preventing fat mass gain are essential for maintaining metabolic health and optimizing treatment response, as they are associated with improvements in markers such as insulin sensitivity, glycemic control, and acute anti-inflammatory responses (20,21). Importantly, exercise-induced benefits on mitochondrial and metabolic health appear independent of weight loss from fat reduction (20,21).
In summary, cancer patients-particularly those with TNBC-may experience systemic metabolic dysfunction due to disease pathophysiology, treatment toxicity, and suboptimal lifestyle habits (4,5,7,8,10,14,18,22,23,24,25,26). However, to date, no studies have described the metabolic response to exercise in this population.
Thus, the primary aim of this study is to describe the metabolic flexibility of patients with early-stage TNBC across different phases of the disease. This approach may allow indirect determination of the preferred energy substrate in muscle fibers and identification of the optimal intensity for fatty acid oxidation to improve metabolic profiles in these patients.
Additionally, the study will evaluate the effects of two cardiovascular training interventions and one strength training intervention on the metabolic profile of patients with early-stage TNBC.
This pilot study will initially adopt a descriptive, longitudinal design, followed by an open, randomized experimental phase in early-stage TNBC patients. First, a descriptive observational analysis will be conducted, followed by an experimental study with four groups using a pre-post design, including a control group (CG).
A group consisting exclusively of newly diagnosed TNBC patients (D1) meeting inclusion criteria will be established. This group will receive only general physical activity recommendations provided by the World Health Organization (WHO) during neoadjuvant treatment and prior to breast surgery.
The sample will include 40 TNBC patients selected by convenience sampling from Hospital Universitario Severo Ochoa (Av. de Orellana, s/n, 28914 Leganés, Madrid), Hospital Universitario Infanta Leonor (Av. Gran Vía del Este, 80, Vallecas, 28031 Madrid), and Hospital de la Princesa (Calle de Diego de León, 62, Salamanca, 28006 Madrid), all located in the Community of Madrid.
To determine the most effective exercise intervention for enhancing metabolic flexibility and function, the study will consider: the group with the highest number of patients demonstrating decreased RER and lactate during the exercise test (ET) at the end of each incremental protocol stage post-surgery compared with pre-intervention; the group with the most patients showing increased FATox and CHOox, as well as associated kcal values, at the same stage-defined ET points post-surgery; and the experimental group exhibiting statistically significant changes in these variables.
