Cardio-Oncology Rehabilitation in Breast Cancer Patients Undergoing Chemotherapy

Breast cancer (BC) is highly prevalent worldwide, and in Brazil, particularly in the state of Rio Grande do Sul (RS), it is the leading cause of morbidity and mortality from malignant neoplasms among women. Five-year survival rates exceed 80% in developed countries, whereas in Brazil there is considerable variation across regions and cities. Studies indicate that Porto Alegre, the capital of RS, has one of the highest incidence rates of breast cancer among women under 50 years of age, with 165.5 cases per 100,000 women aged 40 to 49 years. Several risk factors are associated with the development of breast cancer, including family history of the disease, use of oral contraceptives, obesity, and alcohol consumption. Notably, obesity and alcohol consumption differentially increase the risk of specific molecular subtypes of breast cancer. In addition, physical inactivity and elevated body mass index (BMI) are significant risk factors for breast cancer in postmenopausal women. Although chemotherapy is essential in oncologic treatment, it is associated with adverse effects on the cardiovascular system. Advances in pharmacologic therapy, together with a greater understanding of disease mechanisms, have led to increased survival and improved health-related well-being among cancer patients. However, this increased survival is accompanied by greater exposure to cardiovascular risk factors and clinically unfavorable outcomes, such as cardiotoxicity caused by chemotherapeutic agents. Cardiotoxicity, classified as acute, subacute, or chronic, is generally assessed based on changes in left ventricular ejection fraction (LVEF). Nevertheless, there is no universally accepted conceptual definition of chemotherapy-induced cardiotoxicity; definitions vary according to study design, etiology, epidemiology, and prevention strategies. Adjuvant chemotherapy is used in up to 27% of breast cancer cases. The mechanisms underlying cardiotoxicity and the progression of cardiac dysfunction over time may be explained by: (1) increased myocardial oxidative stress; (2) disruption of mitochondrial calcium homeostasis; (3) impairment of mitochondrial energy metabolism; (4) degradation of ultrastructural proteins; (5) direct DNA damage via inhibition of topoisomerase 2β; and (6) direct cytotoxic effects on cardiac progenitor cells, reducing the heart's reparative capacity following myocardial injury. Clinical diagnosis of cardiotoxicity cannot be limited to a simple measurement of LVEF. Evidence highlights the importance of evaluating additional outcomes beyond structural changes and reduced LVEF, including cardiac arrhythmias, coronary artery disease, blood biomarkers, and vascular function. Cardiotoxicity and Vascular Function Endothelial cells are characterized by heterogeneous structure and function, with phenotypic variation according to their location in different organs, tissues, or blood vessel types. Positioned at the interface between blood and tissue, the endothelium plays a key role in the cardiovascular system, including regulation of vascular tone, synthesis and secretion of signaling molecules, and control of hemostasis, coagulation, inflammatory response, and atherogenesis. Chemotherapeutic agents are generally administered via the systemic circulation. As a result, endothelial cells are among the first to be affected by these drugs, even before cardiac tissue itself. Vascular endothelial health is progressively compromised, with endothelial cells becoming increasingly vulnerable to inflammatory stressors, generation of reactive oxygen species, and reduced nitric oxide bioavailability - factors that directly contribute to the development and progression of atherosclerotic disease. In addition to inflammatory markers and adhesion molecules, endothelial function can be assessed using brachial artery flow-mediated dilation (FMD), a technique first developed in 1992. This non-invasive method measures brachial artery diameter before and after forearm ischemia induced by inflating a cuff on the distal portion of the arm; FMD is expressed as the percentage increase in brachial artery diameter following release of the ischemic stimulus (reactive hyperemia). This vasodilation is mediated by endothelial release of nitric oxide in response to arterial wall shear stress. Nagy et al. evaluated 22 patients with a clinical diagnosis of lymphoma treated with doxorubicin (DOX), measuring FMD before and after (at 6, 12, 24, and 48 hours) chemotherapy administration. The study's main finding was a significant reduction in FMD values (9.9±4.4% vs. 6.1±4.6%, P<0.02). In the same line of research, other findings established significant associations between baseline FMD values and changes in LVEF at 3 months (r = 0.433; p = 0.044) and at 6 months (r = 0.581; p = 0.023) among patients who developed cardiotoxicity following anthracycline treatment. Based on these results, the authors suggest that FMD assessment may play an important role as a risk-stratification tool and an early marker of chemotherapy-induced cardiotoxicity. Breast Cancer and Physical Exercise As noted above, several risk factors are associated with the development of breast cancer, including family history, use of oral contraceptives, obesity, and alcohol consumption, with obesity and alcohol consumption differentially increasing the risk of specific molecular BC subtypes. Physical inactivity and elevated BMI are also significant risk factors for breast cancer in postmenopausal women. Regular physical exercise has been shown to be an effective strategy in both the prevention and management of breast cancer. During chemotherapy treatment, physical activity may reduce fatigue, improve quality of life, and increase cardiorespiratory fitness. Studies indicate that supervised exercise programs combining aerobic and resistance training are particularly effective in reducing fatigue among women undergoing adjuvant chemotherapy. After completion of chemotherapy, continued engagement in physical exercise remains equally beneficial. Evidence suggests that regular physical activity is associated with lower all-cause and breast-cancer-specific mortality among survivors. In addition, exercise interventions have been shown to improve self-reported cognitive function, physical fitness, fatigue, and quality of life, and to reduce depressive symptoms in breast cancer patients exposed to chemotherapy. Given this context, this project proposes to study the clinical profile of women diagnosed with breast cancer with respect to the effects of chemotherapy treatment and the implementation of a physical exercise program on the cardiovascular system and functional capacity, through an integrated cardio-oncology rehabilitation approach, in patients treated within the Brazilian Unified Health System (SUS), cared for at a university hospital or referred from the RS public health network. Hypotheses Null Hypothesis (H0): In women diagnosed with breast cancer, chemotherapy treatment does not produce statistically significant changes in the following clinical and laboratory outcomes: vascular function (assessed by flow-mediated dilation or ankle-brachial index); cardiac function (assessed by echocardiography or other complementary tests); functional capacity (assessed by the six-minute walk test or VO2 consumption); and inflammatory, endothelial, and cardiovascular biomarkers. Alternative Hypothesis (H1): In women diagnosed with breast cancer, chemotherapy treatment produces statistically significant changes in the following clinical and laboratory outcomes: reduced vascular function; impaired cardiac function; decreased functional capacity; and altered levels of inflammatory, endothelial, and cardiovascular biomarkers.