Development of a Pharmacogenomic Panel for Early Detection of Chemotherapy- and Immunotherapy-Induced Cardiotoxicity.

Cardiotoxicity induced by cancer therapies, such as chemotherapy and immunotherapy, represents a critical health challenge, as it may result in left ventricular dysfunction and heart failure, complications associated with high mortality rates. This risk is particularly elevated in patients treated with anthracyclines, which are widely used in cancers such as breast cancer. The mortality associated with post-treatment cardiac dysfunction, together with its substantial economic burden on the healthcare system, highlights the urgent need for early identification and prevention of cardiotoxicity.

The primary objective of this study is to develop a pharmacogenomic panel capable of predicting cardiotoxicity in patients receiving chemotherapy or immunotherapy, enabling preventive interventions before the initiation of cancer treatment. To achieve this, 1,000 breast cancer patients aged 18 years or older who are scheduled to begin cancer therapy will be enrolled. Patients with a left ventricular ejection fraction (LVEF) < 50%, those who have undergone chemotherapy and/or radiotherapy within the previous year, patients with chronic kidney disease and a glomerular filtration rate below 30 mL/min/1.73 m², uncontrolled hypertension, or complex congenital heart disease will be excluded.

Participants will be monitored for 12 months and will undergo cardiologic assessments, including electrocardiography, echocardiography with strain analysis, and measurement of Pro-BNP, BNP, Troponin I, and Troponin T levels, as well as blood sample collection. Blood samples will be used for exome sequencing, miRNA sequencing, plasma protein quantification, lipid peroxide formation analysis, metabolomic and proteomic studies, and measurement of plasma drug concentrations. Exome libraries will be prepared using the Illumina® DNA Prep with Exome 2.0 Plus Enrichment kit, while plasma-derived miRNA libraries will be prepared using the QIAseq miRNA Library Kit. Sequencing will be performed on the NextSeq 2000 Sequencing System.

In addition, the plasma proteins angiopoietin-2, VCAM-1, and VEGF-A will be quantified using the Luminex® Multiplex Assay platform, and lipid peroxide formation will be monitored as a marker of oxidative stress. Selected genetic variants and miRNAs will be validated by quantitative PCR (qPCR). Furthermore, metabolomic and proteomic analyses will be conducted to characterize cardiotoxicity. This comprehensive set of analyses, combined with continuous patient monitoring throughout treatment, will enable detailed characterization of cardiotoxicity and facilitate comparisons between patient groups for subsequent genotyping analyses.

The relevance of this research to Brazil's Unified Health System (SUS) is substantial, as it may support the implementation of safer and more effective cancer treatment protocols, reducing the incidence of cardiotoxicity and the resulting hospitalizations. The application of precision medicine strategies has the potential to improve patients' quality of life while optimizing healthcare resources and reducing costs associated with the management of chemotherapy- and immunotherapy-induced cardiovascular complications.

Inclusion criteria

• Patients with a confirmed diagnosis of breast cancer who are scheduled to initiate treatment with anthracyclines and/or HER2-targeted therapies (anti-HER2 therapies).

Exclusion criteria

• Patients with a left ventricular ejection fraction (LVEF) < 50%;
• Patients who have undergone chemotherapy and/or radiotherapy within the previous year;
• Patients with chronic kidney disease and a glomerular filtration rate (GFR) < 30 mL/min/1.73 m²;
• Patients with uncontrolled hypertension;
• Patients with complex congenital heart disease.