Personalized approach to the treatment of Locally Advanced/Metastatic Breast Cancer: the role of Pharmacogenetics integrated with Therapeutic Drug Monitoring in minimizing toxicities

Breast cancer represents the most prevalent cancer among women globally. In patients with advanced or metastatic hormone receptor-positive, HER2-negative (HR+/ HER2−) breast cancer, the therapeutic standard in current clinical practice consists of combining cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy. However, significant interindividual variability in the therapeutic response to CDK4/6 inhibitors (CDKis) has been observed, with some patients experiencing unexpected and severe toxicities. To manage these side effects, around 35–45% of patients require dose reductions, and approximately 10% discontinue treatment altogether. This study focuses on two CDK4/6 inhibitors, Ribociclib and Abemaciclib, each associated with distinct toxicity profiles: Ribociclib is predominantly linked to neutropenia, while Abemaciclib is primarily associated with diarrhea. This research investigates the correlation between patients' pharmacogenetic profiles and observed toxicities. For the pharmacogenetic evaluation, single nucleotide polymorphisms (SNPs) in genes associated with drug pharmacokinetics were assessed using a panel of 136 variants across 58 genes. Additionally, through a Therapeutic Drug Monitoring (TDM) approach, the plasma concentrations of Ribociclib and Abemaciclib were measured to establish a possible correlation between pharmacokinetics and pharmacogenetics. The results suggest that genetic and environmental factors, such as concomitant therapies and pre-existing health conditions, influence the absorption, distribution, metabolism, and elimination of the drugs. The integrated approach based on pharmacogenetic profiling and TDM assessment enables the personalization of oncological therapies involving CDK 4/6 inhibitors thereby enhancing treatment safety, therapeutic adherence, and overall quality of life.