CDK4/6 inhibitors in metastatic breast cancer: Pharmacogenetics of ADME genes to predict differences in toxicity and treatment schedule adherence

CDK4/6 inhibitors, palbociclib, ribociclib, abemaciclib, are the gold standard for the treatment of luminal-like metastatic breast cancer. These drugs are characterised by a narrow therapeutic index and wide interindividual variability in therapeutic response, that could be at least partially ascribed to a different pharmacogenetic profile. Neutropenia is the most frequent dose-limiting toxicity associated with CDK4/6i. Regardless, CDKis have different safety profiles. For this observational study, data and blood samples from patients with metastatic hormone-sensitive HER -2 negative breast cancer who accepted to participate, were collected at the National Cancer Institute CRO Aviano. The aim of this work was to investigate the contribution of pharmacogenetics of ADME genes to the variability of drug response in patients in the study group. Specifically, the clinical endpoint investigated have been: early occurrence of severe toxicity, dose reduction, relative dose intensity, therapeutic response and time to next treatment. Polymorphisms in selected genes encoding proteins involved in ADME were analysed (CYP3A4, CYP3A5, ABCB1, ABCG2).