Does CYP2D6 Genotyping have a Role in Guiding Tamoxifen Therapy?

Abstract

Inter-individual variability to drug response is a major concern in the field of oncology. In the era of "targeted" therapy, optimal treatment outcomes can be achieved by more individualized initial dosing and/or alternative treatment according to the patient's genetic make-up. Although several genes are responsible for the interindividual variability in drug metabolism and response, the Cytochrome P450 enzymes are the most widely validated and clinically utilized. Pharmacogenetic testing of CYP2D6 alleles was the first FDA approved test due to its involvement in the metabolism of a wide range of drugs such as the anti-cancer drug tamoxifen (Nolvadex ® ), to which clinical response varies widely among patients.Identifying determinants and predictors of the variable response or non-response to tamoxifen can facilitate therapeutic dose measurement or even determine the choice of alternative agents (e.g. aromatase inhibitors). Several clinical trials have shown that genetic variants associated with slower metabolism of tamoxifen may lead to lower than expected blood levels of its pharmacologically active metabolites and thus shorter recurrence-free survival. CYP2D6 genotyping can be clinically useful for selecting adjuvant therapy, improving the clinical outcome of tamoxifen and potentially reducing overall costs of treatment. However, CYP2D6 phenotypebased recommendations for tamoxifen have not been developed and guidelines linking the CYP2D6 status to personalized oncologic care do not exist and therefore clinicians' uptake of the testing has remained very low. Large prospective randomized clinical trials are required to assess whether CYP2D6 genotype can robustly predict treatment outcome of tamoxifen and improve overall survival.

Tamoxifen and oxidative stress: an overlooked connection

“…It was noted that there was significant association between intermediate and poor metabolizers of CYP2D6 and CYP2C19 and tamoxifen resistance [ 75 ]. The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early postmenopausal breast cancer has been a matter of debate, the necessity of genotyping to guide tamoxifen therapy is even another ongoing argument [ 74 , 76 , 77 ]. Summary of various factors affecting tamoxifen resistance is summarized in Fig.…”