• Dr. Schwab Matthias

CV

Professor at the University of Tuebingen, head of the Department of Clinical Pharmacology, University Hospital Tuebingen and the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. Schwab holds board certifications in Pediatrics and in Clinical Pharmacology, and was visiting professor at St Jude Children’s Research Hospital Memphis, USA. Schwab’s focus lies on personalized medicine and the elucidation of underlying mechanisms for drug failure and side effects, and on cancer pharmacogenomics (PGx), the application of omics-technologies and ex-vivo models. He is PI of academically initiated drug trials, received funding on European/national level, and is engaged in the implementation of PGx into clinics. He is member of the German National Academia of Sciences Leopoldina, Academia of Sciences&Literature Mainz, Academia Europea, and Fellow of the British Pharmacology Society. He is adjunct professor at the Yerevan State University Armenia, Clarivate Highly Cited Researcher and serves as (Section-)Editor-in-Chief of Pharmacogenetics&Genomics and Drug Research.

ABSTRACT

CYP2D6 and tamoxifen: current status

Schwab (1), (2)

(1) Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376 Stuttgart, Germany

(2) Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany

 

Variation in drug disposition and response among breast cancer patients is a major concern. Estrogen receptor (ER)-positive breast cancer accounts for 75% of cases diagnosed worldwide. The two main options for adjuvant treatment are tamoxifen and aromatase inhibitors. Research into PGx has led to fundamental discoveries regarding whether genetic polymorphisms of CYP2D6 may influence the outcome of tamoxifen treatment. Based on the fact that the pharmacokinetics of tamoxifen and the formation of the active metabolite endoxifen are altered by CYP2D6 variation, a higher risk of recurrence in postmenopausal breast cancer women is associated with the CYP2D6 genotype when strict clinical and genotype eligibility requirements are used. Therefore, testing for the CYP2D6 genotype is recommended prior to tamoxifen therapy. However, several pitfalls in tamoxifen PGx research contribute to conflicting results, including a lack of consideration of the germline and tumour genome and insufficient coverage of CYP2D6 alleles for genetic diagnostics, as well as challenges in translating PGx recommendations into clinical practice. Various therapeutic strategies to overcome impaired CYP2D6-mediated tamoxifen metabolism are discussed. The addition of a low dose of (Z)-endoxifen to standard tamoxifen therapy is a feasible and safe novel strategy for personalised antiestrogen treatment, as has recently been demonstrated.