Genotype and phenotype guided supplementation of TAMoxifen standard therapy with ENDOXifen in breast cancer patients (short TAMENDOX)

Breast cancer is the most frequent malignancy in women with approximately 1.7 Mio new cases per year worldwide. More than ¾ of these tumors overexpress the estrogen receptor and are therefore susceptible to an anti-hormone therapy. The standard-of-care in endocrine treatment is the blockade of estrogen signaling via long-term estrogen deprivation. Tumors are therefore treated with long-term antihormone therapy for at least 5 years. Tamoxifen, a selective estrogen receptor modulator (SERM) blocks 17ß-estradiol binding to stop tumor growth, and aromatase inhibitors (AI) block the aromatase enzyme to prevent conversion of androgens to estrogens. Despite their effectiveness one third of the patients develop recurrences leading to disease progression and death. With regards to Tamoxifen, treatment failure is attributed at least in part to a lack of bioactivation towards its active metabolite endoxifen which is mainly mediated by the polymorphic CYP2D6 enzyme.  Distinct genetically determined variants in the CYP2D6 gene are responsible for inter-individual differences in CYP2D6 enzyme activities throughout the general population. These CYP2D6 phenotypes are grouped into ultra-rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. EM patients have high levels of endoxifen and are likely to benefit from tamoxifen treatment whereas PM patients have low endoxifen levels and a significant risk to relapse. CYP2D6 polymorphism and plasma endoxifen levels have been discussed as tamoxifen outcome predictors and the supplementation of standard tamoxifen (20 mg) with endoxifen is a current clinical trial concept, TAMENDOX, to test whether suboptimal endoxifen levels (< 15 nM) in PM and IM patients can be elevated to clinically meaningful endoxifen concentrations (>32 nm). The purpose of TAMENDOX is to demonstrate feasibility as a prerequisite to pursue this new drug concept of combining the parent drug tamoxifen with its active metabolite endoxifen towards the improvement of tamoxifen outcome which is relevant to millions of women worldwide.

Principal Investigator: Matthias Schwab, MD - Head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology