Prediction of individual tamoxifen activation in breast cancer patients.

Abstract

e13514 Background: Endoxifen (EN), the main active metabolite of tamoxifen (T), reaches steady state (SS) plasma levels after about 4 months of administration. It derives principally by cytochrome CYP2D6 activity, which is highly variable among patients. In order to predict individual SS EN exposure, three different approaches were investigated. Methods: Before starting T administration, 73 breast cancer patients (median age: 59 yrs, range: 30-89) were characterized by means of: 1) a phenotyping test of CYP2D6 activity, based on the urinary metabolic ratio of dextromethorphan/dextrorphan (log transformed, LMR). 2) CYP2D6 genotyping (alleles *1, *3, *4, *5, *6, *9, *10, *41), to classify patients in 3 functional groups: Extensive (EM), Intermediate (IM) and Poor (PM) Metabolizers. After starting T treatment (20mg/day), EN plasma levels were measured after 1 month (1M EN, pre- steady state) and 4 months of therapy (SS EN). ANOVA, paired and unpaired T test and linear regressions were performed to analyze associations between LMR, CYP2D6 genotype, 1M EN and SS EN. Multivariate linear regression was used to create a predictive equation; its mean prediction and absolute errors (MPE% and MAE%) and the positive and negative predictive values (PPV% and NPV%, according to median SS EN) were calculated. Results: SS EN plasma levels varied between 2.4 and 39.2 (median: 8.7) ng/ml. LMR (median: -1.6; range: -3.1- +1.2) showed a significant linear correlation with SS EN (r=-0.59; p<0.0001). CYP2D6 genotypes (EM=35.6%; IM=50.7%; PM=13.7%) were significantly associated with SS EN (ANOVA, p<0.0001). First month EN plasma levels (median: 5.9 ng/mL; range:1.2-27 ng/ml) were significantly lower than (p<0.0001), and correlated (r=0.87; p<0.0001) with, SS EN. Multiple regression analysis including age, LMR, CYP2D6 genotypes and 1M EN gave the following predictive equation: SS EN= 0.055-1.53 x LMR + 1.11 x 1M EN; (r=0.88; p<0.0001). MPE was 4.1% and MAE was 30%; PPV was 88.5% and NPV was 84.6%. Conclusions: Individual EN exposition at steady state can be reliably predicted by measuring baseline CYP2D6 activity, through the log (dextromethorphan/dextrorphan) metabolic ratio, and EN plasma concentration after 1 month of tamoxifen treatment. Funded by Regione Veneto. Clinical trial information: 532.