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CYP2D6 is the critical & prominent enzyme by which tamoxifen is metabolized to the active metabolite endoxifen.Recent literature suggests a minimal concentration threshold of 5.97 ng/mL of endoxifen is required at steady state for tamoxifen to be effective in preventing breast cancer recurrence (Madlensky et al., 2011).The variability of endoxifen blood concentrations in patients on tamoxifen therapy can occur due to genetic factors as well as epigenetic factors like drug-drug interaction (Jin et al., 2005).A prospective multicenter study is ongoing in the Netherlands and Belgium aiming to correlate CYP2D6 genotype and endoxifen serum levels to tamoxifen efficacy in patients with early breast cancer.CYP2D6 genotype was determined by SNP array (Amplichip, Roche).Patients were classified as extensive (EM), intermediate (IM) or poor metabolizer (PM) by genotype, Predicting the CYP2D6 phenotype from genotype is almost impossible.In the 65 patients study at LUMC the CYP2D6 enzyme activity was determined by a 13C-dextrometorphan breath test (DM-BT).Breath samples were collected in 1.3 L breath bags at baseline and at 50 minutes after administration of 0.5 mg/kg of 13C-dextromethorphan.The change in delta over baseline (DOB) calculated from 13CO2/12CO2 ratios in the two breath bags reflects CYP2D6 enzyme activity (phenotype).The median (range) DOBs0 value for each predicted phenotype was: EM: 2.9 (1.2-4.4;n=32);IM: 2.4 (0.4-4.5;n=25);PM: 0.2 (0-0.5;n=8).DOB50 values in CYP2D6 PMs were significantly lower compared to hetEMs and EMs (p<0.001).Median (range) endoxifen levels were significantly (p=0.027) lower in PMs (3.3 ng/mL (1.8-6.3) than in IMs (9.9ng/mL (4.6-24.7)) and in EMs (16.5 ng/mL (6.6-29.7)).Correlation between serum endoxifen levels and DOB50 values was moderate (R2=0.27).DOB50 values were significantly (p=0.023) lower in patients with a serum endoxifen level below the threshold level of 6 ng/mL compared to patients with a higher endoxifen level.With a DOB50 cut-off value of 1.2 and a serum threshold endoxifen level of 6 ng/mL, the sensitivity and specificity of the DM-BT is 95 and 100%respectively, resulting in a positive and negative predictive value of 100 and 75% respectively.In CYP2D6 poor metabolizers, CYP2D6 activity determined by a dextromethorphan breath test (DM-BT) and endoxifen levels in plasma are significantly lower than in IMs and EMs.Our preliminary results in a small number of patients suggest that DM-BT might identify poor responders to tamoxifen prior to initiating endocrine therapy.