Abstract 2664: Biological relevance of CYP2D6 phenotype and low dose tamoxifen activity within a randomized phase II pre-surgical trial.
Authors: Serrano Davide , Lazzeroni Matteo , Gandini Sara , Macis Debora , Johansson Harriet , Feroce Irene , Pruneri Giancarlo , Bassi Fabio , Guerrieri-Gonzaga Aliana , Gjerde Jennifer , Lien Ernst , DeCensi Andrea DeCensi Andrea , Bonanni Bernardo 
Published: August 2012

Abstract
Background: To further investigate tamoxifen (T) minimal active dose, we conducted a window of opportunity study in estrogen receptor (ER) positive breast cancer (BC) patients. The study was a three arms randomized phase II double blind clinical trial. The participants were randomized to tamoxifen 10 mg a week vs. raloxifene 60 mg a day vs. placebo for 6 weeks, which was the average waiting list in our Institute at the time of this study was conducted. The primary endpoint was tissue change of Ki67LI. This result was previously reported and overall we did not observe any KI67LI modulation by treatment. The clinical relevance of CYP2D6 polymorphisms is controversial, and recently negative data have been published. Here we present a significant biomarkers modulation by low dose tamoxifen based on CYP2D6 subjects phenotype. Methods: DNA was extracted from whole blood by the use of QIAamp DNA blood kit. We employed the INFINITI analyzer for CYP2D6 genotyping, according to the protocol of the manufacturer. A total of 14 SNPs were analyzed. To determine the concentrations of tamoxifen and its metabolites, we used a high-pressure liquid chromatography-tandem mass spectrometry system. Expression of Ki-67, ER and PgR were determined by immunohistochemistry. Serum concentration of SHBG and estradiol were measured by chemiluminescent immunometric assay; IGF1 and IGFBP3 were determined by enzymatic colorimetric methods. Results: CYP2D6 was analyzed in the 50 women who took tamoxifen. We found 40% of EM (extensive metabolizer), 48% of IM (intermidiet metabolizer), 6% of PM (poor metabolizer) and 6% UM (ultra-rapid metabolizer). The phenotypes were grouped in two classes: active (EM + UM) and with a reduced activity (IM + PM). Among T metabolites a significant accumulation of N-desmethyl-Tamoxifen was present in the reduced activity group (mean plasma level 19.9 vs. 14.4 ng/ml reduced vs. active group p=.05). Endoxifen and 4-OH-Tamoxifen were not significantly different in the two phenotype groups. Then we correlated the phenotype with biomarkers modulations. The active phenotype showed a significant different modulation in Ki67 with a median chage of −2.5 in the active group and +3 in the reduced one. No differences on ER or PgR expression were determined by the phenotype. Among the circulating biomarkers, SHBG in the active group showed a significant difference compared to the reduced one (median change 8.35 and 2 p=0.05) whereas the estradiol and IGF1/BP3 did not show any difference between groups. Conclusions: CYP2D6 phenotypes interact with the biological activity of low dose T. A reduced activity of the enzyme induces an accumulation of N-desmethyl-Tamoxifen, whereas no significant differences for Endoxifen. In spite of a similar Endoxifen concentration, a reduced activity phenotype may influence T activity as demonstrated by the different modulation of Ki67 and SHBG biomarkers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2664. doi:1538-7445.AM2012-2664