title: Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer.
abstract: BACKGROUND
  Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy.
  
  
  METHODS
  Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.
  
  
  RESULTS
  In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 null allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10(-16)) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10(-43)).
  
  
  CONCLUSIONS
  The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.
authors.affiliation: Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. hennige@coi.waw.pl.|Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. hennige@coi.waw.pl.|Cancer Center-Institute, Roentgena 5, 02-781, Warsaw, Poland. hennige@coi.waw.pl.
authors.forename: Ewa E
authors.initials: EE
authors.lastname: Hennig
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. mpiatkowska@coi.waw.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Piatkowska
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. pocztakuby@gmail.com.
authors.forename: Jakub
authors.initials: J
authors.lastname: Karczmarski
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. kgoryca@gmail.com.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Goryca
authors.affiliation: Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. brewela@coi.waw.pl.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Brewczynska
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. rjazwiec@gmail.com.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Jazwiec
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. akluska@coi.waw.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Kluska
authors.affiliation: Department of Internal Medicine and Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. robert.omiotek@gmail.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Omiotek
authors.affiliation: Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. agapaziewska@poczta.onet.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Paziewska
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. michald@ibb.waw.pl.
authors.forename: Michal
authors.initials: M
authors.lastname: Dadlez
authors.affiliation: Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow@warman.com.pl.|Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. jostrow@warman.com.pl.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ostrowski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D002853:Chromatography, Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D011044:Poland; D057285:Precision Medicine; D013629:Tamoxifen / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6