title: The rs1800716 variant in CYP2D6 is associated with an increased double endometrial thickness in postmenopausal women on tamoxifen.
abstract: BACKGROUND
  Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU).
  
  
  METHODS
  We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression.
  
  
  RESULTS
  Data were available for 184 women: 47 with a DET of <5 mm on all ultrasounds and 137 with a DET of ≥5 mm on at least one ultrasound. The rs1800716 variant in CYP2D6 showed a statistically significant association with DET. In particular, mutant carriers of rs1800716 had an increased chance of having a DET of ≥5 mm (P = 0.0022, false discovery rate 0.0179). None of the other variants were associated with DET.
  
  
  CONCLUSIONS
  Although mutant carriers of rs1800716 are characterized by reduced CYP2D6 enzyme activity and by low levels of endoxifen, we observed that mutant alleles of rs1800716 were associated with an increased chance of having a DET of ≥5 mm in postmenopausal women on tamoxifen. We conclude that the increase in endometrial thickness seen under tamoxifen cannot be used as a marker for favorable genotypes.
  
  
  BACKGROUND
  B32220084284.
authors.affiliation: Department of Oncology, KU Leuven, Leuven.
authors.forename: A-S
authors.initials: AS
authors.lastname: Dieudonné
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.forename: D
authors.initials: D
authors.lastname: Smeets
authors.forename: A
authors.initials: A
authors.lastname: Belmans
authors.forename: H
authors.initials: H
authors.lastname: Wildiers
authors.forename: R
authors.initials: R
authors.lastname: Paridaens
authors.forename: C
authors.initials: C
authors.lastname: Hyonil
authors.forename: D
authors.initials: D
authors.lastname: Timmerman
authors.forename: M-R
authors.initials: MR
authors.lastname: Christiaens
authors.forename: I
authors.initials: I
authors.lastname: Vergote
authors.forename: P
authors.initials: P
authors.lastname: Neven
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009929:Organ Size / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: breast cancer; cyp2d6; endometrial thickness; tamoxifen