title: Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites.
abstract: BACKGROUND
  Tamoxifen has dramatically reduced the recurrence and mortality rate of estrogen receptor positive breast cancer. However, the efficacy of tamoxifen varies between individuals and 40% of patients will have a recurrence despite adjuvant tamoxifen treatment. Factors that predict tamoxifen efficacy would be helpful for optimizing treatment. Serum concentrations of the active metabolite, endoxifen, may be positively related to treatment outcome. In addition, hot flashes are suggested to be positively associated with tamoxifen treatment outcome.
  
  
  METHODS
  We investigated in a series of 109 patients whether the frequency and severity of hot flashes were related to concentrations of tamoxifen and its metabolites. A serum sample of all patients was analyzed for the concentration of tamoxifen, N-desmethyltamoxifen, endoxifen and 4-hydroxytamoxifen, as well as for estradiol concentrations and several single nucleotide polymorphisms in CYP2D6. Additionally, these patients completed a questionnaire concerning biometric data and treatment side effects.
  
  
  RESULTS
  We found no evidence supporting an association between concentrations of tamoxifen or metabolites and either the frequency or severity of hot flashes in the covariate unadjusted analyses. However, including interactions with menopausal status and pre-treatment hot flash (PTHF) history indicated that post-menopausal women with PTHF experienced an increasing frequency of hot flashes with increasing serum concentrations of tamoxifen and its metabolites. This finding was not altered when adjusting for potential confounding factors (duration of tamoxifen treatment, CYP2D6 phenotype, estradiol serum concentration, age and body mass index). In addition we observed a positive association between body mass index and both hot flash frequency (p = 0.04) and severity (p < 0.0001). We also observed that patients with lower estradiol levels reported more severe hot flashes (p = 0.02).
  
  
  CONCLUSIONS
  No univariate associations were observed between concentrations of active tamoxifen metabolites and either the frequency or severity of hot flashes during treatment. However, the frequency of hot flashes may be exacerbated by higher serum concentrations of tamoxifen and its metabolites in post-menopausal women with a history of hot flashes prior to tamoxifen treatment.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Nynke.Jager@slz.nl.
authors.forename: Nynke G L
authors.initials: NG
authors.lastname: Jager
authors.forename: Rutger H T
authors.initials: RH
authors.lastname: Koornstra
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Vincent
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Tiny M
authors.initials: TM
authors.lastname: Korse
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005838:Genotype; D019584:Hot Flashes / Q000378:metabolism*; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone; D011795:Surveys and Questionnaires; D013629:Tamoxifen / Q000378:metabolism* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019389:Cytochrome P-450 CYP2D6; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen