title: Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity.
abstract: Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races.
  
  
  
  PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months.
  
  
  
  In 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients.
  
  
  
  Differences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy.
  
  
  
  This secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life.
authors.affiliation: University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Deal
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.affiliation: Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Walko
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.affiliation: Laboratory Corporation of America, Burlington, North Carolina, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Moses Cone Health Cancer Center, Greensboro, North Carolina, USA.
authors.forename: Gustav
authors.initials: G
authors.lastname: Magrinat
authors.affiliation: REX Hematology Oncology Associates, Raleigh, North Carolina, USA.
authors.forename: Oludamilola
authors.initials: O
authors.lastname: Olajide
authors.affiliation: REX Hematology Oncology Associates, Raleigh, North Carolina, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.affiliation: Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Raab
authors.affiliation: Levine Cancer Institute, Charlotte, North Carolina, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrizosa
authors.affiliation: Palmetto Hematology Oncology, Spartanburg, South Carolina, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Corso
authors.affiliation: Levine Cancer Institute Concord, Concord, North Carolina, USA.
authors.forename: Garry
authors.initials: G
authors.lastname: Schwartz
authors.affiliation: Waverly Hematology/Oncology, Cary, North Carolina, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peppercorn
authors.affiliation: Indiana University, Indianapolis, Indiana, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Indiana University, Indianapolis, Indiana, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Indiana University, Indianapolis, Indiana, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Evans
authors.affiliation: Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Bon Secours Cancer Institute, Richmond, Virginia, USA william_irvin@bshsi.org.
authors.forename: William J
authors.initials: WJ
authors.lastname: Irvin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D011788:Quality of Life; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; Endoxifen; Genotype; Pharmacogenetics; Quality of life; Race; Tamoxifen; Toxicity