title: Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.
abstract: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels.
  
  
  
  Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA.
  
  
  
  Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07).
  
  
  
  Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121.
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Peter
authors: P
authors: Fox
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Pathology West, Institute for Clinical Pathology and Medical Research, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia. Westmead Millennium Institute for Medical Research, Westmead, Australia.
authors: Rosemary L
authors: RL
authors: Balleine
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Clara
authors: C
authors: Lee
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Bo
authors: B
authors: Gao
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Bavanthi
authors: B
authors: Balakrishnar
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Alexander M
authors: AM
authors: Menzies
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Shang Heng
authors: SH
authors: Yeap
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Sayed Sahanawaz
authors: SS
authors: Ali
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia.
authors: Val
authors: V
authors: Gebski
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Pamela
authors: P
authors: Provan
authors: Westmead Millennium Institute for Medical Research, Westmead, Australia.
authors: Sally
authors: S
authors: Coulter
authors: Sydney Medical School - Westmead, University of Sydney, Sydney, Australia. Westmead Millennium Institute for Medical Research, Westmead, Australia. Storr Liver Centre, Westmead Hospital, Westmead, Australia.
authors: Christopher
authors: C
authors: Liddle
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Rina
authors: R
authors: Hui
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Richard
authors: R
authors: Kefford
authors: St George Hospital, Kogarah, Australia.
authors: Jodi
authors: J
authors: Lynch
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Mark
authors: M
authors: Wong
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia.
authors: Nicholas
authors: N
authors: Wilcken
authors: Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia. Sydney Medical School - Westmead, University of Sydney, Sydney, Australia. Faculty of Medicine and Health Sciences, Macquarie University, Sydney Australia. howard.gurney@mq.edu.au.
authors: Howard
authors: H
authors: Gurney
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6