Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism

A multicenter study

William J. Irvin, Christine M. Walko, Karen E. Weck, Joseph G. Ibrahim, Wing K. Chiu, E. Claire Dees, Susan G. Moore, Oludamilola A. Olajide, Mark L. Graham, Sean T. Canale, Rachel E. Raab, Steven W. Corso, Jeffrey M. Peppercorn, Steven M. Anderson, Kenneth J. Friedman, Evan T. Ogburn, Zeruesenay Desta, David A. Flockhart, Howard L. McLeod, James P. Evans & 1 others Lisa A. Carey

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Purpose: We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. Patients and Methods: One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. Results: As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still signifi- cantly lower. Conclusion: This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

Original languageEnglish
Pages (from-to)3232-3239
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number24
DOIs
StatePublished - Aug 20 2011

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Cytochrome P-450 CYP2D6
Tamoxifen
Multicenter Studies
Genotype
Feasibility Studies
4-hydroxy-N-desmethyltamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism : A multicenter study. / Irvin, William J.; Walko, Christine M.; Weck, Karen E.; Ibrahim, Joseph G.; Chiu, Wing K.; Dees, E. Claire; Moore, Susan G.; Olajide, Oludamilola A.; Graham, Mark L.; Canale, Sean T.; Raab, Rachel E.; Corso, Steven W.; Peppercorn, Jeffrey M.; Anderson, Steven M.; Friedman, Kenneth J.; Ogburn, Evan T.; Desta, Zeruesenay; Flockhart, David A.; McLeod, Howard L.; Evans, James P.; Carey, Lisa A.

In: Journal of Clinical Oncology, Vol. 29, No. 24, 20.08.2011, p. 3232-3239.

Research output: Contribution to journalArticle

Irvin, WJ, Walko, CM, Weck, KE, Ibrahim, JG, Chiu, WK, Dees, EC, Moore, SG, Olajide, OA, Graham, ML, Canale, ST, Raab, RE, Corso, SW, Peppercorn, JM, Anderson, SM, Friedman, KJ, Ogburn, ET, Desta, Z, Flockhart, DA, McLeod, HL, Evans, JP & Carey, LA 2011, 'Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: A multicenter study', Journal of Clinical Oncology, vol. 29, no. 24, pp. 3232-3239. https://doi.org/10.1200/JCO.2010.31.4427
Irvin, William J. ; Walko, Christine M. ; Weck, Karen E. ; Ibrahim, Joseph G. ; Chiu, Wing K. ; Dees, E. Claire ; Moore, Susan G. ; Olajide, Oludamilola A. ; Graham, Mark L. ; Canale, Sean T. ; Raab, Rachel E. ; Corso, Steven W. ; Peppercorn, Jeffrey M. ; Anderson, Steven M. ; Friedman, Kenneth J. ; Ogburn, Evan T. ; Desta, Zeruesenay ; Flockhart, David A. ; McLeod, Howard L. ; Evans, James P. ; Carey, Lisa A. / Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism : A multicenter study. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 24. pp. 3232-3239.
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abstract = "Purpose: We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. Patients and Methods: One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. Results: As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still signifi- cantly lower. Conclusion: This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.",
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T1 - Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism

T2 - A multicenter study

AU - Irvin, William J.

AU - Walko, Christine M.

AU - Weck, Karen E.

AU - Ibrahim, Joseph G.

AU - Chiu, Wing K.

AU - Dees, E. Claire

AU - Moore, Susan G.

AU - Olajide, Oludamilola A.

AU - Graham, Mark L.

AU - Canale, Sean T.

AU - Raab, Rachel E.

AU - Corso, Steven W.

AU - Peppercorn, Jeffrey M.

AU - Anderson, Steven M.

AU - Friedman, Kenneth J.

AU - Ogburn, Evan T.

AU - Desta, Zeruesenay

AU - Flockhart, David A.

AU - McLeod, Howard L.

AU - Evans, James P.

AU - Carey, Lisa A.

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N2 - Purpose: We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. Patients and Methods: One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. Results: As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still signifi- cantly lower. Conclusion: This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

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