Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen

Stephanie L. Safgren, Vera Jean Suman, Matthew L. Kosel, Judith A. Gilbert, Sarah A. Buhrow, John L. Black, Donald W Northfelt, Anil S. Modak, David Rosen, James N. Ingle, Matthew M. Ames, Joel M Reid, Matthew Philip Goetz

Research output: Contribution to journalArticle

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Abstract

Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The 13C-dextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored. Results A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. Conclusion In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.

Original languageEnglish (US)
Pages (from-to)157-163
Number of pages7
JournalPharmacogenetics and Genomics
Volume25
Issue number4
DOIs
StatePublished - Mar 27 2015

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Dextromethorphan
Cytochrome P-450 CYP2D6
Breath Tests
Tamoxifen
Enzymes
Genotype
Recurrence
Pharmacokinetics

Keywords

  • C-dextromethorphan breath test
  • CYP2D6
  • tamoxifen

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. / Safgren, Stephanie L.; Suman, Vera Jean; Kosel, Matthew L.; Gilbert, Judith A.; Buhrow, Sarah A.; Black, John L.; Northfelt, Donald W; Modak, Anil S.; Rosen, David; Ingle, James N.; Ames, Matthew M.; Reid, Joel M; Goetz, Matthew Philip.

In: Pharmacogenetics and Genomics, Vol. 25, No. 4, 27.03.2015, p. 157-163.

Research output: Contribution to journalArticle

Safgren, Stephanie L. ; Suman, Vera Jean ; Kosel, Matthew L. ; Gilbert, Judith A. ; Buhrow, Sarah A. ; Black, John L. ; Northfelt, Donald W ; Modak, Anil S. ; Rosen, David ; Ingle, James N. ; Ames, Matthew M. ; Reid, Joel M ; Goetz, Matthew Philip. / Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. In: Pharmacogenetics and Genomics. 2015 ; Vol. 25, No. 4. pp. 157-163.
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abstract = "Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The 13C-dextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored. Results A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78{\%}) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2{\%}) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. Conclusion In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.",
keywords = "C-dextromethorphan breath test, CYP2D6, tamoxifen",
author = "Safgren, {Stephanie L.} and Suman, {Vera Jean} and Kosel, {Matthew L.} and Gilbert, {Judith A.} and Buhrow, {Sarah A.} and Black, {John L.} and Northfelt, {Donald W} and Modak, {Anil S.} and David Rosen and Ingle, {James N.} and Ames, {Matthew M.} and Reid, {Joel M} and Goetz, {Matthew Philip}",
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T1 - Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen

AU - Safgren, Stephanie L.

AU - Suman, Vera Jean

AU - Kosel, Matthew L.

AU - Gilbert, Judith A.

AU - Buhrow, Sarah A.

AU - Black, John L.

AU - Northfelt, Donald W

AU - Modak, Anil S.

AU - Rosen, David

AU - Ingle, James N.

AU - Ames, Matthew M.

AU - Reid, Joel M

AU - Goetz, Matthew Philip

PY - 2015/3/27

Y1 - 2015/3/27

N2 - Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The 13C-dextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored. Results A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. Conclusion In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.

AB - Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The 13C-dextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored. Results A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. Conclusion In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.

KW - C-dextromethorphan breath test

KW - CYP2D6

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