Evaluation of CYP2D6 enzyme activity using a 13C-dextromethorphan breath test in women receiving adjuvant tamoxifen. Issue 4 (April 2015)

• Record Type: Journal Article
• Authors: Safgren, Stephanie L.; Suman, Vera J.; 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 P.
• Is Part Of: Pharmaocogenetics and genomics. Volume 25:Issue 4(2015:Apr.)
• Publication Date: 2015-04
• Subjects: Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000121
• Languages: English
• ISSNs: 1744-6872

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background</title> <p>In tamoxifen-treated patients, breast cancer recurrence differs according to <italic>CYP2D6</italic> genotype and endoxifen steady-state concentrations (Endx Css). The <sup>13</sup>C-dextromethorphan breath test (DM-BT), labeled with <sup>13</sup>C at the O-CH<sub>3</sub> 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.</p> </sec> <sec> <title>Methods</title> <p>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 <italic>CYP2D6</italic> genotype and Endx Css was determined. The association between baseline DM-BT (where values ⩽0.9 is an indicator of poor <italic>in vivo</italic> CYP2D6 metabolism) and Endx Css (using values⩽11.2 known to be associated with poorer recurrence free survival) was explored.</p> </sec> <sec> <title>Results</title> <p>A total of 91 patients were enrolled and 77 were eligible. <italic>CYP2D6</italic> genotype was positively correlated with baseline, 3, and 6 months DM-BT (<italic>r</italic> ranging from 0.457–0. 60; <italic>P</italic><0.001). Both <italic>CYP2D6</italic> genotype (<italic>r</italic>=0.47, 0.56, <italic>P</italic><0.0001), and baseline DM-BT (<italic>r</italic>=0.60, 0.54, <italic>P</italic><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.</p> </sec> <sec> <title>Conclusion</title> <p>In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with <italic>CYP2D6</italic> genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with <italic>CYP2D6</italic> genotype alone. Further studies are needed to identify additional factors which alter Endx Css.</p> </sec> </abstract>