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In Reply

Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN

James M. Rae

Department of Medicine, Division of Hematology/Oncology, University of Michigan School of Medicine, Ann Arbor, MN

Stephanie L. Safgren, Matthew M. Ames, Daniel W. Visscher, Carol Reynolds, Fergus Couch, Wilma L. Lingle

Departments of Oncology, Biostatistics, Pathology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN

David A. Flockhart, Zeruesenay Desta

Department of Medicine, Division of Clinical Pharmacology, Indiana University, Indianapolis, IN

Edith A. Perez

Department of Medicine, Division of Hematology and Oncology, Mayo Clinic Jacksonville, Jacksonville, FL

James N. Ingle

Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN

In Reply:

The determination of CYP2D6 enzyme status in women receiving tamoxifen for the prevention of breast cancer is critically important because our data^1,2 suggest that the benefit of tamoxifen in preventing breast cancer might be restricted to those patients who are able to fully activate tamoxifen to its active metabolite, endoxifen. Bonanni et al, in response to our article,² evaluated the frequency of the CYP2D6 *4 genotype in a nested case-control study derived from the Italian chemoprevention trial and found the frequency of the CYP2D6 *4/*4 genotype to be higher in 46 tamoxifen-treated women who developed breast cancer (cases) than in 136 tamoxifen-treated women who did not develop breast cancer (controls). They also noted that the three tamoxifen-treated women who were homozygous for the CYP2D6 *4 genotype and developed breast cancer experienced hot flashes, but the grades were not reported.

We commend Bonanni et al for their assessment of the role of CYP2D6 in women who received tamoxifen for the prevention of breast cancer and are pleased that their findings support the importance of CYP2D6 genotype in determining efficacy of tamoxifen. The findings in their relatively small study should provide a strong incentive to examine larger and available datasets to more robustly establish the relationship between CYP2D6 genotype and outcomes in women treated with tamoxifen in the prevention setting. When this is performed, attention should be paid to examining coadministration of CYP2D6 inhibitors such as those commonly used for the treatment of hot flashes. This suggestion is based on the fact that antidepressants commonly coprescribed with tamoxifen for the treatment of depression or hot flashes confound the effect of CYP2D6 genotype on plasma endoxifen levels by significantly lowering plasma endoxifen concentrations in CYP2D6-intermediate and -extensive metabolizers.¹ Despite supporting our report relating genotype to tamoxifen efficacy, it should be noted that the patients and controls in the report by Bonanni et al were matched for age but apparently not for length of follow-up or breast cancer risk profile (eg, Gail model).

Finally, the authors noted that all of the tamoxifen-treated women who were homozygous for the CYP2D6 *4 genotype and who developed breast cancer also experienced hot flashes and that this finding was in variance with ours. We demonstrated that none (0%) of the women homozygous for the *4 allele experienced grade 2 (moderate) or grade 3 (severe) hot flashes compared with 20% of women homozygous or heterozygous for the wild-type allele. In these same patients, there was no difference in the incidence of grade 1 (mild) hot flashes. These data suggest that hot flash intensity (not incidence) is dependent on the metabolic activation of tamoxifen by CYP2D6, with the most intense hot flashes occurring in patients with maximal metabolic activation.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005[Abstract/Free Full Text]

2. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005[Abstract/Free Full Text]

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