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1. Breast Cancer Res Treat. 2012 Feb 1. [Epub ahead of print]

Estimation of tamoxifen metabolite concentrations in the blood of breast cancer
patients through CYP2D6 genotype activity score.

Wu AH, Lorizio W, Tchu S, Lynch K, Gerona R, Ji W, Ruan W, Ruddy KJ, Desantis SD,
Burstein HJ, Ziv E.

Department of Laboratory Medicine, San Francisco General Hospital, 1001 Potrero
Ave., Room 2M27, San Francisco, CA, 94110, USA, wualan@labmed2.ucsf.edu.

Tamoxifen, a prodrug used for adjuvant breast cancer therapy, requires conversion
to the active metabolite endoxifen through CYP 2D6. We aimed to construct an
algorithm to predict endoxifen concentrations based on a patient's CYP 2D6
genotype, demographic factors, and co-medication use. Eighty-eight women enrolled
in the UCSF TamGen II study and 81 women enrolled in a prospective study at
Dana-Farber Cancer Institute were included in this analysis. All the women had
been on tamoxifen for at least 3 months before blood collection. Demographic
information included the patient's age, race/ethnicity, body mass index (where
available), and self-reported and measured medications and herbals that affect
2D6 activity. DNA was extracted and genotyped for 2D6 (Amplichip, Roche
Diagnostics). An activity score was calculated based on genotypes and adjusted
for use of medications known to inhibit 2D6. Serum was tested for tamoxifen and
metabolite concentrations and for the presence of drugs by liquid
chromatography/mass spectrometry. Univariate and multivariate regression analysis
were computed for age, body mass index, ethnicity, and adjusted activity score to
predict tamoxifen metabolite concentrations in the training data-set of UCSF
patients, and the resulting algorithm was validated in the Dana-Farber patients.
For the training set, the correlation coefficient (r (2)) for log endoxifen and
N-desmethyltamoxifen:endoxifen ratio to activity score, age, and race, were 0.520
and 0.659, respectively; 0.324 and 0.567 for the validation; and 0.396 and 0.615
for both the datasets combined. An algorithm that incorporates genotype and
demographic variables can be used to predict endoxifen concentrations for women
on tamoxifen therapy. If endoxifen levels are confirmed to be predictive of
tamoxifen benefit, then this algorithm may be helpful to determine which women
warrant endoxifen testing.

PMID: 22294487 [PubMed - as supplied by publisher]