Black, John L.

Abstract Abstract #6037 Background: Tamoxifen (Tam) is biotransformed to the potent antiestrogen, endoxifen, by the CYP2D6 enzyme. We previously demonstrated that patients (pts) receiving adjuvant TAM with impaired CYP2D6 metabolism due to CYP2D6 (*4) and/or concurrent administration of a CYP2D6 inhibitor had a higher risk of recurrence. Other studies suggest CYP2C19*17 (Schroth JCO 2007) and SULT1A1*2 (Nowell JNCI 2002) may be associated with treatment outcome. With extended follow-up, we sought to evaluate the importance of comprehensive CYP2D6 genotyping as well as the potential association between CYP2C19*17 and SULT1A1 copy number with clinical outcome in pts randomized to TAM in NCCTG 89-30-52.
 Methods: Using DNA derived from paraffin embedded sections, CYP2D6 and SULT1A1 genotype were determined using quantitative multiplex PCR and CYP2C19 by sequencing. Pts administered the following CYP2D6 inhibitors (fluoxetine, paroxetine, sertraline, cimetidine, amiodarone, doxepin, ticlopidine and haloperidol) were considered as intermediate (IM) or poor metabolizers (PM) based on the potency of CYP2D6 inhibition. CYP2D6 phenotype was defined as follows: extensive metabolizers (EM) were pts not administered an inhibitor who did not carry a null allele (*3, *4, *6) and who were not homozygous for an IM allele (*10, *17, *41). CYP2D6 IM were either heterozygous for a null allele or homozygous for an IM allele but not administered an inhibitor or CYP2D6 EM administered a weak inhibitor. PM were pts homozygous for a null allele, or any patient administered a potent inhibitor. The association between genotype or CYP2D6 phenotype and clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors.
 Results: The median follow-up of living pts is now 14.5 years. Of 256 pts. randomized to TAM, genotype was determined for CYP2D6 (n=210), CYP2C19*17 (n=170), and SULT1A1 (n=169) with the following allele frequencies: CYP2D6 *3 (.02), *4(.20), *6 (.01), *10 (.03), *17 (.00), *41(.08), and CYP2C19*17 (.22). The frequency of SULT1A1 copy number alleles (CNA) was 1 (4%), 2 (67%), 3 (20%), and 4+ (9%). 14/227 patients (6%) were administered an inhibitor. A multivariate analysis accounting for nodal status and tumor size demonstrated that compared to CYP2D6 EM, CYP2D6 PM had significantly shorter time to recurrence (TTR) (HR 4.0, p=0.001) and DFS (HR 2.0, p=0.02) and CYP2D6 IM tended to have shorter TTR (HR 1.8, p=0.08) and DFS (HR 1.4, p=0.10). DFS did not differ by SULT1A1 copy number (p=0.62) or CYP2C19 *17 (p=0.47)
 Conclusion: Long term follow-up of pts in NCCTG 89-30-52 confirms the importance of CYP2D6 metabolism and further demonstrates the importance of comprehensive genotyping and phenotyping with CYP2D6 inhibitors. We could not identify an association between CYP2C19*17 or SULT1A1 copy number with recurrence but further evaluation is needed in larger cohorts. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6037.

Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen.