Tamoxifen pharmacogenetics of CYP2D6, CYP2C19, and SULT1A1: long term follow-up of the North Central Cancer Treatment Group 89-30-52 adjuvant trial.

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.

The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review.

“…All three cohorts 83,91,108 that measured TTR also reported significant differences between PMs and EMs, although this applied only when patients whose phenotype was modified to PM were included in the group of PMs in one cohort. 91 Intermediate metaboliser versus extensive metaboliser Two studies 83,110 from one cohort 83 genotyped for *4 only when IMs were considered to be wt/*4. This cohort also accounted for CYP2D6 inhibitors by classifying patients who were wt/wt (but taking a moderate CYP2D6 inhibitor) to be IMs.…”

Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort

“…[2] Most but not all studies reported to date suggested that subjects with reduced or absent CYP2D6 activity have reduced serum concentrations of endoxifen, and may have worse long term tamoxifen-associated benefits than those with normal enzyme activity. [2-10]…”

CYP2D6 Genotyping and Tamoxifen: An Unfinished Story in the Quest for Personalized Medicine

“…In multivariate analysis, women who were homozygous for this nonfunctional allele (*4/*4) tended to have shorter relapse-free times (hazard ratio [HR] 1.85, P = .176) and worse relapse-free survival (HR 1.86, P = .089) than heterozygous women (*4/wt) or women without this allele (wt/wt). These findings were confirmed in a further study with the same group of patients, where the concomitant prescription of CYP2D6 inhibitors was an independent predictor of worse outcome 18,19…”