P4-01-04: Effects of CYP2D6 Phenotype and Drug Adherence on Tamoxifen Metabolite Levels.

Abstract

Abstract Background Although the activity of cytochrome P450 2D6 (CYP2D6), the enzyme responsible for conversion of tamoxifen (TAM) to its most important active metabolite endoxifen, varies significantly with genotype. Routine genotype testing in patients on TAM has recently been discouraged. Conflicting results in publications regarding the prognostic utility of this test remain unexplained. Confounding factors could be lack of predicted correlation between CYP2D6 genotype and TAM active metabolites, or variability of patient compliance Methods: Consecutive breast cancer patients on TAM were asked to enroll in a study to examine the relationship between CYP 2D6 phenotype, patient-reported treatment adherence, and TAM metabolites levels. Patients were genotyped for CYP2D6 polymorphisms using long-range PCR allele-specific amplification and single-nucleotide primer extension assay. From the genotypes, four phenotype groups were defined: Ultra rapid Metabolizer (UM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM) and Poor Metabolizer (PM). Plasma was collected after at least 6 weeks of TAM (20 mg daily). The parent drug TAM, as well as 4-hydroxy N-desmethyl tamoxifen (endoxifen), 4 hydroxy tamoxifen (4OHtam) and N-desmethyl-tamoxifen (NDtam), were determined by Liquid Chromatography tandem mass-spectrometry (LC-MS/MS). Patients also completed a questionnaire about ethinicity, side effects, concurrent medications and tamoxifen adherence. Correlation between metabolite/TAM ratio and phenotype was tested by Spearman correlation test. Relationship between metabolite levels and adherence was tested by Wilcoxon rank sum test. Chi square test was used to compare proportions. Results: Of the 100 patients enrolled there were 62 Caucasians, 25 Asians, 4 Africans and 6 Unknown. We found a strong correlation between ratio of endoxifen/TAM and phenotype (p <.0001) (Table 1) Over a 2 week period 68 never missed a TAM dose, 25 missed 1–2 times, 2 missed 3–5 times and 2 > 5times (2 missing data). In EM group we found significantly lower levels of TAM (p <.0001), NDtam (p=.008), 4OHtam (p=.003) in less adherent patients. A trend to decreased levels was also shown for endoxifen (p=.081). No associations were found between adherence or phenotype activity and side effects. Conclusions: Our data suggests the predicted association between endoxifen levels and genotype. However, non-adherence may have a significant confounding effect. Prospective studies to evaluate the prognostic impact of CYP2D6 variants for patients on adjuvant tamoxifen should be done but results could be confounded by variable drug adherence if this is not measured concurrently. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-04.