Abstract P1-08-02: CYP2D6 gene variants and effectiveness of adjuvant tamoxifen in breast cancer: A population-based case-control study

Abstract

Abstract Tamoxifen, a cornerstone of adjuvant therapy for hormone-receptor-positive breast cancer, is metabolized to the active metabolite endoxifen through enzymatic activity of cytochrome P450 2D6. CYP2D6 has numerous alleles that affect metabolizing phenotype. Among women who take tamoxifen, those homozygous for inactive alleles (poor metabolizers) have lower levels of serum endoxifen than those with two functional alleles (extensive metabolizers). Several studies have reported increased risk of breast cancer recurrence or death in women homozygous for CYP2D6 inactive alleles, but others have found no association between CYP2D6 function and outcome. We explored this question in the large member population of the Kaiser Permanente Northwest (KPNW) integrated health plan. We conducted a population-based case-control study to evaluate the hypothesis that, after adjuvant tamoxifen treatment for breast cancer, women with CYP2D6 genotypes associated with poor metabolism of tamoxifen have an elevated risk of breast cancer recurrence compared to women with CYP2D6 genotypes associated with extensive metabolism of tamoxifen. We further hypothesized that women with CYP2D6 genotypes associated with intermediate metabolism of tamoxifen are at intermediate risk of recurrence. Study subjects were women who were diagnosed from 1980 to 2011 with hormone-receptor positive breast cancer, who received at least 180 days of adjuvant tamoxifen treatment, and for whom stored formalin-fixed paraffin-embedded (FFPE) normal tissue was available for laboratory analysis. Cases (358) were women with breast cancer recurrence recorded in the KPNW Tumor Registry and validated by medical record review. Randomly selected controls (833), without recurrent breast cancer, were matched to cases on tumor stage, diagnosis year, diagnosis age, race/ethnicity, and patterns of health plan membership. We collected data from medical records and from pharmacy, laboratory, tumor registry, and membership health plan databases. The Oregon Health & Science University Molecular Genetics Laboratory extracted genomic DNA from stored FFPE tissue blocks and performed allelic discrimination assays and pyrosequencing to accurately determine CYP2D6 variant status for the alleles, *3, *4, *5, *10, *17, and *41. All assays have been completed and study subjects have been categorized according to CYP2D6 metabolizer phenotype (poor, intermediate, extensive) and activity score (0-2). Based on the ethnicities in our study population, the CYP2D6 allele frequencies are in Hardy-Weinberg equilibrium, and the frequencies of the predicted metabolizer phenotypes also fall within the expected range. Using multivariable logistic regression analysis, we will assess CYP2D6 functional status and activity score in relation to breast cancer recurrence, taking into account factors that may alter the association, including tamoxifen dose and duration of use, as well as concomitant medications that alter the activity of the CYP2D6 enzyme. Results will be available by 12/1/2015. Citation Format: Weinmann S, Richert–Boe K, Goddard K, Chen C, Punj S, Schwarzkopf D, Kalter M, Richards CS. CYP2D6 gene variants and effectiveness of adjuvant tamoxifen in breast cancer: A population-based case-control study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-02.