Comprehensive CYP2D6 genotyping in a multiracial U.S. breast cancer population

Abstract

553 Background: CYP2D6 genotyping has been suggested to avoid suboptimal responses to tamoxifen (T). Most studies to date are in white patients (pts) and focus on a limited number of genetic variants. In this clinical trial, we comprehensively examined CYP2D6 allele frequencies in women of heterogenous ethnicity taking tamoxifen (T). Methods: In LCCC 0801, pts on T ≥ 4 months and not on potent CYP2D6 inhibiting medications were genotyped using the CYP450 AmpliChip for 2D6 alleles: *1-*11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41XN. T dose was increased in pts with any intermediate or poor metabolizing (IM or PM) alleles [but not in pts homozygous for extensive metabolizing (EM) alleles]. Serial T metabolite levels are being assessed. Here we report the allele frequency data from this study compared to previously published cohorts. Results: 108 pts participated in the study: 24 (22%) African-Americans (AA), 76 (70%) non-Hispanic whites, 4 Asians, 3 Hispanics and 1 Spanish European. Genotyping revealed 28 (26%) EM/EM, 1 EM/UM (ultra-rapid), 29 (27%) EM/IM, 22 (20%) EM/PM, 8 (7%) IM/IM, 10 (9%) IM/PM, 9 (8%) PM/PM and 1 unknown. Conclusions: Pts in this trial had a similar frequency of PM alleles to previous reports, however a high proportion of pts have IM alleles. In particular, the majority (79%) of AA pts possess at least one variant allele. Since PM and IM genotypes have been associated with reduced T metabolism, this may have implications for T efficacy and emphasizes the importance of trials examining CYP2D6 genotyping as a determinant of T use. (Supported by Laboratory Corporation of America, Roche Diagnostics, NC UCRF, NCI SPORE.) [Table: see text] [Table: see text]