Role of SULT1A1 copy number in tamoxifen treated breast cancer: Findings from the North Central Cancer Treatment Group (NCCTG) adjuvant trial 89–30–52

Abstract

22041 Background: Tamoxifen is biotransformed to the potent antiestrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme, followed by conjugation by SULT1A1. While we (Goetz JCO 2005) and others (Schroth JCO 2007) have published that patients (pts) with impaired CYP2D6 metabolism have significantly shorter disease-free survival (DFS), the role of SULT1A1 genetic variation on treatment outcome is unclear (Nowell JNCI 2002). We previously discovered that SULT1A1 liver and enzyme activity was highly correlated with SULT1A1 copy number (p<0.0001), which explained the majority of the variation in SULT1A1 in vitro activity after considering all known sources of SULT1A1 genetic variability (Hebbring Hum Mol Genet 2007). Therefore, we examined whether SULT1A1 copy number differences influenced DFS in pts receiving tamoxifen as adjuvant therapy for breast cancer. Methods: We determined SULT1A1 copy number from paraffin-embedded tissues using a quantitative multiplex PCR assay in pts randomized to tamoxifen alone for 5 years in NCCTG 89–30–52. Additionally, we evaluated the effect of SULT1A1 copy number in the subset of patients in which CYP2D6 genotype (*4) and drug history were known. The relationship between genotype and disease outcome was determined using the log-rank test. Results: SULT1A1 copy number genotype was obtained in 170/223 pts with available tissue. The frequency of SULT1A1 copy number alleles was similar to those for Caucasian-Americans in our original report and was as follows: 1 (5%), 2 (67%), 3 (19%), and 4 or more alleles (9%). We observed no difference in DFS among pts stratified by SULT1A1 copy number alleles (log rank p=0.74). In the subset of pts classified as intermediate or extensive CYP2D6 metabolizers (defined as pts with 1 or no CYP2D6 *4 alleles who were not co-administered a potent CYP2D6 inhibitor) (n=158), we observed a non-significant trend towards improved DFS in women with 1 SULT1A1 allele (SULT1A1 gene deletion) compared to patients with ≥ 2 alleles (HR 0.76; p=0.22). Conclusion: SULT1A1 copy number did not influence DFS in this tamoxifen-treated cohort. Further study in larger cohorts is needed to determine if SULT1A1 gene deletion is a predictor of tamoxifen benefit. No significant financial relationships to disclose.