Plasma levels of estrone sulfate (ES) in postmenopausal women with breast cancer (BC) during letrozole (L) treatment: Association with single nucleotide polymorphisms (SNPs) of CYP19A1

Abstract

555 Background: The CYP19A1 gene encodes aromatase, a key enzyme for estrogen biosynthesis. We investigated the association between four CYP19A1 SNPs, affecting different circulating estrogen levels (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G), and suppression of plasma ES levels induced by 6 weeks (time needed to reach L steady-state concentrations) of L (25 mg/d). Methods: Patients were enrolled into a prospective, italian multi-centre trial (GIM5) testing the correlation of CYP19A1 SNPs with the efficacy of L adjuvant therapy, after 5 years of tamoxifen, in postmenopausal early BC patients. Blood samples for hormone measurements were obtained immediately before starting L (baseline) and following 6 wks of treatment. SNPs were identified from DNA obtained from peripheral blood cells by Hexaprimer Amplification Refractory Mutation System PCR (H-ARMS-PCR). Plasma ES levels were evaluated by Radio Immuno Assay (RIA). Results: SNPs and hormone levels were evaluated in at least 129 patients. SNPs of CYP19A1 were associated with different baseline plasma ES levels. Mean inhibition of aromatase activity induced by L ranges from 71% to 79%, as a function of the SNPs. After 6 weeks of L no difference in ES levels was observed between patients with different SNPs (Table). Conclusions: L therapy induces a higher aromatase suppression in patients with SNPs associated with higher baseline plasma ES levels. The difference in ES levels associated with genetic variation at the CYP19A1 locus disappeared after L therapy. [Table: see text] [Table: see text]