Prognostic impact of genetic variants of CYP19A1and UGT2B17in a randomized trial for endocrine-responsive postmenopausal breast cancer

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1and estrogen receptor α (ESR1)in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2was estimated by copy number variation assays and the CYP19A1rs10046/rs4646 and ESR1rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2was associated with higher levels of 17-hydroxy exemestane (P= 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20–1.01; P= 0.05) compared with homozygote UGT2B17wt. The CYP19A1rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P= 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P< 0.004). After a median follow-up of 7 years, women carrying the “low estrogen” alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17–0.93; P= 0.03). Our analysis points to an impact of UGT2B17and CYP19A1in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2and CYP19A1low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.