Abstract P4-08-05: Impact of common polymorphisms of CYP19A1 and UGT2B17 gene deletion on early endocrine-responsive postmenopausal breast cancer
Authors: Johansson H , Gandini S , Aristarco V , Macis D , Guerrieri-Gonzaga A , Serrano D , Pruneri G , Lazzeroni M , Viale G , Toesca A , Rajasekaran A , Bonanni B , DeCensi A 
Published: February 2018

Abstract
Background Polymorphisms of genes involved in estrogen production have been linked to breast cancer risk, prognosis and treatment response. Polymorphisms of the aromatase gene CYP19A1 influence its activity. The UGT2B17 catalyzes glucuronic acid transfer to a variety of substrates, including steroids and drugs like the aromatase inhibitor exemestane. We investigated the impact of two variants of CYP19A1 (rs10046, rs4646) and the UGT2B17 gene deletion on disease outcome in 125 postmenopausal women operated for ER-positive primary breast cancer enrolled in a randomized pre-surgical trial.
Patients Briefly, upon informed consent, postmenopausal patients with ER-positive breast cancer (stage T1–2, N0–1, M0) eligible for surgery were randomized to receive either exemestane (25 mg/day), or celecoxib (800 mg/day), or placebo for 6 weeks prior to surgery at the European Institute of Oncology (2004-2008). Exemestane showed a significant 10% absolute reduction in Ki67 labeling index compared to the other two arms. Serum and whole blood was taken at baseline and the day before surgery and stored at -80°C until assayed.
Methods DNA was extracted from blood by QIAamp DNA Blood Kits. The CYP19A1 rs1004/rs46466 were analyzed by Taqman genotyping assays in real-time PCR. The UGT2B17 deletion was estimated by copy number assay (Lifetechnologies). Serum estradiol (E2) and estrone (E1) levels were measured by gas chromatography tandem mass spectrometry detection (GS-MS/MS) after liquid-liquid extraction. The lower limit of quantitation were 0.625 pg/mL for estradiol and 1.56 pg/mL for estrone. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders.
Results The genetic polymorphisms did not deviate from Hardy-Weinberg equilibrium (P-value &gt;0.41) and minor allele frequency of rs10046 (A/G), rs4646 (C/A), and UGT2B17Del were 0.45, 0.22, and 0.31, respectively. The rs10046 A and rs4646 C alleles were associated with higher estrogen levels. Carriers of rs10046 AA had median levels of 7.57 pg/ml E2 and 35.9 pg/mL E1 versus 3,9 pg/mL E2 and 27.4 E1 pg/mL in CA/AA genotypes (P&lt;0.003). Carriers of rs4646 CC had 5.6 pg/ml E2 and 30.45 pg/mL E1 versus 3,95 pg/mL E2 and 27.4 E1 pg/mL in CA/AA genotypes (P=0.05 only for E1). After 6 weeks treatment with exemestane, we observed steeper decreases in estrogen levels in the rs10046 AA/rs4646 CC carriers (P=0.02 for E2). After a median follow-up of 7 years we found that women carrying at least one SNP of rs10046 and one SNP of rs4646 had a better prognosis compared with women carrying homozygote wt SNPs (HR=0.44; 95% CI: 0.2-0.99 P=0.049). Similarly, the UGT2B17 deletion was associated with a better prognosis (HR= 0.43; 95% CI: 0.19-0.97; P=0.0439). There was no interaction with pre-surgical or adjuvant treatment.
Conclusions Our analysis confirms previous findings of an association of CYP19A1 rs10046/rs4646 with estrogen levels in postmenopausal women. Interestingly, the carriers of the variants associated with lower estrogen levels at diagnosis had better prognosis. Further genomic profiling in larger trials aimed to enhance tailored treatment efficacy in endocrine-responsive postmenopausal breast cancer are warranted.
Citation Format: Johansson H, Gandini S, Aristarco V, Macis D, Guerrieri-Gonzaga A, Serrano D, Pruneri G, Lazzeroni M, Viale G, Toesca A, Rajasekaran A, Bonanni B, DeCensi A. Impact of common polymorphisms of CYP19A1 and UGT2B17 gene deletion on early endocrine-responsive postmenopausal breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-05.