Format

Send to

Choose Destination
Pharmacogenomics J. 2019 Apr 10. doi: 10.1038/s41397-019-0087-z. [Epub ahead of print]

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

Author information

1
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy. harriet.johansson@ieo.it.
2
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
3
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.
4
Department of Clinical Science, University of Bergen, Bergen, Norway.
5
Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
6
Syneos Health, Princeton, NJ, 08540, USA.
7
Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy.
8
Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

Abstract

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 UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/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*2 was 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 UGT2B17 wt. The CYP19A1 rs10046 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 UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low 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 .

PMID:
30967597
DOI:
10.1038/s41397-019-0087-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center