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

The Pharmacogenomics Journal volume 20, pages 19–26 (2020)Cite this article

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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.

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Availability of data and materials

The dataset generated and analyzed during the current study are not publicly available. At the time of recruitment to the trial, the legal policies on confidentiality and data protection did not specifically include a consent for patient data sharing. Data are however available from the authors upon reasonable request and with the permission from the local ethics committee.

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Acknowledgements

We acknowledge Syneos Health who gave their support for estradiol and estrone measurements at no cost. The authors thank the patients who participated, and Claudia Passoni, research nurse at the European Institute of Oncology.

Funding

Financial support for the study was provided by the Foundation of the European Institute of Oncology (FIEO).

Author contributions

HJ, DS, ADC, and BB contributed to conception and design of the study. AGG gave administrative support of study procedures. DS, ML, and AGG contributed to collection of clinical data. HJ coordinated biobanking and oversaw the laboratory analysis. VA, and DM performed DNA extraction and genotyping analysis. AR and CW were responsible for estradiol/estrogen evaluations. JG and GM performed exemestane measurements. SG performed the statistical HJ, DS, VA, SG, BB, and ADC contributed to analysis and interpretation of data and drafted the manuscript. All authors participated in writing and revising the manuscript, and approved the final version.

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Author notes

  1. These authors contributed equally: Dr Andrea DeCensi, Dr Bernardo Bonanni

Authors and Affiliations

  1. Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Harriet Johansson, Valentina Aristarco, Debora Macis, Aliana Guerrieri-Gonzaga, Davide Serrano, Matteo Lazzeroni & Bernardo Bonanni

  2. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy

    Sara Gandini

  3. Department of Clinical Science, University of Bergen, Bergen, Norway

    Jennifer Gjerde & Gunnar Mellgren

  4. Hormone Laboratory, Haukeland University Hospital, Bergen, Norway

    Jennifer Gjerde & Gunnar Mellgren

  5. Syneos Health, Princeton, NJ, 08540, USA

    Agnita Rajasekaran & Clark V Williard

  6. Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy

    Andrea DeCensi

  7. Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK

    Andrea DeCensi

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  1. Harriet Johansson
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Correspondence to Harriet Johansson.

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The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study was conducted at the IEO, European Institute of Oncology IRCCS, Milan, Italy and approved by the Institutional Review Board. Written informed consent was obtained for all patients enrolled in the trial. Consent to use collected blood samples was obtained prior to sample collection.

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Johansson, H., Aristarco, V., Gandini, S. et al. Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer. Pharmacogenomics J 20, 19–26 (2020). https://doi.org/10.1038/s41397-019-0087-z

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