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ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer

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Abstract

Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95 % CI = 0.67–1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95 % CI = 0.53–0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95 % CI = 0.58–0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95 % CI = 1.01–1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.

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Acknowledgments

We are indebted to the women, physicians, nurses, and data managers who participated in this clinical trial; to the many pathologists who submitted tumor blocks; to the BIG 1-98 Steering Committee; to Novartis for funding of the clinical trial and of the collection of tumor blocks; to the IBCSG for the design of the trial, coordination, data management, medical review, and statistical support; to the IBCSG Central Pathology Office for collection and processing of tumor blocks; to the BIG-198 Collaborative Group (members who submitted tumor blocks are listed in Supplementary Appendix, available online); and to Susan G. Komen for the Cure Promise Grant.

Funding

The BIG 1-98 trial sponsor, Novartis, contracted with the IBCSG to design the BIG 1-98 trial; collect, analyze, and interpret the data; and report the results. This report presents a study based on collected tumor material (collection partially funded by Novartis) and genotyping (funded by a Promise Grant from the Susan G. Komen for the Cure). The translational research, including DNA extraction and genotyping, was funded by Susan G. Komen for the Cure Promise Grant (KG080081 to GV, OP, MMR), the Breast Cancer Research Foundation (BCRF) (N003173 to JMR), and the National Institutes of Health (1RO1GM099143 to JMR). The Breast International Group (BIG) 1-98 trial was funded by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Other support for the IBCSG: United States National Cancer Institute (CA75362 to MMR). The writing of this manuscript did not include representatives from Novartis or Susan G. Komen for the Cure. The BIG 1-98 Steering Committee reviewed the article, suggested changes, and is responsible for the decision to publish.

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Authors and Affiliations

  1. Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA

    Brian Leyland-Jones & Brandon Young

  2. Department of Biostatistics and Computational Biology, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard T. H. Chan School of Public Health, 450 Brookline Ave, Boston, MA, 02215, USA

    Kathryn P. Gray

  3. VM Institute of Research, 6100 Av Royalmount, Montréal, QC, H4P 2R2, Canada

    Mark Abramovitz

  4. AKESOgen, Inc., 3155 Northwoods Pl NW, Norcross, GA, 30071, USA

    Mark Bouzyk

  5. Genomic and Molecular Pathology, University of Chicago, 900 E 57th St. Room 1260D, Chicago, IL, 60637, USA

    Bradley Long

  6. International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Effingerstrasse 40, 3008, Bern, Switzerland

    Roswitha Kammler

  7. Division of Pathology and Laboratory Medicine, International Breast Cancer Study Group Central Pathology Office, European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy

    Patrizia Dell’Orto

  8. Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy

    Maria Olivia Biasi

  9. Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland

    Beat Thürlimann

  10. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland

    Beat Thürlimann

  11. International Breast Cancer Study Group, Bern, Switzerland

    Beat Thürlimann, Vernon Harvey, Alan S. Coates, Aron Goldhirsch & Olivia Pagani

  12. Auckland City Hospital, PO Box 26498, Epsom, Auckland, 1344, New Zealand

    Vernon Harvey

  13. Australia and New Zealand Breast Cancer Trials Group, Newcastle, Australia

    Vernon Harvey

  14. Department of Oncology, Multidisciplinary Breast Center, KULeuven (University of Leuven), University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Patrick Neven

  15. Institute Georges François Leclerc, 1 Rue Professeur Marion, BP 77 980, 21079, Dijon Cedex, France

    Laurent Arnould

  16. International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland

    Rudolf Maibach

  17. International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA, 02215, USA

    Karen N. Price

  18. University of Sydney, Sydney, Australia

    Alan S. Coates

  19. Program for Breast Health (Senology), European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy

    Aron Goldhirsch

  20. International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA, 02215, USA

    Richard D. Gelber

  21. Institute of Oncology of Southern Switzerland (IOSI), Ospedale Italiano, Via Capelli, 6962, Viganello, Switzerland

    Olivia Pagani

  22. International Breast Cancer Study Group Central Pathology Office, Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Via Ripamonti 435, 20146, Milan, Italy

    Giuseppe Viale

  23. Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E Medical Cntr Drive/SPC 5946, Ann Arbor, MI, 48109, USA

    James M. Rae

  24. Department of Biostatistics and Computational Biology, International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA

    Meredith M. Regan

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  1. Brian Leyland-Jones
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  2. Kathryn P. Gray
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  4. Mark Bouzyk
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  5. Brandon Young
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  6. Bradley Long
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  8. Patrizia Dell’Orto
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  9. Maria Olivia Biasi
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  10. Beat Thürlimann
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  11. Vernon Harvey
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  13. Laurent Arnould
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  15. Karen N. Price
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  18. Richard D. Gelber
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  19. Olivia Pagani
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  20. Giuseppe Viale
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BIG 1-98 Collaborative Group

Corresponding author

Correspondence to Brian Leyland-Jones.

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None of the authors have any conflict of interest.

Additional information

On behalf of the BIG 1-98 Collaborative Group. Members of the BIG 1-98 Collaborative Group who submitted tumor blocks are listed in Supplementary Appendix, available with the full text of this article at (journal website).

The BIG 1-98 trial registration ID: NCT00004205.

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Leyland-Jones, B., Gray, K.P., Abramovitz, M. et al. ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer. Breast Cancer Res Treat 154, 543–555 (2015). https://doi.org/10.1007/s10549-015-3634-6

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