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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• 作者：Brian Leyland-Jones ; Kathryn P. Gray…
• 关键词：ESR1 ; ESR2 ; Letrozole ; Tamoxifen ; Polymorphism
• 刊名：Breast Cancer Research and Treatment
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：154
• 期：3
• 页码：543-555
• 全文大小：688 KB
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• 作者单位：Brian Leyland-Jones (1)
  Kathryn P. Gray (2)
  Mark Abramovitz (3)
  Mark Bouzyk (4)
  Brandon Young (1)
  Bradley Long (5)
  Roswitha Kammler (6)
  Patrizia Dell’Orto (7)
  Maria Olivia Biasi (8)
  Beat Thürlimann (10) (11) (9)
  Vernon Harvey (11) (12) (13)
  Patrick Neven (14)
  Laurent Arnould (15)
  Rudolf Maibach (16)
  Karen N. Price (17)
  Alan S. Coates (11) (18)
  Aron Goldhirsch (11) (19)
  Richard D. Gelber (20)
  Olivia Pagani (11) (21)
  Giuseppe Viale (22)
  James M. Rae (23)
  Meredith M. Regan (24)
  BIG 1-98 Collaborative Group
  
  1. Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA
  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
  3. VM Institute of Research, 6100 Av Royalmount, Montréal, QC, H4P 2R2, Canada
  4. AKESOgen, Inc., 3155 Northwoods Pl NW, Norcross, GA, 30071, USA
  5. Genomic and Molecular Pathology, University of Chicago, 900 E 57th St. Room 1260D, Chicago, IL, 60637, USA
  6. International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Effingerstrasse 40, 3008, Bern, Switzerland
  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
  8. Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy
  10. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland
  11. International Breast Cancer Study Group, Bern, Switzerland
  9. Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland
  12. Auckland City Hospital, PO Box 26498, Epsom, Auckland, 1344, New Zealand
  13. Australia and New Zealand Breast Cancer Trials Group, Newcastle, Australia
  14. Department of Oncology, Multidisciplinary Breast Center, KULeuven (University of Leuven), University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
  15. Institute Georges Fran?ois Leclerc, 1 Rue Professeur Marion, BP 77 980, 21079, Dijon Cedex, France
  16. International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland
  17. International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA, 02215, USA
  18. University of Sydney, Sydney, Australia
  19. Program for Breast Health (Senology), European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy
  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
  21. Institute of Oncology of Southern Switzerland (IOSI), Ospedale Italiano, Via Capelli, 6962, Viganello, Switzerland
  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
  23. Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E Medical Cntr Drive/SPC 5946, Ann Arbor, MI, 48109, USA
  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
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

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-.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95 % CI = 0.53-.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-.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-.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. Keywords ESR1 ESR2 Letrozole Tamoxifen Polymorphism