PMID- 26590813 OWN - NLM STAT- MEDLINE DCOM- 20160906 LR - 20210816 IS - 1573-7217 (Electronic) IS - 0167-6806 (Print) IS - 0167-6806 (Linking) VI - 154 IP - 3 DP - 2015 Dec TI - ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer. PG - 543-55 LID - 10.1007/s10549-015-3634-6 [doi] AB - 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. FAU - Leyland-Jones, Brian AU - Leyland-Jones B AD - Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA. bleylandj@aol.com. FAU - Gray, Kathryn P AU - Gray KP AD - 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. pkruan@jimmy.harvard.edu. FAU - Abramovitz, Mark AU - Abramovitz M AD - VM Institute of Research, 6100 Av Royalmount, Montreal, QC, H4P 2R2, Canada. mark.abramovitz@gmail.com. FAU - Bouzyk, Mark AU - Bouzyk M AD - AKESOgen, Inc., 3155 Northwoods Pl NW, Norcross, GA, 30071, USA. mbouzyk@akesogen.com. FAU - Young, Brandon AU - Young B AD - Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA. brandon.young@avera.org. FAU - Long, Bradley AU - Long B AD - Genomic and Molecular Pathology, University of Chicago, 900 E 57th St. Room 1260D, Chicago, IL, 60637, USA. bradley.long@uchospitals.edu. FAU - Kammler, Roswitha AU - Kammler R AD - International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Effingerstrasse 40, 3008, Bern, Switzerland. rosita.kammler@ibcsg.org. FAU - Dell'Orto, Patrizia AU - Dell'Orto P AD - 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.dellorto@ieo.it. FAU - Biasi, Maria Olivia AU - Biasi MO AD - Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy. olivia.biasi@ieo.it. FAU - Thurlimann, Beat AU - Thurlimann B AD - Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland. AD - Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. AD - International Breast Cancer Study Group, Bern, Switzerland. FAU - Harvey, Vernon AU - Harvey V AD - International Breast Cancer Study Group, Bern, Switzerland. vernonh@adhb.govt.nz. AD - Auckland City Hospital, PO Box 26498, Epsom, Auckland, 1344, New Zealand. vernonh@adhb.govt.nz. AD - Australia and New Zealand Breast Cancer Trials Group, Newcastle, Australia. vernonh@adhb.govt.nz. FAU - Neven, Patrick AU - Neven P AD - Department of Oncology, Multidisciplinary Breast Center, KULeuven (University of Leuven), University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.neven@uzleuven.be. FAU - Arnould, Laurent AU - Arnould L AD - Institute Georges Francois Leclerc, 1 Rue Professeur Marion, BP 77 980, 21079, Dijon Cedex, France. larnould@dijon.fnclcc.fr. FAU - Maibach, Rudolf AU - Maibach R AD - International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland. rudolf.maibach@ibcsg.org. FAU - Price, Karen N AU - Price KN AD - International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA, 02215, USA. price@jimmy.harvard.edu. FAU - Coates, Alan S AU - Coates AS AD - International Breast Cancer Study Group, Bern, Switzerland. alan.coates@ibcsg.org. AD - University of Sydney, Sydney, Australia. alan.coates@ibcsg.org. FAU - Goldhirsch, Aron AU - Goldhirsch A AD - International Breast Cancer Study Group, Bern, Switzerland. aron.goldhirsch@ibcsg.org. AD - Program for Breast Health (Senology), European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy. aron.goldhirsch@ibcsg.org. FAU - Gelber, Richard D AU - Gelber RD AD - 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. gelber@jimmy.harvard.edu. FAU - Pagani, Olivia AU - Pagani O AD - International Breast Cancer Study Group, Bern, Switzerland. olivia.pagani@ibcsg.org. AD - Institute of Oncology of Southern Switzerland (IOSI), Ospedale Italiano, Via Capelli, 6962, Viganello, Switzerland. olivia.pagani@ibcsg.org. FAU - Viale, Giuseppe AU - Viale G AD - 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@ieo.it. FAU - Rae, James M AU - Rae JM AD - Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, 1500 E Medical Cntr Drive/SPC 5946, Ann Arbor, MI, 48109, USA. jimmyrae@med.umich.edu. FAU - Regan, Meredith M AU - Regan MM AD - 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. mregan@jimmy.harvard.edu. CN - BIG 1-98 Collaborative Group LA - eng SI - ClinicalTrials.gov/NCT00004205 GR - R01 GM099143/GM/NIGMS NIH HHS/United States GR - U24 CA075362/CA/NCI NIH HHS/United States GR - 1R01GM099143/GM/NIGMS NIH HHS/United States GR - CA75362/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151121 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (Antineoplastic Agents) RN - 0 (ESR1 protein, human) RN - 0 (ESR2 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (Nitriles) RN - 0 (Triazoles) RN - 094ZI81Y45 (Tamoxifen) RN - 7LKK855W8I (Letrozole) SB - IM MH - Antineoplastic Agents/adverse effects/*therapeutic use MH - Breast Neoplasms/*drug therapy/*genetics MH - Chemotherapy, Adjuvant MH - Double-Blind Method MH - Early Detection of Cancer MH - Estrogen Receptor alpha/*genetics MH - Estrogen Receptor beta/*genetics MH - Female MH - Hot Flashes/chemically induced/genetics MH - Humans MH - Letrozole MH - Middle Aged MH - Nitriles/adverse effects/*therapeutic use MH - Polymorphism, Single Nucleotide MH - Postmenopause MH - Tamoxifen/adverse effects/*therapeutic use MH - Treatment Outcome MH - Triazoles/adverse effects/*therapeutic use PMC - PMC4730949 MID - NIHMS740336 OTO - NOTNLM OT - ESR1 OT - ESR2 OT - Letrozole OT - Polymorphism OT - Tamoxifen COIS- Conflicts of Interest None of the authors have a conflict of interest. EDAT- 2015/11/23 06:00 MHDA- 2016/09/07 06:00 PMCR- 2016/12/01 CRDT- 2015/11/23 06:00 PHST- 2015/11/04 00:00 [received] PHST- 2015/11/05 00:00 [accepted] PHST- 2015/11/23 06:00 [entrez] PHST- 2015/11/23 06:00 [pubmed] PHST- 2016/09/07 06:00 [medline] PHST- 2016/12/01 00:00 [pmc-release] AID - 10.1007/s10549-015-3634-6 [pii] AID - 10.1007/s10549-015-3634-6 [doi] PST - ppublish SO - Breast Cancer Res Treat. 2015 Dec;154(3):543-55. doi: 10.1007/s10549-015-3634-6. Epub 2015 Nov 21.