title: ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer.
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.
authors.affiliation: Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA. bleylandj@aol.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.affiliation: 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.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.affiliation: VM Institute of Research, 6100 Av Royalmount, Montréal, QC, H4P 2R2, Canada. mark.abramovitz@gmail.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Abramovitz
authors.affiliation: AKESOgen, Inc., 3155 Northwoods Pl NW, Norcross, GA, 30071, USA. mbouzyk@akesogen.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Bouzyk
authors.affiliation: Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA. brandon.young@avera.org.
authors.forename: Brandon
authors.initials: B
authors.lastname: Young
authors.affiliation: Genomic and Molecular Pathology, University of Chicago, 900 E 57th St. Room 1260D, Chicago, IL, 60637, USA. bradley.long@uchospitals.edu.
authors.forename: Bradley
authors.initials: B
authors.lastname: Long
authors.affiliation: International Breast Cancer Study Group Coordinating Center and Central Pathology Office, Effingerstrasse 40, 3008, Bern, Switzerland. rosita.kammler@ibcsg.org.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Kammler
authors.affiliation: 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.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dell'Orto
authors.affiliation: Division of Pathology and Laboratory Medicine, European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy. olivia.biasi@ieo.it.
authors.forename: Maria Olivia
authors.initials: MO
authors.lastname: Biasi
authors.affiliation: Breast Center, Kantonsspital St. Gallen, Rorschacher Strasse 95, 9007, St. Gallen, Switzerland.|Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.|International Breast Cancer Study Group, Bern, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Thürlimann
authors.affiliation: International Breast Cancer Study Group, Bern, Switzerland. vernonh@adhb.govt.nz.|Auckland City Hospital, PO Box 26498, Epsom, Auckland, 1344, New Zealand. vernonh@adhb.govt.nz.|Australia and New Zealand Breast Cancer Trials Group, Newcastle, Australia. vernonh@adhb.govt.nz.
authors.forename: Vernon
authors.initials: V
authors.lastname: Harvey
authors.affiliation: Department of Oncology, Multidisciplinary Breast Center, KULeuven (University of Leuven), University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. patrick.neven@uzleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Institute Georges François Leclerc, 1 Rue Professeur Marion, BP 77 980, 21079, Dijon Cedex, France. larnould@dijon.fnclcc.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: International Breast Cancer Study Group Coordinating Center, Effingerstrasse 40, 3008, Bern, Switzerland. rudolf.maibach@ibcsg.org.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Maibach
authors.affiliation: International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, 450 Brookline Ave, Boston, MA, 02215, USA. price@jimmy.harvard.edu.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.affiliation: International Breast Cancer Study Group, Bern, Switzerland. alan.coates@ibcsg.org.|University of Sydney, Sydney, Australia. alan.coates@ibcsg.org.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.affiliation: International Breast Cancer Study Group, Bern, Switzerland. aron.goldhirsch@ibcsg.org.|Program for Breast Health (Senology), European Institute of Oncology, Via Ripamonti 435, 20146, Milan, Italy. aron.goldhirsch@ibcsg.org.
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.affiliation: 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.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.affiliation: International Breast Cancer Study Group, Bern, Switzerland. olivia.pagani@ibcsg.org.|Institute of Oncology of Southern Switzerland (IOSI), Ospedale Italiano, Via Capelli, 6962, Viganello, Switzerland. olivia.pagani@ibcsg.org.
authors.forename: Olivia
authors.initials: O
authors.lastname: Pagani
authors.affiliation: 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.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: 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.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.affiliation: 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.
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D055088:Early Detection of Cancer; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005260:Female; D019584:Hot Flashes / Q000139:chemically induced / Q000235:genetics; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D013629:Tamoxifen / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; C000600034:ESR2 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole
keywords: ESR1; ESR2; Letrozole; Polymorphism; Tamoxifen