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: Brian Leyland-Jones, Kathryn P Gray, Mark Abramovitz, Mark Bouzyk, Brandon Young, Bradley Long, Roswitha Kammler, Patrizia Dell'Orto, Maria Olivia Biasi, Beat Thürlimann, Vernon Harvey, Patrick Neven, Laurent Arnould, Rudolf Maibach, Karen N Price, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Olivia Pagani, Giuseppe Viale, James M Rae, Meredith M Regan, BIG 1-98 Collaborative Group
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 154 Issue 3 Pg. 543-55 (Dec 2015) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 26590813 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• ESR1 protein, human
• ESR2 protein, human
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Nitriles
• Triazoles
• Tamoxifen
• Letrozole

Topics

• Antineoplastic Agents (adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy, genetics)
• Chemotherapy, Adjuvant
• Double-Blind Method
• Early Detection of Cancer
• Estrogen Receptor alpha (genetics)
• Estrogen Receptor beta (genetics)
• Female
• Hot Flashes (chemically induced, genetics)
• Humans
• Letrozole
• Middle Aged
• Nitriles (adverse effects, therapeutic use)
• Polymorphism, Single Nucleotide
• Postmenopause
• Tamoxifen (adverse effects, therapeutic use)
• Treatment Outcome
• Triazoles (adverse effects, therapeutic use)