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.

Trial registration: ClinicalTrials.gov NCT00004205.

Keywords: ESR1; ESR2; Letrozole; Polymorphism; Tamoxifen.

Conflict of interest statement

Conflicts of Interest

None of the authors have a conflict of interest.

Figures

Figure 1

Flow diagram showing the derivation of the analytic cohort of 3401 patients.

Figure 2(A, B, C)

Kaplan-Meier estimates of breast cancer-free interval (BCFI) (A) and distant recurrence-free interval (DRFI) according to ESR1 SNP rs9340799(XbaI)(T>C) variants (B) and DRFI according to ESR1 SNP rs2077647(T>C) variants (C) for patients in the BIG 1-98 trial. Hazard ratios (HR) and confidence intervals (CI) were estimated using the adjusted Cox proportional hazards model.

Figure 3 (A, B, C, D)

Kaplan-Meier estimates of freedom from adverse bone events according to ESR1 SNP rs2077647(T>C) variants (A and B); and according to ESR2 SNP rs4986938(G>A) variants (C and D) for patients in the BIG 1-98 trial assigned to treatment 5-years letrozole (A and C) or 5-years tamoxifen (B and D). Hazard ratios (HR) and confidence intervals (CI) were estimated using the adjusted Cox proportional hazards model in which treatment-by-genotype interaction for rs2077647 was P=0.08 and for rs4986938 was P=0.07.

Figure 4

Kaplan-Meier estimates of hot flushes or night sweats according to ESR2 SNP rs4986938(G>A) variants for patients in the BIG 1-98 trial. Hazard ratios (HR) and confidence intervals (CI) were estimated using the adjusted Cox proportional hazards model.