CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial

Abstract

To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.

Trial registration: ClinicalTrials.gov NCT00004205.

Conflict of interest statement

Conflict of interest: The remaining authors have no conflicts to declare.

Figures

Fig. 1

Flow diagram of the Breast International Group (BIG) 1–98 trial DNA samples included in the study. Collection of tumor tissue blocks, DNA extraction, CYP19A1 genotyping, and patient cohorts for analysis are shown. FFPE formalin-fixed paraffin-embedded

Fig. 2

Kaplan–Meier estimates of breast cancer-free interval (BCFI) according to CYP19A1 SNP rs700518(T>C) variants for patients in the Breast International Group (BIG) 1–98 trial assigned to: a 5-year letrozole; b 5-year tamoxifen. Hazard ratios (HR) and confidence intervals (CI) estimated using adjusted Cox proportional hazards model in which treatment-by-genotype interaction P = 0.08

Fig. 3

Kaplan–Meier estimate of musculoskeletal adverse event-free interval according to CYP19A1 SNP rs700518(T>C) variants for patients in the Breast International Group (BIG) 1–98 trial assigned to 5-year letrozole or tamoxifen. Hazard ratios (HR) and confidence intervals (CI) estimated using adjusted Cox proportional hazards model

Fig. 4

Kaplan–Meier estimates of bone adverse event-free interval according to CYP19A1 SNP genotypes for patients in the Breast International Group (BIG) 1–98 trial assigned to 5-year letrozole or tamoxifen. Hazard ratios (HR) and confidence intervals (CI) estimated using adjusted Cox proportional hazards models. a SNP rs4646(C>A) letrozole; b SNP rs4646(C>A) tamoxifen; c SNP rs10046(C>A) letrozole; d SNP rs10046(C>A) tamoxifen; e SNP rs936308(C>G) letrozole; f SNP rs936308(C>G) tamoxifen