Aromatase SNPs Predict Survival and aromatase inhibitor Toxicity in Breast Cancer
Background: In estrogen receptor-positive (ER+) breast cancer (BC), single-nucleotide polymorphisms (SNPs) in the aromatase gene might affect aromatase inhibitors (AIs) metabolism and efficacy. Here, we assessed the impact of SNPs on prognosis and toxicity of patients receiving adjuvant letrozole.  Patients and methods: We enrolled 886 postmenopausal patients treated with 2-5 years letrozole after 2-6 years tamoxifen until the completion of 5-10 years of therapy. Germline DNA was genotyped for SNPs rs4646, rs10046, rs749292, rs727479. Log-rank test and Cox model were used for disease-free (DFS) and overall survival (OS). Cumulative incidence (CI) of BC metastasis was assessed through competing risk analysis, with contralateral BC, second malignancies non-BC death as competing events. CIs of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution hazard ratio (sHR) with 95% confidence intervals were calculated through Fine-Gray method. Results: No SNP was associated with DFS. Variants rs10046 (sHR 2.03 [1.04-2.94]), rs749292 (sHR 2.11, [1.12-3.94]), and rs727479 (sHR 2.62, [1.17-5.83]) were associated with BC metastasis. Three groups were identified based on the number of these variants (0, 1, >1). Variant-based groups were associated with BC metastasis (10-year CI 2.5%, 7.6%, 10.7%, p=0.035), and OS (10-year estimates 96.5%, 93.0%, 89.6%, p=0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% versus 10%, p=0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% versus 2.1%, p=0.026).  Conclusions: SNPs of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early BC, opening an opportunity for better treatment individualization.