35P SNPs of aromatase gene (CYP19A1) and outcomes of patients with estrogen receptor-positive (ER+) early breast cancer (eBC) treated with aromatase inhibitors (AIs): A multicenter, prospective study

In ER+ eBC, extending AIs beyond 5 years reduces late recurrences at the price of increased skeletal events. Germline SNPs CYP19A1 may affect aromatase activity, potentially leading to decreased efficacy and toxicity. We conducted a prospective study assess impact on outcomes 886 postmenopausal patients treated with AIs. The included 2 cohorts who were free relapse 3-6 from diagnosis. Patients GIM5 cohort received letrozole after 4-6 tamoxifen. Those GIM4 randomized 3-2 or 2-3 DNA was genotyped PCR for rs4646, rs10046, rs749292, rs727479. Cumulative incidence metastasis analyzed in competing risk model (CRM) contralateral BC, second malignancy, death without BC as risk. events CRM invasive BC/relapse, Fine-Gray used estimate subdistribution HR (sHR) CRM. Overall survival log-rank Cox model. Homozygosis T allele (T/T) hetero homozygosis rs727479 (T/G + T/T) high-risk genotypes associated worse OS (Table). 3 groups identified based number (0, 1, >1). Genotypes-based 15-year 2.5%, 8.3%, 10.9%, respectively, multivariable Genotype-based negatively (p=0.025); even adjusting age, BMI, smoke (p=0.028). Table: 35PCum. metastasisOverall survivalSNPs CYP19A1subdistribution (sHR, 95% CIs)p value (CIF)*HR (95% (Log-rank)rs10046 (T/T vs C/T C/C)1.57 (0.96-2.57)0.0711.51 (0.97-2.39)0.070rs749292 C/C)1.83 (1.09-3.08)0.0231.64 (1.04-2.67)0.050rs727479 T/G G/G)2.62 (1.17-5.83)0.0602.20 (1.02-4.78)0.040Composite genotypeadjusted sHR CIs)covar: T, N, cohortp (CIF)*adjusted (Log-rank)0 genotype, N=1321 (ref.)0.0351 (ref.)0.0301 N=5242.54 (1.00-6.41)2.30 (0.99-5.36)>1 genotypes, N=2223.45 (1.32-9.04)2.90 (1.19-7.05)*cumulative function Open table new tab *cumulative CYP19 predict receiving AIs, opening opportunity individualize therapy survivors.