Genetic variants associated with toxicity-related discontinuation of adjuvant aromatase inhibitor (AI) therapy.

Abstract

525 Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003. Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in ESR1, which encodes estrogen receptor (ER) alpha, and one in CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity. Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy. [Table: see text]