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.

Statistical model	Gene	SNP	AI	HR (95% CI)	p value
Recessive	CYP19A1	rs28566535	Either	8.2 (2.7-24.9)	<0.0002
			Exe	8.1 (1.6-41)	0.012
			Let	7.5 (1.5-38.1)	0.016
	ESR1	rs9322335	Either	4.2 (2-8.6)	<0.0001
			Exe	10.5 (2.9-38.7)	<0.0004
			Let	3.3 (1.2-9.1)	0.018
	ESR1	rs9322336	Either	3.7 (1.8-7.4)	<0.0004
			Exe	7.2 (2.7-19.5)	0.0001
			Let	3 (1-8.8)	0.050
Additive	NCOR1	rs1065822	Either	0.7 (0.5-0.9)	0.015
			Exe	1.1 (0.7-1.6)	0.77
			Let	0.3 (0.2-0.6)	<0.0002