title: Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer.
abstract: Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. 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. 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 versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Med Inn Bldg C450, Ann Arbor, MI 48109-5843, USA. norahh@med.umich.edu
authors.forename: N Lynn
authors.initials: NL
authors.lastname: Henry
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.forename: Jessica
authors.initials: J
authors.lastname: Dantzer
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.forename: Kelley
authors.initials: K
authors.lastname: Kidwell
authors.forename: Christina
authors.initials: C
authors.lastname: Gersch
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nguyen
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.forename: Santosh
authors.initials: S
authors.lastname: Philips
authors.forename: Janet S
authors.initials: JS
authors.lastname: Carpenter
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D007438:Introns; D000077289:Letrozole; D008875:Middle Aged; D008957:Models, Genetic; D015999:Multivariate Analysis; D009570:Nitriles / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017211:Treatment Failure; D014230:Triazoles / Q000009:adverse effects
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; C056516:exemestane
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