Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer

N. Lynn Henry, Todd C. Skaar, Jessica Dantzer, Lang Li, Kelley Kidwell, Christina Gersch, Anne T. Nguyen, James M. Rae, Zeruesenay Desta, Steffi Oesterreich, Santosh Philips, Janet S. Carpenter, Anna M. Storniolo, Vered Stearns, Daniel F. Hayes, David A. Flockhart

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)807-816
Number of pages10
JournalBreast Cancer Research and Treatment
Issue number3
StatePublished - Apr 2013


  • Aromatase inhibitor
  • Breast cancer
  • Single-nucleotide polymorphism
  • Toxicity
  • Treatment discontinuation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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