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

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)807-816
Number of pages10
JournalBreast Cancer Research and Treatment
Volume138
Issue number3
DOIs
StatePublished - Apr 2013

Fingerprint

Aromatase Inhibitors
exemestane
Breast Neoplasms
letrozole
Estrogens
Therapeutics
Genetic Models
Statistical Models
Genes
Randomized Controlled Trials
Hormones
DNA

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. / Henry, N. Lynn; Skaar, Todd; Dantzer, Jessica; Li, Lang; Kidwell, Kelley; Gersch, Christina; Nguyen, Anne T.; Rae, James M.; Desta, Zeruesenay; Oesterreich, Steffi; Philips, Santosh; Carpenter, Janet; Storniolo, Anna Maria; Stearns, Vered; Hayes, Daniel F.; Flockhart, David A.

In: Breast Cancer Research and Treatment, Vol. 138, No. 3, 04.2013, p. 807-816.

Research output: Contribution to journalArticle

Henry, NL, Skaar, T, Dantzer, J, Li, L, Kidwell, K, Gersch, C, Nguyen, AT, Rae, JM, Desta, Z, Oesterreich, S, Philips, S, Carpenter, J, Storniolo, AM, Stearns, V, Hayes, DF & Flockhart, DA 2013, 'Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer', Breast Cancer Research and Treatment, vol. 138, no. 3, pp. 807-816. https://doi.org/10.1007/s10549-013-2504-3
Henry, N. Lynn ; Skaar, Todd ; Dantzer, Jessica ; Li, Lang ; Kidwell, Kelley ; Gersch, Christina ; Nguyen, Anne T. ; Rae, James M. ; Desta, Zeruesenay ; Oesterreich, Steffi ; Philips, Santosh ; Carpenter, Janet ; Storniolo, Anna Maria ; Stearns, Vered ; Hayes, Daniel F. ; Flockhart, David A. / Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. In: Breast Cancer Research and Treatment. 2013 ; Vol. 138, No. 3. pp. 807-816.
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