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

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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.

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Acknowledgments

We thank the patients who participated in the study, and the treating physicians, research nurses and data managers at the three sites. Supported in part by Pharmacogenetics Research Network Grant # U-01 GM061373 (DAF) and Clinical Pharmacology training Grant: 5T32-GM08425 (DAF) from the National Institute of General Medical Sciences, National Institutes of Health (NIH), Bethesda, MD and by Grant numbers M01-RR000042 (UM), M01-RR00750 (IU), and M01-RR00052 (JHU) from the National Center for Research Resources (NCRR), a component of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. NLH is a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (CI#53-10). In addition, these studies were supported by Grants from Pfizer, Inc. (DFH), Novartis Pharma AG (DFH), and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale™ (DFH). Study medication was provided by Pfizer, Inc. and Novartis Pharma AG.

Conflict of interest

NLH receives research funding from AstraZeneca, Eli Lilly, and Sanofi Aventis. DFH receives research funding from AstraZeneca, Novartis, Pfizer, Veridex, and Janssen. DAF receives research funding from Novartis and Pfizer. VS receives research funding from Abbott, Abraxis, Merck, Novartis, and Pfizer. JMR received a research Grant from Pfizer. TCS, JD, LL, KK, CG, ATN, ZD, SO, SP, JSC, and AMS reported no conflicts of interest.

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Authors and Affiliations

  1. Breast Oncology Program, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Drive, Med Inn Bldg C450, Ann Arbor, MI, 48109-5843, USA

    N. Lynn Henry, Christina Gersch, James M. Rae & Daniel F. Hayes

  2. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Todd C. Skaar, Jessica Dantzer, Lang Li, Anne T. Nguyen, Zeruesenay Desta, Santosh Philips & David A. Flockhart

  3. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA

    Kelley Kidwell

  4. Women’s Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Steffi Oesterreich

  5. Indiana University School of Nursing, Indianapolis, IN, 46202, USA

    Janet S. Carpenter

  6. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA

    Anna M. Storniolo

  7. Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA

    Vered Stearns

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  1. N. Lynn Henry
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  2. Todd C. Skaar
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  3. Jessica Dantzer
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Correspondence to N. Lynn Henry.

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Daniel F. Hayes and David A. Flockhart served as co-senior authors.

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Henry, N.L., Skaar, T.C., Dantzer, J. et al. Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast Cancer Res Treat 138, 807–816 (2013). https://doi.org/10.1007/s10549-013-2504-3

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  • DOI: https://doi.org/10.1007/s10549-013-2504-3

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