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Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study

  • Epidemiology
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Abstract

A major side effect of aromatase inhibitor (AI) therapy is AI-related arthralgia (AIA), which often leads to therapy discontinuation. We aimed to identify genetic variants associated with AIA and therapy discontinuation in the first year of AI treatment. Our prospective cohort study included 343 postmenopausal women with early breast cancer starting AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes involved in estrogen and vitamin D signaling were selected. Univariate and multivariate linear/logistic regressions were fitted in order to asses the association between studied SNPs and AIA intensity (visual analogic scale score) at 3 and 12 months of follow-up, worsening pain, and therapy discontinuation. We also tested for a priori-defined interactions by introducing multiplicative terms in the regression equations. SNPs in CYP17A1 and VDR genes appeared significantly associated with AIA (P = 0.003, P = 0.012, respectively). One SNP in CYP27B1 gene was related to therapy discontinuation [P = 0.02; OR 0.29 (0.09–0.99)]. We revealed interactions between CYP27B1 and both CYP17A1 (P = 0.01) and VDR SNPs (P = 0.06). Furthermore, an additive effect on pain intensity was shown for unfavorable alleles, with two points higher mean absolute pain increase and up to 5.3-fold higher risk of worsening pain compared to favorable genotypes. SNPs in CYP17A1, VDR, and CYP27B1 genes predict the risk of AIA. Their determination would be useful to trigger the monitoring strategies in women at risk of therapy discontinuation.

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Acknowledgments

This work was supported by Grants from the Generalitat de Catalunya (DIUE 2009 SGR 818) and the Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF). Grant FIS PI10/01464 (Carlos III Health Institute, Science and Innovation Ministry) is also acknowledged. The authors thank Elaine M. Lilly, Ph.D., for helpful advice and critical reading of the manuscript.

Disclosures

The authors state that they have no conflicts of interest.

Ethics Approval

The protocol of this study was approved by the local ethics committee (CEIC Parc de Salut Mar). Written informed consent was obtained from all participants for their inclusion in the study as well as for DNA extraction.

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Authors and Affiliations

  1. URFOA-IMIM Department, Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), Instituto de Salud Carlos III FEDER, Parc de Salut Mar, C/Dr Aiguader, 88, 2nd Floor, 08003, Barcelona, Spain

    Natalia Garcia-Giralt, María Rodríguez-Sanz, Daniel Prieto-Alhambra, Elisa Torres-del Pliego, Adolfo Diez-Perez & Xavier Nogués

  2. Internal Medicine Department, Parc de Salut Mar, Universitat Autònoma de Barcelona, Barcelona, Spain

    Natalia Garcia-Giralt, María Rodríguez-Sanz, Daniel Prieto-Alhambra, Adolfo Diez-Perez & Xavier Nogués

  3. IDIAP Jordi Gol Primary Care Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

    Daniel Prieto-Alhambra

  4. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK

    Daniel Prieto-Alhambra

  5. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

    Daniel Prieto-Alhambra

  6. Medical Oncology Department, Parc de Salut Mar, Barcelona, Spain

    Sonia Servitja, Joan Albanell & Ignasi Tusquets

  7. Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain

    Sonia Servitja, Joan Albanell & Ignasi Tusquets

  8. Departament de Genètica, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Universitat de Barcelona, Barcelona, Spain

    Susana Balcells & Daniel Grinberg

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  1. Natalia Garcia-Giralt
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  2. María Rodríguez-Sanz
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  3. Daniel Prieto-Alhambra
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  5. Elisa Torres-del Pliego
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  6. Susana Balcells
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  7. Joan Albanell
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  8. Daniel Grinberg
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  9. Adolfo Diez-Perez
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  10. Ignasi Tusquets
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  11. Xavier Nogués
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Corresponding author

Correspondence to Daniel Prieto-Alhambra.

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Garcia-Giralt, N., Rodríguez-Sanz, M., Prieto-Alhambra, D. et al. Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study. Breast Cancer Res Treat 140, 385–395 (2013). https://doi.org/10.1007/s10549-013-2638-3

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