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Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients

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Abstract

Single nucleotide polymorphisms (SNPs) in the gene encoding aromatase (CYP19A1) have been associated with differential benefit from letrozole treatment in metastatic breast cancer (mBC) patients, but validation is lacking. The aim was to investigate whether polymorphic variation of CYP19A1 and enzymes involved in estrogen and aromatase inhibitors (AIs) metabolism are associated with efficacy of AIs. 308 Women with estrogen-receptor-positive metastatic mBC treated with a third-generation AI were identified retrospectively. DNA was extracted from archival formalin-fixed paraffin embedded tumors and genotyped for 71 variants in 16 candidate genes, including CYP19A1. Time to treatment failure (TTF) was significantly improved in patients carrying the minor (T) allele of rs4775936 when compared to patients with the reference allele [HR = 0.79 per T allele (0.66–0.95); P = 0.012]. Patients with >7 TTTA repeats on either allele of CYP19A1 intron 4 had a lower risk of failure than those with a smaller repeat size [HR = 0.84 per >7 TTTA repeats (0.7–0.99); P = 0.04]. However, importantly in multivariate analysis, adjusting for the number of disease sites; disease-free interval from diagnosis to first recurrence, grade at diagnosis and first recurrence type neither variant maintained independent predictive significance. None of the 56 SNPs analyzed as an exploratory set showed significant association with TTF. Variants in CYP19A1 or other selected genes associated with AI metabolism were not independently associated with improved AI efficacy and emphasize the importance in pharmacogenetic studies of considering genetic biomarkers in the context of relevant prognostic factors.

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Acknowledgments

RF was supported by a Fellowship from the European Society of Medical Oncology (ESMO), Viganello-Lugano, Switzerland. MA performed this project with a grant from the Cridlan Fund, UK. This study has been also supported by grants from Breast Cancer Campaign (KDH, WGN, DGE, AW and AH) and by the NIHR Manchester and Royal Marsden BRCs (WGN, DGE and IS, MD respectively) and from Breakthrough Breast Cancer.

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None.

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Authors and Affiliations

  1. Department of Medical Oncology, University of Manchester and The Christie NHS Foundation Trust, Manchester, UK

    Roberta Ferraldeschi, Andrew Wardley & Anthony Howell

  2. Genetic Medicine, Manchester Academic Health Science Centre (MAHSC), University of Manchester and Central Manchester NHS Foundation Trust, Manchester, UK

    Roberta Ferraldeschi, Kristen D. Hadfield, D. Gareth Evans & William G. Newman

  3. Academic Department Biochemistry, The Royal Marsden Hospital, Fulham Road, SW3 6JJ, London, UK

    Monica Arnedos, Roger A’Hern & Mitch Dowsett

  4. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    Suzie Drury & Mitch Dowsett

  5. Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, School of Cancer, Enabling Science and Technology, University of Manchester, Manchester, UK

    Anthony Howell

  6. Health Sciences, Methodology, School of Community Based Medicine, University of Manchester, and Central Manchester NHS Foundation Trust, Manchester, UK

    Stephen A. Roberts

  7. Breast Unit, Department of Medicine, The Royal Marsden Hospital, London, UK

    Ian Smith

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  1. Roberta Ferraldeschi
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  2. Monica Arnedos
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Correspondence to Mitch Dowsett.

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Ferraldeschi, R., Arnedos, M., Hadfield, K.D. et al. Polymorphisms of CYP19A1 and response to aromatase inhibitors in metastatic breast cancer patients. Breast Cancer Res Treat 133, 1191–1198 (2012). https://doi.org/10.1007/s10549-012-2010-z

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