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Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

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Abstract

Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess ACT occurrence and clinical and genetic risk factors in early breast cancer patients. In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy-seven patients treated between 2000 and 2010 with 3–6 cycles of (neo) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) > 10 % and cardiac failure grade 3–5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, left-sided radiotherapy, occurrence of febrile neutropenia, and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni- and multivariable logistic regression analysis. Additionally, exploratory analyses including 11 additional SNPs related to the metabolism of anthracyclines were performed. After a median follow-up of 3.62 years (range 0.40–9.60), a LVEF decline of > 10 % occurred in 153 patients (17.5 %) and cardiac failure in 16 patients (1.8 %). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of > 10 % (OR 1.3, 95 % CI 1.1–1.4, p < 0.001 and OR 1.6, 95 % CI 1.1–2.3, p = 0.02). Radiotherapy for left-sided breast cancer was associated with cardiac failure (OR 3.7, 95 % CI 1.2–11.5, p 0.026). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to anthracycline metabolism were retained in the multivariate model for prediction of LVEF decline. ACT in breast cancer patients is related to number of received cycles of epirubicin and left-sided radiotherapy. Additional studies should be performed to independently confirm the potential association between rs246221 in ABCC1 and LVEF.

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Acknowledgments

AMP’s institution of employment receives unrestricted scientific/educational grants from Amgen. MS’ institution of employment receives unrestricted scientific/educational grants from Amgen, and he has served on advisory boards for Amgen. RPe is on the speaker bureau for Amgen.

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All the other authors declare no conflicts of interest related to this article.

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    Authors and Affiliations

    1. Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, Belgium

      Christof Vulsteke

    2. Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland

      Alena M. Pfeil, Matthias Schwenkglenks & Thomas D. Szucs

    3. Department of Gynaecology and Obstetrics, University Hospitals Leuven, Louvain, Belgium

      Charlotte Maggen, Anne-Sophie Dieudonné & Patrick Neven

    4. Cellular and Molecular Medicine, St. George’s University of London, London, United Kingdom

      Ruth Pettengell

    5. Vesalius Research Center, Vlaams Instituut voor Biotechnologie (VIB), Louvain, Belgium

      Diether Lambrechts

    6. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Louvain, Belgium

      Diether Lambrechts

    7. Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Herestraat 49, 3000, Louvain, Belgium

      Sigrid Hatse, Robert Paridaens & Hans Wildiers

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    Correspondence to Christof Vulsteke.

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    Christof Vulsteke and Alena M. Pfeil have contributed equally to this work.

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    Vulsteke, C., Pfeil, A.M., Maggen, C. et al. Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Breast Cancer Res Treat 152, 67–76 (2015). https://doi.org/10.1007/s10549-015-3437-9

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    • DOI: https://doi.org/10.1007/s10549-015-3437-9

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