title: Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients.
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.
authors.affiliation: Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, Belgium. christof.vulsteke@azmmsj.be.
authors.forename: Christof
authors.initials: C
authors.lastname: Vulsteke
authors.affiliation: Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland.
authors.forename: Alena M
authors.initials: AM
authors.lastname: Pfeil
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Maggen
authors.affiliation: Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwenkglenks
authors.affiliation: Cellular and Molecular Medicine, St. George's University of London, London, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pettengell
authors.affiliation: Institute of Pharmaceutical Medicine (ECPM), University of Basel, Basel, Switzerland.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Szucs
authors.affiliation: Vesalius Research Center, Vlaams Instituut voor Biotechnologie (VIB), Louvain, Belgium.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Louvain, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dieudonné
authors.affiliation: 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.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Louvain, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Paridaens
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: Wildiers
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D066126:Cardiotoxicity / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D015251:Epirubicin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D013318:Stroke Volume; D055815:Young Adult
chemical_list: C000715087:ABCC2 protein, human; D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D000089762:Multidrug Resistance-Associated Protein 2; D015251:Epirubicin