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

Breast Cancer Res Treat. 2015 Jul;152(1):67-76. doi: 10.1007/s10549-015-3437-9. Epub 2015 May 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / therapeutic use
  • Biomarkers, Tumor
  • Breast Neoplasms / complications*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cardiotoxicity / diagnosis
  • Cardiotoxicity / etiology*
  • Cardiotoxicity / physiopathology
  • Epirubicin / adverse effects*
  • Epirubicin / therapeutic use
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Heart Failure / diagnosis
  • Heart Failure / etiology
  • Heart Failure / physiopathology
  • Humans
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • Neoplasm Grading
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide
  • Stroke Volume
  • Young Adult

Substances

  • ABCC2 protein, human
  • Antibiotics, Antineoplastic
  • Biomarkers, Tumor
  • Multidrug Resistance-Associated Protein 2
  • Epirubicin