title: Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.
abstract: Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk.
  
  
  
  We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group.
  
  
  
  RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice.
  
  
  
  Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Folefac
authors.initials: F
authors.lastname: Aminkeng
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Colin J D
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Division of Pediatric Hematology/Oncology/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shahrad R
authors.initials: SR
authors.lastname: Rassekh
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Soomi
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, University of Western Ontario, London, ON, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rieder
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Amit P
authors.identifier: 0000-0003-3336-9288
authors.initials: AP
authors.lastname: Bhavsar
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Pharmaceutical Outcomes & Policy Innovations Programme, BC Children's Hospital, Vancouver, BC, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Smith
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.affiliation: British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.affiliation: Department of Pediatrics, Division of Cardiology, Stanford University, Stanford, CA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.|Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Translational Laboratory in Genetic Medicine, National University of Singapore and Association for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.|University Institute of Clinical Chemistry, Inselspital Bern University Hospital and University of Bern, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.affiliation: Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.|Pharmaceutical Outcomes & Policy Innovations Programme, BC Children's Hospital, Vancouver, BC, Canada.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
mesh_terms: D018943:Anthracyclines / Q000009:adverse effects*; D066126:Cardiotoxicity / Q000517:prevention & control*; D019317:Evidence-Based Medicine; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D012307:Risk Factors
chemical_list: C000715087:ABCC2 protein, human; D018943:Anthracyclines; D000089762:Multidrug Resistance-Associated Protein 2
keywords: anthracycline; cancer; cardiotoxicity; guidelines; heart-failure; pharmacogenomics