title: DNA Repair in Prostate Cancer: Biology and Clinical Implications.
abstract: For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification.
  
  
  
  To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease.
  
  
  
  A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer.
  
  
  
  We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC.
  
  
  
  Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies.
  
  
  
  Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed.
authors: Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research, London, UK; Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: Joaquin
authors: J
authors: Mateo
authors: Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research, London, UK.
authors: Gunther
authors: G
authors: Boysen
authors: Department of Urology, Weill Cornell Medicine, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
authors: Christopher E
authors: CE
authors: Barbieri
authors: Sheffield Institute for Nucleic Acids, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
authors: Helen E
authors: HE
authors: Bryant
authors: Prostate Cancer Unit, Spanish National Cancer Research Centre, Madrid, Spain.
authors: Elena
authors: E
authors: Castro
authors: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
authors: Pete S
authors: PS
authors: Nelson
authors: Prostate Cancer Unit, Spanish National Cancer Research Centre, Madrid, Spain; Medical Oncology Department, CNIO-IBIMA Genitourinary Cancer Unit, Hospital Virgen de la Victoria and Hospital Regional de Malaga, Malaga, Spain.
authors: David
authors: D
authors: Olmos
authors: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors: Colin C
authors: CC
authors: Pritchard
authors: Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine. New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
authors: Mark A
authors: MA
authors: Rubin
authors: Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research, London, UK; Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: johann.de-bono@icr.ac.uk.
authors: Johann S
authors: JS
authors: de Bono
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use; D057285:Precision Medicine; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics*; D059767:Recombinational DNA Repair / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C501486:MLH1 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: BRCA; DNA damage; DNA repair; PARP; Personalized medicine; Prostate cancer