title: Homologous recombination deficiency and ovarian cancer.
abstract: The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation.
authors.affiliation: UCL Cancer Institute, London, UK. Electronic address: j.ledermann@ucl.ac.uk.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ledermann
authors.affiliation: Northern Institute for Cancer Research and Northern Centre for Cancer Care, Newcastle University, UK.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drew
authors.affiliation: UCL Cancer Institute, London, UK.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Kristeleit
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005260:Female; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib
keywords: BRCA1; BRCA2; DNA repair; HRD; Homologous recombination deficiency; Homologous recombination repair; Olaparib; Ovarian cancer; PARP inhibitors