title: Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency.
abstract: The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed "BRCAness"). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.
authors.affiliation: From the Department of Medical Oncology, University College London Hospital, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom; Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Kristeleit
authors.affiliation: From the Department of Medical Oncology, University College London Hospital, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom; Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
authors.forename: Rowan E
authors.initials: RE
authors.lastname: Miller
authors.affiliation: From the Department of Medical Oncology, University College London Hospital, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom; Clinical Investigations Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D059766:DNA End-Joining Repair / Q000187:drug effects; D053843:DNA Mismatch Repair / Q000187:drug effects; D049914:DNA Repair-Deficiency Disorders / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D000067856:Poly(ADP-ribose) Polymerase Inhibitors