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Homologous recombination deficiency and ovarian cancer |
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| Institution: | 1. Division of Medical Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, USA;2. SWOG Statistical Center, Seattle, USA;3. Cancer, Research and Biostatistics (CRAB), Seattle, USA;4. Myriad Genetics, Inc., Salt Lake City, USA;5. Department of Medicine, University of Washington, Seattle, USA;6. Seattle Cancer Care Alliance, Seattle, USA;7. Department of Breast Medical Onocolgy, The University of Texas MD Anderson Cancer Center, Houston, USA;8. Department of Internal Medicine, University of Michigan, Ann Arbor, USA;1. Division of Gynecologic Surgery, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, United States;2. Department of Oncology, Mayo Clinic, Rochester, MN, United States;3. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, United States;4. Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States;5. TesaroBio, Inc, Waltham, MA, United States;6. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, United States |
| 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. |
| Keywords: | PARP inhibitors DNA repair Homologous recombination repair HRD Homologous recombination deficiency BRCA1 BRCA2 Ovarian cancer Olaparib |
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