Roshni D Kalachand1, Britta Stordal2, Stephen Madden3, Benjamin Chandler4, Julie Cunningham5, Ellen L Goode6, Ilary Ruscito7,8, Elena I Braicu7, Jalid Sehouli7, Atanas Ignatov9, Herbert Yu10, Dionyssios Katsaros11, Gordon B Mills12, Karen H Lu13, Mark S Carey14, Kirsten M Timms15, Jolanta Kupryjanczyk16, Iwona K Rzepecka16, Agnieszka Podgorska16, Jessica N McAlpine14, Elizabeth M Swisher17, Sarah S Bernards17, Ciaran O'Riain18, Sharon O'Toole19,20, John J O'Leary18,20, David D Bowtell21, David M Thomas22, Katharina Prieske23, Simon A Joosse24, Linn Woelber23, Parvesh Chaudhry25, Norman Häfner26, Ingo B Runnebaum26, Bryan T Hennessy1,27,28. 1. Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. 2. Department of Natural Sciences, Middlesex University, Hendon, London NW4 4BT, UK. 3. Data Science Centre, Royal College of Surgeons in Ireland, Beaux Lane House, Dublin, Ireland. 4. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. 5. Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. 6. Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 7. Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. 8. Cell Therapy Unit and Laboratory of Tumor Immunology, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 9. Department of Gynecology and Obstetrics, University Medical Center, Regensburg, Germany. 10. University of Hawaii Cancer Centre, Honolulu, HI, USA. 11. AOU Citta della Salute and Department of Surgical Sciences, Gynecologic Oncology, University of Torino, Italy. 12. Department of Cell, Development and Cancer Biology Knight Cancer Institute, Oregon Health and Sciences University, Portland, OR, USA. 13. University of Texas MD Anderson Cancer Center, Houston, TX, USA. 14. Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada. 15. Myriad Genetics, Inc, Salt Lake City, UT, USA. 16. Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. 17. University of Washington School of Medicine, Seattle, WA, USA. 18. Department of Histopathology, Trinity College Dublin, Central Pathology Laboratory, St. James's Hospital, Dublin, Ireland. 19. Department of Obstetrics and Gynaecology/Histopathology, Trinity College Dublin, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland. 20. Emer Casey Research Laboratory, Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, Dublin, Ireland. 21. Peter MacCallum Cancer Centre, Melbourne, Australia. 22. Genomic Cancer Medicine, Cancer Division, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, Australia. 23. Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 24. Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 25. Department of Radiotherapy, Postgraduate Institute of Medical Education and Research, Chandigarh, India. 26. Department for Gynaecology and Reproductive Medicine, Jena University Hospital-Friedrich Schiller University Jena, Jena, Germany. 27. Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland. 28. Our Lady of Lourdes Hospital, Drogheda, Ireland.
Abstract
BACKGROUND: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. METHODS: Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. RESULTS: 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling. CONCLUSION: BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
BACKGROUND:BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. METHODS: Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. RESULTS: 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P = .98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P = .96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P = .02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P = .05) on mixed-effects modeling. CONCLUSION:BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.
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