BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis

Author:

Kalachand Roshni D1ORCID,Stordal Britta2ORCID,Madden Stephen3,Chandler Benjamin4ORCID,Cunningham Julie5,Goode Ellen L6,Ruscito Ilary78,Braicu Elena I7,Sehouli Jalid7,Ignatov Atanas9,Yu Herbert10,Katsaros Dionyssios11,Mills Gordon B12ORCID,Lu Karen H13,Carey Mark S14,Timms Kirsten M15,Kupryjanczyk Jolanta16,Rzepecka Iwona K16,Podgorska Agnieszka16,McAlpine Jessica N14ORCID,Swisher Elizabeth M17ORCID,Bernards Sarah S17,O’Riain Ciaran18,O’Toole Sharon1920,O’Leary John J1820,Bowtell David D21,Thomas David M22ORCID,Prieske Katharina23,Joosse Simon A24,Woelber Linn23,Chaudhry Parvesh25,Häfner Norman26,Runnebaum Ingo B26,Hennessy Bryan T12728

Affiliation:

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

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.

Funder

North East Cancer Research and Education Trust

St Luke’s Institute for Cancer Research

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Oncology

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