Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

BRCA1 promoter methylation and clinical outcomes in epithelial ovarian cancer a pooled analysis of individual patient data (#301)

Roshni D Kalachand 1 , Britta Stordal 2 , Stephen Madden 3 , Ben Chandler 4 , Julie Cunningham 5 , Ellen L Goode 6 , Ilary Ruscito 7 , Elena I Braicu 8 , Jalid Sehouli 8 , Atanas Ignatov 9 , Herbert Yu 10 , Dionyssios Katsaros 11 , Lingeng Lu 12 , Gordon B Mills 13 , Russell Broaddus 13 , Karen Lu 13 , Mark Carey 13 , Kirsten Timms 14 , Iwona Rzepecka 15 , Jolanta Kupryjanczyk 15 , Elizabeth M Swisher 16 , Maria I Harrell 16 , Karen Agnew 16 , Ciaran O'Riain 17 , Sharon O'Toole 18 , John J O'Leary 17 , David Thomas 19 , Parvesh Chaudhry 20 , Radhika Srinivasan 21 , Bryan T Hennessy 1
  1. Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
  2. Middlesex University, London, LONDON, United Kingdom
  3. Data Science Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
  4. Department of Cancer Biology, University of Michigan, Detroit, Michigan, United States of America
  5. Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
  6. Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, United States of America
  7. Department of Gynecology and Obstetrics, Sapienza University of Rome, Rome, Italy
  8. Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum,, Charité Universitätsmedizin Berlin, Berlin, Germany
  9. Department of Obstetrics and Gynaecology, Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany
  10. University of Hawaii Cancer Centre, University of Hawaii, Honolulu, Hawaii, United States of America
  11. Department of Obstetrics and Gynaecology, Gynaecologic Oncology and Breast Cancer Unit, University of Turin, Turin, Italy
  12. Department of Epidemiology and Public Health, Yale Cancer Centre, Yale University, New Haven, Connecticut, United States of America
  13. MD Anderson Cancer Center, University of Texas, Houston, Texas, United States of America
  14. Myriad Genetics, Salt Lake City, Utah, United States of America
  15. Department of Molecular Pathology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
  16. University of Washington School of Medicine, Seattle, Washington, United States of America
  17. Department of Histopathology, Trinity College Dublin and St James' Hospital, Dublin, Ireland
  18. Department of Obstetrics and Gynaecology, Trinity College Dublin and St James' Hospital, Dublin, Ireland
  19. Ovarian Cancer Research Group, Garvan Institute of Medical Research, Sydney, Australia
  20. Department of Radiotherapy, , Postgraduate Institute of Medical Education and Research, Chandigarh, India
  21. Department of Cytology and Gynaecologic Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Importance: BRCA1 promoter methylation has been proposed as a mechanism of homologous recombination deficiency in epithelial ovarian cancer (EOC). Studies evaluating BRCA1-methylated EOC (BMEOC) do not consistently support improved survival outcomes following platinum chemotherapy.

Objective: To determine the clinical characteristics and survival outcomes in BMEOC.

Methods: We searched PubMed and conference abstracts combining the terms “BRCA1” and “methylat*” in October 2014 and 2016.  We selected studies examining clinical and survival characteristics of BMEOC. The search retrieved 132 publications, of which 15 were eligible. Two further unpublished cohorts were obtained. Data was not available for 6 eligible studies. Data for 2322 patients from 11 retrospective studies was analysed. Associations between BRCA1 methylation and clinico-pathological characteristics were evaluated (Cochran-Mantel-Haenzel test). Overall survival (OS) and progression-free survival (PFS) were determined by Kaplan Meier statistics (Log rank test). 

Results: 338 (14.6%) patients’ tumours were BRCA1-methylated. Like BRCA1 mutation, BRCA1 methylation was associated with younger age at diagnosis and advanced-stage high-grade EOC. There was no difference in PFS or OS between BMEOC and non-BMOC median PFS 21 vs 19 months (HR 0.98, 95% CI [0.85 – 1.14], p=0.82); median OS 48 vs 48 months, (HR 1.00 95% CI [0.84 – 1.18], p=0.98). On multivariate analyses, both BRCA1- and BRCA2-mutated EOC were associated with improved PFS (HR 0.71, 95% CI [0.55 -0.93], p=0.01 and HR 0.53 [0.37 – 0.74], p<0.0001, respectively) and OS (HR 0.74, 95% CI [0.59 – 0.98], p=0.03 and HR 0.54 [0.38 -0.79], p=0.001). Interestingly, BMEOC was associated with an improved PFS and OS (multivariate HR for PFS 0.69, 95% CI [0.54 – 0.90], p=0.005; multivariate HR for OS 0.71, 95% CI [0.52 – 0.97], p=0.03) as compared to non-BMEOC in the subset of cohorts utilising methylation-specific PCR.

Conclusion: BMEOC displays similar clinico-pathological features to BRCA1-mutated EOC. Heterogeneity within methylation methodology influences survival outcomes, with BMEOC being associated with improved survival solely in cohorts utilising methylation-specific PCR to detect BRCA1 methylation.