Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

©American Society of Clinical Oncology

Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

1. Elena Castro,


2. Chee Goh,


3. David Olmos⇑,


4. Ed Saunders,


5. Daniel Leongamornlert,


6. Malgorzata Tymrakiewicz,


7. Nadiya Mahmud,


8. Tokhir Dadaev,


9. Koveela Govindasami,


10. Michelle Guy,


11. Emma Sawyer,


12. Rosemary Wilkinson,


13. Audrey Ardern-Jones,


14. Steve Ellis,


15. Debra Frost,


16. Susan Peock,


17. D. Gareth Evans,


18. Marc Tischkowitz,


19. Trevor Cole,


20. Rosemarie Davidson,


21. Diana Eccles,


22. Carole Brewer,


23. Fiona Douglas,


24. Mary E. Porteous,


25. Alan Donaldson,


26. Huw Dorkins,


27. Louise Izatt,


28. Jackie Cook,


29. Shirley Hodgson,


30. M. John Kennedy,


31. Lucy E. Side,


32. Jacqueline Eason,


33. Alex Murray,


34. Antonis C. Antoniou,


35. Douglas F. Easton,


36. Zsofia Kote-Jarai and


37. Rosalind Eeles

+ Author Affiliations

1. 
   Elena Castro, Chee Goh, Ed Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Nadiya Mahmud, Tokhir Dadaev, Koveela Govindasami, Michelle Guy, Emma Sawyer, Rosemary Wilkinson, Zsofia Kote-Jarai, and Rosalind Eeles, Institute of Cancer Research; Elena Castro, Chee Goh, Audrey Ardern-Jones, and Rosalind Eeles, Royal Marsden National Health Service (NHS) Foundation Trust; Louise Izatt, Guy's and St Thomas' NHS Foundation Trust; Shirley Hodgson, St George's, University of London; Lucy E. Side, Great Ormond St Hospital for Children NHS Trust, London; Steve Ellis, Debra Frost, Susan Peock, Marc Tischkowitz, Antonis C. Antoniou, and Douglas F. Easton, University of Cambridge, Cambridge; D. Gareth Evans, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Trevor Cole, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Rosemarie Davidson, Yorkhill Hospitals, Glasgow; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Carole Brewer, Royal Devon & Exeter Hospital, Exeter; Fiona Douglas, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Mary E. Porteous, Western General Hospital, Edinburgh; Alan Donaldson, St Michael's Hospital, Bristol; Huw Dorkins, Kennedy-Galton Centre, Harrow; Jackie Cook, Sheffield Children's Hospital, Sheffield; Jacqueline Eason, Nottingham University Hospitals NHS Trust, Nottingham; Alex Murray, All Wales Medical Genetics Services, Singleton Hospital, Swansea, United Kingdom; Elena Castro and David Olmos, Spanish National Cancer Research Centre, Madrid, Spain; and M. John Kennedy, Trinity College Dublin and St James's Hospital, Dublin, Ireland.
   
   

1. Corresponding author: David Olmos, MD, PhD, Spanish National Cancer Research Centre 3, Melchor Fernández Almagro, Madrid, 28029, Spain; e-mail: dolmos@cnio.es.

Abstract

Purpose To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.

Patients and Methods This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M₀), metastasis-free survival (MFS), and CSS from metastasis (CSS_M₁).

Results PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.

Conclusion Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.