BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotypeResearch in context
Heidi Fettke,
Chao Dai,
Edmond M. Kwan,
Tiantian Zheng,
Pan Du,
Nicole Ng,
Patricia Bukczynska,
Maria Docanto,
Louise Kostos,
Siavash Foroughi,
Stephen Brown,
Lisa-Jane K. Graham,
Kate Mahon,
Lisa G. Horvath,
Shidong Jia,
Manish Kohli,
Arun A. Azad
Affiliations
Heidi Fettke
Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Corresponding author. Cancer Research, Peter MacCallum Cancer Centre, 305 Grattan Street, Parkville, Melbourne, VIC 3000, Australia.
Chao Dai
Predicine Inc., Hayward, CA, USA
Edmond M. Kwan
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia
Tiantian Zheng
Predicine Inc., Hayward, CA, USA
Pan Du
Predicine Inc., Hayward, CA, USA
Nicole Ng
Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
Patricia Bukczynska
Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
Maria Docanto
Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
Louise Kostos
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
Siavash Foroughi
Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia; Personalized Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Stephen Brown
Medical Oncology, Ballarat Base Hospital, Ballarat, Australia
Lisa-Jane K. Graham
Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia
Kate Mahon
Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia; University of Sydney, Sydney, Australia; Garvan Institute of Medical Research, Darlinghurst, Australia
Lisa G. Horvath
Medical Oncology, Chris O'Brien Lifehouse, Camperdown, Australia; University of Sydney, Sydney, Australia; Garvan Institute of Medical Research, Darlinghurst, Australia; Royal Prince Alfred Hospital, Camperdown, Australia
Shidong Jia
Predicine Inc., Hayward, CA, USA
Manish Kohli
Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
Arun A. Azad
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
Summary: Background: Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes. Methods: Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2. Findings: At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9–6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1–4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months). Interpretation: These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
