Please use this identifier to cite or link to this item:
Title: BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype.
Author: Fettke, H.
Dai, C.
Kwan, E.
Zheng, T.
Ng, N.
Bukczynska, P.
Docanto, M.
Kostos, L.
Foroughi, S.
Brown, Stephen
Graham, L.
Mahon, K.
Horvath, L.
Jia, S.
Kohli, M.
Azad, A.
Issue Date: 2023
Publication Title: eBioMedicine
Volume: 95
Start Page: 104738
Abstract: 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.
Internal ID Number: 02320
Health Subject: BIOMARKER
Type: Journal Article
Appears in Collections:Research Output

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.