The following is a summary of “BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype,” published in the August 2023 issue of Oncology by Fettke et al.
Mutations in DNA damage response (DDR) genes are frequent in metastatic castration-resistant prostate cancer (mCRPC). Researchers performed a retrospective study to investigate how the genomic alterations in DDR genes, commonly found in mCRPC, influence prognosis and/or treatment response to optimize clinical outcomes.
In this study, 407 plasma samples from 375 men with mCRPC underwent targeted sequencing. The PredicineCARE™ cfDNA assay examined pathogenic changes in 152 genes (including 27 DDR-related genes) and detected a biallelic loss in BRCA2.
Results demonstrated that DDR alterations were found in 34.5% (129/375) of patients (including monoallelic changes). Commonly affected genes included BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%), and BRCA1 (3%). Patients with BRCA alterations, particularly BRCA2, had significantly worse progression-free survival (HR 3.3 [95% CI 1.9-6.0]; p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; p = 0.02), and lower PSA response rates to AR pathway inhibitors (32% vs 60%, p = 0.02). BRCA-deficient tumors also had multiple alterations, including in 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).
The study highlighted the BRCA genes, especially BRCA2, as important prognostic markers in mCRPC. BRCA2’s predictive value for poor outcomes remains significant even in cfDNA assays, regardless of zygosity. The presence of actionable genomic changes in BRCA-deficient mCRPC cfDNA suggests the potential for targeted treatment combinations in future trials.