Concordance of BRCA1, BRCA2 (BRCA), and ATM mutations identified in matched tumor tissue and circulating tumor DNA (ctDNA) in men with metastatic castration-resistant prostate cancer (mCRPC) screened in the PROfound study.

Abstract

26 Background: Not all mCRPC patients have available or sufficient tissue for multigene molecular testing. In the Phase 3 PROfound study, olaparib significantly improved radiographic progression-free survival compared with physician’s choice of abiraterone or enzalutamide in men with homologous recombination repair (HRR)-gene-mutated mCRPC (de Bono et al. N Engl J Med 2020). Overall, 31% of patients’ tissue samples failed molecular screening during the study, showing the need for additional testing methods to detect patients with HRR-gene-mutated cancers. We evaluated the utility of plasma-derived ctDNA to identify deleterious BRCA and ATM mutations in screened patients from PROfound. Methods: Tumour samples were prospectively tested at Foundation Medicine, Inc (FMI) using an investigational next-generation sequencing test (based on FoundationOne CDx) to inform trial eligibility. Matched ctDNA samples were sequenced at FMI with the FoundationOne Liquid CDx assay. Tissue samples were clinically heterogeneous regarding location and timing of collection; plasma samples were collected as part of screening in PROfound. Results: 81% (503/619) of ctDNA samples tested yielded a result, of which 491 had a tumour result. BRCA and ATM status in tissue compared with ctDNA reported 81% (95% CI 75–87%) positive percentage agreement (PPA) and 92% (95% CI 89–95%) negative percentage agreement (NPA), with tissue as reference (Table). Further concordance and discordance measures will be presented. Conclusions: High concordance between tumour tissue and ctDNA supports the development of ctDNA testing as a minimally invasive method to identify patients with HRR-gene-mutated mCRPC and guide treatment decisions, particularly for those with insufficient tissue for genomic analyses. Clinical trial information: NCT02987543. [Table: see text]

Optimal Sequencing and Predictive Biomarkers in Patients with Advanced Prostate Cancer

“…It has been shown that ctDNA can sufficiently identify all driver DNA alterations found in matched metastatic tissue in the majority of patients with mCRPC [ 156 ]. Data from the PROFOUND trial found a high concordance between tumor tissue and circulating tumor DNA (ctDNA), supporting the development of ctDNA testing as a minimally invasive method to identify patients with DDR-altered mCRPC [ 157 ]. In metastatic disease, ctDNA can identify somatic mutations, copy-number variations, and structural rearrangements that are predictive of response to therapies.…”

Prostate cancer and PARP inhibitors: progress and challenges

“…Eighty-one percent (503/619) of ctDNA samples tested yielded a result. High concordance between tumor tissues and ctDNA was found, with 81% positive percentage agreement and 92% negative percentage agreement [93]. Of the 181 patients in the BRCA/ATM cohort of the study who consented and provided a plasma sample for ctDNA testing, 42 (23.2%) samples failed analyses.…”

“…For instance, in the PROfound trial screening, 30% of biopsies were not suitable for DNA analysis [96]. High concordance between tumor tissues and ctDNA was found, with 81% positive percentage agreement and 92% negative percentage agreement [93]. Liquid biopsies may then be helpful.…”

Molecular Characterization of Prostate Cancers in the Precision Medicine Era

“…Another limitation for ctDNA analyses relates to the detection of larger genomic alterations. For example, durable responses to PARP inhibitors in prostate cancers are associated to homologous deletions of the BRCA2 gene [157], but the rate of concordance between tissue and blood based NGS is definitely low for the detection of deletion/rearrangement for BRCA2/1 and ATM (43%), in favor of the former [158]. This must be taken into account when choosing the analysis to be performed.…”