ASCO GU 2021: Concordance of BRCA1, BRCA2, and ATM Mutations Identified in Matched Tumor Tissue and Circulating Tumor DNA in Men with Metastatic Castration-Resistant Prostate Cancer Screened in the PROfound Study

( In 2016, Colin Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC). This opened the potential for targeted therapy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors which lead to an accumulation of DNA single-stranded breaks which have particularly profound clinical consequences for patients who lack standard homologous recombination repair mechanisms as a result of mutations in important genes in this pathway, including BRCA1 and BRCA2. Early data supporting the use of the PARP inhibitor olaparib from the TOPARP-A trial found improvements in progression-free and overall survival in men with heavily pre-treated mCRPC.

Similar results were observed in the phase II TOPARP-B trial and subsequently confirmed in the phase III PROfound trial which demonstrated improved progression-free survival and overall survival for men with homologous recombination repair-deficient mCRPC following treatment with abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer who received olaparib, as compared to a switch in novel oral androgen-axis targeting agent. Inclusion in this trial required evidence of homologous recombination repair (HRR) gene alteration, which is typically determined by tumor tissue testing. However, tumor tissue testing will not be feasible for all patients with mCRPC. Notably, in PROfound, 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. In a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Kim Chi and colleagues evaluated the utility of plasma-derived ctDNA to identify deleterious BRCA and ATM mutations in screened patients from PROfound.

The methodology of PROfound has been previously reported and published but, to summarize, men with metastatic castrate-resistant prostate cancer who had progressed on previous abiraterone acetate or enzalutamide administered at the time of non-metastatic castrate-resistant prostate cancer or at the time of metastatic castrate-sensitive prostate cancer were recruited. Patients with prior taxane exposure were allowed. The investigators then used an investigational assay based on the FoundationOne CDx to identify alterations in one of 15 pre-specified genes involved in homologous recombination repair (BRCA 1/2, ATM, BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). The samples for this testing were clinically heterogeneous regarding location and timing of collection. Matched ctDNA samples were sequenced at Foundation Medicine, Inc with the FoundationOne Liquid CDx assay using plasma samples collected as part of screening in PROfound.

Among 619 ctDNA samples, 502 (815) 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), using the tissue assay result as reference.

Further, the authors found that concordance was high at a gene-specific level, including with respect to variant subtype detection.

The authors, therefore, conclude that there is high concordance between tumour tissue and ctDNA for the detection of HRR mutations. This may allow the use of ctDNA as a minimally invasive method to identify patients with HRR-gene-mutated mCRPC and guide treatment decisions.

Presented by: Kim N. Chi, MD, FRCPC, University of British Columbia, Vancouver, British Columbia

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021