Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms

Abstract

Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care. Experimental Design: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8. Conclusions: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants. See related commentary by Hawkey and Armstrong, p. 2961

Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples

“…33 In prostate cancer, liquid biopsy may be particularly appealing in patients with very old diagnostic tissue or bone-only disease. 37 Encouragingly, sensitivity for actionable BRCA1/2 mutations was 93% in a comparison of cfDNA FoundationACT/One Liquid versus FoundationOne tissue testing in CRPC rucaparib screening studies; however, cfDNA-exclusive mutations had low VAF relative to cfDNA-based TC, 38 suggesting that they may be subclonal and thus of unclear therapeutic relevance. Likewise, BRCA2 deep deletion detection is critical but challenging as detection (via tissue or cfDNA) requires 30%-40% TC; however, < 25% of patients in the cfDNA-based rucaparib studies had ≥ 35% cfDNA TC 38 versus 79.5% of the 2,045 prostate cancer samples having ≥ 35% tissue TC herein.…”

“… 37 Encouragingly, sensitivity for actionable BRCA1/2 mutations was 93% in a comparison of cfDNA FoundationACT/One Liquid versus FoundationOne tissue testing in CRPC rucaparib screening studies; however, cfDNA-exclusive mutations had low VAF relative to cfDNA-based TC, 38 suggesting that they may be subclonal and thus of unclear therapeutic relevance. Likewise, BRCA2 deep deletion detection is critical but challenging as detection (via tissue or cfDNA) requires 30%-40% TC; however, < 25% of patients in the cfDNA-based rucaparib studies had ≥ 35% cfDNA TC 38 versus 79.5% of the 2,045 prostate cancer samples having ≥ 35% tissue TC herein. Last, CHIP is particularly relevant in prostate cancer as a recent cfDNA-based laboratory-developed test found 10% of men harbored CHIP variants in olaparib-associated HRD genes, most frequently ATM .…”

Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic

“…The most recent and largest study on ctDNA in advanced PCa demonstrated high concordance between alterations identified by liquid and tissue biopsy and, moreover, proved the added value of liquid biopsy [ 42 ]. Out of the 3334 plasma samples from patients with mCRPC (including 1674 screening samples from TRITON2/3), 94% had detectable ctDNA (median ctDNA fraction, 7.5%; interquartile range, 0.8–34%).…”

Prostate Cancer in 2021: Novelties in Prognostic and Therapeutic Biomarker Evaluation

“…However, the NGS assay used should be designed to reveal deletions and rearrangements in the target genes. In the recently published study by Tukachinsky et al on the genomic analysis of circulating tumor DNA (ctDNA) in 3334 patients with advanced PCa, only 9% of patients reported an alteration in this pathway because the platforms used in the study were not designed to detect deletions, leading to marked under-detection [ 30 ].…”

“…However, the NGS assay used should be designed to reveal deletions and rearrangements in the target genes. In the recently published study by Tukachinsky et al on the genomic analysis of circulating tumor DNA (ctDNA) in 3334 patients with advanced PCa, only 9% of patients reported an alteration in this pathway because the platforms used in the study were not designed to detect deletions, leading to marked under-detection [30]. BRCA2-mutant PCa harbor increased genomic instability and a mutational profile similar to metastatic rather than localized disease BRCA2-mutant PCa are uniquely aggressive, often occur in young men, have higher rates of lymph node and distant metastasis, and increased mortality, justifying aggressive initial treatment RNA-based analyses have been developed in order to guide management decisions for very low-risk and low-risk primary PCa.…”