Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound

Purpose: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evalu-ated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.Patients and Methods: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an in-vestigational next-generation sequencing (NGS) assay based on FoundationOne (R) CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investi-gational assay based on FoundationOne (R) Liquid CDx.Results: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agree-ment and 92% negative percentage agreement, using tissue as refer-ence. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozy-gous deletions (27%), with low ctDNA fraction being a limiting factor.Conclusions: We demonstrate that ctDNA can greatly comple-ment tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.

Automated summary

This study evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying BRCA1, BRCA2, and ATM alterations in patients with metastatic castration-resistant prostate cancer. The results showed that ctDNA detection can complement tissue testing and serve as a valuable alternative for patients with no or insufficient tissue for genomic analyses.