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

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 evaluated 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.

Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®Liquid to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.

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 agreement and 92% negative percentage agreement, using tissue as reference. 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 homozygous deletions (27%), with low ctDNA fraction being a limiting factor.

We demonstrate that ctDNA can greatly complement 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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Aug 31 [Epub ahead of print]

Kim N Chi, Alan Barnicle, Caroline Sibilla, Zhongwu Lai, Claire Corcoran, J Carl Barrett, Carrie A Adelman, Ping Qiu, Ashley Easter, Simon Dearden, Geoffrey R Oxnard, Neeraj Agarwal, Arun Azad, Johann de Bono, Joaquin Mateo, David Olmos, Antoine Thiery-Vuillemin, Elizabeth A Harrington

BC Cancer Agency, Vancouver, Canada., Translational Medicine, AstraZeneca, Cambridge, United Kingdom., Precision Medicine and Biosamples, AstraZeneca, Cambridge, United Kingdom., Translational Medicine, AstraZeneca, Waltham, Massachusetts., Merck & Co., Inc., Rahway, New Jersey., Oncology Business Unit, AstraZeneca, Cambridge, United Kingdom., Foundation Medicine, Inc., Cambridge, Massachusetts., Huntsman Cancer Institute, University of Utah (NCI-CCC), Salt Lake City, Utah., Peter MacCallum Cancer Centre, Melbourne, Australia., The Institute of Cancer Research and The Royal Marsden, London, United Kingdom., Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain., Department of Medical Oncology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., PH Medical Oncology Unit, CHU Besançon, Besançon, France.