Related Experiment Video
Updated: Aug 30, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with
Kim N Chi1, Alan Barnicle2, Caroline Sibilla3
1BC Cancer Agency, Vancouver, Canada.
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 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.
Patients And Methods:
Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®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 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.
Conclusions:
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.
Insights
Plasma circulating tumor DNA (ctDNA) testing effectively identifies BRCA and ATM alterations in metastatic castration-resistant prostate cancer (mCRPC) patients. This method complements tissue testing, especially when tumor tissue is insufficient for genomic analysis.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) diagnosis often requires multigene molecular testing.
- Tumor tissue availability can be a limitation for comprehensive genomic profiling.
- Identifying alterations in homologous recombination repair genes is crucial for targeted therapy selection.
Purpose of the Study:
- To evaluate the utility of plasma-derived circulating tumor DNA (ctDNA) for detecting BRCA1, BRCA2 (BRCA), and ATM alterations in mCRPC patients.
- To assess ctDNA as an alternative or complementary method to tumor tissue testing for genomic profiling.
- To determine the concordance between ctDNA and tumor tissue in identifying specific genetic alterations.
Main Methods:
- Prospective sequencing of tumor tissue using FoundationOne®CDx (FMI).
- Retrospective sequencing of matched plasma ctDNA using FoundationOne®Liquid CDx (FMI).
- Comparison of ctDNA and tissue sequencing results to determine concordance rates for BRCA and ATM alterations.
Main Results:
- 81% of ctDNA samples yielded a successful next-generation sequencing (NGS) result.
- High concordance was observed between ctDNA and tissue for BRCA and ATM status (81% positive, 92% negative agreement).
- Concordance varied by alteration type, with lower agreement for large rearrangements and homozygous deletions, influenced by ctDNA fraction.
Conclusions:
- Plasma ctDNA testing is a valuable tool to complement tumor tissue analysis in mCRPC.
- ctDNA testing can identify patients with BRCA or ATM alterations suitable for PARP inhibitor therapy.
- This approach is particularly beneficial for patients lacking sufficient tumor tissue for genomic evaluation.
