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Updated: Aug 16, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Detection of BRCA1, and BRCA2 Alterations in Matched Tumor Tissue and Circulating Cell-Free DNA in Patients with
Taylor Ryan McFarland1, Vinay Mathew Thomas1, Roberto Nussenzveig2
1Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Background:
Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious BRCA1 and/or 2 mutations. Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of BRCA mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting.
Methods:
Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect.
Results:
The presence or absence of mutations in the BRCA gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0-232) months. BRCA mutation was present in the patient's original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% [95% CI, 95.3-99.1%]. The adjusted concordance between metastatic samples and cfDNA was 93.5% [95% CI, 86.4-97.3%]. Of the patients who had a BRCA mutation detected in their prostate tissue, there was a 70% probability of detecting a BRCA mutation in the patient's cfDNA as well. For patients who did not have a detectable BRCA mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%.
Conclusion:
There is a high level of concordance between tissue and blood for BRCA mutations. Testing cfDNA can provide reliable information on BRCA mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new BRCA mutation later in the disease course is a rare event.
Insights
Circulating cell-free DNA (cfDNA) testing shows high concordance with tumor tissue for detecting BRCA mutations in metastatic prostate cancer. This blood test offers a reliable alternative when tissue biopsy is not feasible.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors are effective for metastatic castration-resistant prostate cancer (mCRPC) with BRCA mutations.
- Identifying patients with these mutations can be challenging.
- Circulating cell-free DNA (cfDNA) offers a less invasive method for mutation detection.
Purpose of the Study:
- To evaluate the concordance of BRCA mutations between tumor tissue and cfDNA in real-world mCRPC patients.
- To assess the reliability of cfDNA for BRCA mutational status determination.
Main Methods:
- Somatic genomic profiling of paired tumor tissue and cfDNA samples from 260 mCRPC patients.
- Analysis of concordance rates, adjusting for cfDNA platform limitations.
- Assessment of mutation detection probability in cfDNA based on tissue results.
Main Results:
- High adjusted concordance between primary tumor tissue and cfDNA (97.9%) and between metastatic tissue and cfDNA (93.5%).
- BRCA mutations were found in 3.9% of patients' original prostate tissue.
- A 70% probability of detecting a BRCA mutation in cfDNA if present in primary tissue; subsequent mutations are rare.
Conclusions:
- High concordance supports cfDNA as a reliable alternative to tissue biopsy for assessing BRCA mutational status in mCRPC.
- cfDNA testing provides actionable information for PARP inhibitor eligibility.
- De novo BRCA mutations developing later in the disease course are infrequent.
