Association of Clonal Hematopoiesis in DNA Repair Genes with Prostate Cancer Plasma Cell-Free DNA Testing Interference
This week we profile a recent publication in JAMA Oncology
from Dr. Colin Pritchard (pictured) at UW Medicine / Brotman Baty.
Can you provide a brief overview of your lab’s current research focus?
My research program is focused on developing and implementing innovative diagnostics for cancer patients. We have a specific focus on prostate cancer genetics. You can view my short bio here.
What is the significance of the findings in this publication?
Our study highlights an important limitation of most current cfDNA or “liquid biopsy” testing for men with prostate cancer. We found that blood cell mutations were commonly detected in blood plasma, and that these mutations could be misinterpreted as coming from prostate cancer. The results have important implications for guiding therapy with a newer class of cancer drugs called PARP inhibitors. Almost half the time that mutations related to FDA-approved indications for PARP inhibitor eligibility were detected in cfDNA they were derived from blood cell clonal hematopoiesis, and not related to prostate cancer. These interfering clonal hematopoiesis mutations were particularly common in older age groups.
Fortunately, there is a simple solution to improve the performance of cfDNA tests. We found that by using a paired whole blood control sample we were easily able to distinguish prostate cancer mutations in plasma cfDNA from blood cell clonal hematopoiesis. We have been using this paired testing approach for cfDNA testing at UW Medicine and the Brotman Baty Institute for Precision Medicine, but most of the currently available commercial cfDNA assays test only plasma, and cannot readily distinguish cancer mutations from blood cell interference. For this reason, we are concerned that men with the most advanced forms of prostate cancer may be incorrectly receiving PARP inhibitor therapy based on false positive cfDNA testing results.
What are the next steps for this research?
The next steps will include evaluating the scope of this issue in other cancer types where liquid biopsy is commonly done, and working with stakeholders to advocate for use of a whole blood control sample in liquid biopsy tests.
This work was funded by:
Brotman Baty Institute for Precision Medicine, Department of Defense, Prostate Cancer Foundation, Institute for Prostate Cancer Research, National Institutes of Health