In a study reported in JAMA Oncology, Jensen and colleagues found that clonal hematopoiesis of indeterminate potential (CHIP) involving DNA repair genes can interfere with prostate cancer plasma cell-free DNA testing used to determine eligibility for poly (ADP-ribose) polymerase (PARP) inhibitor treatment and produce false-positive results in a sizable proportion of patients.
The study involved a retrospective review of data from 69 patients at the University of Washington, Seattle, with advanced prostate cancer, defined as metastatic disease or rising prostate-specific antigen following localized therapy. Plasma cell-free DNA and a paired whole-blood control sample were tested in all patients. CHIP interference was defined as a pathogenic variant with variant allele fractions of ≥ 2% in both whole blood and plasma. Germline variants were distinguished from CHIP clones via tumor sequencing.
CHIP interference clones with variant allele fractions of ≥ 2% were identified in cell-free DNA from 13 patients (19%). A total of seven men (10%) had CHIP variants in DNA repair genes used to determine PARP inhibitor candidacy, including ATM in five, BRCA2 in one, and CHEK2 in one.
Overall, 23 pathogenic variants in DNA repair genes used for the selection of PARP inhibitor therapy were detected in 20 patients; 8 were CHIP interference somatic variants, 9 were non-CHIP somatic variants, and 6 were germline variants. Germline variants and non-CHIP somatic variants (n = 15) were considered true positives, and CHIP interference variants (n = 8) were considered false positives.
On plasma-only analysis, 15 (65%) of the 23 variants were true positives. When the paired whole-blood control was used to eliminate CHIP interference variants, all 15 DNA repair gene variants were true positives (100%).
The presence of CHIP interference variants was correlated with increasing age (R2 = 0.82), with variants detected in 0% (0 of 6) of men aged 40 to 50, 12.5% (2 of 16) of men aged 51 to 60, 6.3% (1 of 16) of men aged 61 to 70, 20.8% (5 of 24) of men aged 71 to 80, and 71% (5 of 7) of men aged 81 to 90.
The investigators concluded, “In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cell-free DNA in DNA repair genes that are used for eligibility of PARP inhibitor therapy, most frequently in ATM. Clinical cell-free DNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.”
Colin C. Pritchard, MD, PhD, of the Department of Laboratory Medicine, University of Washington, Seattle, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by U.S. Department of Defense awards, grants from the National Cancer Institute, and others. For full disclosures of the study authors, visit jamanetwork.com.