Liquid-Biopsy Testing in Prostate Cancer May Lead to Inappropriate Treatment

By David Douglas

November 12, 2020

NEW YORK (Reuters Health) - In men with prostate cancer, cell-free DNA (cfDNA) testing may be confounded by clonal hematopoiesis (CHIP) gene variants, leading some patients to be treated inappropriately with poly(ADP) ribose polymerase (PARP) inhibitors.

"Our study highlights an important limitation of most current cfDNA or 'liquid biopsy' testing for men with prostate cancer," Dr. Colin C. Pritchard of the University of Washington, in Seattle, told Reuters Health by email. "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 drugs called PARP inhibitors."

"Almost half the time that mutations related to (U.S. Food and Drug Administration)-approved indications for PARP inhibitor eligibility were detected in cfDNA, they were derived from blood-cell clonal hematopoiesis, and not related to prostate cancer," he said. "These interfering clonal hematopoiesis mutations were particularly common in older age groups."

Dr. Pritchard and colleagues examined 69 men with advanced prostate cancer who underwent cfDNA variant testing. To determine the source of variants, they also tested paired whole blood control samples.

Twenty patients showed pathogenic variants in relevant DNA repair gene variants, the researchers report in JAMA Oncology. CHIP variants at 2% or more variant fraction in cfDNA were seen in 13. Of these men, seven had variants in DNA-repair genes used to determine PARP inhibitor candidacy and would have been misdiagnosed and incorrectly deemed eligible for PARP-inhibitor therapy.

In fact, unknown to the researchers at the time, one of this latter group had already had a recommendation for PARP-inhibitor therapy from a commercial laboratory which used only plasma testing.

"Fortunately," continued Dr. Pritchard, "there is a simple solution to improve the performance of cfDNA tests. We found that by incorporating a paired whole-blood control sample into the test 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 . . . 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," he concluded, "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."

Dr. Joshi J. Alumkal of the University of Michigan, in Ann Arbor, who co-wrote an accompanying editorial, told Reuters Health by email that the results "provide a cautionary note on using cell-free DNA sequencing to identify patients with mutations in homologous recombination DNA-repair genes - gene mutations that are routinely used for PARP inhibitor treatment selection."

He added, "Understanding whether these mutations are due to tumor cells versus clonal hematopoiesis is critical to make the most well-informed decisions about patient management."

SOURCE: https://bit.ly/3n2pQCm and https://bit.ly/35eWOtp JAMA Oncology, online November 5, 2020.

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