Unrelated mutations can result in false-positive ends in males with superior prostate most cancers

Unrelated mutations, if present in the blood, can cause false positive results in men with advanced prostate cancer who are undergoing liquid biopsy. Such tests, which look for variants of the cell-free DNA that tumors release into the blood plasma, help determine appropriate treatment options.

You can actually measure what is happening to a patient’s tumor by taking a blood sample. “

Dr. Colin Pritchard, Associate Professor of Laboratory Medicine and Pathology in the University of Washington School of Medicine

Dr. Pritchard is also assistant director of the Genetics and Solid Tumors Laboratory at UW Medicine.

The tests can guide therapy for previously diagnosed cancers by finding mutations that may indicate an accurate medicine choice. Cell-free DNA testing offers the ease and convenience of testing a blood sample for patients with advanced cancer.

Still, Pritchard and his team point out the urgency to evaluate the performance of cell-free DNA testing in the field and to understand the sources of potential interference with the accuracy of the test results.

Two cancer treatment drugs recently approved by the U.S. Food and Drug Administration (FDA) are indicated for potential use when certain cell-free DNA mutations appear in the plasma of men whose prostate cancer has spread.

However, other types of non-cancer DNA mutations can leave blood cells and enter the plasma.

Precision medicine scientists are learning more about a phenomenon called “clonal hematopoiesis,” which can often interfere with cancer fluid biopsy results, Pritchard said. Mutations in some DNA repair genes – BRCA1, BRCA2, and ATM – are associated with male and female cancers.

“Unfortunately, the same genes are often mutated due to clonal hematopoiesis,” said Pritchard.

He and his research team from UW Medicine and the Brotman Baty Institute for Precision Medicine, a partnership between UW Medicine, Seattle Children’s, and the Fred Hutchinson Cancer Research Center, studied the extent to which clonal hematopoiesis adulterated prostate cancer fluid biopsy results.

They examined both the prevalence and the range of genes for this interference in patients who underwent cell-free DNA testing.

Her research report appears this week in the November 5th issue of the medical journal JAMA Oncology.

The researchers discovered that CHIP (clonal hematopoiesis with undetermined potential) variants accounted for almost half of the somatic DNA repair mutations detected by the fluid biopsy. The presence of these CHIP variants became exponentially more common as the patient ages.

False positives became an even bigger problem when two new classes of PARP inhibitors were approved for prostate cancer in May 2020 – rucaparib and olaparib. People with a positive fluid biopsy test may be candidates for these drugs. A false positive for these biomarker-driven treatments can lead to misdiagnosis and patients who receive unnecessary, unhelpful therapy.

About half the time the plasma is thought to contain a mutation that would guide therapy with these drugs, it actually contains CHIP variants, not prostate cancer DNA variants.

That means that in about half of the patients tested, a patient could be told to be given a drug that is not indicated for treating their cancer, Pritchard said.

Fortunately, solving this problem of possible misdiagnosis and misdirected treatment is fairly straightforward. Pritchard said that at UW Medicine and the Brotman Baty Institute for Precision Medicine, laboratory medicine workers are studying a type of paired control: the whole blood cells that hold the clonal hematopoiesis and the plasma.

“The good news is that you can tell with pretty good certainty whether something is cancer or something is hematopoiesis by looking at the blood cell compartment,” he said.

The research team noted that some of the limitations of their study were its small sample size (69 men), its retrospective approach, and the similarities within their patient population, including the men’s previous therapies.

Source:

University of Washington Health Sciences / UW Medicine

Journal reference:

Jensen, K. et al. (2020) Association of clonal hematopoiesis in DNA repair genes with cell-free DNA test interference in prostate cancer plasma. JAMA oncology. doi.org/10.1001/jamaoncol.2020.5161.

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