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Liquid Biopsy Shows Promise in Prostate Cancer Across Multiple Biomarkers

NEW YORK (GenomeWeb) – A study published today by researchers from the Karolinska Institute in Sweden has added robust new data on the ability of liquid biopsy to detect a range of tumor-associated genomic alterations in the blood of advanced prostate cancer patients.

Although biomarker-directed therapy is in its infancy in prostate cancer compared to some other tumor types, there is a great need for predictive biomarker testing, and great interest in noninvasive methods, the authors wrote. However, comprehensive analysis of patients' cell-free DNA has been limited to date.

In their study, published in Genome Medicine today, the group sequenced cell-free DNA from 364 blood samples taken from 217 prostate cancer patients with metastatic, castration-resistant disease, using a combination of targeted and low-pass whole-genome sequencing.

Overall, the team detected circulating tumor DNA in 86 percent of samples. They were also able to measure differences in the levels of circulating tumor DNA that corresponded to how many treatments a patient had had.

Looking at specific biomarkers, such as the androgen receptor, that have emerged as potential clinical predictors for prostate tumors, the group found for example that the fraction of patients with intra-AR structural variation increased from about 15 percent during first-line therapy to over 45 percent in fourth-line treatment.

Overall, the genetic profiles of circulating tumor DNA the researchers measured closely mirrored that of metastatic tissue. They could detect a range of different genetic alterations, including single nucleotide variants, copy number alterations, and structural changes. About 18 percent of the patients displayed frequent alterations in DNA repair genes, also a growing focus of clinical biomarker efforts for these tumors.

In samples from patients with high tumor burden, inactivation of key tumor suppressors was biallelic rather than monoallelic, with only one exception, which they wrote "provides rationale for assuming a second hit in low ctDNA fraction samples with insufficient sensitivity to detect [this] second hit."

The investigators also calculated the level of microsatellite instability in a subset of samples, a measure that is increasingly used in the clinic to identify patients who are eligible for immunotherapies. About 3.8 percent of the cohort had high MSI based on the circulating DNA analysis.

Detecting MSI and other immunotherapy biomarkers in blood is a growing focus among liquid biopsy companies, with academic centers like Memorial Sloan Kettering Cancer Center reporting on blood-based MSI analysis, and firms like Guardant Health, Foundation Medicine, and Personal Genome Diagnostics now including MSI in their blood-based test products.

Another interesting finding in the Karolinska prostate cancer cohort was that the overall concentration of cell-free DNA in patients' blood was strongly correlated with the ctDNA fraction — something that is being investigated as a way of monitoring patients on or after certain treatments to try to anticipate, or catch, relapses.

Evidence in this prostate cancer cohort suggests that a simpler measure of overall cfDNA concentration could be a surrogate for tumor fraction in the blood.

Like some other studies, the Karolinska authors also detected genetic alterations and clonal expansion in patients' white blood cells, which they wrote could lead to false positives. A significant number of the patients had alterations representing this phenomenon, sometimes called clonal hematopoiesis of indeterminate potential, or CHIP.

There were 40 presumably false positive variants in 31 patients that would have been included in ctDNA mutational profiles if matched while blood cell DNA had not also been sequenced, the authors wrote.

Test makers have identified CHIP as a potential confounding factor for all liquid biopsy sequencing, but especially for academic groups and commercial firms working to train classifiers that can detect signs of early cancer in otherwise healthy people.

The Karolinska team's results supported a conclusion that matched normal sequencing may be necessary in blood-based assays to provide more accurate results and avoid false positives, authors wrote.

Based on the findings of the current study, the group has now initiated a prospective outcome-adaptive randomized biomarker-driven trial in patients with metastatic prostate cancer where ctDNA profiling will be applied to identify somatic alterations.

"The goal is to determine whether treatment choice based on a biomarker signature can improve progression-free survival compared to standard of care … and to evaluate the predictive capability of the investigated biomarker," they wrote.