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Tumor assay identifies DNA alterations in castration-resistant prostate cancer
A circulating tumor DNA assay sufficiently identified driver DNA alterations in metastatic tissue in patients with castration-resistant prostate cancer, according to findings published in the Journal of the National Cancer Institute.
“Circulating cell-free tumor DNA is an emerging biomarker across a range of solid malignancies, including metastatic castration-resistant prostate cancer,” Alexander J. Wyatt, PhD, the department of urologic sciences at the Vancouver Prostate Centre, University of British Columbia, and colleagues wrote. “Cell-free DNA is shed into the bloodstream by nonmalignant and cancer cells, but in metastatic castration-resistant prostate cancerthe proportion of tumor-derived cell-free tumor DNA is frequently greater than 1%, enabling comprehensive tumor genome profiling.
with somatic previously metastatic tissue profilingmatched liquid and solid biopsies
The researchers performed targeted sequencing on 72 genes in 45 plasma samples of cell-free DNA collected during metastatic tissue biopsy. Wyatt and colleagues then compared alterations in circulating tumor DNA with exome sequencing data from matched tissuequantify the coper number alterations and concordance of mutations.
75.6% showed a proportion of circulating tumor DNA that was more than 2% of total cell-free DNA. All somatic mutations in those samples also present in patients’ circulating tumor DNA.
Circulating tumor DNA and tissue samples also showed “a remarkably similar” hierarchy of variant allele fractions for shared mutations. strong correlation between copy number profiles of the matched solid and liquid biopsies, with an 88.9% concordance of individual copy number cells in clinically actionable genes.
Among the alterations researchers detected, 22 (64.7%) samples showed AR amplifications and (8.8%) showed SPOP mutations. Inactivating alterations occurred in tumor suppressors TP53, PTEN, RB1, APC, CDKN1B, BRCA2 and PIK3R1.
Circulating tumor DNA sequencing showed “robust changes” that did not appear in solid biopsies in several men. These changes included clinically relevant in the pathways of AR, WNT and P13K.
“The interrogation of metastatic tissue biopsies has suggested that real-time knowledge of the somatic genome can influence clinical management,” the researchers wrote. “A ‘liquid’ biopsy using plasma circulating tumor DNA offers a minimally invasive and practical tool to access such information.
Importantly, this supports the development of DNA biomarkers to guide metastatic castration-resistant prostate cancer management based on circulating tumor DNA alone” – by Andy Polhamus
Disclosure : The researchers report no relevant financial disclosures.
Perspective
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The increasing appreciation that molecular characterization can aid in clinical decision making has been informed by work from a number of groups around the world demonstrating that as many as 25% of men with metastatic castration-resistant prostate cancer harbor mutations of DNA repair. Obtaining tumor tissue in prostate cancer can be challenging given that it is a bone-predominant disease, thus the increasing interest in liquid biopsies. In an effort to characterize the accuracy of liquid biopsies versus data obtained from analysis of biopsy/surgical material Wyatt and colleagues conducted a trial to compare the results of liquid biopsies vs. exome sequencing from matched tissue. Their findings — which are limited to some extent by the lack of control of the sequencing methods used — suggests a relatively high rate of concordance between these two methods. If their findings are supported by additional evidence, this will provide patients and clinicians a far more patient-friendly means to ascertain the somatic mutational status, which will likely help guide therapy.