CHICAGO – An experimental liquid biopsy method plumbs the depths of the genome to detect a broad array of mutations in blood samples that closely correspond to variants in tumors.
The high-intensity method for detecting circulating free DNA (cfDNA) in plasma detected at least one significant genetic variant in samples from 89% of patients with advanced breast, lung, and prostate cancers.
If validated in further studies, the technique could inform more accurate drug selection in patients with refractory disease and eventually may form the basis for plasma-based assays to detect early-stage cancers, said Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
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Dr. Pedram Razavi
“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to previous assays. High levels of concordance for variants between plasma and tissue provide strong evidence for high rates of tumor DNA detection in plasma,” he said at a press briefing at the annual meeting of the American Society of Clinical Oncology.
The technique also provides important insights into tumor biology, “including first exploration of mutational signatures in the plasma,” he added.
Deep scanning
The high-intensity sequencing method scans for 508 genes in a 2 million base-pair swath of genome, performing 60,000 repeat reads on each genome region to improve the assay’s sensitivity, and deep sequencing allows for detection of rare “needle-in-a-haystack” variants.
Dr. Razavi and his colleagues examined prospectively collected blood and tissues from 161 patients, 124 of whom had samples sufficient for concordance studies.
The samples were collected within 6 weeks of a de novo cancer diagnosis or evidence of disease progression, before the initiation of therapy.
Both cfDNA and genomic data from white blood cells (WBCs) of each patient were sequenced with the aforementioned 508-gene panel covering a broad range of known cancer variants and mutations.
Tumor tissues were sequenced with MSK-IMPACT, a 410 gene assay, with blinding of results in regard to plasma and WBC sequencing. Variants were classified as clonal or subclonal based on tumor sequencing in breast cancer and non–small cell lung cancer (NSCLC).
As noted before, 89% of patients had at least one genetic variant detected in both the tumor and in plasma, including 97% of patients with metastatic breast cancer, 85% of those with NSCLC, and 84% of patients with metastatic prostate cancer.
The investigators identified 864 clonal or subclonal variants in tissue samples from all three of these cancers, and 627 of the variants also were found in plasma.
In addition, 76% of clinically actionable somatic mutations identified in tumors also were found in plasma, which suggests that the high-intensity sequencing technique may be able to identify tumor heterogeneity that is not always evident in single tumor biopsies, Dr. Razavi said.
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Dr. John Heymach
‘A clear advance’
“The work by Dr. Razavi and colleagues is a clear advance in the field because it surveys for the first time a much broader panel of genes – 508 genes in this case – and it does it with much deeper sequencing, which means it can detect much rarer alterations,” commented ASCO expert John Heymach, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.
The study “helps illuminate a path toward a day when we will be using circulating tumor DNA assays for early detection of cancer, and not just for selecting certain therapies,” he added.
“We’re a long way from utilizing liquid biopsy for detecting cancers; already though, we’re seeing some utility of circulating tumor DNA in the domain of identifying novel alterations as a means of segmentation clinical trials,” commented ASCO expert Sumanta Kumar Pal, MD, from City of Hope in Duarte, Calif.
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Dr. Sumanta Kumar Pal
Dr. Heymach and Dr. Pal were not involved in the study, but were invited discussants at the briefing.
The study was funded in part by GRAIL. Dr. Razavi reported institutional research funding from the company. Multiple coauthors are employees of the company.