Novel Sequencing Approach Detects Circulating Tumor DNA in 89% of Patients with Advanced Cancer

June 3, 2017

Conference | ASCO Annual Meeting

A new, high-intensity genomic sequencing approach for circulating tumor DNA uncovered at least 1 genetic change in both the tumor DNA and the blood of 89% of patients, demonstrating a high rate of concordance between 2 approaches for detecting molecular aberrations, according to a study presented at the 2017 ASCO Annual Meeting.

Pedram Razavi, MD, PhD

Overall, 73% of genetic changes found in tumor samples were also found in blood samples. Also, without any prior knowledge of the analysis of tumor tissue, researchers detected 76% of the actionable mutations in blood samples that were also found in the tumor samples, said lead study author Pedram Razavi, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

In a statement, ASCO said that this assay, “heralds the development of future tests for early cancer detection.”

“This novel, high-intensity sequencing assay incorporates an unprecedented combination of depth and breadth of coverage compared to the previous assays,” Razavi said at the Chicago meeting. He noted the ”high levels of concordance for variants between plasma and tissue provide evidence for high rates of tumor DNA detection in plasma.”

The assay detected at least 1 genetic change in 97% (95% CI, 87-100) of patients with metastatic breast cancer, 85% (95% CI, 71-94) of those with non—small cell lung cancer (NSCLC), and 84% (95% CI, 70-93) of those with metastatic prostate cancer.

Razavi et al detected a total of 864 genetic changes in tissue samples across the 3 tumor types including all genomic variations present in both clonal and subclonal tumor tissue; 627 (73%) of those genomic variations were also found in the blood.

“Across all tumor types, we found a very strong association between the fraction of cancer cells that harbor the mutation and detection rates of that particular mutation in the plasma,” Razavi said.

ASCO said the sequencing approach used in this study had a unique combination of breadth and depth, scanning 508 genes and more than 2 million base pairs or letters of the genome. Other liquid biopsies, including already available commercial tests, profile a much smaller portion of the genome in patients already diagnosed with cancer. The tests help to monitor disease and detect actionable alterations that can be matched to available drugs or clinical trials.

In this sequencing approach, each region of the genome was sequenced 60,000 times, yielding about 100 times more data than other sequencing approaches, researchers said. They said they hope this high-sequencing method will eventually lead to the development of an early-detection blood test for cancer in undiagnosed patients.

Razavi et al collected blood and tissue samples from 161 patients. Of those, 39 patients with metastatic breast cancer, 41 with metastatic NSCLC, and 44 with castration-resistant prostate cancer were evaluable for concordance analysis. Thirty-seven patients were excluded due to unavailability of the results of the genetic analysis of the tumor or cell-free DNA samples.

Researchers analyzed tumor tissues using MSK-IMPACT, a 410-gene diagnostic test that provides detailed genetic information about a patient’s cancer, and compared genetic changes in the tumors to those in circulating tumor DNA from the blood samples. Cell-free DNA and the genome of white blood cells were then sequenced separately using the high-intensity, 508-gene sequencing assay.

Todd M. Morgan, MD, a urological surgeon specializing in the treatment of genitourinary malignancies at the Michigan Medicine Urology Oncology Clinic in Ann Arbor, reviewed the data for OncLive^®. He said these results could eventually have an enormous effect in oncology practice.

“The concept of using ctDNA for early cancer detection is exciting and has great potential for use as a diagnostic tool given the mediocre performance of most tumor markers in the screening setting. That said, the barriers in this setting—both technological and biological—are tremendous, and that’s why most attention in the liquid biopsy field has been on developing assays that can help guide treatment decisions in patients with advanced disease,” he said. “This is an exponential leap forward for the liquid biopsy field. The sequencing depth, the concordance of the findings with the tissue-based analysis, and perhaps most importantly, the detection of some potential driver mutations only through plasma-based sequencing, are remarkable and suggest potential clinical utility of this platform in the advanced disease setting, at a minimum.”

Razavi P, Li BT, Abida W, et al. Performance of a high-intensity 508-gene circulating-tumor DNA (ctDNA) assay in patients with metastatic breast, lung, and prostate cancer. J Clin Oncol. 2017:(suppl 35; abstr LBA11516).

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