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Advanced Lung Cancer Drivers, Targetable Mutations Identified in Liquid Biopsy Study

NEW YORK (GenomeWeb) – Results from a prospective analysis by researchers in the US and Australia suggests that targeted sequencing on circulating tumor DNA (ctDNA) can pick up actionable mutations in the majority of advanced non-small cell lung cancer (NSCLC) cases.

Investigators at Memorial Sloan Kettering Cancer Center, the University of Sydney's Northern Cancer Institute (NCI), and Resolution Bioscience — a liquid biopsy company that markets the hybrid-capture, next-generation sequencing-based 21-gene ctDx lung assay used in the analysis — used the ResBio assay to search for informative mutations in blood samples from 210 individuals with NSCLC who were enrolled consecutively at MSKCC or NCI.

For 106 of the cases, they also had access to targeted NGS data across 468 cancer-related genes, generated on tumor tissue biopsy samples analyzed with the MSK-IMPACT capture assay. Sufficient tumor tissue was not available for molecular testing in 39 of the cases. Additionally, the researchers assessed a subset of the blood plasma samples with an Archer RACE NGS assay to verify the accuracy of the ctDNA findings.

Overall, the results the team reported online today in the Journal of the National Cancer Institute suggest that ctDNA NGS can quickly and accurately identify targeted treatment-relevant mutations in patients with lung cancer.

"We are encouraged by these findings as we have demonstrated that plasma NGS genotyping is feasible, rapid, and useful in the real-world clinical practice for this patient population," corresponding author Bob Li, a medical oncologist with MSKCC's thoracic oncology service who also consults for Genentech Roche, Thermo Fisher Scientific, and Guardant Health, said in a statement.

With the ctDNA NGS approach, the team tracked down somatic mutations in 135 of the cases with a test turnaround time span of four to 22 days, and a median of nine days. Nearly 90 percent of the somatic changes found by ctDNA testing also turned up with NGS on tissue biopsies, which took 13 to 69 days, with a median of 20 days. Conversely, NGS on ctDNA in the non-invasively collected blood samples identified almost 61 percent of the somatic mutations detected using the tissue NGS analysis.

The researchers reported that the overall concordance between the somatic mutations found by NGS on the ctDNA and tissue biopsy samples increased to more than 96 percent when it came to uncovering oncogenic driver gene mutations, including mutations that pointed to targeted treatments with clinical responses in 46 of the cases.

"These findings provide prospective evidence to support the incorporation of plasma NGS into lung cancer practice guidelines," Li said.

In general, such sequencing analyses are especially informative for advanced NSCLC cases, since "tumors may harbor somatic alterations that are sensitized to targeted therapies," the authors noted, adding that sequencing "can also detect mutations mediating resistance in patients with known driver alterations after exposure to targeted agents."

The team noted that ctDNA detection rates tended to be lower in the 70 individuals with advanced NSCLC who were receiving systemic therapy. There, ctDNA NGS uncovered somatic mutations in almost 43 percent of cases compared to 75 percent detection in the 105 advanced NSCLC cases not receiving systemic treatment.

"Based on our findings," the authors wrote, "plasma NGS genotyping is best performed at initial diagnosis in conjunction with tissue biopsy and at the time of clinical or radiological progression, as the yield of ctDNA might be highest at those times based on its correlation with tumor burden."

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