medwireNews: Comprehensive circulating tumor (ct)DNA analysis can identify therapeutically targetable driver and resistance mutations in patients with advanced non-small-cell lung cancer (NSCLC), research indicates.
“These findings add support for comprehensive ctDNA testing in patients who are incompletely tested at the time of diagnosis and as a primary option at the time of progression on targeted therapies,” say Philip Mack (The Tisch Cancer Institute, New York, USA) and colleagues.
As described in Cancer, the researchers analyzed genomic data from 8388 patients who underwent ctDNA profiling between June 2014 and October 2016 with the 54-, 68-, or 70-gene panel version of the Guardant360 (Guardant Health, Inc, Redwood City, California, USA) next-generation sequencing platform, either at the time of diagnosis or progression.
Somatic alterations were detected in 86% of all analyzed samples, while driver oncogene mutations were found in 48.4% of the 6087 patients tested using the 70-gene panel.
EGFR mutations were the most common of the driver mutations, observed at a rate of 26.4%, followed by KRAS mutations and MET amplification, at 17.2% and 5.7%, respectively. Other driver mutations, such as BRAF and ERBB2 mutations, ALK fusions, and MET exon 14 skipping mutations were detected at rates ranging from 2.8% to 0.4%.
Among the 447 patients who had available samples at the time of progression on an EGFR–tyrosine kinase inhibitor (TKI), 50% harbored the EGFR T790M resistance mutation, with MET amplification (11.4%), PIK3CA activating mutations (8.9%), and ERBB2 amplification (5.4%) the next most common resistance mechanisms. The EGFR C797S resistance mutation was present in five patients, all of whom had progressed on a third-generation TKI.
Reporting data on the subset of 1288 patients who underwent both liquid and tissue-based testing, Mack and team highlight that “[t]he clinical utility of liquid biopsies is enhanced by the identification of actionable biomarkers that are not detected in the diagnostic tissue specimen.”
Specifically, ctDNA genotyping identified driver mutations in an additional 252 patients, half of whom became eligible for targeted therapy, while the remainder were ruled out due to the detection of KRAS mutations.
And a literature review of 10 studies that reported on outcomes of ctDNA-directed targeted therapy showed comparable pooled response rates to those seen in the pivotal trials of the agents, which relied on tissue biopsies.
Mack and team therefore conclude that “clinicians may consider a plasma-first option, defaulting to a new tissue biopsy only in the absence of a clinically meaningful finding in the plasma.”
In an accompanying commentary, Maisam Makarem and Natasha Leighl, both from the University of Toronto in Ontario, Canada, emphasize that “plasma first does not mean plasma only.”
They continue: “It is time to integrate plasma [ct]DNA testing into the molecular diagnosis of lung cancer and acquired resistance to targeted therapy.
“In the near future, we anticipate evidence to support its utility in screening, detection of minimal residual disease after curative therapy, response monitoring, and adaptive treatment planning, as well as growing use of other technologies, including the use of exosomes, circulating tumor cells, methylation, DNA fragment length analysis, and more.”
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