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Novel liquid biopsy assay rapidly identifies mutations in NSCLC
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The use of a rapid plasma genotyping assay exhibited high specificity in detecting epidermal growth factor receptor and KRAS mutations in patients with advanced non–small cell lung cancer, according to the results of a prospective validation study.
This assay may be used to effectively select treatment and avoid unnecessary repeat biopsies, according to the researchers.
Geoffrey R. Oxnard
“We see plasma genotyping as having enormous potential as a clinical test — a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies,” Geoffrey R. Oxnard, MD, assistant professor of medicine at Harvard Medical School and thoracic oncologist at Dana-Farber Cancer Institute, said in a press release. “Our study is the first to demonstrate prospectively that a liquid biopsy technique can be a practical tool for making treatment decisions in patients with cancer.”
Oxnard and colleagues conducted a study of 180 patients with advanced, nonsquamous NSCLC (median age, 62 years; range, 37-93; 62% women), the majority of whom (n = 120) were newly diagnosed. The remaining patients (n = 60) had acquired resistance to an EGFR kinase inhibitor and were scheduled for rebiopsy.
After initial blood sampling, the patients underwent an immediate plasma droplet digital polymerase chain reaction (ddPCR) for EGFR and KRAS mutations, including EGFR exon 19 deletion, EGFR L858R, KRAS G12X and EGFR T790M acquired resistance mutation.
All patients also underwent a biopsy for tissue genotyping to use as a reference standard for comparison with the liquid biopsy results.
Key study measures included the sensitivity and specificity of the plasma ddPCR assay, as well as test turnaround time, which the researchers defined as the number of business days between blood sampling and test reporting.
Tumor genotypes identified 80 EGFR exon 19 or L858R mutations, 35 EGFR T790M mutations, and 25 KRAS G12X mutations.
The assay had a median turnaround time of 3 days (range, 1-7). In contrast, tissue genotyping had a median turnaround of 12 days (range, 1-54) for newly diagnosed patients and 27 days (range, 1-146) for patients with acquired resistance.
ddPCR exhibited a positive predictive value of 100% for each EGFR exon 19 deletion (95% CI, 91-100), EGFR L858R (95% CI, 85-100) and KRAS (95% CI, 79-100). The predictive value for EGFR T790M acquired resistance mutation was 79% (95% CI, 62-91).
The sensitivity analysis showed an 82% sensitivity (95% CI, 69-91) for detecting EGFR exon 19 deletion, 74% sensitivity (95% CI, 55-88) for EGFR L858R mutation and 77% (95% CI, 60-90) for EGFR T790M acquired resistance mutation. The sensitivity for detecting KRAS mutations was 64% (95% CI, 43-82).
The test demonstrated greater sensitivity for patients with hepatic metastases (P = .001), bone metastases (P = .007) and multiple metastatic sites (P = .001).
The researchers acknowledged the assay’s inability to detect copy number alterations and rearrangements as a limitation.
Barbara A. Conley
“In some patients with the EGFR resistance mutation, ddPCR detected mutations missed by standard tissue biopsy,” Oxnard said. “A resistant tumor is inherently made up of multiple subsets of cells, some of which carry different patterns of genetic mutations. A single biopsy is only analyzing a single part of the tumor and may miss a mutation present elsewhere in the body. A liquid biopsy, in contrast, may better reflect the distribution of mutations in the tumor as a whole.”
These results were then validated at Dana-Farber Cancer Institute’s Lowe Center for Thoracic Oncology. Based on results of the validation study, the center now offers the assay to all patients with lung cancer, Lynette Scholl, MD, a pathologist as Dana-Farber Cancer Institute, said in a press release.
“We validated the authors’ findings by cross-comparing results from liquid and tissue biopsies in 34 patients with NSCLC," Scholl said. “To work as a real-world clinical test, liquid biopsy needs to provide reliable, accurate data and be logistically practical. That’s what we’ve seen with the ddCPR-based blood test.”
Although the study outcomes are encouraging, the use of genotyping assays will likely not be appropriate in all cases, P. Mickey Williams, PhD, director of the molecular characterization laboratory at the NCI’s Frederick National Laboratory for Cancer Research, and Barbara A. Conley, MD, associate director of the Cancer Diagnosis Program at the NCI, wrote in an accompanying editorial.
“This study is a step in the right direction of preparing needed clinical validation for the use of [liquid biopsy] for detection and serial monitoring of clinically relevant tumor mutations,” Williams and Conley wrote. “Owing to low sensitivity and high positive-predictive value and specificity, this approach is probably best suited for detection of resistance mutations and for serial plasma testing to assess treatment response, and should not replace tumor biopsy assessment for initial treatment decision making.” – by Cameron Kelsall
Disclosure: Oxnard reports honoraria from or consultant roles with Ariad, AstraZeneca, Boehringer Ingelheim, Chugai, Clovis Oncology and Sysmex. Please see the full study for a list of all other researchers’ relevant financial disclosures. Williams and Conley report no relevant financial disclosures.
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