Plasma Genotyping Shows High Specificity For EGFR, KRAS NSCLC Mutations

Noninvasive liquid biopsy assay could help avoid repeated tissue biopsies in treatment-naïve patients with non-small-cell lung cancer and those with acquired resistance

medwireNews: Plasma genotyping using droplet digital Polymerase chain reaction (ddPCR) has high specificity for the detection of driver mutations in EGFR and KRAS in newly diagnosed patients with nonsquamous non-small-cell lung cancer (NSCLC), report US researchers.

The assay also identified the EGFR T790M mutation in patients who had developed resistance to an EGFR kinase inhibitor, although the specificity was lower than that for activating mutations, they add in JAMA Oncology.

A total of 180 patients with advanced nonsquamous NSCLC, of whom 120 were newly diagnosed and 60 had acquired resistance to previous anti-EGFR therapy, underwent plasma genotyping for various EGFR and KRAS mutations. The reference standard was tissue genotyping of initial biopsy or rebiopsy samples, as appropriate.

ddPCR-based plasma genotyping had a specificity and a positive predictive value of 100% for identifying the EGFR Exon 19 deletion (19 del) and the EGFR L858R and KRAS G12X mutations. But among patients with acquired resistance, the specificity and positive predictive value for detecting the EGFR T790M mutation were lower, at 63% and 79%, respectively.

The study authors hypothesise that the lower assay specificity for the T790M mutation “is due to the genomic heterogeneity whereby the T790M status of the biopsied site is not representative of all metastatic sites in a patient”.

They also report that the sensitivity of the assay was “more modest”, with values of 82%, 74% and 77%, for the EGFR 19 del, L858R and T790M mutations, respectively, and 64% for KRAS G12X. Test sensitivity was significantly associated with the presence of hepatic and bone metastases and the number of metastatic sites, such that sensitivity improved with more extensive disease.

Researcher Adrian Sacher, from Dana-Farber Cancer Institute, Boston, Massachusetts, and team say that the assay is “ready to be used for clinical decision making in patients with advanced NSCLC” as it rapidly detects driver mutations with “minimal false-positive test results and with the robustness needed for real-world testing.”

“It has great utility for the detection of actionable genomic alterations in patients who are unable to a undergo repeat biopsy and may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity”, they conclude.

In an accompanying editorial, P Mickey Williams, from the Frederick National Laboratory for Cancer Research in Maryland, USA, and Barbara Conley, from the National Cancer Institute in Bethesda, Maryland, USA, point out that “the same sensitivity, specificity, and [positive predictive value] may not be replicated in a different clinical laboratory.”

“However, if this performance were generally applicable, this would indeed be an advance in clinical care, reducing the proportion of patients requiring biopsy, at least in the resistance setting.”

Although it is “a step in the right direction”, they write, in light of the low sensitivity of the assay and its inability to detect all molecular variants – such as ALK and ROS1 rearrangements – it “should not replace tumor biopsy assessment for initial treatment decision making.”

References

Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol 2016; Advance online publication 7 April. doi: 10.1001/jamaoncol.2016.0173

Williams PM, Conley BA. Clinical application of liquid biopsies. JAMA Oncol 2016; Advance online publication 7 April. doi: 10.1001/jamaoncol.2016.0240

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