EGFR mutations in circulating tumor DNA (ctDNA) can be used in place of tumor tissue in non-small cell lung cancer (NSCLC) diagnostics

Epidermal growth factor receptor (EGFR) mutations found in circulating free tumor DNA (ctDNA) in the plasma of patients with advanced non-small cell lung cancer (NSCLC) correlates well with the EGFR mutations from patient-matched tumor tissue DNA.

EGFR tyrosine kinase inhibitor (TKI) therapy is approved for patients with advanced NSCLC that is positive for the EGFR-activating mutation. However, the standard for determining mutation status is with DNA derived directly from tumor tissue, which can be limited or not available. A more abundant and less invasive source of tumor DNA may be cell-free tumor DNA found circulating in the blood.

International researchers prospectively analyzed and compared tumor and matched plasma DNA for EGFR mutations from 1,060 patients who were screened as part of a phase IV, open-label, single-arm, first-line gefitinib in EGFR mutation-positive Caucasian patients. Also, when two plasma samples from the same patient were available, the mutation status of each was compared. The study was published in the Journal of Thoracic Oncology (2014;9[9]:1345-1353).

The mutation status concordance between tumor and matched plasma for 652 patients that had results for both was 94%, and their sensitivity was 66% and specificity was 100%. The reproducibility between two plasma specimens from the same patient was also high with a mutation concordance of 97% for 224 matched specimens. Post-hoc analysis of the efficacy of first-line gefitinib revealed that progression-free survival (PFS) was similar for those with EGFR mutation-positive tissue (9.7 months) versus both mutation-positive tissue and plasma (10.2 months).

The authors acknowledged that "tumor tissue should be considered the preferred sample type when available, however, our encouraging results suggest that a single plasma-derived ctDNA sample may be considered appropriate for assessment of EGFR mutation status when tumor tissue is unavailable or exhausted.”

"As there are no published guidelines for the use of ctDNA for EGFR mutation analysis in the absence of tumor tissue, these results may help address this current unmet need," said lead author Jean-Yves Douillard, MD, PhD, of Institut de Cancerologie, Centre René Gauducheau in Nantes, France. He added that his next steps are to "look for resistance mutations, like T790M, during treatment to better understand mechanisms of resistance and anticipate later line treatment at progression".

For future research, Douillard also suggests "searching for other resistance mutations along the EGFR pathway, as well as other related pathways, and improving the sensitivity by using more powerful testing methods, like next generation sequencers."

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