High Concordance Between EGFR Mutations From ctDNA and Tumour Tissue in NSCLC

ctDNA as a surrogate for determination of EGFR status

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

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

International researchers prospectively analysed and compared tumour and matched plasma DNA for EGFR mutations from 1060 patients that were screened as part of a phase IV, open-label, single-arm, first-line gefitinib study in EGFR mutation positive Caucasian patients (NCT01203917). Also, when two plasma samples from the same patient were available the mutation status of each was compared.

The researchers reported their findings in the September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC). Available baseline tumour samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known).

EGFR mutation status can be accurately assessed using ctDNA

The mutation status concordance between tumour and matched plasma for 652 patients that had results for both was 94,3% with a sensitivity of 66,7% and specificity of 99,8%. The reproducibility between two plasma specimens from the same patient was also high with a mutation concordance of 96,9% for 224 matched specimens.

Objective response rates were as follows: mutation-positive tumour, 70%; mutation-positive tumour and plasma 1, 76.9%; and mutation-positive tumour and mutation-negative plasma 1, 59.5%.

Post-hoc analysis of the efficacy of first-line gefitinib revealed there was similar progression-free survival for those with EGFR mutation positive tissue (9.7 months) versus both mutation positive tissue and plasma (10.2 months).

The authors acknowledge 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."

Prof. Jean-Yves Douillard, lead author of the study, said in the IASLC press release 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 Prof. 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".

Reference

Douillard JY, Ostoros G, Cobo M,et al.Gefitinib Treatment in EGFR Mutated Caucasian NSCLC: Circulating-Free Tumor DNA as a Surrogate for Determination of EGFR Status. J Thorac Oncol 2014; 9(9):1345-53.