Guide to detecting epidermal growth factor receptor (EGFR) mutations in ctDNA of patients with advanced non-small-cell lung cancer

Nicola Normanno _, Marc G. Denis, Kenneth S. Thress, Marianne Ratcliffe and Martin  Reck

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Oncotarget. 2017; 8:12501-12516. https://doi.org/10.18632/oncotarget.13915

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Nicola Normanno1, Marc G. Denis2, Kenneth S. Thress3, Marianne Ratcliffe4 and Martin Reck5

1 Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori “Fondazione Giovanni Pascale”, IRCCS, Napoli, Italy

2 Department of Biochemistry, Nantes University Hospital, Nantes, France

3 AstraZeneca, Waltham, MA, USA

4 AstraZeneca, Macclesfield, UK

5 Department of Thoracic Oncology, LungenClinic Grosshansdorf, Grosshansdorf, Airway Research Center North (ARCN), Member of the German Centre for Lung Research (DZL), Germany

Correspondence to:

Nicola Normanno, email:

Keywords: ctDNA, NSCLC, EGFR, T790M

Received: September 18, 2016 Accepted: November 24, 2016 Published: December 12, 2016


Cancer treatment is evolving towards therapies targeted at specific molecular abnormalities that drive tumor growth. Consequently, to determine which patients are eligible, accurate assessment of molecular aberrations within tumors is required. Obtaining sufficient tumor tissue for molecular testing can present challenges; therefore, circulating free tumor-derived DNA (ctDNA) found in blood plasma has been proposed as an alternative source of tumor DNA. The diagnostic utility of ctDNA for the detection of epidermal growth factor receptor (EGFR) mutations harbored in tumors of patients with advanced non-small-cell lung cancer (NSCLC) is supported by the results of several large studies/meta-analyses. However, recent real-world studies suggest that the performance of ctDNA testing varies between geographic regions/laboratories, demonstrating the need for standardized guidance. In this review, we outline recommendations for obtaining an accurate result using ctDNA, relating to pre-analytical plasma processing, ctDNA extraction, and appropriate EGFR mutation detection methods, based on clinical trial results. We conclude that there are several advantages associated with ctDNA, including the potential for repeated sampling – particularly following progression after first-line tyrosine kinase inhibitor (TKI) therapy, as TKIs targeting resistance mutations (eg T790M) are now approved for use in the USA/EU/Japan (at time of writing). However, evidence suggests that ctDNA does not allow detection of EGFR mutations in all patients with known mutation-positive NSCLC. Therefore, although tumor tissue should be the first sample choice for EGFR testing at diagnosis, ctDNA is a promising alternative diagnostic approach.

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