Abstract
ObjectivesCirculating tumor (ct)DNA analysis is rapidly gaining acceptance as a diagnostic tool to guide clinical management of advanced non-small cell lung cancer (NSCLC). Clinically-actionable EGFR mutations can be detected in ctDNA before or after first-line EGFR-Tyrosine Kinase Inhibitor (TKI) treatment, but data are limited for patients with a complex treatment history. This study aimed to explore the feasibility of ctDNA testing in a clinical setting of NSCLC patients receiving osimertinib as a second or third line EGFR-TKI. Materials and MethodsTwenty EGFR T790M-positive NSCLC patients, who had received osimertinib as a second or third line EGFR-TKI and had donated blood samples while attending routine follow-up consultations between April and November 2016, were retrospectively selected to test plasma cfDNA for tumor-guided EGFR mutations. We used EGFR mutations previously identified in tumor-tissue to retrospectively test plasma ctDNA from 20 patients who had received osimertinib as a second or third line EGFR-TKI. Both EGFR-TKI sensitising and T790 M resistance mutations were analysed by droplet digital PCR (ddPCR) in plasma taken alongside routine consultations and ctDNA detection was correlated with response under osimertinib. Follow-up solid-tissue biopsies were obtained after disease progression. ResultsCtDNA was detected under osimertinib treatment in four out of the eight patients (50 %) who showed no response, two out of the seven (29 %) who showed an initial response and none of the five patients (0 %) who showed an ongoing response. The fraction of EGFR-mutant ctDNA in plasma tended to be higher in non-responders (0.1–68 %), compared to the initial responders (0.2–1.1 %). Blood samples were donated up to 34, 27 and 49 weeks after the start of osimertinib for the non-, initial and ongoing responders, respectively. ConclusionsThese findings support a potential role for ctDNA analysis in response monitoring of NSCLC patients with a complex EGFR-TKI treatment history. The weak trend between ctDNA detection and disease progression warrants larger studies to further investigate potential clinical utility.
Highlights
Mutations in the epidermal growth factor receptor (EGFR) gene are among the most clinically relevant biomarkers in non-small cell lung cancer (NSCLC) [1]
Using the highly sensitive droplet digital PCR technique, we aimed to investigate the relationship between the detection of tumorguided EGFR mutations in the ctDNA of patients receiving osimertinib as a second or third line EGFR-Tyrosine Kinase Inhibitor (TKI) and to explore the relationship with disease progression
This study shows the feasibility of EGFR-mutant ctDNA detection in patients treated with osimertinib after previous lines of EGFR-TKI
Summary
Mutations in the epidermal growth factor receptor (EGFR) gene are among the most clinically relevant biomarkers in non-small cell lung cancer (NSCLC) [1]. A more accessible bio-source may be circulating tumor (ct)DNA, the portion of cell-free (cf)DNA that originates from tumor cells [3]. In studies of NSCLC patients, ctDNA was shown to give a good representation of tumor EGFR status before EGFR-Tyrosine Kinase Inhibitor (TKI) treatment [4,5]. A significant correlation was found between pre-treatment ctDNA quantity and tumor volume, which can serve as a dynamic measure of tumor response under EGFR-TKIs [6,7,8]. The detection of emerging mutations in ctDNA can provide early signs of resistance, even before clinical confirmation using standard radiographic techniques [6,9]
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