High frequency of Exon 20 S768I EGFR mutation detected in malignant pleural effusions: a poor prognosticator of NSCLC?

Abstract

Lung cancer is the cause of a fourth of all cancer-related deaths. About a third of all lung adenocarcinoma tumours harbour mutations on exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. Detection of these mutations allows for targeted therapies in the form of EGFR Tyrosine kinase inhibitors. In our study, we utilized malignant pleural effusions (MPEs) as "liquid biopsies" to detect EGFR mutations when tissue biopsies were unavailable. We showed that a direct sequencing approach was likely to miss SNVs in MPEs. We then optimized an EGFR mutant-specific quantitative polymerase chain reaction-based assay and piloted it on n=10 pleural effusion samples (1 non-malignant pleural effusion as a negative control). 5/9 (55.55%) samples harboured EGFR mutations with 2/9 (22.22%) being exon 19 deletions and 3/9 (33.33%) had the S768I exon 20 mutation. The frequency of the S768I SNV in our study was significantly higher than that observed in other studies ([~]0.3%). Utilizing publicly available cBioPortal data, we report that patients with the S768I SNV had a shorter median survival time, progression-free survival time and lower tumor mutation count compared to patients with other EGFR mutations. These data suggest that this point mutation predicts poor prognosis as a result of aggressive disease, though studies in larger cohorts are necessary to confirm these findings. The high frequency of S768I mutations seen in our study also suggests that cancer cells harbouring these mutations may be superior in their ability to migrate, home or reside in pleural fluid.