P2.03-03 Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions

Abstract

Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (∼10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers). Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line. Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown. In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.