Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

Abstract

The aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma. We enrolled 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors. Of 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p = 0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, lymph node metastasis, and adjuvant chemotherapy use (p = 0.022; hazard ratio, 2.11; 95% confidence interval, 1.19-4.30). The difference in DFS between fusion-positive and fusion-negative patients was more prominent among patients with stage IB to IIB tumors (20.7 vs. 38.2 months; p = 0.046). Pleural (38.5% vs. 23.9%) and extrathoracic distant (46.2% vs. 35.8%) metastasis rates at the first recurrence were higher in fusion-positive patients. This study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.