Background: ALK rearrangement and EGFR mutation are significant molecular subtypes of non-small cell lung cancer (NSCLC) that are targets for different tyrosine kinase inhibitors (TKIs). We tested a large cohort of NSCLC patients for ALK, EGFR and KRAS abnormalities and correlated clinical factors with the ALK fusion gene and overall survival (OS). Methods: ALK status was detected by RACE sequencing; EGFR and KRAS status were also detected by direct DNA sequencing. OS was estimated by the Kaplan-Meier method. Results: 294 consecutive, unselected, banked NSCLC cases were tested; 27 (9.2%), 79 (29.2%) and 26 (9.6%) patients were ALK-, EGFR- and KRAS-positive, respectively. ALK rearrangement and EGFR mutation were largely exclusive (r=−0.15, P=0.007) although two cases were both ALK- and EGFR-positive. In non-parametric tests, ALK-positivity was associated with female gender (χ2=5.189; P=0.023), non/light-smoking (χ2=6.067; P=0.014) and adenocarcinoma (χ2=4.301; P=0.038). The ALK fusion partner was EML4 in all 27 cases; EML4-ALK fusion variants V1, V2 and V3 (V3a/V3b/V3c) made up the majority (24/27) of EML4-ALK fusions. There were no significant OS differences between ALK-positive, EGFR-mutant, KRAS-mutant and triple-negative groups, between ALK-positive and -negative patients, or when ALK-positive cases were matched 1:2 or 1:1 with (non-TKI-treated) controls balancing for disease stage, gender, histology and EGFR/KRAS status. In ALK-positive patients, bivariate analysis found that non- or light-smoking status (P=0.016) and prior surgery (P=0.024) were associated with increased OS and a multivariate Cox regression model found that disease stage and surgical treatment were prognostic for OS. In a multivariate logistic regression model, female gender (HR=2.793; P=0.041), wild type EGFR (HR=15.147; P=0.001), non/light-smoking (HR=3.572; P=0.020) and adenocarcinoma (HR=5.713; P=0.024) were significantly associated with ALK-rearrangement. Conclusion: Overall, the ALK fusion gene occurred in 9.2% of NSCLC patients, and was associated with non/light-smoking history, adenocarcinoma histology and female gender. ALK fusion variants were mostly V1-3, which may inform ALK screening by RT-PCR. ALK rearrangement was not a favorable prognostic factor in NSCLC, although smoking history may influence OS in ALK-positive patients. A TKI (crizotinib) now exists for ALK-positive NSCLC and may improve OS in these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4504. doi:1538-7445.AM2012-4504