OBJECTIVE: Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. MATERIALS AND METHODS: To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR(+) NSCLC patients with validation of results in an independent cohort (n = 130). RESULTS: EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR(+)NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. CONCLUSIONS: EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR(+) NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR(+) NSCLC.
- Christopoulos, P.
- Kirchner, M.
- Roeper, J.
- Saalfeld, F.
- Janning, M.
- Bozorgmehr, F.
- Magios, N.
- Kazdal, D.
- Volckmar, A. L.
- Bruckner, L. M.
- Bochtler, T.
- Kriegsmann, M.
- Endris, V.
- Penzel, R.
- Kriegsmann, K.
- Eichhorn, M.
- Herth, F. J. F.
- Heussel, C. P.
- El Shafie, R. A.
- Schneider, M. A.
- Muley, T.
- Meister, M.
- Faehling, M.
- Fischer, J. R.
- Heukamp, L.
- Schirmacher, P.
- Bischoff, H.
- Wermke, M.
- Loges, S.
- Griesinger, F.
- Stenzinger, A.
- Thomas, M.
Keywords
- Brain metastases
- Egfr(+) nsclc
- Overall survival
- TP53 mutation
- Treatment failure
- Tyrosine kinase inhibitor
