Next-Generation Sequencing May Discriminate Extreme Long-term versus Short-term Survival in Patients with Metastatic Small Cell Lung Cancer (SCLC)

BACKGROUND: Molecular underpinnings that may prognosticate survival could increase understanding of small cell lung cancer (SCLC) tumor behavior. Here, we report the clinicopathological characteristics and biomarker profiles of short-term (ST) versus long-term (LT) survival in patients with metastatic SCLC. METHODS: Of the 876 consecutive metastatic SCLC patients receiving standard of care therapy, 44 met the definition of LT and 91 for ST, respectively. Available FFPE tumor tissue blocks were analyzed by next-generation sequencing (NGS). Analysis included gene mutations, copy number variations, mRNA expression, and protein expression by immunohistochemistry, followed by correlation with clinicopathological characteristics. RESULTS: There were no statistically significant and clinically relevant differences in cases with or without FFPE according to major clinicopathological variables in ST and LT. However, according to NGS, five mutually exclusive gene mutations were identified (E1A binding protein P300 [EP300] p.N217S; p.E152K; human epidermal growth factor receptor 4 [ERBB4] p.E317K; BRCA1, DNA repair associated [BRCA1] p.E1661N, and epidermal growth factor receptor [EGFR] p.V742A). Comparing LT vs. ST survivals, a twofold increase was found in the average predicted number of drugs per patient off compendium. We found high SSTR2 mRNA expressions in all LT patients (vs. two [20%] ST patients), which may reflect more benign neuroendocrine tumor characteristics. CONCLUSIONS: Consolidation radiation therapy and higher predicted drug sensitivity for off compendium were associated with LT compared to ST patients in SCLC. NGS profiling of extreme survivals may improve classification of SCLC and possibly identify clinically relevant new targets.