Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome

Abstract

<b>Purpose:</b> Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the <i>RB1</i> mutated (mostly comutated with <i>TP53</i>) and the <i>RB1</i> wild-type groups. We assessed whether these subtypes have a predictive value on chemotherapy outcome.<b>Experimental Design:</b> Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for <i>TP53, RB1, STK11,</i> and <i>KEAP1</i> genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non-small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE).<b>Results:</b><i>RB1</i> mutation and protein loss were detected in 47% (<i>n</i> = 37) and 72% (<i>n</i> = 78) of the cases, respectively. Patients with <i>RB1</i> wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS [9.6; 95% confidence interval (CI), 7.7-11.6 months] than those treated with SCLC-PE [5.8 (5.5-6.1); <i>P</i> = 0.026]. Similar results were obtained for patients expressing RB1 in their tumors (<i>P</i> = 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an <i>RB1</i> mutation or lost RB1 protein.<b>Conclusions:</b> Patients with LCNEC tumors that carry a wild-type <i>RB1</i> gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for <i>RB1</i> mutated or with lost protein expression. <i>Clin Cancer Res; 24(1); 33-42. ©2017 AACR</i>.