New insights into the molecular characteristics of pulmonary carcinoids and large-cell neuroendocrine carcinomas, and the impact on their clinical management.

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New insights into the molecular characteristics of pulmonary carcinoids and large-cell neuroendocrine carcinomas, and the impact on their clinical management.

J Thorac Oncol. 2018 Feb 14;:

Authors: Derks JL, Leblay N, Lantuejoul S, Dingemans AM, Speel EJM, Fernandez-Cuesta L

Abstract
Carcinoids and large-cell neuroendocrine carcinomas (LCNEC) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g. MEN1), and few affect genes of the PI3K-AKT-mTOR pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of OTP/CD44, and upregulation of RET gene expression. In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with bi-allelic inactivation of TP53 and RB1, a hallmark of small-cell lung cancer (SCLC); and the other one with bi-allelic inactivation of TP53 and STK11/KEAP1, genes that are frequently mutated in non-small cell lung cancer (NSCLC). These data, together with the identification of common mutations in the different components of combined LCNEC-NSCLC tumors, provides further evidence of the close molecular relation of LCNEC with other lung tumor types. In terms of therapeutic options, future studies should explore the association between mTOR pathway mutations and response to mTOR inhibitors in carcinoids. For LCNEC, preliminary data suggest that the two molecular subtypes might have a predictive value for chemotherapy response, but this observation needs to be validated in randomized prospective clinical trials. Finally, DLL3 inhibitors and immunotherapy may provide alternative options for patient-tailored therapy in LCNEC.

PMID: 29454048 [PubMed - as supplied by publisher]

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