New molecular classification of large cell neuroendocrine carcinoma and small cell lung carcinoma with potential therapeutic impacts

Large cell neuroendocrine carcinoma (LCNECs) and small cell lung carcinomas (SCLCs) are high-grade neuroendocrine carcinomas of the lung with very aggressive behavior and poor prognosis. Their histological classification as well as their therapeutic management has not changed much in recent years, but genomic and transcriptomic analyses have revealed different molecular subtypes raising hopes for more personalized treatment. Indeed, four subtypes of SCLCs have been recently described, SCLC-A driven by the master gene ASCL1, SCLC-N driven by NEUROD1, SCLC-Y by YAP1 and SCLC-P by POU2F3. Whereas SCLC standard of care is based on concurrent chemoradiation for limited stages and on chemotherapy alone or chemotherapy combined with anti-PD-L1 checkpoint inhibitors for extensive stage SCLC, SCLC-A variants could benefit from DLL3 or BCL2 inhibitors, and SCLC-N variants from Aurora kinase inhibitors combined with chemotherapy, or PI3K/mTOR or HSP90 inhibitors. In addition, a new SCLC variant (SCLC-IM) with high-expression of immune checkpoints has been also reported, which could benefit from immunotherapies. PARP inhibitors also gave promising results in combination with chemotherapy in a subset of SCLCs. Regarding LCNECs, they represent a heterogeneous group of tumors, some of them exhibiting mutations also found in SCLC but with a pattern of expression of NSCLC, while others harbor mutations also found in NSCLC but with a pattern of expression of SCLC, questioning their clinical management as NSCLCs or SCLCs. Overall, we are probably entering a new area, which, if personalized treatments are effective, will also lead to the implementation in practice of molecular testing or biomarkers detection for the selection of patients who can benefit from them.