Lantuejoul Sylvie, Fernandez-Cuesta Lynnette, Damiola Francesca, Girard Nicolas, McLeer Anne
Department of Biopathology, Pathology Research Platform- Synergie Lyon Cancer- CRCL, Centre Léon Bérard Unicancer, Lyon, France.
Université Grenoble Alpes, Grenoble, France.
Transl Lung Cancer Res. 2020 Oct;9(5):2233-2244. doi: 10.21037/tlcr-20-269.
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.
大细胞神经内分泌癌（LCNEC）和小细胞肺癌（SCLC）是肺部的高级别神经内分泌癌，具有极强的侵袭性且预后较差。近年来，它们的组织学分类以及治疗管理变化不大，但基因组和转录组分析揭示了不同的分子亚型，为更个性化的治疗带来了希望。事实上，最近已描述了SCLC的四种亚型，由主控基因ASCL1驱动的SCLC-A、由NEUROD1驱动的SCLC-N、由YAP1驱动的SCLC-Y以及由POU2F3驱动的SCLC-P。SCLC的标准治疗方案是，局限期采用同步放化疗，广泛期采用单纯化疗或化疗联合抗PD-L1检查点抑制剂，而SCLC-A变体可能受益于DLL3或BCL2抑制剂，SCLC-N变体可能受益于极光激酶抑制剂联合化疗，或PI3K/mTOR或HSP90抑制剂。此外，还报道了一种具有高表达免疫检查点的新SCLC变体（SCLC-IM），其可能受益于免疫疗法。PARP抑制剂与化疗联合在一部分SCLC中也取得了有前景的结果。关于LCNEC，它们代表了一组异质性肿瘤，其中一些表现出在SCLC中也发现的突变，但具有NSCLC的表达模式，而另一些则具有在NSCLC中也发现的突变，但具有SCLC的表达模式，这对将它们作为NSCLC或SCLC进行临床管理提出了质疑。总体而言，我们可能正在进入一个新领域，如果个性化治疗有效，这也将导致在实践中实施分子检测或生物标志物检测，以选择能够从中受益的患者。
