Expanding therapeutic opportunities for Extra-Pulmonary Neuroendocrine Carcinoma

Poorly-Differentiated NeuroEndocrine Carcinomas (PD-NECs) are rare cancers garnering interest as they become more commonly encountered in clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of ‘NE lineage plasticity’, whereby non-NeuroEndocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC is challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Whilst advances have been made pertaining to molecular subtyping of Small Cell Lung Cancer (SCLC), a PD-NEC of lung origin, Extra-Pulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumour type-agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how ‘NE lineage plasticity’ can be leveraged for therapeutic purposes is discussed. SCLC is herein proposed as a paradigm for supporting progress towards precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.