Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma

Abstract

Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage plasticity," whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are 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. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-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 are discussed. SCLC is herein proposed as a paradigm for supporting progress toward 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.

Figure 1. Classification of Neuroendocrine Neoplasms.

A) Table describing the current nomenclature according to the 2018 International Agency for Research on Cancer and World Health Organisation (WHO) consensus framework(3), and the 2019 WHO Classification of Tumours of the Digestive System(1). Categories are based on morphological features for Neuroendocrine Neoplasms of pulmonary origin, and a combination of morphological features and Ki-67 expression for Neuroendocrine Neoplasms of extra-pulmonary origin. B) Simplified graphic representation of Table A. NET = neuroendocrine tumour; this refers to a neuroendocrine neoplasm with a well-differentiated morphology (WD). NEC = neuroendocrine carcinoma; this refers to a neuroendocrine neoplasm with a poorly-differentiated morphology (PD). G1 (grade 1) and G2 (grade 2) identify low grades of proliferative activity and biological aggressiveness, and are defined by a Ki-67 index ≤20% for neuroendocrine neoplasm of extra-pulmonary origin. G3 (grade 3) identifies a high grade of proliferative activity and biological aggressiveness, and is defined by a Ki-67 index >20% for neuroendocrine neoplasms of extra-pulmonary origin. MiNEN = mixed neuroendocrine non neuroendocrine neoplasm; this definition applies to cancer from the gastro-entero-pancreatic tract composed of both neuroendocrine and non-neuroendocrine histology, each accounting for at least 30% of the tumour mass.

Figure 2. Common genomic alterations in Extra-Pulmonary NeuroEndocrine Carcinomas

Frequency (median and interquartile range) of samples harboring any genomic alteration (point mutation, copy number gain, copy number loss, amplification, deletion, chromosomal rearrangement) is reported for a selection all genomic studies in extra-pulmonary neuroendocrine carcinomas presented in this review. GEP = gastro-entero-pancreatic tract. UNK = unknown primary origin. H&N = head and neck. DDR = DNA damage repair. Remaining acronyms are defined in Table 4. Studies selected were those where samples included were from ≥10 patients.

Figure 3

Molecular vulnerabilities of Extra-Pulmonary NeuroEndocrine Carcinomas, associated therapeutic opportunities and supporting preclinical and clinical evidence. Part A presents SCLC-like and tumour-type agnostic molecular vulnerabilities. Part B presents same-organ non-NE cancer-like molecular vulnerabilities. mAB = monoclonal antibody. CTLA-4=cytotoxic T-lymphocyte antigen 4. ICB=immune checkpoint blockade. TMB=tumour mutation burden. MHC I or II=major histocompatibility complex I or II. TCR=T cell receptor. APC=cell presenting antigen. ADI-PEG-20=pegylated arginine deiminase. BET=bromodomain and extra-terminal domain proteins. BiTE=bispecific T cell engager. CAR T cell=chimeric antigen receptor T cell. HDAC=histone deacetylase. KMT2=histone lysine methyltransferase 2 family. KMD=histone lysine demethylase family. MAPKs=mitogen activated protein kinases. RTK=receptor tyrosine kinase. GF=growth factor. MSI=microsatellite instability. The suffix “i” after the name of the protein means “inhibitor”. Remaining acronyms are defined in Table 4.

Figure 4. Summary of emerging therapeutic strategies for Extra-Pulmonary NeuroEndocrine Carcinomas

DDR = DNA damage repair. ICB = immune checkpoint blockade. BiTE = bispecific T cell engager. CAR T cell therapy = chimeric antigen receptor T cell therapy. TMB = tumour mutation burden. The ‘i’ as suffix of the name of a molecular marker means “inhibitor”. Remaining acronyms are defined in Table 4.