TY - JOUR
T1 - Extrapulmonary poorly differentiated NECs, including molecular and immune aspects
AU - McNamara, Mairéad G.
AU - Scoazec, Jean Yves
AU - Walter, Thomas
N1 - Publisher Copyright:
© 2020 Society for Endocrinology Published by Bioscientifica Ltd. Printed in Great Britain
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.
AB - Patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PD-NECs) have a poor prognosis. Surgery is offered for those with localised disease, but the majority of patients present with advanced disease. Treatment strategies adopted are analogous to that of high grade NECs of the lung, with platinum/etoposide-based regimens advocated in the first-line setting for advanced disease. There is no standard second-line therapy. Research into their molecular and immune pathways may pave the way for novel drug discovery. The molecular drivers of NEC are best identified in small cell lung carcinoma, which present with near universal genomic alterations in TP53 and RB1. The genetics of EP-PD-NEC remain poorly understood; TP53, KRAS, PIK3CA/PTEN and BRAF mutations have been identified, with alterations in the BRCA pathway reported additionally in small cell NEC of the cervix and absence of argininosuccinate synthetase 1 expression in NEC of the urinary bladder. The use of cell lines and patient-derived xenografts (PDX) to predict response to treatment in NEC and the emergence of alternative biomarkers, such as circulating tumour cells and cell-free DNA, will also be explored. Despite limited published data on the immune microenvironment of EP-NEC, there are a number of clinical trials investigating the use of immune-targeted agents in this disease category, with conflicting emerging data from studies thus far. This review will summarise the treatment and available molecular and immune data in this under researched diagnosis and may stimulate the direction of future exploratory studies.
KW - Extra-pulmonary
KW - Immune landscape
KW - Molecular profile
KW - Neuroendocrine carcinoma
KW - Poorly differentiated
KW - Treatment
UR - http://www.scopus.com/inward/record.url?scp=85085905665&partnerID=8YFLogxK
U2 - 10.1530/ERC-19-0483
DO - 10.1530/ERC-19-0483
M3 - Review article
C2 - 32357308
AN - SCOPUS:85085905665
SN - 1351-0088
VL - 127
SP - R219-R238
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 7
ER -