Extrapulmonary poorly differentiated NECs, including molecular and immune aspects

Abstract

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.

A Patient with an Ileocecal MiNEN and a Synchronous Squamous Non-Small-Cell Lung Cancer: Case Report and Review of the Literature

“…This result correlates to other phase 2 studies showing RRs ranging from 5 to 17.9% [25,37,38]. On the contrary, some other phase 1 studies describing results of monotherapy with pembrolizumab have concluded that this was not effective in biomarker 5 Case Reports in Oncological Medicine unselected populations of patients with poorly differentiated extrapulmonary NECs, like the one by Mulvey et al, describing a median PFS of 58 days, with almost half of the study population (n = 14) presenting early progression (PD) before the first checkup [25,39,40]. Another phase 2 study of pembrolizumab as monotherapy (Keynote-158) in welldifferentiated NETs concluded that the PD-1 inhibitor was ineffective, with only 3% of the entire population studied (n = 107) presenting an objective partial radiographic response [41,42].…”

“…Among these, a phase 1b trial (Keynote-028) which included patients with advanced solid tumors in different locations treated with pembrolizumab as monotherapy described an objective response rate (RR) of 12% for advanced PD-L1-positive carcinoid patients, as well as a 6% RR, 27% 12-month progression-free survival (PFS), and 87% overall survival (OS) for pancreatic NEC patients [26,29,35,36]. This result correlates to other phase 2 studies showing RRs ranging from 5 to 17.9% [25,37,38]. On the contrary, some other phase 1 studies describing results of monotherapy with pembrolizumab have concluded that this was not effective in biomarker 5 Case Reports in Oncological Medicine unselected populations of patients with poorly differentiated extrapulmonary NECs, like the one by Mulvey et al, describing a median PFS of 58 days, with almost half of the study population (n = 14) presenting early progression (PD) before the first checkup [25,39,40].…”

“…There are no standard second-line therapy schemes for poorly differentiated neuroendocrine carcinomas [25] and as the therapeutic option scenario broadens taking into account immunotherapy; predictive molecular/genetic biomarkers have been studied to guide clinical and therapeutic decisions [26]. Among these, MSI (microsatellite instability), which reflects a high mutational load and antigenicity with a consequent response to immunotherapy, is higher in NECs than NETs [27][28][29] and has been described in up to 12.4% of NEC/MANECs [25,29,30]. Also, a high tumor mutational burden (TMB) has been described as a positive predictive biomarker for response to PD-1/PD-L1 inhibition [26,29,[31][32][33][34].…”

“…Also, a high tumor mutational burden (TMB) has been described as a positive predictive biomarker for response to PD-1/PD-L1 inhibition [26,29,[31][32][33][34]. Several studies of immunotherapy in NEC are currently under investigation, prompted by previous positive results found in Merkel cell carcinoma, a tumor that is closely related to NEC [25]; however, mostly conflicting results from phase 1 and phase 2 trials have been encountered. Among these, a phase 1b trial (Keynote-028) which included patients with advanced solid tumors in different locations treated with pembrolizumab as monotherapy described an objective response rate (RR) of 12% for advanced PD-L1-positive carcinoid patients, as well as a 6% RR, 27% 12-month progression-free survival (PFS), and 87% overall survival (OS) for pancreatic NEC patients [26,29,35,36].…”

Systemic Treatment of Gastroenteropancreatic Neuroendocrine Carcinoma

“…The genetic landscape of GEP-NEC is incompletely characterised, but it is clear that mutations in TP53, KRAS, PIK3CA/PTEN, or BRAF play an important role in malignant transformation and progression (reviewed in [25,26]). Girardi et al [27] performed a systematic review on this topic and identified 33 relevant studies.…”