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(PPoma) or vasoactive peptide (VIPoma) and those in the 11.6 months in the sunitinib group compared to 5.5 months
GI tract can secrete high levels of gastrin (gastrinoma). in the placebo arm. The RADIANT-3 and the sunitinib
[40]
The classification of NETs clinically is based on study both resulted in FDA approval of these drugs for
immunohistochemical staining for low molecular weight patients with pancreatic NETs. The RADIANT-4 trial
keratins, chromogranin and somatostatin, as well as an (NCT01524783) further confirmed the role of everolimus
assessment of Ki-67 index from within the region of in adult patients with advanced, progressive, well-
highest mitotic density. Other observable factors such differentiated, non-functional endocrine tumors of the lung
[31]
as anatomical site, histology, grade, level of differentiation or gastrointestinal tract. Patients receiving everolimus
[41]
and hormone secretion are also used but this phenotypic had a 7.1 month increase in PFS compared to placebo.
[41]
classification system has led to confusion in both the A comprehensive review of carcinoid and NET clinical
clinical and research settings due to the molecularly trials is available. The heterogeneity of NETs requires a
[33]
heterogeneous nature of these diseases. For clinical trial deeper understanding of tumorigenic mechanisms and drug
purposes, enteropancreatic NETs have historically been function that will guide future therapeutic development,
grouped together in clinical trials, with enrollment open patient management strategies and eventually, genomics-
to all patients with gut NETs regardless of subtype. It driven clinical trial design.
is now recognized that NETs must be subdivided into
pancreatic and non-pancreatic subgroups to reduce Genetic syndromes account for 15-20% of NETs. The
heterogeneity in clinical trials and that progression free most common syndromes include multiple endocrine
[32]
survival (PFS) may be a more relevant primary endpoint neoplasia type 1 and type 2A/B (MEN1 and MEN2A/B),
in clinical trial design than OS because most patients von Hippel-Lindau syndrome (VHL), neurofibromatosis
have indolent disease. Additionally, a key predictor of type 1 (NF1) and tuberous sclerosis complex (TSC), and in
[33]
outcome in enteropancreatic NETs is the degree of tumor each of these syndromes, specific loss- or gain-of-function
differentiation. Well-differentiated tumors have a better mutations have been identified in causative genes. The
prognosis than poorly differentiated tumors, which can remaining 80-85% of NETs is considered sporadic and
have a 5 year overall survival of less than 4%. [30] genome-wide studies have been performed in an attempt
to understand driver genetic mutations. Jiao et al.
[42]
Enteropancreatic NETs are relatively slow-growing and performed whole exome sequencing of 10 pancreatic NETs
traditional chemotherapy regimens have limited efficacy. that resulted in the identification of somatic mutations in
[34]
The selection of therapy is driven by the staging, location a number of known cancer-associated genes including
of the tumor and symptom profile. Surgery is often used MEN1, DAXX, ATRX, a number of genes involved in the
in the management of NETs for both curative (localized mTOR pathway, and to a lesser extent TP53. Banck et al.
[43]
disease) and palliative care (widespread metastases). First studied forty-eight well-differentiated, small intestinal
line therapy for enteropancreatic NETs is somatostatin NETs (carcinoids) by whole exome sequencing and also
analogs (SSAs), with VEGF pathway inhibitors, identified somatic mutations in many cancer-associated
[34]
mTOR inhibitors or peptide receptor radionuclide therapy genes including FGFR2, MEN1, HOOK3, EZH2, MLF1,
(PRRT) as additional options. Many of these compounds CARD11, VHL, NONO, SMAD1, FANCD2 and BRAF, yet
are currently in clinical practice and/or clinical trials and only 21 genes were in common with a subsequent study
have exhibited moderate success. SSAs such as octreotide, that analyzed an additional 55 well-differentiated small
lanreotide and pasireotide help control symptoms of intestinal NETs. Upon further comparison with the Jiao
[44]
hormone hypersecretion (carcinoid syndrome), and more study, only 17 genes with somatic mutations found in
[42]
recently have been noted to have anti-proliferative effects small intestinal NETs were in common with pancreatic
on well or moderately differentiated NETs. [35,36] For NETs. These data highlight that this group of tumors
[44]
example, the PROMID trial (NCT00171873) examined needs to be carefully studied, subgrouped and analyzed
metastatic midgut NETs and the CLARINET trial to account for heterogeneity in terms of site of origin,
[37]
(NCT00353496) focused on pancreatic, midgut or level of differentiation and underlying driver mutations.
hindgut NETs, both noting prolonged PFS in the SSA Interestingly and despite the somewhat disparate results,
[38]
treatment arms compared to placebo. The NETTER-1 trial all of these studies highlight the putative role of chromatin
(NCT01578239) uses radiolabeled SSA ([ Lu-DOTA , remodeling, perhaps in concert with Notch signaling, in
177
0
Tyr ] octreotate) in PRRT for a localized anticancer therapy the etiology of enteropancreatic NETs.
3
in patients with inoperable, somatostatin receptor positive
metastatic midgut NETs with the primary endpoint of PFS. A popular model of cancer formation is that tumors are
The RADIANT-3 trial (NCT00510068) demonstrated an dependent on a subset of highly tumorigenic cells, so-
increased median PFS in patients treated with the mTOR called cancer stem cells, for initiation, maintenance and
inhibitor everolimus/RAD001 (11 months compared to 4.6 propagation. Cancer stem cells have been identified
[45]
months for placebo) in patients with advanced pancreatic in a number of solid tumors [46-48] and leukemias, and
[49]
NETs. Finally, the oral tyrosine kinase inhibitor are noted for their pluripotency, unique complement of
[39]
sunitinib was studied in a prospective trial in patients with cell-surface antigens, ability to self-renew, and ability
advanced, well differentiated pancreatic NETs. PFS was to form xenografts in immunocompromised mice from
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 281