ABSTRACT: The diagnosed incidence rate of neuroendocrine tumors (NETs) is on the rise. Prevalence calculations show NETs to be more common then previously thought. Although generally thought to be indolent, advanced NETs remain incurable and are resistant to most cytotoxic agents. The available biologic agents have limited activity against these tumors. Novel and active agents are clearly needed. The recent emergence of molecularly targeted therapy in oncology has brought renewed interest in the development of novel agents for this group of diseases. This paper will review the molecular biology of NETs, promising novel targeted therapy approaches including agents targeting angiogenesis and mammalian target of rapamycin (mTOR) pathways, as well as pivotal phase III studies that may set new standards of care for this disease.
One hundred years after Oberndorfer coined the word “carcinoid,” neuroendocrine tumors (NETs) are thought to be rare tumors characterized by the capacity for hormone production and often an indolent course. Recent data from population-based registries have shown a significant rise in the diagnosed incidence of NETs over the past 3 decades. The possible explanation for this increasing incidence is multifactorial, including better diagnostics, improved awareness, and other undetermined environmental and genetic factors. Our analysis of the Surveillance, Epidemiology, and End Results (SEER) program database showed an age-adjusted incidence of 5.25 cases per 100,000 in 2004, accounting for just over 1% of diagnosed malignancies. This, together with a generally longer associated survival, leads to a prevalence of 35 per 100,000, which exceeds that of esophageal, gastric, pancreatic, or hepatobiliary cancer.
The management of NETs is generally guided by histology. High-grade or poorly differentiated NETs have an aggressive course, and their management parallels that of small-cell carcinoma of the lung.
In this manuscript, we will focus on the well- to moderately differentiated groups of neuroendocrine tumors that are more indolent but more resistant to cytotoxic chemotherapy. Today, “carcinoid” is typically used to describe a well- to moderately differentiated NET arising outside the pancreas. Those arising from the pancreas—pancreatic NET (PNET), or islet cell carcinoma—are recognized to have a different genetic profile, more aggressive clinical course, and different pattern of response to cytotoxic chemotherapy. These more differentiated tumors are also more likely to produce hormonal syndromes such as carcinoid syndrome (manifesting as flushing and diarrhea) and Verner-Morrison syndrome (watery diarrhea, hypokalemia, and achlorhydria, or WDHA syndrome). Advanced NETs are incurable. The median overall survival duration among patients with advanced well- to moderately differentiated NETs of the small bowel, cecum, appendix, pancreas, and rectum are 65, 55, 31, 27, and 26 months, respectively.
Current Systemic Therapy Options
Therapeutic objectives for patients with NETs include control of the paraneoplastic hormonal syndrome and tumor growth. Treatment often includes the use of somatostatin(Drug information on somatostatin) analogs (SSAs), interferon, chemotherapy, liver-directed therapy, surgical resection, or ablation of hepatic metastases, and radiation therapy for palliative benefit. Peptide receptor radiotherapy with [177Lu-DOTA0,Tyr3] octreotate or [90Y-DOTA0,Tyr3] octreotide(Drug information on octreotide) represents an additional option in Europe.
Somatostatin receptors (SSTRs) are expressed on the majority of NETs. Somatostatin is a peptide hormone that decreases hormone leading to inactivation of the gene encoding menin located on chromosome 11 (11q13). The classic syndrome includes neoplasia of the parathyroid glands, anterior pituitary, endocrine pancreas, and endocrine duodenum, but rarely adrenal neoplasms and neuroendocrine tumors of the lung, thymus, and stomach. The MEN1 gene may also be involved in the tumorigenesis of sporadic carcinoid tumors. The loss of heterozygosity (LOH) on chromosome 11, the site of the MEN1 gene, is frequently found in pulmonary carcinoids. Menin appears to be involved in the regulation of gene transcription through its interaction as part of a histone methyltransferase complex. Menin also appears to be involved in the control of cell-cycle regulation through control of p27 expression.
Neurofibromatosis (NF) and tuberous sclerosis (TSC) can manifest with benign lesions, such as hamartomas and astrocytomas, as well as together with well-differentiated tumors in the brain, heart, skin, kidney, lung, and endocrine pancreas. The genes associated with TSC are TSC-1 (located on 9q34) and TSC-2 (located on 16p13.3), and they encode the proteins hamartin and tuberin, respectively. The development of PNETs in patients with TSC is thought to be particularly related to mutations in TSC2. TSC-1/2 complex functions as our endogenous inhibitor of mTOR, and is normally expressed in neuroendocrine cells. The loss of TSC function leads to constitutive activation of the mTOR pathway.
Patients with NF-1 may also develop ampullary of Vater carcinoids, as well as duodenal and pancreatic NETs. The NF-1 gene is a tumor-suppressor gene that is located on 17q11.2 and encodes a protein called neurofibromin. The latter is also linked with mTOR through regulation of TSC function. It has been shown that NF-1 acts as a negative regulator of mTOR—specifically, LOH of the NF-1 gene results in the loss of neurofibromin expression, constitutive mTOR activation, and, therefore, tumor development.
The main clinical features of VHL syndrome include retinal or central nervous system hemangioblastomas, clear cell renal carcinomas, pheocromocytomas, and pancreatic cystic tumors or PNETs. Pancreatic lesions can be seen in 20% to 75% of patients with VHL. In the largest series with 94 VHL families, it was reported that the majority of pancreatic lesions were true cysts (91%), whereas NETs represented 12% of cases. The VHL gene is a tumor-suppressor gene that is located on chromosome 3p25–26 and regulates hypoxia-induced cell proliferation and angiogenesis. Specifically, the VHL protein, acting mainly as E3 ubiquitin ligase, would target many proteins for degradation.
The most well known target of VHL protein is the hypoxia inducible factor 1α (HIF-1α). Under hypoxic conditions, HIF-1α is produced, translocates to the nucleus, and combines with HIF-1β, initiating the transcription of hypoxia-regulated genes such as vascular endothelial growth factor (VEGF). PNETs, are generally vascular but continue to express a large amount of HIF-1α, suggesting that aberrant regulation of HIF-1α expression may be involved in pathogenesis. Allelic deletion at chromosome 3p, the site of the VHL gene, has also been described as occurring frequently in sporadic NETs.
Molecular Genetics of Sporadic NETs
Outside of defined genetic syndromes, the genes responsible for the development of NETs are unknown. Recent studies using comparative genomic hybridization (CGH), or high-density single-nucleotide polymorphism arrays, suggest that the genetics of most sporadic NETs are far more complex than previously thought, and likely involve many genes in a multistep process in their development and progression. For example, on a genetic level, allelic deletion of chromosome 18 is frequently observed in midgut carcinoid tumors. On an epigenetic level, hypomethylation of LINE-1 elements is associated with chromosome 18 loss. The molecular genetics of PNETs is even more complex. Our most recent study, using a high-density single-nucleotide polymorphism array, showed a pattern of gain and loss across multiple chromosomes.