What does Quora know about neuroendocrine cancer? by Connie b. Dellobuono

Answer by Connie b. Dellobuono:

Many types of neuroendocrine tumors traditionally have been called “carcinoids” (meaning “cancer-like”) or “carcinoid tumors,” but these terms do not accurately account for their variable biology, histologic differences, and secretory potential.
Neuroendocrine tumors (NETs): Well-differentiated neoplasms that can be divided into grade 1 (G1) and grade 2 (G2) depending on proliferation and histology
Neuroendocrine carcinomas: Poorly differentiated grade 3 (G3) neuroendocrine neoplasms.
2.7-fold increase in incidence: According to Surveillance, Epidemiology, and End Results (SEER) data, the age-adjusted incidence of NETs rose from 1.9 to 5.25 cases per 100,000 people between 1973 and 2004.4 Diagnosed incidence of NETs is predicted to continue rising at a faster rate than other malignant neoplasms.
SEER data also demonstrate that the prevalence of NETs is similar to that of other types of gastrointestinal cancers. Most NETs occur sporadically. However, some may be associated with genetic syndromes, notably multiple endocrine neoplasia type 1 (MEN-1), as well as MEN-2a and MEN-2b. As with other solid tumors, 5-year survival rates for patients with NETs depend largely on the tumor histology and extent of disease.
About 50% of patients with reported disease stage have either regional or distant metastases at diagnosis.
Metastasis: Liver > Lung > bones
Primary/occurrence sites: lungs (25%), pancreas (20%), small intestines (55%), rectum (5%), others – 3% (adrenals,thyroid,cervix)
O. http://trp.cancer.gov/spores/abstracts/uiowa_neuroendocrine.htm
a. The pre-clinical component of this proposal will identify new theranostic targets on neuroendocrine tumor cells, design and synthesize peptides to hit these new targets, and test the most promising theranostic compounds in vivo. Oxytocin, melanocortin, and glucose-dependent insulinotropic peptide receptors are expressed on neuroendocrine tumors and are prime new targets in neuroendocrine tumors. We will design and synthesize peptides that can bind to each receptor; peptides that demonstrate high affinity and stability in vitro will then be tested as diagnositic PET imaging agents in pre-clinical models of bronchial, small bowel and pancreatic NETs.
b. It builds upon our discovery that RABL6A (a novel oncoprotein) is essential for PNET cell survival and proliferation, Akt/mTOR activity, and control of other clinically relevant PNET pathways, such as Rb1. Aim 2 is to identify genetic and proteomic biomarkers that discriminate NET type and prognosis.
c. The incidence of Neuroendocrine Tumors (NETs) has increased five-fold over the last three decades, and many patients do not develop symptoms until the tumors have metastasized. Further understanding of the molecular biologic basis of NETs holds the promise for improved diagnosis, imaging, and therapy.
d. targeting unique G-protein coupled receptor hetero-dimers such as somatostatin receptor/dopamine receptor conjugates that we have identified in NETs. Preliminary data demonstrate that these new targeting agents have high affinity binding to tumor cells; they are predicted to be highly specific for tumor cells as the hetero-dimeric receptors are rarely expressed in normal tissues.
1. Pancreatic neuroendocrine tumors(pNET) are rare tumors accounting for less than 5% of pancreatic cancer. They are functionally and biologically heterogeneous and have not been studied in great detail until recently. Methods: We conducted a retrospective review of 79 consecutive patients with pNET diagnosed and treated at Thomas Jefferson University Hospital between the years of 2000 and 2010. Results: Of the 79 patients whose records were reviewed, 32 were male and 47 were female. Median age at diagnosis was 61 years. Two cases were associated with MEN1 syndrome. Primary tumor arose in the head, body and tail of the pancreas in 15, 10 and 26 patients, resp. In 6 patients, the tumor was multifocal. The neuroendocrine tumor was accompanied by pancreatic adenocarcinoma in 1 patient and intraductal papillary mucinous neoplasm in 3. In 10 patients, distant metastasis was detected, involving liver only. Tumor was functional in 9 patients: 5 insulinoma, 2 gastrinoma,1 glucagonoma and 1 VIPoma. As per TNM staging, 28, 22 and 10 patients were Stage I, II and III, and IV at diagnosis. Treatment by surgical resection was undertaken in 54 patients. In 21 patients, the tumor was discovered incidentally; 21 patients presented with abdominal pain. Other symptoms were irregular bowel movements, weight loss and jaundice. 51 of the 79 (64.5%) patients were alive at last follow up. On univariate analysis, median survival for females was 137 months vs 114 months for male. Median survival for patients with functional tumors was similar to those with nonfunctioning tumors (118 and 115 months, resp). Median survival for patients with Stage I, II, and III and Stage IV patients were 234,112 and 40 months resp. Median survival for patients who underwent surgical resection was 130 months vs those who did not (30 months). Conclusions: Majority of pNET were located in the body and tail of pancreas; an area requiring thorough scrutiny with special imaging studies for diagnosis. Only a minority of patients presented with liver metastasis(12%) and a smaller number showed hormonal activity (11%). Prognosis improved markedly in patients who underwent surgical resection. Therefore, whenever appropriate, surgical resection should be the treatment of choice in patients with pNET.
Current therapeutic options for patients with progressive metastatic gastroenteropancreatic neuroendocrine tumour/neoplasm (GEP-NET/NEN) are limited. Treatment with SST analogues is method of choice, due to good symptoms control. [DOTA0, D-Phe1,Tyr3] octreotate[DOTATATE] has a higher affinity for SST2 receptors and thus is able to achieve longer disease control. The aim of this study was to evaluate long term radiological and clinical therapeutic effect of 90Y-DOTATATE in patients with progressive somatostatin receptor–positive small bowel and pancreatic neuroendocrine tumour/neoplasm (GEP-NET/NEN).The primary end point was assessing OS and PFS in long term follow-up. Methods: 67 patients progressing after treatment with SST analogues were inlcuded in the study. The mean treatment activity was 3.8GBq. The mean interval between therapies was 7 weeks (range 6 -9 weeks). Patients were treated up to mean a cumulative activity of 11.2 GBq. Due to pure beta emission (90Y) internal dosimetry was evaluated. Results: Median overall survival (OS) and progression-free survival (PFS) are shown in the Table. In univariate analysis Ki-67 (p=0.048) was the only significant factor influencing OS in pancreatic tumors. That was not confirmed in multivariate analysis. In small bowel tumors we defined three factors influencing survival in univariate analysis. These were: female gender (p=0.023), performance status at the beginning of therapy (p=0.031) and presence of liver metastases (p=0.026). Female gender (HR=0.30, 95% CI 0.11-0.81; p=0.018) was confirmed as positive prognostic factor in multivariate analysis. Factos influencing PFS were also assessed and will be presented as well. Conclusions: 90Y DOTATATE PRRT is effective in long term outcome (OS and PFS) in patient with advances progressive pancreatic and small bowel GEP-NET. This therapy is relatively safe as initial systemic therapy and after previous treatment with chemotherapy or somatostatine analogues as well.
3. NETs are a heterogeneous group of rare neoplasms. Preclinical studies have shown that IGFR overestimulation can lead to constitutional activation of mTOR pathway. The main objective of this study is to describe the activation status of IGF1R-mTOR pathway by immunohistochemistry in a series of NETs and to assess the association with IGF1R expression. Methods: We studied 69 paraffin tumour blocks: 28 pancreatic NETs (pNETs) (2 gastrinomas, 1 glucagonoma, 4 insulinomas and 21 non-functioning (nf) pNETs), 32 GI NETs (4 stomach, 8 colorectum, 18 ileum and 2 dudodenum) and 9 NETs from other origins (2 anterior mediastinum, 2 ovary, 3 bile duct and 2 kidney). The expression of IGF1R, phosphorylated (p) mTOR and (p)S6 has been determined by immunohistochemistry using anti-IGF1Rβ (sc-713), anti-Phospho-mTOR (S2448) (49F9, Cell Signaling) and anti-Phospho-S6 Ribosomal Protein (S235/336)(91B2, Cell Signaling). Results: Expression of IGF1R has been observed in 46 of 69 (66%) samples with the highest expression in 2/4 (50%) insulinomas, 5/21 nf pNETs (23%) and 3/18 ileum (17%). We have observed activation of the mTOR pathway by immunodetection of (p)mTOR in 14 of 69 samples (20%): 2/21 nf pNETs (9.5%), 1/8 colorectum (12.5%), 8/18 ileum (44%), 1/2 anterior mediastinum, 1/2 ovary, 1/3 biliar tract. We haven’t detected any (p)S6 activation in these samples. Consistent IGF1R-mTOR pathway activation was detected in 11/14 (78%) samples with mTOR positivity that also showed expression of IGF1R. The most relevant finding is that all of the 8 samples from ileum with activation of mTOR showed some degree of expression of IGF1R. Conclusions: 2/3 of NETs show varying levels of expression of IGF1R, but only 16% demonstrate activation of the IGF1R-mTOR pathway. While the positivity of (p)mTOR in pNETs is lower than expected, we have identified a subgroup of ileal NETs with consistent activation of both IGF1R and (p)mTOR which could help stratify patients in clinical trials involving modulation of this pathway. In contrast, none of the 69 samples studied was positive for (p)S6 which suggests this marker is not valid to be used in the clinic. Further validation studies are required to help clinical stratification for therapies against IGF1R mTOR pathways
4. Peptide receptor radionuclide therapy targets somatostatin receptors expressed on well differentiated neuroendocrine neoplasms. Retrospective monocentric studies indicate that peptide receptor radionuclide therapy is an effective treatment for patients with neuroendocrine neoplasms. Methods: We initiated a multi-institutional, prospective and board reviewed registry study for patients treated with peptide receptor radionuclide therapy. 450 patients were included and followed for a mean of 24.4 months. Patients were treated with Lutetium-177 (54%), Yttrium-90 (17%) or both radionuclides (29%). Primary neuroendocrine neoplasms were derived of pancreas (38%), small bowel 30%), unknown primary (19%), lung (4%) and colorectum (3,5%). Most neuroendocrine neoplasms were well differentiated with a proliferation rate below 20% in 54% and were pretreated by 1 or more therapies in 73%. Results: Overall survival of all patients from the beginning of therapy was 59 months in median. Median survival depended on radionuclides used (Yttrium-90: 38 months; Lutetium-177: not reached; both: 58 months), proliferation rate (G1: median not reached; G2: 58 months; G3: 33 months; unknown: 55 months) and origin of primary tumors (pancreas: 53 months; small bowel: not reached; unknown primary: 47 months; lung: 38 months) but not upon number of previous therapies. Median progression-free survival measured from last cycle of therapy accounted to 41 months for all patients. Progression-free survival of pancreatic neuroendocrine neoplasms was 39 months in median. Similar results were obtained for neuroendocrine neoplasms of unknown primary with a median of 38 months whereas neuroendocrine neoplasm of small bowel were progression-free for a median of 51 months. Side effects like G3-G4 nephrotoxicity or hematological function were observed in 0.2% and 2% of patients. Conclusions: Peptide receptor radionuclide therapy is effective for patients with G1-G2 neuroendocrine tumors irrespective of previous therapies with a survival advantage of several years compared to other therapies and only minor side effects.

What does Quora know about neuroendocrine cancer?