Well-differentiated Pancreatic Neuroendocrine Tumors Research Articles

Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2

We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.

Response by Choi criteria to sunitinib plus octreotide LAR in a functional heavily pretreated advanced pancreatic neuroendocrine tumor

Pancreatic neuroendocrine tumors (PNETs) are rare malignancies that arise from the islets of Langerhans. The role of standard chemotherapy in advanced well-differentiated PNETs remains to be defined. Sunitinib is an oral multitargeted inhibitor with antiangiogenic and antitumor properties that has shown significant improvement in survival in metastatic PNETs, although objective responses by Response Evaluation Criteria in Solid Tumors were only 9%. We herein report on the case of a middle-aged woman with metastatic PNET who was heavily pretreated for her advanced disease with limited success, and who showed clinical, biochemical, and radiological responses by using Choi criteria but not Response Evaluation Criteria in Solid Tumors criteria. To our knowledge, this is the first reported case of treatment with sunitinib in a patient with PNET in response to Choi criteria.

Sunitinib (SU) pharmacokinetic (PK)–pharmacodynamic (PD) modeling with respect to safety and efficacy endpoints in Asian patients (pts) with gastrointestinal stromal tumor (GIST) or renal cell carcinoma (RCC) in pursuit of a therapeutic window.

e15128 Background: SU is an oral multitargeted tyrosine kinase inhibitor, approved multinationally for the treatment of advanced RCC, imatinib-resistant or -intolerant GIST, and well-differentiated pancreatic neuroendocrine tumor. We explored SU PK–PD relationships with respect to safety and efficacy endpoints to determine a therapeutic window for SU in Asian pts with GIST and RCC. Methods: We analyzed pooled PK–PD data from two Japanese phase II studies in pts with GIST and RCC (N=81 combined) using NONMEM V7.0. We initially built a PK model (2-compartments with 1st order absorption and elimination) to describe SU PK data. Subsequently, different sequential semi-mechanistic or mechanism-based (i.e., transit compartments with feedback loop [TCF] or indirect response [IDR] with Emax or sigmoid Emax drug effect) PK–PD models were built and compared for selection of a PK–PD model to describe each PD endpoint; these models were internally validated by Visual Predictive Check using PsN and Xpose. Results: Key PK–PD model characteristics or parameter estimates are shown in the table below. There appeared to be great inter-pt variability in, and overlap between, the exposure-response curves for safety endpoints and that of the efficacy endpoint. Conclusions: We could not identify a therapeutic window for SU in Asian pts with GIST and RCC. SU dose modification based on individual pt safety/tolerability appears to be the best approach to ensure maximum SU plasma exposure and efficacy, consistent with the SU label recommendation. PD endpoint PK–PD model EC50 Mean (CV) ng/mL (%) γ Mean Safety Absolute neutrophil count TCF 6.91 (146) 1(F) Platelet count TCF 55.7 (27) 5.22 Lymphocyte count IDR 98.6 (NE) 3.09 LVEF IDR 1050 (180) 1(F) Diastolic blood pressure IDR 318 (44) 1(F) AST TCF 74.7 (NE) 4.66 Efficacy SLD IDR 80.1 (248) 1(F) Abbreviations: CV, coefficient of variation; EC50, SU concentration at which 50% of the maximum effect is achieved; F, fixed; γ (gamma), Hill coefficient; LVEF, left ventricular ejection fraction; NE, not estimable; SLD, sum of the largest diameters of target tumors.

Comparison of Methods for Grading Gastrointestinal and Pancreatic Well-Differentiated Neuroendocrine Tumors

Comparison of Methods for Grading Gastrointestinal and Pancreatic Well-Differentiated Neuroendocrine Tumors

PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma

PAX (paired box) genes encode a family of transcription factors that regulate organogenesis in a variety of organs. Very little is known about the role of PAX8 in endocrine cell development and the expression of PAX8 in neuroendocrine tumors. The purpose of this study was to analyze PAX8 immunohistochemical expression in gastroenteropancreatic and pulmonary well-differentiated neuroendocrine tumors to determine whether PAX8 can reliably distinguish pancreatic neuroendocrine tumors from neuroendocrine tumors of other anatomic sites and other pancreatic non-ductal neoplasms. In total, 221 well-differentiated neuroendocrine tumors were evaluated: 174 primary neuroendocrine tumors (66 pancreatic, 31 ileal, 21 pulmonary, 20 gastric, 17 rectal, 11 appendiceal, and 8 duodenal) and 47 neuroendocrine tumors metastatic to the liver (31 pancreatic, 11 ileal, 2 pulmonary, 2 duodenal, and 1 rectal). Fifteen solid-pseudopapillary neoplasms and six acinar cell carcinomas of the pancreas were also evaluated. PAX8 was positive in 49/66 (74%) primary pancreatic neuroendocrine tumors. PAX8 expression did not correlate with World Health Organization categorization, grade, size, functional status, or the presence of liver or lymph node metastasis. PAX8 expression was identified in 0/31 (0%) ileal, 0/21 (0%) pulmonary, 2/20 (10%) gastric, 5/17 (29%) rectal, 1/11 (9%) appendiceal, and 6/8 (75%) duodenal neuroendocrine tumors. PAX8 was positive in 4/15 (27%) solid-pseudopapillary neoplasms of the pancreas, whereas all acinar cell carcinomas (0/6) lacked immunoreactivity. Among liver metastases, only pancreatic neuroendocrine tumors (20/31, 65%) were PAX8 positive, whereas no cases of ileal (0/11), pulmonary (0/2), duodenal (0/2), and rectal (0/1) neuroendocrine tumor metastases were PAX8 positive. PAX8 is expressed in primary and metastatic pancreatic well-differentiated neuroendocrine tumors, and its expression can reliably distinguish pancreatic from ileal and pulmonary well-differentiated neuroendocrine tumors. Duodenal neuroendocrine tumors and a subset of rectal, gastric, and appendiceal neuroendocrine tumors may also express PAX8. PAX8 expression can distinguish pancreatic neuroendocrine tumors from acinar cell carcinomas, but its utility in distinguishing neuroendocrine tumors from solid-pseudopapillary neoplasms is limited.

PAX8 is expressed in pancreatic well‐differentiated neuroendocrine tumors and in extrapancreatic poorly differentiated neuroendocrine carcinomas in fine‐needle aspiration biopsy specimens

PAX (paired box) genes encode a family of transcription factors important for organogenesis. Recently, PAX8 has been recognized as a potential immunohistochemical marker of pancreatic neuroendocrine tumors. The authors evaluated PAX8 expression in fine-needle aspiration biopsies of neuroendocrine tumors to establish whether PAX8 immunohistochemistry can be used as an ancillary marker of pancreatic origin for neuroendocrine tumors. Fine-needle aspiration biopsies from 72 neuroendocrine tumors were evaluated for PAX8 expression: 32 primary and 23 metastatic well-differentiated neuroendocrine tumors (25 pancreatic, 13 pulmonary, 3 ileal, 2 duodenal, 1 rectal, 1 ovarian, and 10 primary site unknown) and 17 poorly differentiated neuroendocrine carcinomas (11 pulmonary, 1 pancreas, 1 breast, 1 thymus, and 3 primary site unknown). Among well-differentiated neuroendocrine tumors, only tumors from the pancreas were PAX8 positive (14 of 25, 56%) whereas no cases of pulmonary (0 of 13), ileal (0 of 3), duodenal (0 of 2), rectal (0 of 1), or ovarian (0 of 1) well-differentiated neuroendocrine tumors were positive for PAX8. One of 10 (10%) well-differentiated neuroendocrine tumors of unknown primary origin was PAX8 positive. Among poorly differentiated neuroendocrine carcinomas, PAX8 expression was identified in 1 of 1 (100%) pancreatic, 1 of 1 (100%) thymic, 4 of 11 (36%) pulmonary, and 0 of 1 (0%) breast carcinomas. One of 3 (33%) poorly differentiated neuroendocrine carcinomas of unknown primary origin was PAX8 positive. Pancreatic well-differentiated neuroendocrine tumors frequently express PAX8, which can help distinguish pancreatic primary tumors from tumors of other anatomic sites. In contrast, PAX8 expression in poorly differentiated neuroendocrine carcinomas is not specific for pancreatic origin and can be seen in extrapancreatic poorly differentiated neuroendocrine carcinomas.

Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.

249 Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans. Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist. Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results. Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib. [Table: see text]

Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway

Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease.

Intraductal Pancreatic Neuroendocrine Tumor

Intraductal lesions of the pancreas are usually due to intraductal papillary mucinous neoplasms and the less common intraductal tubular adenoma. Cases of acinar cell carcinoma within intraductal location have also been encountered recently. Pancreatic neuroendocrine tumors are rarely encountered within the main pancreatic duct. A 74-year-old male presented with non-specific abdominal symptoms and was found to have an obstructive lesion in the main pancreatic duct with associated chronic pancreatitis. A distal pancreatectomy was performed which revealed a solid and cystic tumor measuring 6 x 3 x 2 cm situated wholly within the main pancreatic duct. It formed an obstructing intraluminal polypoid lesion that resulted in surrounding chronic pancreatitis. Microscopic evaluation of the mass showed it to be a well-differentiated pancreatic neuroendocrine tumor with entrapped, non-malignant tubules. Intraductal pancreatic neuroendocrine tumors may occur in two settings. Firstly, and more commonly, there is a parenchymal-based tumor that then encroaches on and pushes into the main pancreatic duct. The less common scenario is of a primary intraductal location without a pancreatic parenchymal lesion. While an intraductal location of a pancreatic neuroendocrine tumor is rare, it should be borne in mind when confronted by an intraductal lesion in the pancreas.