Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors: A new category in the World Health Organization classification.
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SUBMITTER: Xu JX
PROVIDER: S-EPMC8704278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:: In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification 2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well-differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%-8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified, calling for a new category, well-differentiated grade 3 NET (NET G-3). Studies that have reported the characteristics of neuroendocrine neoplasms have identified more well-differentiated NET G-3 than neuroendocrine carcinomas. The main localizations of NET G-3 are the pancreas, stomach, and colon. Treatment for NET G-3 is not standardized and is balanced between G-1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G-3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G-3.Implications for practiceNeuroendocrine tumors presenting a number of mitoses or a Ki-67 index higher than 20% and a well-differentiated morphology have been identified and named well-differentiated grade 3 neuroendocrine tumors (NET G-3). The main localizations of NET G-3 are the pancreas, stomach, and colon. The prognosis is worse than that for NET G-2. In nonmetastatic NET G-3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G-3 should be in line with that implemented in NET G-1/2 when the Ki-67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki-67 is above 55%.
| S-EPMC5061528 | biostudies-literature
Project description:Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent the most common subtype of NETs. The incidence of all NETs, and specifically GEP NETs, has risen exponentially over the last three decades. Only within the past several years have these tumors been appropriately classified, allowing for meaningful drug development. Broadly, some of the most exciting drug classes being developed for patients with well-differentiated GEP NETs include newer types of peptide receptor radionuclide therapy (PRRT) or combinations which increase the potency of lutetium-177 (177Lu)-Dotatate, novel multi-target receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy modalities, beyond checkpoint inhibitors, which seek to unleash the immune system against NETs. Specifically looking at newer types of PRRT, somatostatin receptor antagonists and alpha-emitter radionuclides each have demonstrated the ability to elicit greater DNA damage than 177Lu-Dotatate in preclinical models. Early clinical experiences with each of these agents suggest they may be more cytotoxic than 177Lu-Dotatate. Other approaches seeking to build upon the DNA damage created by 177Lu-Dotatate include combinations of PRRT with radiosensitizers such as heat shock protein 90 inhibitors, hedgehog inhibitors, chemotherapy combinations, and triapine. Many of these combinations have just begun to be tested clinically. With regards to novel RTKIs, some of the ones which have demonstrated potent cytoreductive potential include cabozantinib and lenvatinib. Other RTKIs which are further along the clinical development spectrum and have demonstrated benefit in randomized trials include surufatinib and pazopanib. And though single-agent immune checkpoint inhibitors have not demonstrated significant anti-tumor activity in patients with GEP NETs, outside of certain biomarker selected subsets, somatostatin receptor-directed chimeric antigen receptor (CAR) T cells and vaccines such as SurVaxM, which targets survivin, represent two means through which NET-directed immunity may be modulated. The potential of these agents, if clinically realized, will likely improve outcomes for patients with well-differentiated GEP NETs.
| S-EPMC8141991 | biostudies-literature
Project description:BackgroundThe prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms.MethodsCirculating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals.ResultsUnivariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors.ConclusionsThe circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.
| S-EPMC8011407 | biostudies-literature
Project description:IntroductionRecent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens.Materials and methodsThis was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR).ResultsTreatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months.ConclusionAmong patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy.Implications for practiceHigh-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.
| S-EPMC8100548 | biostudies-literature
Project description:Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.
| S-EPMC8170837 | biostudies-literature
Project description:Pancreatic neuroendocrine neoplasms (PanNENs) represent a minority of pancreatic neoplasms that exhibit variability in prognosis. Ongoing mutational analyses of PanNENs have found recurrent abnormalities in chromatin remodeling genes (e.g., DAXX and ATRX), and mTOR pathway genes (e.g., TSC2, PTEN PIK3CA, and MEN1), some of which have relevance to patients with related familial syndromes. Most recently, grade 3 PanNENs have been divided into two groups based on differentiation, creating a new group of well-differentiated grade 3 neuroendocrine tumors (PanNETs) that have had a limited whole-genome level characterization to date. In a patient with a metastatic well-differentiated grade 3 PanNET, our study utilized whole-genome sequencing of liver metastases for the comparative analysis and detection of single-nucleotide variants, insertions and deletions, structural variants, and copy-number variants, with their biologic relevance confirmed by RNA sequencing. We found that this tumor most notably exhibited a TSC1-disrupting fusion, showed a novel CHD7-BEND2 fusion, and lacked any somatic variants in ATRX, DAXX, and MEN1.
| S-EPMC6549554 | biostudies-literature
Project description:Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.
| S-EPMC8158108 | biostudies-literature
Project description:Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.
| S-EPMC7735636 | biostudies-literature
Project description:High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.
| S-EPMC8630776 | biostudies-literature
Project description:BACKGROUND:Pancreatic neuroendocrine neoplasms with a Ki-67 labeling index greater than 20% were reclassified in 2017 by the World Health Organization into well differentiated (WD) and poorly differentiated grade 3 neuroendocrine carcinoma (NEC). The authors describe the cytologic features of grade 3 WD pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NEC. METHODS:Fine-needle aspirates from 65 pancreatic neuroendocrine neoplasms were reviewed, and their cytomorphologic features were compared across grade 2, WD grade 3, and PD small cell type (PD-S), large cell type (PD-L), and type not otherwise specified (PD-NOS) neoplasms. RESULTS:The 65 aspirates consisted of 19 grade 2 neoplasms, 32 WD grade 3 neoplasms, and 14 NECs (6 PD-S, 5 PD-L, and 3 PD-NOS). The medians Ki-67 proliferation index was 11% (range, 3.2%-17%) in grade 2 neoplasms, 40% (range, 21%-89%) in WD grade 3 neoplasms, 80% (range, 63%-95%) in PD-S neoplasms, 39% (range, 25%-61%) in PD-L neoplasms, and 70% (range, 30%-80%) in PD-NOS neoplasms. Both grade 2 and WD grade 3 neoplasms were associated with plasmacytoid morphology and smooth nuclear contours, but WD grade 3 neoplasms had significant increases in abundant cytoplasm (72% vs 17%; P = .007), nuclear tangles (75% vs 42%; P = .006), and apoptosis (86% vs 58%; P = .005). Compared with NECs, WD grade 3 neoplasms had increased plasmacytoid morphology (75% vs 7%; P < .001), smooth nuclear contours (94% vs 64%; P = .02), round nuclei (59% vs 21%; P = .01), and less pleomorphism (13% vs 50%; P = .004), molding (9% vs 79%; P < .001), and necrosis (13% vs 43%; P = .003). WD grade 3 neoplasms had less pleomorphism (13% vs 50%; P = .04), less necrosis (13% vs 60%; P = .04), and more plasmacytoid morphology (75% vs 20%; P = .03) than PD-L. CONCLUSIONS:The prevalence of cytologic features differs in WD grade 3 pancreatic neuroendocrine neoplasms compared with grade 2 neoplasms and NECs, and these differences assist in the recognition of this newly classified entity. Cancer Cytopathol 2018;126:326-35. © 2018 American Cancer Society.
| S-EPMC5992011 | biostudies-literature