Mini-Review Article

Genomic Profiles and Current Therapeutic Agents in Neuroendocrine Neoplasms

Author(s): Akihiro Ohmoto* and Chigusa Morizane

Volume 21, Issue 4, 2020

Page: [389 - 405] Pages: 17

DOI: 10.2174/1389450119666191014105211

Price: $65

Abstract

Neuroendocrine neoplasms (NENs) are rare tumors that mainly occur in the gastroenteropancreatic (GEP) tract and lungs. According to the current World Health Organization classification for GEP-NENs and lung NENs, treatment strategies differ for well-differentiated and poorly differentiated subtypes. For well-differentiated GEP-NENs, somatostatin analogues (SSA), peptide receptor radionuclide therapy, and molecular-targeted agents are approved as the standards of care based on phase III clinical trial data. Promising data regarding the use of everolimus and the novel SSA pasireotide for lung NENs are emerging, though additional studies are required to confirm these effects. For poorly differentiated tumors from the GEP tract and lung, a platinum-based cytotoxic regimen is widely used. Genomic analysis has recently revealed a diverse pattern of primary organ-dependent mutations, and the use of traditional treatment strategies versus organ-specific strategies is currently under discussion. In addition, clinical trials for several molecular-targeted agents and immune checkpoint inhibitors for the treatment of NENs are currently underway. Accumulating genomic information is expected to contribute to the development of novel therapies for other organ-derived NENs or poorly differentiated neuroendocrine carcinomas (NECs). Here, we provide an updated overview of the current knowledge regarding genomic profiles and representative agents for NENs and highlight the prospects for future investigations.

Keywords: Neuroendocrine neoplasms, WHO classification, genomic analysis, somatostatin analogue, peptide receptor radionuclide therapy, molecular-targeted agent, everolimus, sunitinib.

Graphical Abstract
[1]
Solcia E, Kloppel G, Sobin LH, et al. World Health Organization (WHO) international histological classification of tumors. 2nd ed. Berlin, Germany: Springer 2000.
[2]
Travis WD, Brambilla E. Burke, et al World Health Organization (WHO) classification of tumours of the lung, pleura, thymus and heart. 4th ed. Geneva, Switzerland: WHO Press 2015.
[3]
Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017; 3(10): 1335-42.
[http://dx.doi.org/10.1001/jamaoncol.2017.0589] [PMID: 28448665]
[4]
Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97(4): 934-59.
[http://dx.doi.org/10.1002/cncr.11105] [PMID: 12569593]
[5]
Bosman FT, Carneiro F, Hruban RH, et al. World Health Organization (WHO) classification of tumours of the digestive system. 4th ed. Geneva, Switzerland: WHO Press 2010.
[6]
Lloyd RV, Osamura RY, Klöppel G, et al. World Health Organization (WHO) classification of tumours of endocrine organs. 4th ed. Geneva, Switzerland: WHO Press 2017.
[7]
Caplin ME, Baudin E, Ferolla P, et al. ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 2015; 26(8): 1604-20.
[http://dx.doi.org/10.1093/annonc/mdv041] [PMID: 25646366]
[8]
Yao JC, Shah MH, Ito T, et al. RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364(6): 514-23.
[http://dx.doi.org/10.1056/NEJMoa1009290] [PMID: 21306238]
[9]
Yao JC, Fazio N, Singh S, et al. RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387(10022): 968-77.
[http://dx.doi.org/10.1016/S0140-6736(15)00817-X] [PMID: 26703889]
[10]
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364(6): 501-13.
[http://dx.doi.org/10.1056/NEJMoa1003825] [PMID: 21306237]
[11]
Rinke A, Müller HH, Schade-Brittinger C, et al. PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27(28): 4656-63.
[http://dx.doi.org/10.1200/JCO.2009.22.8510] [PMID: 19704057]
[12]
Caplin ME, Pavel M, Ćwikła JB, et al. CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371(3): 224-33.
[http://dx.doi.org/10.1056/NEJMoa1316158] [PMID: 25014687]
[13]
Strosberg J, El-Haddad G, Wolin E, et al. NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376(2): 125-35.
[http://dx.doi.org/10.1056/NEJMoa1607427] [PMID: 28076709]
[14]
Yamaguchi T, Machida N, Morizane C, et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci 2014; 105(9): 1176-81.
[http://dx.doi.org/10.1111/cas.12473] [PMID: 24975505]
[15]
Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24(1): 152-60.
[http://dx.doi.org/10.1093/annonc/mds276] [PMID: 22967994]
[16]
Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014; 38(4): 437-47.
[http://dx.doi.org/10.1097/PAS.0000000000000169] [PMID: 24503751]
[17]
Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 2015; 39(5): 683-90.
[http://dx.doi.org/10.1097/PAS.0000000000000408] [PMID: 25723112]
[18]
Walter T, Tougeron D, Baudin E, et al. CEPD investigators. Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort. Eur J Cancer 2017; 79: 158-65.
[http://dx.doi.org/10.1016/j.ejca.2017.04.009] [PMID: 28501762]
[19]
Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 2011; 331(6021): 1199-203.
[http://dx.doi.org/10.1126/science.1200609] [PMID: 21252315]
[20]
Heaphy CM, de Wilde RF, Jiao Y, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 2011; 333(6041): 425.
[http://dx.doi.org/10.1126/science.1207313] [PMID: 21719641]
[21]
Singhi AD, Liu TC, Roncaioli JL, et al. Alterative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors. Clin Cancer Res 2017; 23(2): 600-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1113] [PMID: 27407094]
[22]
Raj N, Soumerai T, Valentino E, et al. Next-generation sequencing (NGS) in advanced well differentiated pancreatic neuroendocrine tumors (WD pNETs): A study using MSK-IMPACT J Clin Oncol 2016; 34(suppl): abstr 246..
[23]
Scarpa A, Chang DK, Nones K, et al. Australian Pancreatic Cancer Genome Initiative. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017; 543(7643): 65-71.
[http://dx.doi.org/10.1038/nature21063] [PMID: 28199314]
[24]
Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 2013; 45(12): 1483-6.
[http://dx.doi.org/10.1038/ng.2821] [PMID: 24185511]
[25]
Karpathakis A, Dibra H, Pipinikas C, et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clin Cancer Res 2016; 22(1): 250-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0373] [PMID: 26169971]
[26]
Park C, Ha SY, Kim ST, et al. Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors. Oncotarget 2016; 7(4): 4024-35.
[http://dx.doi.org/10.18632/oncotarget.6602] [PMID: 26684240]
[27]
Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol 2012; 36(2): 173-84.
[http://dx.doi.org/10.1097/PAS.0b013e3182417d36] [PMID: 22251937]
[28]
Klempner SJ, Gershenhorn B, Tran P, et al. BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov 2016; 6(6): 594-600.
[http://dx.doi.org/10.1158/2159-8290.CD-15-1192] [PMID: 27048246]
[29]
Bergsland EK, Roy R, Stephens P, et al. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising in different sites. J Clin Oncol 2016.
[30]
Hijioka S, Hosoda W, Matsuo K, et al. Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study. Clin Cancer Res 2017; 23(16): 4625-32.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-3135] [PMID: 28455360]
[31]
Ohmoto A, Rokutan H, Yachida S. Pancreatic neuroendocrine neoplasms: basic biology, current treatment strategies and prospects for the future. Int J Mol Sci 2017; 18(1)E143
[http://dx.doi.org/10.3390/ijms18010143] [PMID: 28098761]
[32]
Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 2014; 5: 3518.
[http://dx.doi.org/10.1038/ncomms4518] [PMID: 24670920]
[33]
Simbolo M, Mafficini A, Sikora KO, et al. Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D. J Pathol 2017; 241(4): 488-500.
[http://dx.doi.org/10.1002/path.4853] [PMID: 27873319]
[34]
George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015; 524(7563): 47-53.
[http://dx.doi.org/10.1038/nature14664] [PMID: 26168399]
[35]
Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 2017; 17(12): 725-37.
[http://dx.doi.org/10.1038/nrc.2017.87] [PMID: 29077690]
[36]
Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res 2016; 22(14): 3618-29.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2946] [PMID: 26960398]
[37]
George J, Walter V, Peifer M, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 2018; 9(1): 1048.
[http://dx.doi.org/10.1038/s41467-018-03099-x] [PMID: 29535388]
[38]
Witkowski L, Carrot-Zhang J, Albrecht S, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 2014; 46(5): 438-43.
[http://dx.doi.org/10.1038/ng.2931] [PMID: 24658002]
[39]
Patibandla JR, Fehniger JE, Levine DA, Jelinic P. Small cell cancers of the female genital tract: Molecular and clinical aspects. Gynecol Oncol 2018; 149(2): 420-7.
[http://dx.doi.org/10.1016/j.ygyno.2018.02.004] [PMID: 29458976]
[40]
Yaghmour G, Prouet P, Wiedower E, et al. Genomic alterations in neuroendocrine cancers of the ovary. J Ovarian Res 2016; 9(1): 52.
[http://dx.doi.org/10.1186/s13048-016-0259-2] [PMID: 27566252]
[41]
Jelinic P, Schlappe BA, Conlon N, et al. Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type. Mod Pathol 2016; 29(1): 60-6.
[http://dx.doi.org/10.1038/modpathol.2015.129] [PMID: 26564006]
[42]
McCullar B, Pandey M, Yaghmour G, et al. Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung. Breast Cancer Res Treat 2016; 158(1): 195-202.
[http://dx.doi.org/10.1007/s10549-016-3867-z] [PMID: 27329168]
[43]
Lavigne M, Menet E, Tille JC, et al. Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. Mod Pathol 2018; 31(1): 68-82.
[http://dx.doi.org/10.1038/modpathol.2017.107] [PMID: 28884749]
[44]
Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012; 61(1): 6-32.
[http://dx.doi.org/10.1136/gutjnl-2011-300831] [PMID: 22052063]
[45]
Pavel M, O’Toole D, Costa F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016; 103(2): 172-85.
[http://dx.doi.org/10.1159/000443167] [PMID: 26731013]
[46]
Masab M, Saif MW. Telotristat ethyl: proof of principle and the first oral agent in the management of well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea. Cancer Chemother Pharmacol 2017; 80(6): 1055-62.
[http://dx.doi.org/10.1007/s00280-017-3462-y] [PMID: 29051994]
[47]
Öberg K, Knigge U, Kwekkeboom D, Perren A. Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23(Suppl. 7): vii124-30.
[http://dx.doi.org/10.1093/annonc/mds295] [PMID: 22997445]
[48]
Bertani E, Ravizza D, Milione M, et al. Neuroendocrine neoplasms of rectum: A management update. Cancer Treat Rev 2018; 66: 45-55.
[http://dx.doi.org/10.1016/j.ctrv.2018.04.003] [PMID: 29684743]
[49]
Yao J, Phan AT. Optimising therapeutic options for patients with advanced pancreatic neuroendocrine tumours. Eur Oncol Haematol 2012; 8: 217-23.
[http://dx.doi.org/10.17925/EOH.2012.08.4.217]
[50]
Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 2016; 103(2): 186-94.
[http://dx.doi.org/10.1159/000443172] [PMID: 26731334]
[51]
Melosky B. Low grade neuroendocrine tumors of the lung. Front Oncol 2017; 7: 119.
[http://dx.doi.org/10.3389/fonc.2017.00119] [PMID: 28660170]
[52]
Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 2015; 26(8): 1604-20.
[http://dx.doi.org/10.1093/annonc/mdv041] [PMID: 25646366]
[53]
Ferolla P, Brizzi MP, Meyer T, et al. Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol 2017; 18(12): 1652-64.
[http://dx.doi.org/10.1016/S1470-2045(17)30681-2] [PMID: 29074099]
[54]
NCCN Clinical Practice Guidelines in Oncology, Small Cell Lung Cancer (Version 2. 2017), National Comprehensive Cancer Network..
[55]
NCCN Clinical Practice Guidelines in Oncology. Non-small Cell Lung Cancer (Version 7 2015). National Comprehensive Cancer Network 2015.
[56]
Niho S, Kenmotsu H, Sekine I, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol 2013; 8(7): 980-4.
[http://dx.doi.org/10.1097/JTO.0b013e31828f6989] [PMID: 23774385]
[57]
Naidoo J, Santos-Zabala ML, Iyriboz T, et al. Large cell neuroendocrine carcinoma of the lung: clinico-pathologic features, treatment, and outcomes. Clin Lung Cancer 2016; 17(5): e121-9.
[http://dx.doi.org/10.1016/j.cllc.2016.01.003] [PMID: 26898325]
[58]
Sun JM, Ahn MJ, Ahn JS, et al. Chemotherapy for pulmonary large cell neuroendocrine carcinoma: similar to that for small cell lung cancer or non-small cell lung cancer? Lung Cancer 2012; 77(2): 365-70.
[http://dx.doi.org/10.1016/j.lungcan.2012.04.009] [PMID: 22579297]
[59]
Sehouli J, Woopen H, Pavel M, et al. Neuroendocrine Neoplasms of the Ovary: A Retrospective Study of the North Eastern German Society of Gynecologic Oncology (NOGGO). Anticancer Res 2016; 36(3): 1003-9.
[PMID: 26976990]
[60]
Öberg K, Lamberts SW. Somatostatin analogues in acromegaly and gastroenteropancreatic neuroendocrine tumours: past, present and future. Endocr Relat Cancer 2016; 23(12): R551-66.
[http://dx.doi.org/10.1530/ERC-16-0151] [PMID: 27697899]
[61]
Astruc B, Marbach P, Bouterfa H, et al. Long-acting octreotide and prolonged-release lanreotide formulations have different pharmacokinetic profiles. J Clin Pharmacol 2005; 45(7): 836-44.
[http://dx.doi.org/10.1177/0091270005277936] [PMID: 15951474]
[62]
Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 2003; 24(1): 28-47.
[http://dx.doi.org/10.1210/er.2000-0001] [PMID: 12588807]
[63]
Vitale G, Dicitore A, Sciammarella C, et al. Pasireotide in the treatment of neuroendocrine tumors: a review of the literature. Endocr Relat Cancer 2018; 25(6): R351-64.
[http://dx.doi.org/10.1530/ERC-18-0010] [PMID: 29643113]
[64]
Uri I, Avniel-Polak S, Gross DJ, Grozinsky-Glasberg S. Update in the therapy of advanced neuroendocrine tumors. Curr Treat Options Oncol 2017; 18(12): 72.
[http://dx.doi.org/10.1007/s11864-017-0514-9] [PMID: 29143892]
[65]
Modlin IM, Latich I, Kidd M, Zikusoka M, Eick G. Therapeutic options for gastrointestinal carcinoids. Clin Gastroenterol Hepatol 2006; 4(5): 526-47.
[http://dx.doi.org/10.1016/j.cgh.2005.12.008] [PMID: 16630755]
[66]
Sullivan I, Le Teuff G, Guigay J, et al. Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. Eur J Cancer 2017; 75: 259-67.
[http://dx.doi.org/10.1016/j.ejca.2016.11.034] [PMID: 28242503]
[67]
Trendle MC, Moertel CG, Kvols LK. Incidence and morbidity of cholelithiasis in patients receiving chronic octreotide for metastatic carcinoid and malignant islet cell tumors. Cancer 1997; 79(4): 830-4.
[http://dx.doi.org/10.1002/(SICI)1097-0142(19970215)79:4<830: AID-CNCR20>3.0.CO;2-#] [PMID: 9024721]
[68]
Cuyle PJ, Prenen H. Practical management of toxicities associated with targeted therapies for advanced gastroenteropancreatic neuroendocrine tumors. Ann Gastroenterol 2018; 31(2): 140-50.
[http://dx.doi.org/10.20524/aog.2018.0224] [PMID: 29507461]
[69]
Kulke MH, Hörsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 2017; 35(1): 14-23.
[http://dx.doi.org/10.1200/JCO.2016.69.2780] [PMID: 27918724]
[70]
Pavel M, Gross DJ, Benavent M, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer 2018; 25(3): 309-22.
[http://dx.doi.org/10.1530/ERC-17-0455] [PMID: 29330194]
[71]
Cives M, Strosberg J. Radionuclide therapy for neuroendocrine tumors. Curr Oncol Rep 2017; 19(2): 9.
[http://dx.doi.org/10.1007/s11912-017-0567-8] [PMID: 28220446]
[72]
Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29(17): 2416-23.
[http://dx.doi.org/10.1200/JCO.2010.33.7873] [PMID: 21555692]
[73]
Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26(13): 2124-30.
[http://dx.doi.org/10.1200/JCO.2007.15.2553] [PMID: 18445841]
[74]
Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 2017; 23(16): 4617-24.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-2743] [PMID: 28428192]
[75]
Kwekkeboom DJ, Krenning EP. Peptide receptor radionuclide therapy in the treatment of neuroendocrine tumors. Hematol Oncol Clin North Am 2016; 30(1): 179-91.
[http://dx.doi.org/10.1016/j.hoc.2015.09.009] [PMID: 26614376]
[76]
Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326(8): 519-23.
[http://dx.doi.org/10.1056/NEJM199202203260804] [PMID: 1310159]
[77]
Clewemar Antonodimitrakis P, Sundin A, Wassberg C, Granberg D, Skogseid B, Eriksson B. Streptozocin and 5-fluorouracil for the treatment of pancreatic neuroendocrine tumors: efficacy, prognostic factors and toxicity. Neuroendocrinology 2016; 103(3-4): 345-53.
[http://dx.doi.org/10.1159/000439086] [PMID: 26279284]
[78]
Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011; 117(2): 268-75.
[http://dx.doi.org/10.1002/cncr.25425] [PMID: 20824724]
[79]
Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 2013; 71(3): 663-70.
[http://dx.doi.org/10.1007/s00280-012-2055-z] [PMID: 23370660]
[80]
Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOGACRIN Cancer Research Group (E2211) J Clin Oncol 2018; 36(suppl) abstr 4004.
[81]
Campana D, Walter T, Pusceddu S, et al. Correlation between MGMT promoter methylation and response to temozolomide-based therapy in neuroendocrine neoplasms: an observational retrospective multicenter study. Endocrine 2018; 60(3): 490-8.
[http://dx.doi.org/10.1007/s12020-017-1474-3] [PMID: 29150792]
[82]
Lamarca A, Elliott E, Barriuso J, et al. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: A lost cause? Cancer Treat Rev 2016; 44: 26-41.
[http://dx.doi.org/10.1016/j.ctrv.2016.01.005] [PMID: 26855376]
[83]
Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2015; 22(4): 657-64.
[http://dx.doi.org/10.1530/ERC-15-0119] [PMID: 26113608]
[84]
Morizane C, Machida N, Honma Y, et al. Randomized phase III study of etoposide plus cisplatin versus irinotecan plus cisplatin in advanced neuroendocrine carcinoma of the digestive system A Japan Clinical Oncology Group study (JCOG1213).) J Clin Oncol 2015; 33(suppl) abstr TPS4143.
[85]
Crona J, Fanola I, Lindholm DP, et al. Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology 2013; 98(2): 151-5.
[http://dx.doi.org/10.1159/000354760] [PMID: 23969949]
[86]
Cohen JG, Chan JK, Kapp DS. The management of small-cell carcinomas of the gynecologic tract. Curr Opin Oncol 2012 Sep; 24(5): 572-9.
[http://dx.doi.org/10.1097/CCO.0b013e3283565ed6]
[87]
Tempfer CB, Tischoff I, Dogan A, et al. Neuroendocrine carcinoma of the cervix: a systematic review of the literature. BMC Cancer 2018; 18(1): 530.
[http://dx.doi.org/10.1186/s12885-018-4447-x] [PMID: 29728073]
[88]
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 2009; 27(13): 2278-87.
[http://dx.doi.org/10.1200/JCO.2008.20.0766] [PMID: 19332717]
[89]
Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; 28(1): 69-76.
[http://dx.doi.org/10.1200/JCO.2009.24.2669] [PMID: 19933912]
[90]
Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378(9808): 2005-12.
[http://dx.doi.org/10.1016/S0140-6736(11)61742-X] [PMID: 22119496]
[91]
Pusceddu S, Verzoni E, Prinzi N, et al. Everolimus treatment for neuroendocrine tumors: latest results and clinical potential. Ther Adv Med Oncol 2017; 9(3): 183-8.
[http://dx.doi.org/10.1177/1758834016683905] [PMID: 28344663]
[92]
Yao J, Fazio N, Buzzoni R, et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the lung: RADIANT-4 subgroup analysis: topic: medical Oncology. J Thorac Oncol 2016; 11(11S): S253.
[http://dx.doi.org/10.1016/j.jtho.2016.09.011]
[93]
Davies M, Saxena A, Kingswood JC. Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide. Orphanet J Rare Dis 2017; 12(1): 35.
[http://dx.doi.org/10.1186/s13023-017-0581-9] [PMID: 28202028]
[94]
Culler MD, Oberg K, Arnold R, Krenning EP, Sevilla I, Díaz JA. Somatostatin analogs for the treatment of neuroendocrine tumors. Cancer Metastasis Rev 2011; 30(Suppl. 1): 9-17.
[http://dx.doi.org/10.1007/s10555-011-9293-0] [PMID: 21369878]
[95]
Wolin EM, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther 2015; 9: 5075-86.
[http://dx.doi.org/10.2147/DDDT.S84177] [PMID: 26366058]
[96]
Maxwell JE, Sherman SK, Howe JR. Translational diagnostics and therapeutics in pancreatic neuroendocrine tumors. Clin Cancer Res 2016; 22(20): 5022-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0435] [PMID: 27742788]
[97]
Kumar R, Crouthamel MC, Rominger DH, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 2009; 101(10): 1717-23.
[http://dx.doi.org/10.1038/sj.bjc.6605366] [PMID: 19844230]
[98]
Ranieri G, Marech I, Niccoli Asabella A, et al. Tyrosine-kinase inhibitors therapies with mainly anti- angiogenic activity in advanced renal cell carcinoma: Value of PET/CT in response evaluation. Int J Mol Sci 2017; 18(9)E1937
[http://dx.doi.org/10.3390/ijms18091937] [PMID: 28891933]
[99]
Ahn HK, Choi JY, Kim KM, et al. Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. Br J Cancer 2013; 109(6): 1414-9.
[http://dx.doi.org/10.1038/bjc.2013.470] [PMID: 23989950]
[100]
Grande E, Capdevila J, Castellano D, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol 2015; 26(9): 1987-93.
[http://dx.doi.org/10.1093/annonc/mdv252] [PMID: 26063633]
[101]
Phan AT, Halperin DM, Chan JA, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol 2015; 16(6): 695-703.
[http://dx.doi.org/10.1016/S1470-2045(15)70136-1] [PMID: 25956795]
[102]
Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 2008; 14(22): 7272-83.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0652] [PMID: 19010843]
[103]
Strosberg JR, Cives M, Hwang J, et al. A phase II study of axitinib in advanced neuroendocrine tumors. Endocr Relat Cancer 2016; 23(5): 411-8.
[http://dx.doi.org/10.1530/ERC-16-0008] [PMID: 27080472]
[104]
Roth GJ, Binder R, Colbatzky F, et al. Nintedanib: from discovery to the clinic. J Med Chem 2015; 58(3): 1053-63.
[http://dx.doi.org/10.1021/jm501562a] [PMID: 25474320]
[105]
Iyer RV, Konda B, Owen DH, et al. Multicenter phase 2 study of nintedanib in patients (pts) with advanced progressing carcinoid tumors J Clin Oncol 2018; 36(suppl) abstr 4105.
[106]
Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10(12): 2298-308.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0264] [PMID: 21926191]
[107]
Chan JA, Faris JE, Murphy JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). J Clin Oncol 2017; 35(suppl) abstr 228.
[108]
Suyama K, Iwase H. Lenvatinib. A promising molecular targeted agent for multiple cancers cancer control 2018; 25 1073274818789361
[109]
Castillon JC, Fazio N, Lopez C, et al. Efficacy of lenvatinib in patients with advanced pancreatic (panNETs) and gastrointestinal (giNETs) WHO grade 1/2 (G1/G2) neuroendocrine tumors: Results of the international phase II TALENT trial (GETNE 1509). Ann Oncol 2018; 29. [suppl]
[110]
de Dueñas EM, Gavila-Gregori J, Olmos-Antón S, et al. Preclinical and clinical development of palbociclib and future perspectives. Clin Transl Oncol 2018; 20(9): 1136-44.
[http://dx.doi.org/10.1007/s12094-018-1850-3] [PMID: 29564714]
[111]
Tang LH, Contractor T, Clausen R, et al. Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased cdk4/cdk6. Clin Cancer Res 2012; 18(17): 4612-20.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-3264] [PMID: 22761470]
[112]
Pulido EG, Teule A, Alonso-Gordoa T, et al. A phase II trial of palbociclib in metastatic grade 1/2 pancreatic neuroendocrine tumors: The PALBONET study on behalf of the Spanish Taskforce Group of Neuroendocrine Tumors (GETNE). Ann Oncol 2017; 28(Suppl.): 4612-20.
[113]
Chen J, Zhao KN, Li R, Shao R, Chen C. Activation of PI3K/Akt/mTOR pathway and dual inhibitors of PI3K and mTOR in endometrial cancer. Curr Med Chem 2014; 21(26): 3070-80.
[http://dx.doi.org/10.2174/0929867321666140414095605] [PMID: 24735369]
[114]
Salazar R, Garcia-Carbonero R, Libutti SK, et al. Phase II study of BEZ235 versus everolimus in patients with mammalian target of rapamycin inhibitor-naïve advanced pancreatic neuroendocrine tumors. Oncologist 2018; 23(7): 766-e90.
[http://dx.doi.org/10.1634/theoncologist.2017-0144] [PMID: 29242283]
[115]
Beltran PJ, Mitchell P, Chung YA, et al. AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells. Mol Cancer Ther 2009; 8(5): 1095-105.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-1171] [PMID: 19366899]
[116]
von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res 2000; 60(16): 4573-81.
[PMID: 10969809]
[117]
Strosberg JR, Chan JA, Ryan DP, et al. A multi-institutional, phase II open-label study of ganitumab (AMG 479) in advanced carcinoid and pancreatic neuroendocrine tumors. Endocr Relat Cancer 2013; 20(3): 383-90.
[http://dx.doi.org/10.1530/ERC-12-0390] [PMID: 23572164]
[118]
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366(26): 2455-65.
[http://dx.doi.org/10.1056/NEJMoa1200694] [PMID: 22658128]
[119]
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366(26): 2443-54.
[http://dx.doi.org/10.1056/NEJMoa1200690] [PMID: 22658127]
[120]
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015; 14(4): 847-56.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0983] [PMID: 25695955]
[121]
Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013; 499(7457): 214-8.
[http://dx.doi.org/10.1038/nature12213] [PMID: 23770567]
[122]
Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24(9): R315-34.
[http://dx.doi.org/10.1530/ERC-17-0012] [PMID: 28710117]
[123]
Kim ST, Ha SY, Lee S, et al. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J Cancer 2016; 7(5): 484-9.
[http://dx.doi.org/10.7150/jca.13711] [PMID: 26958083]
[124]
Cavalcanti E, Armentano R, Valentini AM, Chieppa M, Caruso ML. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis 2017; 8(8) e3004
[http://dx.doi.org/10.1038/cddis.2017.401] [PMID: 28837143]
[125]
Chauhan A, Horn M, Magee G, et al. Immune checkpoint inhibitors in neuroendocrine tumors: A single institution experience with review of literature. Oncotarget 2017; 9(10): 8801-9.
[PMID: 29507655]
[126]
Mehnert JM, Rugo HS, O’Neil BH, et al. Pembrolizumab for patients with PD-L1–positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Ann Oncol 2017; 28 [suppl]
[127]
Yao JC, Strosberg J, Fazio N, et al. Activity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx). Ann Oncol 2018; 29 [suppl]
[128]
Zhang P, Lu M, Li J, Shen L. Efficacy and safety of PD-1 blockade with JS001 in patients with advanced neuroendocrine neoplasms: a non-randomized, open-label, phase 1b trial. Ann Oncol 2018; 29 [suppl]
[129]
Kulke MH, Siu LL, Tepper JE, et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 2011; 29(7): 934-43.
[http://dx.doi.org/10.1200/JCO.2010.33.2056] [PMID: 21263089]
[130]
Stockley TL, Oza AM, Berman HK, et al. Molecular profiling of advanced solid tumors and patient outcomes with genotype-matched clinical trials: the Princess Margaret IMPACT/COMPACT trial. Genome Med 2016; 8(1): 109.
[http://dx.doi.org/10.1186/s13073-016-0364-2] [PMID: 27782854]
[131]
Tanabe Y, Ichikawa H, Kohno T, et al. Comprehensive screening of target molecules by next-generation sequencing in patients with malignant solid tumors: guiding entry into phase I clinical trials. Mol Cancer 2016; 15(1): 73.
[http://dx.doi.org/10.1186/s12943-016-0553-z] [PMID: 27852271]
[132]
Flynn RL, Cox KE, Jeitany M, et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 2015; 347(6219): 273-7.
[http://dx.doi.org/10.1126/science.1257216] [PMID: 25593184]
[133]
Chan-Penebre E, Armstrong K, Drew A, et al. Selective killing of SMARCA2- and SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type cells by inhibition of EZH2: In vitro and in vivo preclinical models. Mol Cancer Ther 2017; 16(5): 850-60.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0678] [PMID: 28292935]
[134]
Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2012; 2(9): 798-811.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0112] [PMID: 22961666]
[135]
Saito M, Saito K, Shiraishi K, et al. Identification of candidate responders for anti-PD-L1/PD-1 immunotherapy, Rova-T therapy, or EZH2 inhibitory therapy in small-cell lung cancer. Mol Clin Oncol 2018; 8(2): 310-4.
[PMID: 29435295]
[136]
Yanagihara K, Kubo T, Mihara K, et al. Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma. Oncotarget 2018; 9(92): 36503-14.
[http://dx.doi.org/10.18632/oncotarget.26367] [PMID: 30559933]
[137]
Dizdar L, Werner TA, Drusenheimer JC, et al. BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma. Int J Cancer 2019; 144(6): 1379-90.
[http://dx.doi.org/10.1002/ijc.31828] [PMID: 30144031]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy