Nuclear survivin is a prognosticator in gastroenteropancreatic neuroendocrine neoplasms: a meta-analysis

Journal of Cancer Research and Clinical Oncology - Tập 148 Số 9 - Trang 2235-2246 - 2022
Sarah Krieg1, Christoph Roderburg1, Stephen Fung2, Tom Luedde1, Wolfram Trudo Knoefel2, Andreas Krieg2
1Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany
2Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, Bldg. 12.46, 40225, Duesseldorf, Germany

Tóm tắt

Abstract Purpose Gastroenteropancreatic neuroendocrine neosplasms (GEP-NEN) are biologically heterogenous tumors with an increasing incidence over the past decades. Although efforts have been made in the treatment of these tumors, survival rates in metastasized tumor stages remain frustrating. Thus, there is an urgent need to identify novel targets as alternative treatment options. In this regard, the inhibitor of apoptosis protein (IAP) family member survivin could be such an attractive target. Therefore, aim of our meta-analysis was to assess the role of survivin as a biomarker and predictor in GEP-NEN. Methods Medline, Web of Science and Scopus were screened for studies that fulfilled our selection criteria. Quality assessement of the studies was based on design, methodology, generalizability and results analysis. Meta-analyses were conducted using a random-effects model and effect size measures were expressed as pooled Hazard Ratio (HR) or Odds Ratio (OR) with 95% Confidence Interval (CI). Results Six eligible studies with 649 patients (range 77–132) assessed survivin expression in GEP-NEN by immunohistochemistry. High expression levels of nuclear survivin in GEP-NEN correlated with a shorter overall survival (HR 3.10; 95% CI 2.15–4.47; p < 0.0001). In contrast to cytoplasmic survivin (OR 1.24; CI 0.59–2.57; p = 0.57), nuclear survivin was also associated (OR 15.23; CI 3.61–64.23; p = 0.0002) with G3/poorly differentiated GEP-NEN. Conclusion Nuclear Survivin is highly expressed in more aggressive G3 GEP-NEN and correlates with a poor outcome. Survivin is therefore an interesting molecule for a targeted therapy, especially for patients with highly proliferative G3 GEP-NENs.

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Tài liệu tham khảo

Anlauf M (2011) Neuroendocrine neoplasms of the gastroenteropancreatic system: pathology and classification. Horm Metab Res 43:825–831. https://doi.org/10.1055/s-0031-1291307

Aristizabal Prada ET, Auernhammer CJ (2018) Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocr Connect 7:R1-r25. https://doi.org/10.1530/ec-17-0286

Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

Briest F, Wang Y, Arsenic R, Elezkurtaj S, Berg E, Greshake S, Lock AC, Hörsch D, Arnold CN, Hummel M, Siegmund B, Grabowski P (2018) Immunohistochemical study of mitosis-regulatory proteins in gastroenteropancreatic neuroendocrine neoplasms. Anticancer Res 38:3863–3870. https://doi.org/10.21873/anticanres.12670

Buffa R, Rindi G, Sessa F, Gini A, Capella C, Jahn R, Navone F, De Camilli P, Solcia E (1987) Synaptophysin immunoreactivity and small clear vesicles in neuroendocrine cells and related tumours. Mol Cell Probes 1:367–381. https://doi.org/10.1016/0890-8508(87)90018-1

Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224–233. https://doi.org/10.1056/NEJMoa1316158

Cherenfant J, Talamonti MS, Hall CR, Thurow TA, Gage MK, Stocker SJ, Lapin B, Wang E, Silverstein JC, Mangold K, Odeleye M, Kaul KL, Lamzabi I, Gattuso P, Winchester DJ, Marsh RW, Roggin KK, Bentrem DJ, Baker MS, Prinz RA (2014) Comparison of tumor markers for predicting outcomes after resection of nonfunctioning pancreatic neuroendocrine tumors. Surgery 156:1504–1510. https://doi.org/10.1016/j.surg.2014.08.043 (discussion 1510–1501)

Clemens MR, Gladkov OA, Gartner E, Vladimirov V, Crown J, Steinberg J, Jie F, Keating A (2015) Phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 149:171–179. https://doi.org/10.1007/s10549-014-3238-6

Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T, Yao JC (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 3:1335–1342. https://doi.org/10.1001/jamaoncol.2017.0589

Dizdar L, Oesterwind KA, Riemer JC, Werner TA, Mersch S, Möhlendick B, Schütte SC, Verde PE, Raba K, Topp SA, Stoecklein NH, Esposito I, Knoefel WT, Krieg A (2017) Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia. Oncotarget 8:8369–8382. https://doi.org/10.18632/oncotarget.14207

Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, Anlauf M, Schott M, Göring W, Esposito I, Stoecklein NH, Knoefel WT, Krieg A (2019) BRAF(V600E) mutation: a promising target in colorectal neuroendocrine carcinoma. Int J Cancer 144:1379–1390. https://doi.org/10.1002/ijc.31828

Dohi T, Okada K, Xia F, Wilford CE, Samuel T, Welsh K, Marusawa H, Zou H, Armstrong R, Matsuzawa S, Salvesen GS, Reed JC, Altieri DC (2004) An IAP-IAP complex inhibits apoptosis. J Biol Chem 279:34087–34090. https://doi.org/10.1074/jbc.C400236200

Drozdov I, Kidd M, Nadler B, Camp RL, Mane SM, Hauso O, Gustafsson BI, Modlin IM (2009) Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning. Cancer 115:1638–1650. https://doi.org/10.1002/cncr.24180

Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634. https://doi.org/10.1136/bmj.315.7109.629

Ekeblad S, Lejonklou MH, Stålberg P, Skogseid B (2012) Prognostic relevance of survivin in pancreatic endocrine tumors. World J Surg 36:1411–1418. https://doi.org/10.1007/s00268-011-1345-7

Fotouhi O, Kjellin H, Larsson C, Hashemi J, Barriuso J, Juhlin CC, Lu M, Höög A, Pastrián LG, Lamarca A, Soto VH, Zedenius J, Mendiola M, Lehtiö J, Kjellman M (2016) Proteomics suggests a role for APC-survivin in response to somatostatin analog treatment of neuroendocrine tumors. J Clin Endocrinol Metab 101:3616–3627. https://doi.org/10.1210/jc.2016-2028

Fung S, Knoefel WT, Krieg A (2021) Clinicopathological and prognostic significance of inhibitor of apoptosis protein (IAP) family members in lung cancer: a meta-analysis. Cancers (basel). https://doi.org/10.3390/cancers13164098

Giaccone G, Zatloukal P, Roubec J, Floor K, Musil J, Kuta M, van Klaveren RJ, Chaudhary S, Gunther A, Shamsili S (2009) Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. J Clin Oncol 27:4481–4486. https://doi.org/10.1200/jco.2008.21.1862

Grabowski P, Griss S, Arnold CN, Hörsch D, Göke R, Arnold R, Heine B, Stein H, Zeitz M, Scherübl H (2005) Nuclear survivin is a powerful novel prognostic marker in gastroenteropancreatic neuroendocrine tumor disease. Neuroendocrinology 81:1–9. https://doi.org/10.1159/000084892

Hanif A, Lee S, Gupta M, Chander A, Kannisto ED, Punnanitinont A, Fenstermaker R, Ciesielski M, Attwood K, Qiu J, Yendamuri S, Iyer R (2020) Exploring the role of survivin in neuroendocrine neoplasms. Oncotarget 11:2246–2258. https://doi.org/10.18632/oncotarget.27631

Harbord RM, Egger M, Sterne JA (2006) A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 25:3443–3457. https://doi.org/10.1002/sim.2380

Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, Barriuso J, Pavel M, O’Toole D, Walter T (2015) Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 22:657–664. https://doi.org/10.1530/erc-15-0119

Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. https://doi.org/10.1002/sim.1186

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199–1203. https://doi.org/10.1126/science.1200609

Kaemmerer D, Träger T, Hoffmeister M, Sipos B, Hommann M, Sänger J, Schulz S, Lupp A (2015) Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget 6:27566–27579. https://doi.org/10.18632/oncotarget.4491

Kelly RJ, Thomas A, Rajan A, Chun G, Lopez-Chavez A, Szabo E, Spencer S, Carter CA, Guha U, Khozin S, Poondru S, Van Sant C, Keating A, Steinberg SM, Figg W, Giaccone G (2013) A phase I/II study of sepantronium bromide (YM155, survivin suppressor) with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Ann Oncol 24:2601–2606. https://doi.org/10.1093/annonc/mdt249

Klimstra DSKG, La Rosa S, Rindi G (2019) Classification of neuroendocrine neoplasms of the digestive system, 5th edn. WHO Classification of Tumours. W. C. o. T. E. Board, IARC, Lyon

Knösel T, Chen Y, Altendorf-Hofmann A, Danielczok C, Freesmeyer M, Settmacher U, Wurst C, Schulz S, Yang LL, Petersen I (2012) High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event. J Cancer Res Clin Oncol 138:397–403. https://doi.org/10.1007/s00432-011-1107-9

Krieg A, Baseras B, Tomczak M, Verde PE, Stoecklein NH, Knoefel WT (2013a) Role of survivin as prognostic and clinicopathological marker in gastric cancer: a meta-analysis. Mol Biol Rep 40:5501–5511. https://doi.org/10.1007/s11033-013-2650-z

Krieg A, Werner TA, Verde PE, Stoecklein NH, Knoefel WT (2013b) Prognostic and clinicopathological significance of survivin in colorectal cancer: a meta-analysis. PLoS ONE 8:e65338. https://doi.org/10.1371/journal.pone.0065338

Kudchadkar R, Ernst S, Chmielowski B, Redman BG, Steinberg J, Keating A, Jie F, Chen C, Gonzalez R, Weber J (2015) A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. Cancer Med 4:643–650. https://doi.org/10.1002/cam4.363

Lewis KD, Samlowski W, Ward J, Catlett J, Cranmer L, Kirkwood J, Lawson D, Whitman E, Gonzalez R (2011) A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Invest New Drugs 29:161–166. https://doi.org/10.1007/s10637-009-9333-6

Li F, Aljahdali I, Ling X (2019) Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study? J Exp Clin Cancer Res 38:368. https://doi.org/10.1186/s13046-019-1362-1

Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I, Reed JC (2003) HBXIP functions as a cofactor of survivin in apoptosis suppression. Embo J 22:2729–2740. https://doi.org/10.1093/emboj/cdg263

Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC (2010) IAP regulation of metastasis. Cancer Cell 17:53–64. https://doi.org/10.1016/j.ccr.2009.11.021

Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097

Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M (2007) YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67:8014–8021. https://doi.org/10.1158/0008-5472.Can-07-1343

Papadopoulos KP, Lopez-Jimenez J, Smith SE, Steinberg J, Keating A, Sasse C, Jie F, Thyss A (2016) A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma. Leuk Lymphoma 57:1848–1855. https://doi.org/10.3109/10428194.2015.1113275

Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L, Huantes S, Loh M, Conway EM, Kang ES, Hoe Koo H, Hofmann WK, Heisterkamp N, Pelus L, Keerthivasan G, Crispino J, Kahn M, Müschen M, Kim YM (2011) Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 118:2191–2199. https://doi.org/10.1182/blood-2011-04-351239

Paule RC, Mandel J (1977) Consensus Values and Weighting Factors. J Res Natl Bur Stand 1977 87:377–385. https://doi.org/10.6028/jres.087.022

Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295:676–680. https://doi.org/10.1001/jama.295.6.676

Richardson WS, Wilson MC, Nishikawa J, Hayward RS (1995) The well-built clinical question: a key to evidence-based decisions. ACP J Club 123:A12-13

Rindi G, Buffa R, Sessa F, Tortora O, Solcia E (1986) Chromogranin A, B and C immunoreactivities of mammalian endocrine cells. Distribution, distinction from costored hormones/prohormones and relationship with the argyrophil component of secretory granules. Histochemistry 85:19–28. https://doi.org/10.1007/bf00508649

Rindi GAR, Bosman FT, Capella C, Klimstra DS, Klöppel G, Komminoth P, Solcia P (2010) Nomenclature and classifi cation of Neuroendocrine neoplasms of the digestive system. IARC, Lyon

Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R (2009) 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 27:4656–4663. https://doi.org/10.1200/jco.2009.22.8510

Rinke A, Auernhammer CJ, Bodei L, Kidd M, Krug S, Lawlor R, Marinoni I, Perren A, Scarpa A, Sorbye H, Pavel ME, Weber MM, Modlin I, Gress TM (2021) Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? Gut 70:1768–1781. https://doi.org/10.1136/gutjnl-2020-321300

Satoh T, Okamoto I, Miyazaki M, Morinaga R, Tsuya A, Hasegawa Y, Terashima M, Ueda S, Fukuoka M, Ariyoshi Y, Saito T, Masuda N, Watanabe H, Taguchi T, Kakihara T, Aoyama Y, Hashimoto Y, Nakagawa K (2009) Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors. Clin Cancer Res 15:3872–3880. https://doi.org/10.1158/1078-0432.Ccr-08-1946

Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, Lawlor RT, Johns AL, Miller DK, Mafficini A, Rusev B, Scardoni M, Antonello D, Barbi S, Sikora KO, Cingarlini S, Vicentini C, McKay S, Quinn MC, Bruxner TJ, Christ AN, Harliwong I, Idrisoglu S, McLean S, Nourse C, Nourbakhsh E, Wilson PJ, Anderson MJ, Fink JL, Newell F, Waddell N, Holmes O, Kazakoff SH, Leonard C, Wood S, Xu Q, Nagaraj SH, Amato E, Dalai I, Bersani S, Cataldo I, Dei Tos AP, Capelli P, Davì MV, Landoni L, Malpaga A, Miotto M, Whitehall VL, Leggett BA, Harris JL, Harris J, Jones MD, Humphris J, Chantrill LA, Chin V, Nagrial AM, Pajic M, Scarlett CJ, Pinho A, Rooman I, Toon C, Wu J, Pinese M, Cowley M, Barbour A, Mawson A, Humphrey ES, Colvin EK, Chou A, Lovell JA, Jamieson NB, Duthie F, Gingras MC, Fisher WE, Dagg RA, Lau LM, Lee M, Pickett HA, Reddel RR, Samra JS, Kench JG, Merrett ND, Epari K, Nguyen NQ, Zeps N, Falconi M, Simbolo M, Butturini G, Van Buren G, Partelli S, Fassan M, Khanna KK, Gill AJ, Wheeler DA, Gibbs RA, Musgrove EA, Bassi C, Tortora G, Pederzoli P, Pearson JV, Waddell N, Biankin AV, Grimmond SM (2017) Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543:65–71. https://doi.org/10.1038/nature21063

Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, Porter AC, Tugwell P, Moher D, Bouter LM (2007) Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol 7:10. https://doi.org/10.1186/1471-2288-7-10

Shimizu T, Nishio K, Sakai K, Okamoto I, Okamoto K, Takeda M, Morishita M, Nakagawa K (2020) Phase I safety and pharmacokinetic study of YM155, a potent selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer. Cancer Chemother Pharmacol 86:211–219. https://doi.org/10.1007/s00280-020-04112-1

Solcia E KG, Sobin LH (In collaboration with 9 pathologists from 4 coutries) (2000) Histological typing of endocrine tumours. Springer, Berlin

Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP (2001) Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J 18:705–719. https://doi.org/10.1183/09031936.01.00062201

Takizawa N, Ohishi Y, Hirahashi M, Takahashi S, Nakamura K, Tanaka M, Oki E, Takayanagi R, Oda Y (2015) Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor. Hum Pathol 46:1890–1900. https://doi.org/10.1016/j.humpath.2015.08.006

Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S (2008) Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol 26:5198–5203. https://doi.org/10.1200/jco.2008.17.2064

Tolcher AW, Quinn DI, Ferrari A, Ahmann F, Giaccone G, Drake T, Keating A, de Bono JS (2012) A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer. Ann Oncol 23:968–973. https://doi.org/10.1093/annonc/mdr353

Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS (2002) A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA 99:4349–4354. https://doi.org/10.1073/pnas.072586399

Wang C, Yu J, Fan Y, Ma K, Ning J, Hu Y, Niu W, Dong X, Wu Y, Li E, Dong D (2019) The clinical significance of PD-L1/PD-1 expression in gastroenteropancreatic neuroendocrine neoplasia. Ann Clin Lab Sci 49:448–456

Werner TA, Tamkan-Ölcek Y, Dizdar L, Riemer JC, Wolf A, Cupisti K, Verde PE, Knoefel WT, Krieg A (2016) Survivin and XIAP: two valuable biomarkers in medullary thyroid carcinoma. Br J Cancer 114:427–434. https://doi.org/10.1038/bjc.2016.5

Wheatley SP, Altieri DC (2019) Survivin at a glance. J Cell Sci. https://doi.org/10.1242/jcs.223826

Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, de Wilde RF, Maitra A, Hicks J, Demarzo AM, Shi C, Sharma R, Laheru D, Edil BH, Wolfgang CL, Schulick RD, Hruban RH, Tang LH, Klimstra DS, Iacobuzio-Donahue CA (2012) 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 36:173–184. https://doi.org/10.1097/PAS.0b013e3182417d36