25 april 2013: In BMC - British Journal of Cancer verscheen vorig jaar een publicatie van een fase 2 studie waarbij gesteld werd dat verder onderzoek naar herceptin bij alvleesklierkanker niet zinnig wordt veronderstelt. Ook omdat halverwege de studie nog weinig patiënten in leven waren en een minderheid van de patiënten de juiste mutatie hadden, slechts 11% (van ruim 200 deelnemende patienten) toonde een vorm van expressie geschikt voor herceptin. 

Maar wat hier naar mijn bescheiden mening aan de hand is dat deze studie werd uitgevoerd met mensen die uitbehandeld waren en in slechte lichamelijke conditie met al overal uitzaaiingen. Dan heeft een vorm van immuuntherapie, zoals herceptin toch in feite is, weinig zin meer. Gelukkig wordt er nog wel onderzoek gedaan naar aanpak van alvleesklierkanker op basis van zogeheten dual aanpak, een aanpak op basis van een vastgestelde EGFR en Her2Neu expressie vooraf, zie o.a. dit studierapport: In Pancreatic Carcinoma, Dual EGFR/HER2 Targeting with Cetuximab/Trastuzumab Is More Effective than Treatment with Trastuzumab/Erlotinib or Lapatinib Alone: Implication of Receptors' Down-regulation and Dimers' Disruption1

 Het volledige studierapport in BMC waarbij herceptin geen goede aanpak zou zijn kunt u gratis inzien. Het abstract staat onderaan dit artikel.

8 mei 2012: als aanvulling op onderstaande dierstudies van herceptin - trastuzumab bij alvleesklierkanker  het abstract van een fase I studie bij 12 alvleesklierkankerpatiënten toegevoegd met hoopvolle resultaten.

Als u hier klikt kunt u gratis een studierapport inzien waar geanalyseerd is wat een te hoge Her2-Neu expressie betekent voor mensen met spijsverteringskanker zoals alvleesklierkanker. Her2-neu expressie is bepalend of een kankerpatiënt in aanmerking komt voor herceptin of niet.

Onderaan staat het abstract van de studie plus referentielijst.

17 september 2005: Bron: Int J Oncol. 2005 Oct;27(4):1125-30.

Duitse onderzoekers publiceren in oktober a.s. het abstract van een aantal laboratoriumstudies en dierstudies die ze gedaan hebben met Herceptin als basis aangevuld met gemcitabine en/of docetaxel bij inoperabele en gevorderde alvleesklierkanker. Omdat bij 70% van de alvleesklierkankerpatiënten de HER2-Neu expressie oververtegenwoordigd is en juist Herceptin bij borstkankerpatiënten met deze receptor uitstekende resultaten laat zien zijn deze trials opgezet. Nu worden fase I en II studies opgezet bij alvleesklierkankerpatiënten om te zien of de goede resultaten uit de laboratoriumproeven en dierstudies dan ook overeind blijven.

Combination therapy for advanced pancreatic cancer using Herceptintrade mark plus chemotherapy.

Buchler P, Reber HA, Eibl G, Roth MA, Buchler MW, Friess H, Isacoff WH, Hines OJ.
Department of General Surgery, Ruprecht-Karls-University of Heidelberg, D-69120 Heidelberg, Germany. peter.buechler@med.uni-heidelberg.de.

The HER2/neu oncogene is overexpressed in up to 70% of human pancreatic cancer specimens when compared to normal pancreatic tissue. This cell surface receptor can be targeted specifically by the neutralizing antibody Herceptintrade mark. Herceptin has been successfully used in combination with other chemotherapeutic agents in breast cancer, a cancer in which only 30% of patients harbor elevated HER2/neu levels. In the present study, we investigated the therapeutic efficacy of Herceptin in combination with gemcitabine and docetaxel. Gemcitabine is currently the standard chemotherapeutic agent used to treat pancreatic cancer. In contrast, docetaxel, a taxane, is only just being investigated in pancreatic cancer. Tumor cell resistance to taxanes is at least in part mediated by the HER2/NEU oncogene. We have previously characterized HER2/NEU expression in human pancreatic cancer cell lines and studied the anti-tumor activity of Herceptin monotherapy in vitro and in vivo. In the present study, combination therapy resulted in a dramatic improvement of animals bearing human pancreatic cancer xenografts. Furthermore, metastasis and production of ascites was lower when a combination of these three agents was used. We conclude that, as with breast cancer, the anti-tumor activity of Herceptin may be improved by combination with taxanes or gemcitabine.

PMID: 16142331 [PubMed - in process]

HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature

 J Cancer. 2012; 3 : 137–144.
Published online 2012 March 12. doi:  10.7150/jca.4090
PMCID: PMC3319979
HER2 as a Prognostic Marker in Gastric Cancer - A Systematic Analysis of Data from the Literature
Jan Trøst Jørgensen1 and Maria Hersom2
1. Dx-Rx Institute, Baunevaenget 76, DK-3480 Fredensborg, Denmark;
2. Human Biology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Corresponding author: Dx-Rx Institute, Baunevaenget 76, DK-3480 Fredensborg, Denmark, Phone: +45 4074 7846, Fax: +45 8870 8090, E-mail: jan.trost@dx-rx.dk .
Competing Interests: Jan Trøst Jørgensen has worked as a consultant for Dako Denmark A/S, Glostrup, Denmark and has given lectures at meetings sponsored by Roche and AstraZeneca. Maria Hersom has nothing to disclose.
Received January 14, 2012; Accepted March 4, 2012.
Through the recent conduct of the ToGA trial, HER2 has shown to be predictive for the treatment with trastuzumab in advanced gastric and gastro-oesophageal cancer. When it comes to the prognostic properties the situation is different. Despite the fact that it is more than 20 years ago since the first studies demonstrating an association between a positive HER2 status and poor prognosis were published the issue is still controversial. In this current systematic review a large number of studies on HER2 and gastric cancer have been reviewed. The studies included in this review should fulfill the following two criteria. First criterion: The number of patients in each study should be ≥ 100, and the HER2 status should have been determined either by immunohistochemistry (IHC) or in situ hybridization (ISH). Second criterion: The selected articles should include an analysis of the association between the HER2 status and survival or relevant clinicopathological characteristics. Forty-two publications with a total of 12,749 patients fulfilled the two criteria and were reviewed in detail. The majority of the publications (71%) showed that a HER2-postive status measured either by IHC or ISH was associated with poor survival and/or clinicopathological characteristics, such as serosal invasion, lymph node metastases, disease stage, or distant metastases. Based on the current analysis a clear trend towards a potential role for HER2 as a negative prognostics factor in gastric cancer was shown, suggesting that HER2 overexpression and/or amplification is a molecular abnormality that might be linked to the development of gastric cancer.
Keywords: HER2, gastric cancer, prognostic marker, IHC, FISH, CISH.
References
1. Ross JS, Slodkowska EA, Symmans WF. et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14:320–368. [PubMed]
2. Bang YJ, Van Cutsem E, Feyereislova A. et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697. [PubMed]
3. Jørgensen JT. Targeted HER2 treatment in advanced gastric cancer. Oncology. 2010;78:26–33. [PubMed]
4. Slamon DJ, Clark GM, Wong SG. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. [PubMed]
5. Yonemura Y, Ninomiya I, Yamaguchi A. et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991;51:1034–1038. [PubMed]
6. Roh JK, Paik S, Chung HC. et al. Overexpression of erbB-2 protein in gastric adenocarcinoma--a potential role in therapeutic response to adjuvant 5-FU-doxorubicin regimen. Jpn J Cancer Chemother. 1992;19:1207–1219.
7. Coussens L, Yang-Feng TL, Liao YC. et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230:1132–1139. [PubMed]
8. Im SA, Kim JW, Kim JS. et al. Clinicopathologic characteristics of patients with stage III/IV (M(0)) advanced gastric cancer, according to HER2 status assessed by immunohistochemistry and fluorescence in situ hybridization. Diagn Mol Pathol. 2011;20:94–100. [PubMed]
9. Kunz PL, Mojtahed A, Fisher GA. et al. HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population: Clinicopathologic Analysis With Proposed Approach to HER2 Assessment. Appl Immunohistochem Mol Morphol. 2012 Jan;20(1):13–24. [PubMed]
10. Grabsch H, Sivakumar S, Gray S. et al. HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series. Cell Oncol. 2010;32:57–65. [PubMed]
11. Marx AH, Tharun L, Muth J. et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol. 2009;40:769–777. [PubMed]
12. Yan SY, Hu Y, Fan JG. et al. Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma. World J Gastroenterol. 2011;17:1501–1506. [PMC free article] [PubMed]
13. Tanner M, Hollmen M, Junttila TT. et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273–278. [PubMed]
14. Shiraishi N, Sato K, Yasuda K. et al. Multivariate prognostic study on large gastric cancer. J Surg Oncol. 2007;96:14–18. [PubMed]
15. Fornaro L, Lucchesi M, Caparello C. et al. Anti-HER agents in gastric cancer: from bench to bedside. Nat Rev Gastroenterol Hepatol. 2011;8:369–383. [PubMed]
16. Shun CT, Wu MS, Lin JT. et al. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepatogastroenterology. 1997;44:604–609. [PubMed]
17. Wu MS, Shun CT, Wang HP. et al. Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology. 1997;112:1457–1465. [PubMed]
18. Ishikawa T, Kobayashi M, Mai M. et al. Amplification of the c-erbB-2 (HER-2/neu) gene in gastric cancer cells. Detection by fluorescence in situ hybridization. Am J Pathol. 1997;151:761–768. [PMC free article] [PubMed]
19. Yonemura Y, Ninomiya I, Tsugawa K. et al. Prognostic significance of c-erbB-2 gene expression in the poorly differentiated type of adenocarcinoma of the stomach. Cancer Detect Prev. 1998;22:139–146. [PubMed]
20. Nakajima M, Sawada H, Yamada Y. et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85:1894–1902. [PubMed]
21. Lee KE, Lee HJ, Kim YH. et al. Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer. Jpn J Clin Oncol. 2003;33:173–179. [PubMed]
22. Park DI, Yun JW, Park JH. et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51:1371–1379. [PubMed]
23. Zhang XL, Yang YS, Xu DP. et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009;33:2112–2118. [PubMed]
24. Yan B, Yau EX, Bte Omar SS. et al. A study of HER2 gene amplification and protein expression in gastric cancer. J Clin Pathol. 2010;63:839–842. [PubMed]
25. Kim KC, Koh YW, Chang HM. et al. Evaluation of HER2 Protein Expression in Gastric Carcinomas: Comparative Analysis of 1414 Cases of Whole-Tissue Sections and 595 Cases of Tissue Microarrays. Ann Surg Oncol. 2011 Oct;18(10):2833–40. [PubMed]
26. Wang YY, Ye ZY, Li L. et al. ADAM 10 is associated with gastric cancer progression and prognosis of patients. J Surg Oncol. 2011;103:116–123. [PubMed]
27. Barros-Silva JD, Leitao D, Afonso L. et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer. 2009;100:487–493. [PMC free article] [PubMed]
28. Moelans CB, Milne AN, Morsink FH. et al. Low frequency of HER2 amplification and overexpression in early onset gastric cancer. Cell Oncol. 2011;34:89–95.
29. Jain S, Filipe MI, Gullick WJ. et al. c-erbB-2 proto-oncogene expression and its relationship to survival in gastric carcinoma: an immunohistochemical study on archival material. Int J Cancer. 1991;48:668–671. [PubMed]
30. Hofmann M, Stoss O, Shi D. et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805. [PubMed]
31. Tateishi M, Toda T, Minamisono Y, Nagasaki S. Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol. 1992;49:209–212. [PubMed]
32. Yonemura Y, Ninomiya I, Ohoyama S. et al. Correlation of c-erbB-2 protein expression and lymph node status in early gastric cancer. Oncology. 1992;49:363–367. [PubMed]
33. Mizutani T, Onda M, Tokunaga A. et al. Relationship of C-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer. 1993;72:2083–2088. [PubMed]
34. Ohguri T, Sato Y, Koizumi W. et al. An immunohistochemical study of c-erbB-2 protein in gastric carcinomas and lymph-node metastases: is the c-erbB-2 protein really a prognostic indicator? Int J Cancer. 1993;53:75–79. [PubMed]
35. Uchino S, Tsuda H, Maruyama K. et al. Overexpression of c-erbB-2 protein in gastric cancer. Its correlation with long-term survival of patients. Cancer. 1993;72:3179–3184. [PubMed]
36. Kim JP, Oh ST, Hwang TS, Chi JG. The prognostic significance of c-erbB-2 and p53 protein expressions in gastric carcinoma--a multivariate analysis of prognostic factors. J Korean Med Sci. 1994;9:248–253. [PMC free article] [PubMed]
37. Motojima K, Furui J, Kohara N. et al. erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery. 1994;115:349–354. [PubMed]
38. Chariyalertsak S, Sugano K, Ohkura H, Mori Y. Comparison of c-erbB-2 oncoprotein expression in tissue and serum of patients with stomach cancer. Tumour Biol. 1994;15:294–303. [PubMed]
39. Webb A, Scott-Mackie P, Cunningham D. et al. The prognostic value of serum and immunohistochemical tumour markers in advanced gastric cancer. Eur J Cancer. 1996;32A:63–68. [PubMed]
40. Lee HR, Kim JH, Uhm HD. et al. Overexpression of c-ErbB-2 protein in gastric cancer by immunohistochemical stain. Oncology. 1996;53:192–197. [PubMed]
41. Sanz-Ortega J, Steinberg SM, Moro E. et al. Comparative study of tumor angiogenesis and immunohistochemistry for p53, c-ErbB2, c-myc and EGFr as prognostic factors in gastric cancer. Histol Histopathol. 2000;15:455–462. [PubMed]
42. Ougolkov A, Mai M, Takahashi Y. et al. Altered expression of beta-catenin and c-erbB-2 in early gastric cancer. J Exp Clin Cancer Res. 2000;19:349–355. [PubMed]
43. Allgayer H, Babic R, Gruetzner KU. et al. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol. 2000;18:2201–2209. [PubMed]
44. Ghaderi A, Vasei M, Maleck-Hosseini SA. et al. The expression of c-erbB-1 and c-erbB-2 in Iranian patients with gastric carcinoma. Pathol Oncol Res. 2002;8:252–256. [PubMed]
45. Takehana T, Kunitomo K, Kono K. et al. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002;98:833–837. [PubMed]
46. Pinto-de-Sousa J, David L, Almeida R. et al. c-erb B-2 expression is associated with tumor location and venous invasion and influences survival of patients with gastric carcinoma. Int J Surg Pathol. 2002;10:247–256. [PubMed]
47. Wang YL, Sheu BS, Yang HB. et al. Overexpression of c-erb-B2 proteins in tumor and non-tumor parts of gastric adenocarcinoma--emphasis on its relation to H. pylori infection and clinicohistological characteristics. Hepatogastroenterology. 2002;49:1172–1176. [PubMed]
48. Song HS, Do YR, Kim IH. et al. Prognostic significance of immunohistochemical expression of EGFR and C-erbB-2 oncoprotein in curatively resected gastric cancer. Cancer Res Treat. 2004;36:240–245. [PMC free article] [PubMed]
49. Tang Z, Zhao M, Ji J. et al. Overexpression of gastrin and c-met protein involved in human gastric carcinomas and intestinal metaplasia. Oncol Rep. 2004;11:333–339. [PubMed]
50. Yu GZ, Chen Y, Wang JJ. Overexpression of Grb2/HER2 signaling in Chinese gastric cancer: their relationship with clinicopathological parameters and prognostic significance. J Cancer Res Clin Oncol. 2009;135:1331–1339. [PubMed]

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer

British Journal of Cancer (2012) 106, 1033–1038. doi:10.1038/bjc.2012.18 www.bjcancer.com
Published online 28 February 2012

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer

J Harder1, G Ihorst2, V Heinemann3, R Hofheinz4, M Moehler5, P Buechler6, G Kloeppel7, C Röcken7, M Bitzer8, S Boeck3, E Endlicher9, A Reinacher-Schick10, C Schmoor2 and M Geissler11

  1. 1Medizinische Klinik II, Hegau- Bodensee Klinikum, Virchowstraße 10, D-78224 Singen, Germany
  2. 2Clinical Trials Unit, University Medical Center Freiburg, Elsässer Straße 2, D-79110 Freiburg, Germany
  3. 3Klinikum Grosshadern Medizinische Klinik III, L.M.- Universitätsklinikum München, Marchoninistraße 15, D-81377 München, Germany
  4. 4Medizinische Klinik III, Klinikum Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
  5. 5Medizinische Klinik und Poliklinik, Klinikum der Johannes Gutenberg- Universität Mainz, Langenbeckstraße 1, D-55131 Mainz, Germany
  6. 6Abt. Allgemeine,- Viszerale-u. Unfallchirurgie, Chirurgische Universitätsklinik Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany
  7. 7Institut f. Pathologie, Christian-Albrechts-Universität, Arnold Heller-Straße 3, D-24105 Kiel, Germany
  8. 8Medizinische Klinik I, Universitätsklinikum Tübingen, Ottfried-Müller- Straße 10, D-72076 Tübingen, Germany
  9. 9Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany
  10. 10Hämatologie/Onkologie, Knappschaftskrankenhaus Bochum, In der Schornau 23–25, D-44892 Bochum, Germany
  11. 11Klinik für Allg. Innere Medizin, Onkologie/Hämatologie, Gastroenterologie u. Infektiologie, Klinikum Esslingen, Hirschlandstraße. 97, D-73730 Esslingen, Germany

Correspondence: Dr J Harder, E-mail: jan.harder@hbh-kliniken.de

Received 7 July 2011; Revised 6 January 2012; Accepted 12 January 2012
Advance online publication 28 February 2012

Top

Abstract

Background:

  

New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression.

Methods: 

Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression.

Results:

Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months.

Conclusion: 

This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.


Plaats een reactie ...

Reageer op "Alvleesklierkanker: Laboratorium studies en dierstudies geven goed effect van Herceptin in combinatie met gemcitabine en/of docetaxel bij inoperabele alvleesklierkanker"


Gerelateerde artikelen