Top

Published in:

01-08-2012 | Pancreatic Tumors

Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays

Authors: Joo Kyung Park, MD, Min A. Kim, MD, PhD, Ji Kon Ryu, MD, PhD, Yong Bum Yoon, MD, PhD, Sun-Whe Kim, MD, PhD, Ho-Seong Han, MD, PhD, Gyeong Hoon Kang, MD, PhD, Haeryoung Kim, MD, PhD, Jin-Hyeok Hwang, MD, PhD, Yong-Tae Kim, MD, PhD

Published in: Annals of Surgical Oncology | Issue 8/2012

Abstract

Background

Most pancreatic ductal adenocarcinomas (PDACs) metastasize even after curative resection. Our goal was to investigate the important factors affecting metastasis and overall survival (OS).

Methods

We studied 88 PDACs with R0 resection and evaluated immunohistochemical markers on tissue microarrays to assess the expression levels of the following: EGFR, amphiregulin, VEGF, p-c-met, MMP2, MMP7, MMP9, CXCR3, and CXCR4.

Results

The median OS in patients who had positive versus negative expression of AREG and MMP9 were 25 versus 16 months and 24 versus 13 months, respectively (P = 0.03, P = 0.006). However, the median OS in patients with positive versus negative expression of MMP2 was 22 versus 37 months (P = 0.04). Immunoprofiles also revealed that patients with positive expression of p-c-met or VEGF had significantly shorter distant metastasis-free survival. Adjuvant treatment, postoperative decrease of CA 19-9, angiolymphatic invasion, AREG, and MMP2 were independent prognostic factors affecting OS in multivariate analysis.

Conclusions

Immunoprofiles revealed the groups with unfavorable tumor biology: negative expression of AREG and positive expression of MMP2. Also, high immunoreactivity of p-c-met or VEGF seemed to be associated with early distant organ metastasis in R0 resected PDACs; however, they still need to be further investigated. These results may give us useful insights in understanding the tumor biology and the patterns of PDAC dissemination.

Available only for authorised users

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.PubMedCrossRef

Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg. 1997;226:248–57.PubMedCrossRef

Real FX. A “catastrophic hypothesis” for pancreas cancer progression. Gastroenterology. 2003;124:1958–64.PubMedCrossRef

Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.PubMedCrossRef

Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4:448–56.PubMedCrossRef

Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239–52.PubMedCrossRef

Christofori G. New signals from the invasive front. Nature. 2006;441(7092):444–50.PubMedCrossRef

Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72.PubMedCrossRef

Shoyab M, McDonald VL, Bradley JG, et al. Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proc Natl Acad Sci USA. 1988;85:6528–32.PubMedCrossRef

10.

Shoyab M, Plowman GD, McDonald VL, et al. Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science. 1989;243(4894 Pt 1):1074–6.PubMedCrossRef

11.

Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.PubMedCrossRef

12.

Yotsumoto F, Yagi H, Suzuki SO, et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. 2008;365:555–61.PubMedCrossRef

13.

Yamada M, Ichikawa Y, Yamagishi S, et al. Amphiregulin is a promising prognostic marker for liver metastases of colorectal cancer. Clin Cancer Res. 2008;14:2351–6.PubMedCrossRef

14.

Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.PubMedCrossRef

15.

Freije JM, Balbin M, Pendas AM, et al. Matrix metalloproteinases and tumor progression. Adv Exp Med Biol. 2003;532:91–107.PubMedCrossRef

16.

Lopez-Otin C, Matrisian LM. Emerging roles of proteases in tumour suppression. Nat Rev Cancer. 2007;7:800–8.PubMedCrossRef

17.

Bramhall SR, Neoptolemos JP, Stamp GW, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol. 1997;182:347–55.PubMedCrossRef

18.

Gress TM, Muller-Pillasch F, Lerch MM, et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer. 1995;62:407–13.PubMedCrossRef

19.

Scorilas A, Karameris A, Arnogiannaki N, et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer. 2001;84:1488–96.PubMedCrossRef

20.

Takeha S, Fujiyama Y, Bamba T, et al. Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. Jpn J Cancer Res. 1997;88:72–81.PubMedCrossRef

21.

Pozzi A, LeVine WF, Gardner HA. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis. Oncogene. 2002;21:272–81.PubMedCrossRef

22.

Hamano Y, Zeisberg M, Sugimoto H, et al. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell. 2003;3:589–601.PubMedCrossRef

23.

Birkedal-Hansen H. Matrix metalloproteinases. Adv Dental Res. 1995;9(3 Suppl):16.CrossRef

24.

Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995;7:728–35.PubMedCrossRef

25.

Juuti A, Lundin J, Nordling S, et al. Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer. Oncology. 2006;71:61–8.PubMedCrossRef

26.

Desruisseau S, Palmari J, Giusti C, et al. Clinical relevance of amphiregulin and VEGF in primary breast cancers. Int J Cancer. 2004;111:733–40.PubMedCrossRef

27.

Smith RA, Tang J, Tudur-Smith C, et al. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer. 2011;104:1440–51.PubMedCrossRef

28.

Maulik G, Madhiwala P, Brooks S, et al. Activated c-Met signals through PI3 K with dramatic effects on cytoskeletal functions in small cell lung cancer. J Cell Mol Med. 2002;6:539–53.PubMedCrossRef

29.

Pisick E, Jagadeesh S, Salgia R. Receptor tyrosine kinases and inhibitors in lung cancer. Sci World J. 2004;4:589–604.CrossRef

30.

Ide T, Kitajima Y, Miyoshi A, et al. The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol. 2007;14:2600–7.PubMedCrossRef

Title: Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays
Authors: Joo Kyung Park, MD
Min A. Kim, MD, PhD
Ji Kon Ryu, MD, PhD
Yong Bum Yoon, MD, PhD
Sun-Whe Kim, MD, PhD
Ho-Seong Han, MD, PhD
Gyeong Hoon Kang, MD, PhD
Haeryoung Kim, MD, PhD
Jin-Hyeok Hwang, MD, PhD
Yong-Tae Kim, MD, PhD
Publication date: 01-08-2012
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 8/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-012-2277-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Postoperative Prognostic Predictors of Pancreatic Ductal Adenocarcinoma: Clinical Analysis and Immunoprofile on Tissue Microarrays

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2012

Locoregional Recurrence after Mastectomy with Immediate Transverse Rectus Abdominis Myocutaneous (TRAM) Flap Reconstruction

Clinicopathologic Risk Factors for the Local Recurrence of Phyllodes Tumors of the Breast

A 5 Year Analysis of Readmissions after Radical Subtotal Gastrectomy for Early Gastric Cancer

Patterns of Recurrence Following Complete Response to Regional Chemotherapy for In-Transit Melanoma

Racial and Gender Disparities and the Role of Primary Tumor Type on Inpatient Outcomes Following Craniotomy for Brain Metastases

The New American Joint Committee on Cancer/International Union Against Cancer Staging System for Adenocarcinoma of the Stomach: Increased Complexity without Clear Improvement in Predictive Accuracy