Gastroenterology

Gastroenterology

Volume 137, Issue 2, August 2009, Pages 558-568.e11
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Expression of S100A2 Calcium-Binding Protein Predicts Response to Pancreatectomy for Pancreatic Cancer

Presented at the Royal Australasian College of Surgeons, Annual Scientific Congress, 2008, Hong Kong, Digestive Disease Week, 2008, San Diego, CA and American Pancreatic Association, 2008, Chicago, IL.
https://doi.org/10.1053/j.gastro.2009.04.009Get rights and content

Background & Aims

Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival.

Methods

We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients.

Results

Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439; hazard ratio [HR], 2.19; 95% confidence interval [CI]: 1.48–3.25; P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39–4.33; P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months; P = .0007) or lymph node metastases (median, 17.4 months; P = .0002).

Conclusions

S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy samples has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease.

Section snippets

Patients and Tissue Specimens

Detailed clinicopathologic and outcome data for a total of 601 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent pancreatic resection or biopsy were obtained from teaching hospitals associated with the NSW Pancreatic Cancer Network (www.pancreaticcancer.net.au), Sydney, Australia (Table 1). This cohort was the combination of a training cohort of 162 patients (76 resections, which consisted of 62 Whipple pancreaticoduodenectomies and 14 left-sided pancreatectomies, and

Gene Expression and Survival

Seventeen candidate biomarkers were selected based on their potential role in pancreatic cancer and from global analysis of gene expression of pancreatic cancers performed by our group15 and others17, 18, 19 (Table 2 and Supplementary Data). Some of these genes (DPC4/Smad4, LMO4, sFRP4, β-catenin, cyclin E1, HOXB2) have been investigated previously as potential biomarkers in the training cohort prior to its maturation to reach a follow-up of over 5 years.11, 12, 13, 14, 15 The results of

Discussion

Substantial improvements in outcomes have been achieved in some cancers, eg, breast cancer, through defining phenotypic subgroups using molecular markers of outcome and therapeutic responsiveness.21 The ability to forecast an individual patient's response to specific therapies using biomarkers stratifies patients to appropriate therapeutic regimens and facilitates ongoing investigation of treatment-resistant subgroups to identify novel, more effective therapies. This study identifies that high

Acknowledgments

The authors thank all the members and administrative staff of the NSW Pancreatic Cancer Network. For the full list of members, please see online Supplementary Data.

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by the National Health & Medical Research Council of Australia, The Cancer Council NSW, the St. Vincent's Clinic Foundation, the Royal Australasian College of Surgeons, Prostate Cancer Foundation of Australia, and R. T. Hall Trust. AVB, CJS, DKC, EAM and SMH are supported by Fellowships from the Cancer Institute NSW.

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