Prognostic Fifteen-Gene Signature for Early Stage Pancreatic Ductal Adenocarcinoma.

Dung-Tsa Chen,Barbara A Centeno,Jose M Pimiento,Jennifer Permuth-Wey,Mokenge Malafa,Kazim Husain,Po-Yu Huang,Ashley H Davis-Yadley,Francisco X Real

doi:10.1371/journal.pone.0133562

Dung-Tsa Chen, Barbara A Centeno + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0133562

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Journal: PloS one	Publication Date: Aug 6, 2015
Citations: 112	License type: CC BY 4.0

Affiliation: Moffitt Cancer Center, National Chung Hsing University

Abstract

The outcomes of patients treated with surgery for early stage pancreatic ductal adenocarcinoma (PDAC) are variable with median survival ranging from 6 months to more than 5 years. This challenge underscores an unmet need for developing personalized medicine strategies to refine the current treatment decision-making process. To derive a prognostic gene signature for patients with early stage PDAC, a PDAC cohort from Moffitt Cancer Center (n = 63) was used with overall survival (OS) as the primary endpoint. This was further evaluated using an independent microarray cohort dataset (Stratford et al: n = 102). Technical validation was performed by NanoString platform. A prognostic 15-gene signature was developed and showed a statistically significant association with OS in the Moffitt cohort (hazard ratio [HR] = 3.26; p<0.001) and Stratford et al cohort (HR = 2.07; p = 0.02), and was independent of other prognostic variables. Moreover, integration of the signature with the TNM staging system improved risk prediction (p<0.01 in both cohorts). In addition, NanoString validation showed that the signature was robust with a high degree of reproducibility and the association with OS remained significant in the two cohorts. The gene signature could be a potential prognostic tool to allow risk-adapted stratification of PDAC patients into personalized treatment protocols; possibly improving the currently poor clinical outcomes of these patients.

Highlights

Pancreatic cancer is the fourth leading cause of cancer death in the United States with an estimated 38,000 deaths in 2013[1]
We profiled resected primary tumors from early stage pancreatic ductal adenocarcinoma (PDAC) patients and developed a 15-gene signature based on overall survival
The signature was able to identify a low-risk subgroup of PDAC patients who were likely to survive longer than 2 years after surgery and a high-risk subgroup who likely survived less than 1.5 years (Fig 1)

Summary

Introduction

Pancreatic cancer is the fourth leading cause of cancer death in the United States with an estimated 38,000 deaths in 2013[1]. The prognostic performance of AJCC TNM staging for more than 80% of patients with resected pancreatic cancer (Stages IB, IIA, and IIB) is very poor, with the survival curves being virtually identical[4]; the current practice is to uniformly treat all patients with stage I and II PDAC with surgical resection followed by adjuvant therapy. There is an unmet need to develop reliable and robust biomarkers such as gene signatures to better predict outcomes and to help tailor treatment plans (such as use of surgery versus systemic therapy) In response to this unmet need, we have analyzed microarray data from a Moffitt cohort of 63 patients with early stage PDAC (stage IB, IIA and IIB) and developed a prognostic 15-gene signature to predict overall survival (OS). We hypothesize that high risk for poor clinical outcomes in early-stage PDAC are reflected by specific transcriptomic features from this 15-gene signature

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