Gastroenteropancreatic Neuroendocrine Tumors: Potential for New Therapeutic Targets Open Access

Abstract

 

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular tumors. The role of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) in the growth of these tumors, and their association with known prognostic markers (CD31 and Ki-67), adverse clinicopathologic factors, and disease recurrence after resection remains unclear. The purpose of this study was 1) to utilize neuroendocrine tissue samples from Emory through pathologic re-review of STAT3, VEGF, HIF-1α, CD31, and Ki-67 expression to assess the associations between these biomarkers and GEP-NET recurrence; and 2) to use Ki-67 to further stratify low grade pancreatic neuroendocrine tumors (PanNETs), a subset of GEP-NETs, to more accurately predict recurrence of disease.

 

All patients with non-metastatic primary GEP-NETs who underwent curative-intent resection from 2000-2013 were included. Immunohistochemistry was performed using tissue microarrays made in triplicate by a pathologist blinded to all other clinicopathologic variables. STAT3, VEGF, and HIF-1α were categorized into high vs. low expression; CD31 was dichotomized at the median value, and Ki-67 was grouped by the World Health Organization’s classification system. The primary outcome was 3-year recurrence-free survival (RFS).

Of 144 GEP-NETs resected, STAT3 expression was high in 12 (8%), VEGF was high in 19 (13%), HIF-1α was high in 2 (1%), CD31 was above the median in 71 (50%), Ki-67 was >3% in 14 (10%). Lower 3-year RFS was associated with high STAT3 expression (55% vs. 84%; p=0.003), CD31 above the median (75% vs. 86%; p=0.043), and Ki-67>3% (51% vs. 84%; p<0.001). High STAT3 expressing tumors were also more likely to have a Ki-67≥3% (42% vs. 7%; p<0.001). Even when controlling for high STAT3 and CD31 expression, Ki-67>3% had a 4-fold increase in risk of recurrence (HR 4.1; p=0.006). Moreover, when further stratifying Ki-67 index among low grade PanNETs, a Ki-67 of 1-2.99% was associated with a decreased RFS compared to a Ki-67<1% (70% vs. 97%; p=0.005). This finding persisted on multivariable analysis (HR 8.6; p=0.045), controlling for tumor size, margin positivity, lymph node involvement, and advanced T-stage.

In conclusion, while multiple biomarkers are associated with worse RFS in GEP-NETs, Ki-67, in particular, may be used to further stratify and predict aggressive behavior for these tumors.

Table of Contents

 

TABLE OF CONTENTS

INTRODUCTION........................................................................................................................................1

METHODS...................................................................................................................................................5

   Aim 1.........................................................................................................................................................6

   Aim 2.........................................................................................................................................................8

RESULTS...................................................................................................................................................10

   Aim 1.......................................................................................................................................................10

   Aim 2.......................................................................................................................................................12

DISCUSSION.............................................................................................................................................15

CONCLUSION...........................................................................................................................................24

REFERENCES............................................................................................................................................25

TABLES......................................................................................................................................................33

   Table 1.1...................................................................................................................................................33

   Table 1.2...................................................................................................................................................35

   Table 1.3...................................................................................................................................................36

   Table 1.4...................................................................................................................................................37

   Table 1.5...................................................................................................................................................38

   Table 2.1...................................................................................................................................................39

   Table 2.2...................................................................................................................................................41

   Table 2.3...................................................................................................................................................43

FIGURES....................................................................................................................................................45

   Figure 1.1a-e............................................................................................................................................45

   Figure 2.1.................................................................................................................................................50

   Figure 2.2a-b............................................................................................................................................51

INTRODUCTIO

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery
Keyword	HIF-1a VEGF Ki-67 Neuroendocrine tumors CD31 STAT3
Committee Chair / Thesis Advisor	Sweeney, John, Emory University Maithel, Shishir, Emory University
Committee Members	Collins, Jeffrey, Emory University Manatunga, Amita, Emory University

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