HER2 in Resected Gastric Cancer: Is there Prognostic Value? Open Access
Fisher, Sarah (2013)
Published
Abstract
Introduction: Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase whose amplification results in protein over-expression and tumorigenesis. Most studied in breast cancer, HER2 amplification and over-expression has been associated with resistance to cytotoxic chemotherapy, presence of adverse pathologic characteristics, and poor overall prognosis. Although documented in gastric cancer, the prevalence and prognostic value of HER2 in patients with early stage/resectable gastric cancer is controversial.
Methods: 111 pts underwent curative intent resection of gastric adenocarcinoma between 1/00-6/11 and had tissue available for analysis. Immunohistochemistry (IHC) for HER2 was performed on banked tumor specimens and graded by two pathologists blinded to outcomes. An IHC score of 0+ or 1+ was regarded as negative, 3+ as positive. Fluorescence in-situ hybridization (FISH) for HER2 was performed on equivocal (2+) IHC samples, and in cases of inter-pathologist disagreement. HER2 status was compared with the presence of known adverse prognostic factors and evaluated as a prognostic marker for overall survival.
Results: The demographics and clinical characteristics of the patient population were representative of patients undergoing resection for gastric cancer, with a median overall survival of 27.2 months. HER2 expression as measured by IHC was negative in 61 (55%), equivocal in 37 (33.3%), and positive in 13 (11.7%) cases. Of the 37 equivocal cases, FISH was positive in 8, for a total of 21 HER2-positive cases (18.9%, 95% C.I. 11.6%-26.2%) and 90 HER2-negative cases (81.1%, 95% C.I. 73.8%-88.3%). Patients with HER2-positive tumors were less likely to have signet ring cell features (23.8% vs 53.9%, p=0.008). HER2 status was not associated with tumor size, presence of perineural or lymphovascular invasion, margin status, nodal metastases, or stage (p>0.05). HER2 status was not associated with overall survival (p=0.385).
Conclusions: HER2 over-expression/amplification is present in a measurable amount but does not appear to be associated with adverse prognostic factors or survival in patients with resected gastric cancer. Our results, combined with the growing body of evidence from others suggest HER2 is not prognostic for patients with early stage gastric cancer.
Table of Contents
TABLE OF CONTENTS
Section Page
Introduction 1
Background 4
Specific Aims and Hypotheses 7
Methods 9
Patients 9
Patient characterization 9
HER2 testing 11
Immunohistochemistry 11
Fluorescence in situ hybridization 11
Definition of HER2 status 12
Statistical analysis 12
Survival analyses 13
Power analysis 14
Results 15
Study population 15
HER2 testing 15
Comparison of HER2-positive to HER2-negative patients 16
Baseline characteristics 16
Pathologic and prognostic characteristics 16
Survival analyses 16
Discussion 19
Limitations 23
Strengths 23
Future directions 24
References 28
Tables 38
Table 1
Summary scoring for HER2
38
Table 2
Sample size calculations
39
Table 3
Clinical characteristics of patients undergoing curative intent resection for gastric adenocarcinoma stratified by HER2 status
40
Table 4
Pathologic characteristics of patients undergoing curative intent resection for gastric adenocarcinoma stratified by HER2 status
41
Table 5
Cox proportional hazards model assessing the association between HER2 status and overall survival controlling for potential confounders
42
Table 6
Comparison of recent literature evaluating HER2 in patients undergoing resection for gastric cancer: patient population, assessment technique(s), and results
43
Figures 45
Figure 1
HER2 testing schematic
45
Figure 2
Immunohistochemistry of HER2 in gastric adenocarcinoma
46
Figure 3
Amplification of HER2 in gastric adenocarcinoma demonstrated by fluorescence in situ hybridization
47
Figure 4
Follow-up and censorship of patients excluding perioperative mortality (n=110)
48
Figure 5
Results of IHC and FISH for HER2 in gastric adenocarcinoma by testing stage
49
Figure 6A-B
Kaplan-Meier survival analysis for known adverse prognostic features and overall survival (n=110)*
A. Relationship between positive resection margin status and overall survival
B. Relationship between AJCC 7th edition TNM stage and overall
survival
50
Figure 7A-B
Kaplan-Meier survival analysis for known adverse prognostic features and overall survival (n=110)*
A. Relationship between presence of signet ring cell features and overall survival
B. Relationship between poor differentiation and overall survival
51
Figure 8
Kaplan-Meier survival analysis for patients stratified by HER2 status (n=110)*
52
Figure 9
Kaplan-Meier survival analysis for patients stratified by HER2 amplification (n=110)*
53
Figure 10
Kaplan-Meier survival analysis for patients stratified by HER2 expression by immunohistochemistry (n=110)*
54
Figure 11
Kaplan-Meier survival analysis for patients stratified by HER2 expression by immunohistochemistry (n=110)*
A. Comparing absent (IHC 0+) to present (IHC 1-3+) expression
B. Comparing strongly present expression (IHC 3+) to all others (IHC 0-2+)
55
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