HER2 in Resected Gastric Cancer: Is there Prognostic Value? 公开

Fisher, Sarah (2013)

Permanent URL: https://etd.library.emory.edu/concern/etds/8s45q940d?locale=zh
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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