Asia-Pacific Journal of Clinical Oncology 2017; 13: 249–260 doi: 10.1111/ajco.

12653

ORIGINAL ARTICLE

Human epidermal growth factor receptor 2 status of gastric

cancer patients in Asia: results from a large, multicountry
study
Nirmala PATHMANATHAN,1 Jing-shu GENG,2 Wencai LI,3 Xiu NIE,4 Januario VELOSO,5
John WANG,6 Julie HILL,7 Philip MCCLOUD7 and Michael BILOUS8
1
Department of Tissue Pathology and Diagnostic Oncology, Pathology West, Westmead Breast Cancer Institute, Westmead Hospital,
Western Sydney University and University of Sydney, Sydney, Australia, 2 Harbin Medical University Cancer Hospital, Harbin, 3 The
First Affiliated Hospital of Zhengzhou University, Zhengzhou, 4 Wuhan Union Hospital, Hubei, China, 5 National Kidney and Trans-
plant Institute, Quezon City, Philippines, 6 China Medical University Hospital, Taichung, Taiwan, 7 McCloud Consulting Group Pty
Ltd, and 8 Australian Clinical Labs, Norwest Private Hospital, Western Sydney University and University of Sydney, Sydney, Australia

Abstract
Aim: Current estimates of the human epidermal growth factor receptor 2 (HER2)-positivity rate in gastric
cancer vary widely in the literature, and there are limited data from countries in Asia. The primary aim of this
study was to conduct a clinical audit of laboratories across seven countries in Asia to determine the incidence
of HER2-positive gastric cancer in this region.
Methods: Pathologists were asked to collect data on patient gender, age, cancer site, specimen type, tumor
spread, type and grade, HER2 test results, including protein and/or gene copy enumeration, and final HER2
status on consecutive gastric cancer cases tested for HER2 in their laboratory over a 2-year period.
Results: HER2 results from 5,301 gastric cancers were submitted by 50 laboratories. The overall HER2-
positivity rate was 9.7% which, after the exclusion of China, increased to 18.1%. The rate between countries
ranged from 0% to 23.1%, and from 0% to 50.0% between laboratories. An equivocal HER2 result was
recorded in 19.5% of cases.
Conclusion: Despite the lack of centralized testing to confirm the accuracy of HER2 diagnoses, the incidence
of HER2-positive gastric cancer observed here was comparable to that reported in the literature. Nevertheless,
rates were highly variable between countries and laboratories, which suggests a lack of HER2 testing expertise
in gastric cancer. Given that the mortality rates for gastric cancer in Eastern Asia are the highest in the world,
efforts should focus on improving HER2 testing expertise in the region so that patients receive the appropriate
treatment early in their disease.
Key words: Asia, gastric cancer, human epidermal growth factor receptor 2

Correspondence: Dr Michael Bilous MA MBChB FRCPA,
Australian Clinical Labs, Norwest Private Hospital, 11
Norbrik Drive, Bella Vista, NSW 2153, Australia.
Email: Michael.Bilous@clinicallabs.com.au
Conflict of interest: none
Accepted for publication 30 October 2016. First published 23
December 2016
This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivs License,
which permits use and distribution in any medium, provided
INTRODUCTION
Gastric cancer, which includes gastroesophageal junction
(GEJ) cancer, is the fifth most common malignancy in the
world, with an estimated 952,000 new cases diagnosed in
2012.1 It is the third leading cause of cancer death in both
sexes, and more than 70% of cases occur in developing
countries with half occurring in Eastern Asia, mostly in
China.1 In Eastern Asia, gastric cancer is the second most
the original work is properly cited, the use is non-commercial
and no modifications or adaptations are made.


C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
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250
common malignancy after lung cancer, and the third lead-
ing cause of death.1 The estimated mortality rates in East-
ern Asia, the highest in the world, are 24 per 100 000 in
men and 9.8 per 100 000 in women.1 Globally, incidence
and mortality are declining, but 5-year relative survival
rates for metastatic gastric cancer remain poor (4.5%).2,3
These statistics demonstrate that gastric cancer represents
a significant health burden in Asia.
The incidence and mortality of gastric cancer varies
according to the geographical area in Asia. These vari-
ations are closely related to the prevalence of gastric can-
cer risk factors, especially Helicobacter pylori infection
and its molecular virulence factors.4 Other contributing
factors may include differences in dietary patterns, salt
intake, and smoking.5 The presence of screening pro-
grams clearly impact survival rates.6,7 In countries with
these programs, such as Korea and Japan, gastric cancer
is more likely to be diagnosed at an early stage, resulting
in more favorable 5-year survival rates of 55.6−66.0%,8
and 50.0%, respectively.9
Human epidermal growth factor receptor 2 (HER2)
is a tyrosine kinase receptor that plays a pivotal role
in growth factor signal transduction pathways leading
to cell survival, division, and differentiation.10,11 The re-
ported rate of overexpression of the HER2 receptor in
gastric cancer varies widely in the literature between
7% and 34%.7,12–15 The prognostic value of the HER2
oncogene in gastric carcinomas is controversial with
some studies identifying it as a negative prognostic fac-
tor for survival, some as positive, and others failing to
find a relationship.12,16–18 The correlation between HER2-
positivity and poorer outcomes has been evidenced by
higher HER2-positivity rates in advanced gastric carci-
nomas and prognostic significance found in early gastric
carcinomas.17,19 However, other studies have cast doubt
on this.17
With regards to the predictive value of HER2 in re-
sponse to biological treatments targeting the receptor,
HER2 overexpression has been shown to be a clear pre-
dictor of response to HER2-targeted therapy.20 For this
reason, HER2 can be considered a valid therapeutic tar-
get and patients with gastric or GEJ cancer are recom-
mended to undergo testing for HER2 at the time of initial
diagnosis to inform decision-making options.7
The Trastuzumab for Gastric Cancer (ToGA) trial was
an open-label, international, phase III, randomized con-
trolled trial that investigated trastuzumab in combination
with chemotherapy versus chemotherapy alone for treat-
ment of HER2-positive advanced gastric or GEJ cancer.20
Results showed that in patients with high HER2 ex-
pression (immunohistochemistry [IHC] 2+ and fluores-

C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
Published by John Wiley & Sons Australia, Ltd
N Pathmanathan et al.
cence in situ hybridization [FISH]-positive or IHC 3+),
the addition of trastuzumab to chemotherapy signifi-
cantly increased median overall survival to 16.0 months
(95% confidence interval [CI], 15–19) compared with
11.8 months (95% CI, 10–13) in the chemotherapy-alone
arm.20 ToGA data emphasized the need for high-quality,
accurate, and standardized HER2 testing to ensure iden-
tification of the patient population that will benefit from
trastuzumab. Based on the results of the ToGA trial, IHC
is the primary test in gastric and GEJ cancer, with FISH
or silver in situ hybridization being used as a reflex test
in cases with an equivocal IHC 2+ result.7,20 To date,
trastuzumab is the only targeted therapy approved for
the first-line treatment of patients with HER2-positive
metastatic gastric cancer which prolongs survival beyond
12 months.20,21
Until recently, recommendations on HER2 testing in
gastric cancer have been primarily based on testing ex-
perience in Europe.7 However, it has become increasingly
apparent that Asia-Pacific-specific guidelines are needed
to account for the difference in testing environments and
challenges faced by laboratories in the region. The result-
ing publication by Kim et al. was developed by a mul-
tidisciplinary panel of experts from the Asia-Pacific re-
gion, who actively work and provide education for HER2
testing in gastric cancer.6 The recommendations highlight
and clarify aspects of testing that are of particular rele-
vance to the region, and emphasize the unique features
of gastric carcinomas compared with breast carcinomas
that must be taken into account during HER2 testing.6
Across Asian populations, HER2 overexpression in
gastric cancer is reported in approximately 9.8−23.0%
of cases, 14,19,22–26 with higher rates generally observed in
GEJ cancer.23,24 Such high variability in HER2-positivity
rates is likely due to the different testing environments
and practices between and within countries; for instance,
the use of non-validated testing kits, or pathologists’ in-
experience with HER2 testing in gastric cancer. Lack of
access to HER2 testing is also a barrier to accurately
determining the true incidence of HER2-positive gastric
cancer in countries in this region. A number of studies
have investigated HER2-positivity rates in China,23,24,27
Korea14,19,22 and Japan,25 but there is limited information
from other Asian countries.
The Scientific Partnership for HER2 testing Excellence
(SPHERE) is an educational initiative that promotes and
facilitates excellence in HER2 testing in breast and gas-
tric cancer across Asia Pacific. SPHERE aims to ensure
that more patients receive an accurate diagnosis and ap-
propriate treatment, by encouraging best practice to im-
prove the reliability and reproducibility of HER2 testing,
Asia-Pac J Clin Oncol 2017; 13: 249–260
HER2 status of gastric cancer in Asia
and the accuracy of interpretation. SPHERE also aims to
enhance multidisciplinary collaboration between pathol-
ogists, technicians, surgeons and oncologists. Established
in 2010, SPHERE has held numerous educational fo-
rums and pathology workshops across the region, as well
as allied activities to support HER2 testing. The latter
include partnership with the UK National External Qual-
ity Assessment Service (UK NEQAS), the external quality
assurance program based in London.
In 2011, SPHERE established a clinical audit to mon-
itor the performance of testing laboratories in Asia, and
to define reference values for expected HER2-positivity
rates among both breast and gastric cancer patients in the
region. Monitoring HER2-positivity rates helped identify
laboratories with inadequate testing procedures, and sup-
ported the development of targeted training programs for
laboratories in this region. The findings of the breast can-
cer audit have been published separately.28
We present findings on the incidence of HER2-positive
gastric cancer diagnosed in laboratories participating in
a clinical audit across seven countries in Asia. This study
also explored the relationship of HER2-positive gastric
cancer status with a number of parameters, including can-
cer site, specimen type and tumor spread, type, and grade.
MATERIALS AND METHODS
Study design
Pathology laboratories from China, Hong Kong,
Malaysia, The Philippines, Taiwan, Thailand, and
Vietnam were invited to submit data on gastric cancer
patients tested for HER2 between October 2011 and
October 2013. Laboratories willing to participate were
provided with a unique reference code to guarantee
confidentiality. Pathologists were asked to collect data
on patient gender, age, cancer site, specimen type, tumor
spread, tumor type, tumor grade, HER2 test results,
including protein and/or gene copy enumeration, and
final HER2 status on consecutive gastric cancer cases
tested for HER2 in their laboratory. At the time of the
study tumor stage was not known.
Participating laboratories were provided with a
SPHERE Regional HER2 Testing Audit Protocol, which
detailed the design, implementation, and data analysis of
the audit. They were required to submit a copy of their
validated HER2 testing protocols along with a partici-
pation agreement. Any deviations from testing protocols
were to be communicated directly to a third party agency.
Data were submitted in a Microsoft Excel spreadsheet
to the third party agency for collation on a monthly basis.
Patient data that were submitted without a HER2 result
Asia-Pac J Clin Oncol 2017; 13: 249–260
251
or a final HER2 status were excluded from the study. This
audit was approved by the Institutional Review Boards of
participating centers, and was conducted in accordance
with the Declaration of Helsinki and local requirements.
HER2 testing
Pathology laboratories were required to establish, vali-
date, and adhere to HER2 testing protocols based on
recommendations developed and provided by SPHERE.
SPHERE recommendations for the classification of
HER2 status in gastric cancer followed the recommended
HER2 testing algorithm for gastric cancer, developed
as a result of the ToGA trial.20 Consequently, HER2-
positivity was defined as IHC 2+ and FISH-positive or
IHC 3+.20 Laboratories’ HER2 testing protocols were
collected and reviewed prior to data collection. The ma-
jority of pathologists from participating laboratories had
attended SPHERE tutorials and workshops, which pro-
vided training on HER2 testing procedures and the accu-
rate interpretation of IHC and in situ hybridization (ISH)
results.
Statistical analysis
For each laboratory, the percentage of patients who
were reported as HER2-positive, HER2-equivocal (i.e.
patients for whom confirmatory ISH testing was not
performed and hence the final diagnosis was recorded
as IHC 2+), or HER2-negative was calculated. The true
percentage of HER2-positive gastric cancer patients at
each laboratory may vary due to inter-laboratory vari-
ables, such as testing method and interpretation, genetic
traits of the respective patient populations, or sample
referral practices between laboratories within a country.
Therefore, each laboratory represents a clustered sample
of patients from its respective patient populations. As a
result, the usual countrywide estimate of the standard
deviation for HER2-positive patients would be an
underestimation of the true standard deviation. Thus,
for each country, the percentage of patients who were
HER2-positive was estimated as a weighted average
of the percentage of HER2-positive patients at each
laboratory, with weights being inversely proportional
to their respective variance. The method of moments29
was used to estimate the variance of the percentage of
patients who were HER2-positive for each country, and
95% CIs were derived based on these estimators. The
percentage of patients who were HER2-equivocal or
HER2-negative was estimated with identical methods.
For each country and tumor grade, the percentage of
patients who were HER2-positive was estimated as a

C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
Published by John Wiley & Sons Australia, Ltd
252
Figure 1 HER2-positivity rates for gastric cancer.†
†
The results for Malaysia and the Philippines are not shown as
there were no HER2-positive patients.
Abbreviations: CI, confidence interval; HER2, human epidermal
growth factor receptor 2.
weighted average of the percentage of HER2-positive
patients at each laboratory, with weights being inversely
proportional to their respective variance. The same
method was applied to cancer site, specimen type,
tumor spread, and tumor type. China did not report
HER2-positivity by age or gender due to patient data
confidentiality restrictions; therefore, an overall analysis
of HER2-positivity by age and gender was not appro-
priate for such small frequencies. The HER2-positivity
rate and 95% CI is presented for each country, and the
region overall, as a forest plot in Figure 1.
RESULTS
Patient and tumor characteristics
Over a 2-year period, data on 5,301 gastric cancer pa-
tients were collected from 50 laboratories; 15 patients
were excluded due to incomplete HER2 testing data be-
ing provided. The majority of patients were from China
(n = 4,018, 76.0%), followed by Taiwan (n = 757,
14.3%), Hong Kong (n = 253, 4.8%), and Vietnam
(n = 206, 3.9%). With regards to age, 15.6% were >60
years, 9.1% were between 41 and 60 years, and 0.9%
were <40 years (Table 1). Age was not reported for
74.4% of patients, almost all of whom were from China.
Of all patients, 17.2% were male and 8.4% were female;
gender was not reported for 74.4% of patients, primarily
from China. The gastric region was reported as the can-
cer site in 73.1% of patients and the GEJ in 10.1% of
patients. Gastric cancer site was not reported for 16.8%
of patients.
In Hong Kong, Malaysia and Thailand, the majority
of patients had a biopsy; in China, Taiwan and Vietnam,
the majority of patients underwent excision of the tu-

C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
Published by John Wiley & Sons Australia, Ltd
N Pathmanathan et al.
mor. Overall, 71.6% of patients underwent excision and
28.1% patients had a biopsy. Specimen type was not re-
ported for 0.3% of patients. Half the patients (50.4%)
had advanced cancer (Stage 3) and 19.4% had metastatic
cancer (Stage 4); tumor spread was not reported for
30.2% of patients. For tumor type, 21.8% of tumors
were classified as intestinal, 16.6% as diffuse, 7.8% as
mixed, 3.5% as “other” and 50.2% were not reported.
Tumor grade was poorly differentiated in 44.9% of pa-
tients, moderately differentiated in 31.8% of patients,
and well differentiated in 3.1% of patients; data were not
reported for 20.3% of patients.
HER2 status by country and region
HER2 results were obtained from 5,286 gastric can-
cer specimens, ranging from six in Malaysia to 4018
in China. The average number of cases per labora-
tory was 106. Overall HER2-positivity rate for the re-
gion was 9.7% (95% CI, 7.84−11.65; Table 2). The
HER2-positivity rate between countries ranged from 0%
in Malaysia and the Philippines to 23.1% (95% CI,
17.91−28.27) in Hong Kong (Fig. 1). Overall, 73.9%
(95% CI, 69.46−78.26) of patients were diagnosed as
HER2-negative and 19.5% (95% CI, 15.96−22.95) as
HER2-equivocal. The proportion of patients diagnosed
as HER2-equivocal varied between countries, from 0%
in Malaysia to 21.0% (95% CI, 17.30−24.65) in China.
Table 2 also shows the HER2 status for all countries
combined except China. When excluding China, the
overall HER2-positivity rate increased from 9.7% to
18.1% (95% CI, 11.63−24.54). The HER2-equivocal
and HER2-negativity rate decreased to 13.8% (95% CI,
7.38−20.22) and 70.9% (95% CI, 60.64−81.18), re-
spectively, when compared with all countries combined.
For China, the combined HER2-positivity rate across the
39 laboratories was 8.0% (95% CI, 6.35−9.68).
HER2-positivity rate and gastric cancer site
Data on HER2 status and gastric cancer site were ob-
tained from 4410 (83.4%) patients. The overall HER2-
positivity rate for patients characterized as having a gas-
tric site was 9.8% (95% CI, 7.68−11.87), and 16.8%
(95% CI, 13.54−20.08) for those with a GEJ site
(Table 3). The results for Malaysia, the Philippines, and
Thailand were not summarized due to absence of HER2-
positive patients or because the frequencies were too
small to permit the calculation of the clustered vari-
ance. After excluding China, the remaining countries
combined (Hong Kong, Taiwan, Vietnam) showed an
Asia-Pac J Clin Oncol 2017; 13: 249–260
HER2 status of gastric cancer in Asia 253

Table 1 Patient demographics

Country (n, %)

Demographic or characteristic China Hong Kong Malaysia Philippines Taiwan Thailand Vietnam Overall

Age, years
<40 6 (0.1) 8 (3.2) 0 (0.0) 2 (22.2) 20 (2.6) 2 (3.8) 12 (5.8) 50 (0.9)
41–60 39 (1.0) 94 (37.2) 2 (33.3) 3 (33.3) 233 (30.8) 16 (30.8) 93 (45.1) 480 (9.1)
>60 33 (0.8) 151 (59.7) 4 (66.7) 4 (44.4) 504 (66.6) 34 (65.4) 99 (48.1) 829 (15.6)
Not reported 3,940 (98.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.0) 3,942 (74.4)
Gender
Female 19 (0.5) 102 (40.3) 2 (33.3) 2 (22.2) 241 (31.8) 17 (32.7) 62 (30.1) 445 (8.4)
Male 59 (1.5) 151 (59.7) 4 (66.7) 7 (77.8) 516 (68.2) 35 (67.3) 142 (68.9) 914 (17.2)
Not reported 3,940 (98.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.0) 3,942 (74.4)
Cancer site
Gastric 2,717 (67.6) 238 (94.1) 6 (100.0) 5 (55.6) 654 (86.4) 48 (92.3) 206 (100.0) 3,874 (73.1)
Gastroesophageal junction 411 (10.2) 15 (5.9) 0 (0.0) 4 (44.4) 102 (13.5) 4 (7.7) 0 (0.0) 536 (10.1)
Not reported 890 (22.2) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) 891 (16.8)
Specimen type
Biopsy 950 (23.6) 153 (60.5) 5 (83.3) 2 (22.2) 337 (44.5) 39 (75.0) 3 (1.5) 1,489 (28.1)
Excision 3,057 (76.1) 100 (39.5) 1 (16.7) 2 (22.2) 420 (55.5) 13 (25.0) 203 (98.5) 3,796 (71.6)
Not reported 11 (0.3) 0 (0.0) 0 (0.0) 5 (55.6) 0 (0.0) 0 (0.0) 0 (0.0) 16 (0.3)
Tumor spread
Advanced 1,997 (49.7) 41 (16.2) 1 (16.7) 1 (11.1) 439 (58.0) 46 (88.5) 147 (71.4) 2,672 (50.4)
Metastatic 796 (19.8) 85 (33.6) 0 (0.0) 2 (22.2) 99 (13.1) 6 (11.5) 41 (19.9) 1,029 (19.4)
Not reported 1,225 (30.5) 127 (50.2) 5 (83.3) 6 (66.7) 219 (28.9) 0 (0.0) 18 (8.7) 1,600 (30.2)
Tumor type
Diffuse 555 (13.8) 92 (36.4) 0 (0.0) 1 (11.1) 215 (28.4) 14 (26.9) 5 (2.4) 882 (16.6)
Intestinal 743 (18.5) 69 (27.3) 1 (16.7) 3 (33.3) 290 (38.3) 37 (71.2) 12 (5.8) 1,155 (21.8)
Mixed 174 (4.3) 11 (4.3) 0 (0.0) 1 (11.1) 229 (30.3) 0 (0.0) 0 (0.0) 415 (7.8)
Other 128 (3.2) 52 (20.6) 0 (0.0) 0 (0.0) 5 (0.7) 1 (1.9) 0 (0.0) 186 (3.5)
Not reported 2,418 (60.2) 29 (11.5) 5 (83.3) 4 (44.4) 18 (2.4) 0 (0.0) 189 (91.7) 2,663 (50.2)
Tumor grade
Moderate 1,224 (30.5) 63 (24.9) 1 (16.7) 3 (33.3) 294 (38.8) 19 (36.5) 80 (38.8) 1,684 (31.8)
Poor 1,707 (42.5) 113 (44.7) 0 (0.0) 1 (11.1) 434 (57.3) 24 (46.2) 100 (48.5) 2,379 (44.9)
Well 136 (3.4) 0 (0.0) 0 (0.0) 0 (0.0) 17 (2.2) 9 (17.3) 1 (0.5) 163 (3.1)
Not reported 951 (23.7) 77 (30.4) 5 (83.3) 5 (55.6) 12 (1.6) 0 (0.0) 25 (12.1) 1,075 (20.3)

increase in HER2-positivity for each of the gastric cancer
sites: 31.1% (95% CI, 22.68−39.62) for the GEJ site,
and 18.7% (95% CI, 12.15–25.28) for the gastric
site.
HER2-positivity rate and specimen type
Data on HER2 status and specimen type were ob-
tained from 5286 (100.0%) patients. The overall HER2-
positivity rate for patients with a biopsy specimen was
30.7% (95% CI, 20.24–41.21), and 9.5% (95% CI,
7.59−11.32) for an excision (Table 3). After excluding
China, the remaining countries combined (Hong Kong,
Taiwan, Vietnam) showed an increase in HER2-positivity
rate for the specimen site: 55.5% (95% CI, 28.59−82.50)
for a biopsy, and 17.7% (95% CI, 11.38−23.92) for an
excision.
HER2-positivity rate and tumor spread
Data on HER2 status and tumor spread were ob-
tained from 3701 (70.0%) patients. The overall HER2-
positivity rate was 9.5% (95% CI, 7.58−11.50) for
advanced disease (Stage 3), and 15.0% (95% CI,
10.18−19.90) for those with metastatic disease (Stage 4;
Table 3). After excluding China, the remaining countries
combined (Hong Kong, Taiwan, Vietnam) showed an in-
crease in HER2-positivity for tumor spread: 16.8% (95%
CI, 9.54−24.15) for advanced disease, and 25.0% (95%
CI, 19.30−30.62) for metastatic disease.

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 C

254

Table 2 HER2 status in gastric cancer

Country Number Number HER2-positive n HER2-equivocal n HER2-negative n Minimum Maximum

of labo- of (%) [95% CI] (%) [95% CI] (%) [95% CI] HER2- HER2-
ratories patients positivity positivity
rate (%) rate (%)

Published by John Wiley & Sons Australia, Ltd

Hong Kong 3 253 59 (23.1) 31 (13.9) 163 (64.6) 20.9 50.0
[17.91−28.27] [0−32.94] (51.00−78.12)
Malaysia 2 6 0 (0) 0 (0) 6 (100) NAa NAa
Philippines 4 9 0 (0) 2 7 NAa NAa
Thailand 1 52 4 (7.7) 7 (13.5) 41 (78.8) Only one Only one
[0.41−14.92] [4.18−22.74] [67.75−89.95] center center

2016 The Authors. Asia-Pacific Journal of Clinical Oncology

Vietnam 2 206 24 (11.5) 21 (14.4) 161 (71.6) 11.0 16.7
[7.13−15.82] [0−30.26] [50.01−93.23]
China 39 4,018 417 (8.0) 949 (21.0) 2,652 (74.6) 0 20.7
[6.35−9.68] [17.30−24.65] [69.66−79.60]
Taiwan 5 757 133 (21.0) 148 (14.8) 476 (72.3) 0 23.9
[9.31−32.70] [3.23−26.45] [53.24−91.35]
Overall 50 5,286 637 (9.7) 1,156 (19.5) 3,493 (73.9) 0 50.0
[7.84−11.65] [15.96−22.95] [69.46−78.26]
Overall 11 1,268 120 (18.1) 207 (13.8) 841 (70.9) 0 50.0
countries [11.63−24.54] [7.38−20.22] [60.64−81.18]
combined,
except China
a
Frequencies were too small to permit calculation of clustered variance. CI, confidence interval; HER2, human epidermal growth factor receptor 2.

Asia-Pac J Clin Oncol 2017; 13: 249–260

N Pathmanathan et al.
 Table 3 HER2-positivity rates by gastric site, specimen type and tumor spread

HER2-positive patients by gastric cancer site, % HER2-positive patients by HER2-positive patients by tumor spread, % (95% CI)
HER2 status of gastric cancer in Asia

(95% CI) specimen type, % (95% CI)

Asia-Pac J Clin Oncol 2017; 13: 249–260

Country Gastric GEJ Not reported Biopsy Excision Advanced Metastatic Unknown

Hong Kong 22.6 30.2 NAa 20.3 26.5 29.3 24.6 20.5
(17.27−27.87) (0−65.01) (6.77−33.79) (17.91−35.11) (15.34−43.20) (15.47−33.77) (13.44−27.49)
China 7.7 14.3 10.1 10.2 8.0 8.3 12.4 10.4
(5.93−9.52) (10.75−17.84) (8.16−12.12) (8.30−12.19) (6.22−9.88) (6.90−9.61) (9.82−15.01) (8.69−12.12)
Taiwan 20.1 32.0 NAa 50.4 16.9 17.1 30.7 56.2
(9.19−31.02) (22.68−41.24) (3.79−96.95) (7.01−26.74) (6.68−27.54) (21.42−40.02) (0−135.44)
Vietnam 11.5 NAa NAa 0.0 11.6 8.4 16.8 33.1

C
(7.13−15.82) (7.22−16.02) (3.94−12.90) (5.37−28.21) (11.46−54.78)


Overall 9.8 16.8 10.1 30.7 9.5 9.5 15.0 26.3
(7.68−11.87) (13.54−20.08) (8.16−12.12) (20.24− 41.21) (7.59−11.32) (7.58−11.50) (10.18−19.90) (10.78−41.78)
Countries 18.7 31.1 NAa 55.5 17.7 16.8 25.0 41.9
combined, (12.15−25.28) (22.68−39.62) (28.59−82.50) (11.38−23.92) (9.54−24.15) (19.30−30.62) (4.17−79.58)
except China
(Hong Kong,
Taiwan,
Vietnam)
a
Frequencies were too small to permit the calculation of the clustered variance. The results for Malaysia, the Philippines and Thailand were not summarized as there were no HER2-positive
patients, or the frequencies were too small to permit the calculation of the clustered variance. CI, confidence interval; GEJ, gastroesophageal junction; HER2, human epidermal growth factor
receptor 2.

Published by John Wiley & Sons Australia, Ltd

2016 The Authors. Asia-Pacific Journal of Clinical Oncology
255
 C

256

Table 4 HER2-positivity rates by tumor type and tumor grade

HER2-positive patients by tumor type (%) (95% CI) HER2-positive patients by tumor grade differentiation (%) (95% CI)
Country Diffuse Intestinal Mixed Other Unknown Moderate Poor Well Unknown

Published by John Wiley & Sons Australia, Ltd

Hong Kong 12.9 37.6 45.4 19.2 19.9 42.8 15.0 0 19.2
(6.08−19.78) (26.21−49.05) (16.08−74.63) (8.52−29.94) (5.53−34.20) (30.64−54.92) (8.45−21.63) (10.42−27.91)
China 7.9 12.2 8.1 0 8.2 13.0 5.4 17.1 9.8
(5.41−10.45) (9.36−14.96) (3.37−12.86) (6.07−10.29) (9.75−16.25) (3.89−6.83) (10.21−24.00) (0−23.72)
Taiwan 51.6 22.4 13.0 50.0 66.9 22.2 15.6 14.3 91.7
(0.53−100) (6.26−38.63) (1.96−24.00) (1.00−99.00) (45.35−88.51) (4.87−39.49) (5.56−25.62) (4.04−32.62) (76.03−100)

2016 The Authors. Asia-Pacific Journal of Clinical Oncology

Vietnam 0 10.0 0 0 11.1 13.5 31.1 0 27.9
(0−28.59) (6.63−15.59) (6.05−21.01) (0−83.24) (10.37−45.52)
Overall 20.4 17.2 11.6 11.9 9.8 16.0 7.6 24.0 32.7
(3.22−37.59) (12.32−22.01) (6.08−17.09) (3.96−19.86) (6.89−12.64) (12.09−19.92) (5.45−9.69) (13.32−34.64) (7.51−57.92)
Countries 38.6 24.7 17.7 24.9 27.4 25.8 15.3 14.3 43.0
combined, (0.69−76.52) (12.83−36.58) (5.98−29.49) (1.49−48.40) (10.23−44.65) (13.96−37.58) (8.54−22.04) (0−32.62) (7.38−78.63)
except
China
(Hong
Kong,
Taiwan,
Vietnam)
CI, confidence interval; HER2, human epidermal growth factor receptor 2.

Asia-Pac J Clin Oncol 2017; 13: 249–260

N Pathmanathan et al.
HER2 status of gastric cancer in Asia
HER2-positivity rate and tumor type
Data on HER2 status and tumor type were obtained from
2638 (50.0%) patients. The overall HER2-positivity rate
for tumor type was 20.4% (95% CI, 3.22–37.59) for dif-
fuse, 17.2% (95% CI, 12.32–22.01) for intestinal, 11.6%
(95% CI, 6.08–17.09) for mixed, and 11.9% (95% CI,
3.96–19.86) for “other”; 9.8% (95% CI, 6.89–12.64)
were unknown (Table 4). After excluding China, the re-
maining countries combined (Hong Kong, Taiwan, Viet-
nam) showed an increase in HER2-positivity for all cat-
egories of tumor type.
HER2-positivity rate and tumor grade
Data on HER2 status and tumor grade were ob-
tained from 4226 (79.9%) patients. The overall HER2-
positivity rate for tumor grade was 16.0% (95% CI,
12.09−19.92) for moderately differentiated, 7.6% (95%
CI, 5.45−9.69) for poorly differentiated, and 24.0%
(95% CI, 13.32−34.64) for well differentiated; 32.7%
(95% CI, 7.51−57.92) were unknown (Table 4). Af-
ter excluding China, the remaining countries combined
(Hong Kong, Taiwan, Vietnam) showed an increase in
HER2-positivity for all categories of tumor grade, ex-
cept for well-differentiated carcinomas for which there
was a decrease in HER2-positivity rate (14.3%; 95%
CI, 0−32.62). For patients with moderately differentiated
carcinomas, Hong Kong (42.8%; 95% CI, 30.64−54.92)
and Taiwan (22.2%; 95% CI, 4.87−39.49) reported
higher rates of HER2-positivity compared to other coun-
tries. For poorly differentiated patients, Vietnam reported
a higher rate of HER2-positivity compared to other coun-
tries. However, there were inflated values present in some
tumor grade categories and this was due to small patient
numbers within the centers.
Statistical significance of HER2-positivity
rates between subgroups
The chi-squared (χ 2 ) test was used to assess the statisti-
cal significance of HER2-positivity rates across the differ-
ent demographic parameters for the following subgroups:
gastric cancer site, specimen type, tumor spread, tumor
type, and tumor grade. For all analyses, the χ 2 test was
highly significant (P < 0.0001), concluding that there
was at least one significant difference between the HER2-
positive rates and the demographic parameters of the in-
dividual subgroups.
Asia-Pac J Clin Oncol 2017; 13: 249–260
257
DISCUSSION
This study describes findings from the largest clinical au-
dit of HER2 testing in gastric cancer in Asia, provid-
ing the first insight into the rate of HER2-positive gas-
tric cancer, and the current standard of HER2 testing
among laboratories in this region. Based on an analy-
sis of 5286 gastric cancer specimens, an overall HER2-
positivity rate of 9.7% was observed. This rate is similar
to the range reported in the literature for Asian popula-
tions (9.8−23.0%).14,19,22–26 The rate of HER2-positivity
varied considerably between countries, and between lab-
oratories within the same country.
To assess the impact of the China data on these anal-
yses (76.0% of data were from China), a further anal-
ysis was performed for all countries combined exclud-
ing China. Consequently, the overall HER2-positivity
rate increased from 9.7% to 18.1%, a rate that is
closer to that seen for Asian patients in the ToGA
trial (23.9%).15
Variance in HER2-positivity rates between and within
countries may be explained in part by the proportion
of carcinomas with certain characteristics with which
HER2-positivity has been correlated. HER2-positivity
rates were higher in the GEJ cancer site than in the gastric
site (16.8% vs 9.8%), a correlation that has been consis-
tently reported in the literature.15,23,24
In addition, higher rates of HER2-positivity were re-
ported in biopsy specimens than for excisions (30.7%
vs 9.5%), which is consistent with findings from the
ToGA study, wherein HER2-positivity rates for biopsy
specimens were also higher than for excisions (23.2% vs
19.7%).15
It is generally agreed that biopsies are preferable to sur-
gical specimens for optimal testing results due to biop-
sies having more standardized fixation conditions,7 and
this may reflect the differences in HER2-positivity rates
seen in this study. Consistent with previous reports,23,30–34
HER2-positivity was more frequent with well- or mod-
erately differentiated carcinomas (24.0% and 16.0%, re-
spectively), compared with poorly differentiated carcino-
mas (7.6%).
Interestingly, contrary to consistent findings pre-
viously reported for both Western and Asian
populations,14,15,19,23,27,35 HER2-positivity rates were
higher for the diffuse-type tumors (20.4%) compared
with intestinal- and mixed-type tumors (17.2% and
11.6%, respectively). Further study of diffuse-type tu-
mors using ISH to evaluate the HER2 gene copy number
and HER2/chromosome enumeration probe 17 (CEP17)

C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
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258
ratio is needed to accurately categorize these tumors.
HER2-positivity rates were higher in metastatic disease
compared with advanced disease (15.0% vs 9.5%).
The high variability in HER2-positivity rates between
and within countries is likely influenced by differences in
testing practices, such as the use of nonvalidated tests
or unfamiliarity with the gastric cancer HER2 testing
guidelines.7 Although all participating laboratories were
provided with comprehensive training prior to the au-
dit, these differences reflect a need for continued partic-
ipation in proficiency testing programs to identify po-
tential errors in HER2 assessment, and for the stan-
dardization of grading and tumor classification prac-
tices. SPHERE partners with the external quality assur-
ance program, UK NEQAS, which provides practical as-
sistance to laboratories, consultation on troubleshooting
sources of testing variation, and guidance to improve test-
ing quality. Participation in such programs is strongly rec-
ommended for the accuracy and consistency of HER2
testing results.7 In addition to differences in testing prac-
tices, the high variability in HER2-positivity rates be-
tween countries is also influenced by the country-specific
nature of gastric cancer. Thus, contribution of the nature
of disease in each country cannot be excluded as a pos-
sible influence on the variable HER2 results seen in our
study.
A number of limitations of this study warrant mention.
Most notably, a considerable amount of patient data were
not collected, particularly on tumor stage, age and gen-
der, preventing further analysis of these parameters. The
main reason for this deficit was due to patient data confi-
dentiality restrictions in China. This is one example of the
considerable challenges faced in obtaining data in this re-
gion; there are hugely different testing environments and
practices between and within countries, as well as differ-
ing data protection and ethics regulations.
There was no centralized testing to confirm the ac-
curacy of HER2 diagnosis and grading, because it was
considered impractical to validate the diagnosis of over
5,000 tumor samples obtained from multiple laboratories
across Asia. However, all participating laboratories were
required to submit their own validated HER2 testing pro-
tocols, and validation of test results was repeatedly em-
phasized during training in the SPHERE program.
The high proportion of equivocal (IHC 2+) HER2
cases is also a concern. Many patients in Asian countries
are not referred for confirmatory ISH testing, primarily
due to the high cost of these assays. In addition, oncolo-
gists may be reluctant to obtain a final HER2 result for
patients that are unable to afford HER2-targeted therapy
should a HER2-positive result be found.

C 2016 The Authors. Asia-Pacific Journal of Clinical Oncology
Published by John Wiley & Sons Australia, Ltd
N Pathmanathan et al.
Given these limitations it is probably unwise to con-
sider these results as a wholly accurate representation of
the incidence of HER2-positive gastric cancer in Asia.
However, in highlighting the variation in HER2 results
between countries, and importantly between laboratories
within the same country, this audit has drawn attention
to the need for ongoing training of pathologists and lab-
oratory staff and provision of access to additional testing
in order to provide a final result for IHC 2+ equivocal
cases.
This is the first study to provide an insight into the rate
of HER2-positive gastric cancer across Asia. Given the
significant burden of gastric cancer in Asia, these data are
important to increase understanding and awareness of
the disease and issues faced by HER2 laboratories in these
countries. Increased education and awareness of HER2
testing in gastric cancer, as well as improved early detec-
tion are needed to improve outcomes for these patients.
ACKNOWLEDGMENTS
NP and MB have received speaker’s and/or consultancy
fees and travel grants from F. Hoffmann-La Roche Ltd.
JH and PM are part of McCloud Consulting Group Pty
Ltd., which provides biostatistical consulting services to
Roche. JSG, JW, JV, WL, and XN have no conflicting in-
terests to disclose. SPHERE is an educational initiative
funded by F. Hoffmann-La Roche Ltd. that promotes and
facilitates excellence in HER2 testing in breast and gastric
cancer across the Asia-Pacific region.
Support for data collection, analysis and third-party
writing assistance was provided by F. Hoffmann-La
Roche Ltd. The authors would like to acknowledge the
following individuals and institutions for submitting data
to the study: China: Wencai Li, the First Affiliated Hospi-
tal of Zhengzhou University; Xianyuan Wang, the Second
Affiliated Hospital of Zhengzhou University; Guangy-
ing Yang, Zhengzhou People’s Hospital; Quanwu Zhang,
Zhengzhou Central Hospital; Qingkai Yu, Henan Can-
cer Hospital; Ming Geng, General Hospital of Jinan Mil-
itary Area; Jiang Wu, Kaifeng Huaihe Hospital; Yangkun
Wang, the 150 Hospital of PLA; Shudong Yang, Wuxi
First People’s Hospital; Haijun Yang, Anyang Cancer
Hospital; Guizhi Wang, Pingdingshan Coal Group Gen-
eral Hospital; Yizhong Feng, the Second Affiliated Hos-
pital of Suzhou University; Xiaowei Qi, Wuxi No.4 Peo-
ple’s Hospital; Qing Sun, Qianfo Hill Hospital; Rong
Yang, Gansu Cancer Hospital; Guanjun Zhang, the First
Affiliated Hospital of Xi’an Jiaotong University; Yong
Yuan, Shanxi Cancer Hospital; Yonghong Shi, the Af-
filiated Hospital of Inner Mongolia Medical University;
Asia-Pac J Clin Oncol 2017; 13: 249–260
HER2 status of gastric cancer in Asia
Jing-shu Geng, Harbin Medical University Cancer Hos-
pital; Yufei Jiao, the 2nd Affiliated Hospital of Harbin
Medical University; Limei Sun, the First Affiliated Hos-
pital of China Medical University; Dan Li, Sheng Jing
Hospital of China Medical University; Jianmin Li, Shanxi
Cancer Hospital; Yueping Liu, Tumor Hospital of Hebei
Province; Yulan Li, Affiliated Hospital of Hebei Uni-
versity; Xuefeng Bai, Baotou Cancer Hospital; Yinping
Wang, the First Bethune Hospital of Jilin University;
Chunyan Xu, Mudanjiang Medical University; Zongkai
Zou, Zhangzhou Affiliated Hospital of Fujian Medi-
cal University; Chao Pan, Zhongshan Affiliated Hospi-
tal of Xiamen University; Zhuofang Hao, the Second
Affiliated Hospital of Guangzhou University; Hong Du,
Guangzhou First People’s Hospital; Bing Chu, Zhong-
shan People’s Hospital; Yang Weng, Hainan Medical Col-
lege; Yuan Luo, Guangxi Medical University Affiliated
Tumor Hospital; Xiaolan Xiao, Hainan General Hos-
pital; Jingping Yuan, the Central Hospital of Wuhan;
Daiqiang Li, Xiangya School of Medicine; Yonghong
Yang, Mianyang Central Hospital. Hong Kong: Wai
Hung Shek and Chiu Kwan-Yi, Queen Mary Hospital;
Patrick Wong, St Teresa’s Hospital; Anthony Lo, The
Chinese University of Hong Kong. Malaysia: Noraidah
Masir, Universiti Kebangsaan Malaysia Medical Center;
Pathmanathan Rajadurai, Sime Darby Medical Center.
Philippines: Manuelito Madrid, St Luke’s Medical Cen-
ter; Rolando Lopez and Manuelito Madrid, St Luke’s
Medical Center – Global City; Evette Lillybelle De-
maisip, Hi_Precision Laboratory. Taiwan: Chao-Cheng
Huang, Chang Gung Memorial Hospital-Kaohsiung;
Anna Fen-Yan Li, Taipei Veterans General Hospital; Hui-
Hwa Tseng, Kaohsiung Veterans General Hospital; John
Wang, Taichung Veterans General Hospital. Thailand:
Nirush Lertprasertsuke, Chiang Mai University. Viet-
nam: Thai Anh Tu, Ho Chi Minh City Oncology Hos-
pital; Nguyen Sao Trung and Phuong Thao, University of
Medicine and Pharmacy.
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