ORIGINAL

García-OrtegaARTICLE
MM, et al.

Prevalence of HER2 overexpression in patients

diagnosed with gastric adenocarcinoma in
Medica Sur Hospital
María del Mar García-Ortega,* Ignacio Tapia-Salas,* Fredy Chable-Montero,**
Santiago Cano-Cancela,* Daniel Motola-Kuba*

RESUMEN ABSTRACT

Antecedentes. El cáncer gástrico es uno de los tumores gastroin-
testinales más frecuentes en todo el mundo, representando la cuar-
ta causa de muerte por cáncer en hombres y quinta causa de muer-
te por cáncer en mujeres en México. Objetivo. Determinar la
prevalencia de HER2/neu sobreexpresión en pacientes diagnosti-
cados de adenocarcinoma gástrico en el Hospital Médica Sur. Ma-
terial y métodos. Diseñamos un estudio observacional retros-
pectivo en el que se realizaron búsquedas en los informes patológi-
cos de adenocarcinoma gástrico de 2010 a 2016, se identificaron
pacientes con inmunohistoquímica para la expresión de HER-2 y el
número de casos positivos para determinar la prevalencia en nues-
tra población. Resultados. Se obtuvieron 70 biopsias, 54.2% con
subtipo difuso y 30% con subtipo intestinal. Treinta y siete pacientes
(53%) tenían inmunohistoquímica para la sobreexpresión de HER2
con cuatro (1.4%) casos positivos (3+) y un caso indeterminado
(2+). Conclusión. Se identificó que sólo en la mitad de las mues-
tras la sobreexpresión de HER2 se determinó con sólo 10.8% de los
casos positivos, resultados similares a los obtenidos en otras institu-
ciones; sin embargo, es necesario obtener esta información en to-
das las muestras de tejido debido a su importancia en tratamiento
y su impacto en el pronóstico.
Background. Gastric cancer is one of the most frequent gastroin-
testinal tumors worldwide, representing the fourth cause of death
because of cancer in men and fifth cause of death because of
cancer in women in México. Aim. To determine the prevalence of
HER2/neu over expression in patients diagnosed with gastric aden-
ocarcinoma in the Hospital Medica Sur. Material and methods.
We designed a retrospective study between 2010 and 2016 to iden-
tified patients with inmunohistochemistry for HER-2 over expression
and the number of positive cases to determine the prevalence in our
population. Results. We obtained 70 biopsies, 38 (54.2%) were
classified as diffuse subtype, 21 (30%) patients were intestinal sub-
type, 7 (10%) mixed type, 2 (2.9%) as other type and, 2 (2.9%)
could not be classified. Immunohistochemistry for HER2 overex-
pression only was investigated in 52.8% of the total biopsies with
positive result in 11%. Conclusion. We identified that only in half
of cases was determinate the overexpression of HER2, although this
evaluation is important for treatment decisions and prognosis.

Palabras clave. Cáncer. Pronóstico. Inmunohistoquímica. Key words. Cancer. Prognosis. Immunohistochemistry.

INTRODUCTION Eighty to 90% of cases present sporadically with the re-

Gastric cancer is one of the most common gastrointes-
tinal malignant tumors worldwide, with an estimate of
18,170 new cases per year and 15,450 deaths, it is con-
sidered the eighth cause of death due to malignant tu-
mors in the United States and the fifth cause worldwide.1-2
maining percentage showing familiar background.3 In
Mexico, it represents the fourth cause of death by cancer
in men and the fifth cause in women, with a downtrend in
the last decade attributed to changes in diet.4 In patients
with gastric cancer, the most frequent histology is the ad-
enocarcinoma that according to Lauren’s classification can

* Oncology Center, Medica Sur Hospital, Mexico City, Mexico.

** Anatomical Pathology, Medica Sur Hospital, Mexico City, Mexico.

Correspondence:

Daniel Motola-Kuba, M.D.

Medica Sur Hospital, Oncology Center
Puente de Piedra, No. 150. Col. Toriello Guerra, Z.P. 14050. Mexico City, Mexico.
Tel.: (+525) 55424-7200
E-mail: danielmotola@yahoo.com.mx
Manuscript received: June 29, 2016. Manuscript accepted: July 20, 2016.

RevMed
Rev Invest Invest
SurMed
Mex,Sur Mex, 2016; 232016;
July-September (3): 137-140
23 (3): 137-140 137
 Her2 Overexpression in Patients Diagnosed with Gastric Adenocarcinoma
be divided into three main subgroups: Intestinal and Dif-
fuse, or mixed.1,3
A big percentage of patients will be diagnosed in ad-
vanced stages of the disease, with an overall survival at 5
years of 20 to 25% for locally advanced tumors and less of
3% for patients with metastatic disease,3 with a median
survival of 8 to 10 months in spite of multidisciplinary treat-
ment. Nearly 2/3 of patients with gastric cancer during
the natural course of the disease will require systemic treat-
ment for metastatic disease, including chemotherapy treat-
ment and in some cases, they will require the use of mon-
oclonal antibodies.1,2
ErbB-2 gen is a proto oncogene that codifies for a
trans membrane tyrosine kinase receptor, member of the
HER family, that includes HER1 (EGFR), HER2, HER3,
and HER4. HER2 forms homo and heterodimers and
works as a co activator of other members of the HER
family with the activation of signal pathways associated
with cellular proliferation, differentiation, survival, and
angiogenesis.1 The amplification and the over expres-
sion of HER2 in patients with gastric cancer is related to
worst prognosis and its presence makes it more likely
that tumor cells acquire the ability to metastasize to dis-
tant organs and lymphatics,5 with a median survival of
12.2 months for HER2-negative tumors and 6.6 months
for HER2-positive tumors. Amplification was not associ-
ated with other clinical factors such as gender, age at
diagnosis or clinical stage despite the association with
worst survival.6 In vitro studies have demonstrated that
c-erbB-2 gen produces an increase of metastatic poten-
tial of malignant cells by stimulation of adhesion, cellu-
lar mobility and invasive potential.5
The over expression of this protein can be identified
by immunohistochemistry or by FISH using biopsy or sur-
gical specimens. The patterns of classification according
to immunohistochemistry are 0 (when there is no staining
or less than 10% of tumor cells is identified), 1+ (mild
perceptive staining in less than 10% of tumor cells), 2+
(mild to moderate stain in less than 10% of tumor cells)
and 3+ (full membrane staining in more than 30% of tu-
mor cells).3 For cases with a 2+ result, it is necessary to
run confirmation by FISH to determine a positive or neg-
ative result.1,7
There is any information about de prevalence of HER2/
neu over expression in patients with gastric adenocarcino-
ma in our medical institution, therefore we conducted a
pathology report revision of the last 5 years to determine
the number of samples with the inmunohistochemistry
determination and the distribution of the positive results
according to histologic subtype.
138 Rev Invest Med Sur Mex, 2016; 23 (3): 137-140
MATERIAL AND METHODS
In this retrospective study, we included patients with
the diagnosis of gastric adenocarcinoma, we differentiat-
ed the samples according to histologic subtype in diffuse,
intestinal and mixed and we identified the percentage of
samples that had immunohistochemistry for HER2/neu
overexpression and the number of positive results.
Pathologic evaluation
and immunohistochemistry
We use pathology reports from 2010 to 2016 with the
diagnosis of gastric adenocarcinoma. We obtained the
histologic diagnosis from the final report registered in the
pathology department database from Medica Sur institu-
tion. Seventy reports of tissue specimens were collected,
34 of them had immunohistochemistry for HER2 overex-
pression. Inmunohistochemistry analysis of samples were
performed using the HercepTestTM kit. All assays were
performed on tissue sections from neutral-buffered, for-
malin-fixed, paraffin embedded tissue blocks. Histopatho-
logical evaluation occurred on haematoxylin and eosin
(H&E)-stained sections. An experienced pathologist eval-
uated all H&E-, and IHC-stained samples. HER2 status
was defined as positive (IHC 3+) or indeterminate (IHC
2+) and negative (IHQ 1+) based on the surgical or biop-
sy specimen staining patterns.
Statistical analysis
The quantitative variables are expressed in mean and
qualitative results are presented as percentages. The sta-
tistical analysis was performed with the software SPSS
version 20.
RESULTS
We evaluated 70 patients with diagnosis of gastric ad-
enocarcinoma between 2010 and 2016. The mean age of
patients was 60.66 years ± 13.30 years (range 33 - 92
years old). Thirty-eight (54.2%) were classified as diffuse
subtype, 21 (30%) patients were intestinal subtype, 7 (10%)
mixed type, 2 (2.9%) as other type and, 2 (2.9%) could
not be classified. Her2 expression using immunohistochem-
istry was obtained in 37 (53%) of cases, 32 (86%) were
negative to the overexpression of Her2, one (3%) case
was equivocal and, 4 (11%) cases had overexpression of
Her2. Of the four patients with Her2 overexpression, two
had metastasic disease at diagnosis (50%), one had local-
 García-Ortega MM, et al.
Table 1. Basal characteristics of the population with Her2 over-
expression.
Gender Age Histological Presence of
subtype metastasis
Patient 1 Female 85 Diffuse ND
Patient 2 Male 64 Mixed Yes
Patient 3 Male 92 Intestinal No
Patient 4 Male 46 Intestinal Yes
ized disease and there was no information regarding the
last patient. There was no difference between Her2 over-
expression and negative expression related to age, or ev-
idence of metastases at the time of diagnosis. There were
more positive results in male patients (75%) and in intesti-
nal subtype (50%) (Table 1).
DISCUSSION
The clinical relevance of this finding was first deter-
mined by the study ToGA, where it was demonstrated the
benefit of adding trastuzumab, a monoclonal antibody
which specifically targets Her2 protein by directly binding
the extracellular domain of the receptor, to chemothera-
py with a response rate of 43.7% and an increase in over-
all survival.8 After this study, it has been tested the use of
lapatinib or the combination of trastuzumab and pertuzu-
mab with satisfactory results.8-11
Her 2 overexpression has been identified more frequent-
ly in gastric adenocarcinoma of intestinal subtype over
the diffuse or mixed subtypes, this is believed to be due to
the development of different molecular pathways specific
to each subtype. On previous reports, the prevalence of
Her2 overexpression has been identified in up to 4.5%,
with some series showing overexpression in the range of
3% to 16%, with reports 3% to 13% for intestinal subtype
and 0.6% to 1% for diffuse subtype.3 In our study, from a
total of 38 patients, analyzed, 4 (11%) were reported with
Her2 overexpression; of them, 2 cases were intestinal sub-
type, one diffuse subtype and one mixed subtype. Similar
data has been reported on institutional studies in our coun-
try, a database from the Instituto Nacional de Cancerología
(INCan) in Mexico showed the following distribution of Her2
overexpression in gastric tumors.
It's been reported on observational studies that patients
with gastric adenocarcinoma in whom Her2 is overexpres-
sed, have a greater metastatic potential, for nodal dis-
ease as for distance metastases, as well as a shorter over-
all survival.3,7,12 In this study, 2 of the patients with Her2
overexpression had metastatic disease, one of them was
Rev Invest Med Sur Mex, 2016; 23 (3): 137-140
diagnosed as locally advanced disease, and in one pa-
tient we did not have enough data to determine the stage
at diagnosis. There is not enough information to deter-
mine median overall survival or time to progression in the
4 positive cases. However, one of the patients with me-
tastasic disease had an overall survival of 10 months, and
the other was still alive at the moment of analysis, with a
survival of 30 months and progression free survival of 9
months receiving Trastuzumab in combination with chem-
otherapy as part of his treatment since diagnosis. There
were no differences between basal characteristics of the
population with Her2 overexpression, however there was
a slight increase of positive results in male patients (75%)
with a distribution according to histologic subtype similar
to previous studies, being more prevalent in intestinal sub-
type (10.8%). However, the percentage of patients with
diffuse subtype was bigger in our population compared
with the data obtained from other series.1,2
It is important to point out that our sample of patients
is small compared to other series making it difficult to
generalize our results. However we can notice that not
enough determinations of HER2 overexpression are being
made in spite of the clinical benefit of this practice. As
mentioned before, the ToGA trial showed an improve-
ment in overall survival of 2.7 months in patients with
gastric adenocarcinoma and HER2 overexpression that
received Trastuzumab as part of their treatment regard-
less of their clinical characteristics,7,13 with a response rate
of 43.7% used in combination with chemotherapy, and
with no increase in toxicity and acceptable quality of
life,14,15 making it an important part of the systemic treat-
ment for metastasic disease.
As with other tumors, like breast cancer, there´s still
pending research regarding the use of target therapy, like
monoclonal antibodies, in combination with chemothera-
py or with other molecules, as well as with immunothera-
py, that could chance the outcomes and the prognosis of
many patients in spite of their clinical stage, allowing less
toxic treatments and improvement in quality of life.16
In conclusion, we identified that only in half of the
samples was determinate the overexpression of HER2.
Eleven percent of investigations resulted positive and were
more frequent in intestinal subtype. It is necessary to point
out the importance of obtaining this information in all the
tissue samples due to its impact on treatment decisions
and prognosis.
REFERENCES
1. Shah Manish. Update on metastasic gastric and esophageal can-
cers. J Clin Oncol 2015; 33: 1760-9.
139
 Her2 Overexpression in Patients Diagnosed with Gastric Adenocarcinoma
2. Tasuku M, Masakazu Y. Recent advances in the HER2 targeted
therapy of gastric cancer. World J Clin Cases 2015; 3: 42-51.
3. Apicella M, Corso S, Giordano S. Targeted therapies for gastric
cancer: failures and hopes from clinical trials. Oncotarget 2017.
4. Sampieri CL, Mora M. Gastric cancer research in Mexico: A pub-
lic health priority. World J Gastroenterology 2014; 20: 4491-
502.
5. Jorgensen Jan Trost. Role of human epidermal growth factor
receptor 2 in gastric cancer: Biological and pharmacological
aspects. World J Gastroenterol 2014; 20: 4526-35.
6. Tanner M, Hollmen M, Junttila T, Kapanen A, et al. Aplification
of HER2in gastric carcinoma: association with Topoisomerasa II
gene amplification, intestinal type, poor prognosis and sensitiv-
ity to trastuzumab. Ann Oncol 2005; 16: 273-8.
7. Shan Ling, Ying Jianming, Lu Ning. HER2 expression and rele-
vant clinicopathological features in gastric and gastroesopha-
geal junction adenocarcinoma in Chinese population. Diagnos-
tic Pathology 2013; 8: 76-83.
8. Bang Y-J, Cutsem EV, Feyereislova A, et al. Trastuzumab in
combination with chemotherapy versus chemotherapy alone for
treatment of HER2-positive advanced gastric or gastro-oesopha-
geal junction cancer (ToGA): A phase III, open-label, randomized
controlled trial. Lancet 2010; 376: 687-97.
9. Satoh Taroh, Xu RUI-Hua, Chung Hyun Cheol, et al. Lapatinib
plus paclitaxel versus paclitaxel alone in the second-line treat-
ment of HER2-amplified advanced gastric cancer in Asian pop-
ulations: TyTAN, a randomized, phase III study”. J Clin Oncol
2014; 32: 2039-49.
Revista de
Investigación
140 Rev Invest Med Sur Mex, 2016; 23 (3): 137-140
10. Hecht Randolph, Bang Yung-Jue, Qin Shukui, Chung, Hyun.
Lapatinib in combination with capecitabine plus oxaliplatin in
Human Epidermal Growth Factor Receptor 2-Positive advanced
or metastasic gastric, esophageal, or gastroesophageal adeno-
carcinoma: TRIO-013/LOGiC- a randomized phase III trial. J
Clin Oncol 2016; 34: 443-51.
11. Kang Y, Rha S, Tassone P, Barriuso J, et al. A phase IIa dose-
finding and safety study of first-line pertuzumab in combination
with trastuzumab, capecitabine and cisplatin in patients with
HER2-positive advanced gastric cancer. Brit J Cancer 2014; 111:
660-6.
12. Gravalos C, Jimeno A. HER2 in gastric cancer: A new prognostic
factor and a novel therapeutic target. Ann Oncol 2008; 19: 1523-9.
13. Ho Yi Jun, Hun Kang Jung, Hwang In Gyu, et al. A retrospective
analysis for patients with HER2-positive gastric cancer who were
treated with trastuzumab-based chemotherapy: In the perspec-
tives of ethnicity and histology. Cancer Research Treatment 2015.
14. Gong, Jifang Liu, Tianshu Fan Qinqxia, et al. Optimal regimen
of trastuzumab in combination with oxaliplatin/capecitabine in
first line treatment of HER2- positive advanced gastric cancer
CGOC1001: a multicenter, phase II trial. BMC Cancer 2016; 16:
68-75.
15. Kurokawa Y, Sugimoto N, Miwa H, Tsuda M. Phase II study of
trastuzumab in combination with S-1 plus cisplatin in HER2-posi-
tive gastric cancer (HERBIS-1). Brit J Cancer 2014; 110: 1163-8.
16. Lam L, McAndrew N, Yee M, et al. Challenges in the clinical
utility of the serum test for HER2 ECD. Biochim Biophys Acta
2012; 1826: 199-208.
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