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- Original Article -
Human epidermal growth factor receptor type 2 protein
expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after
exposure to hormonal therapy
Bo Dai1,3, Yun-Yi Kong2,3, Ding-Wei
Ye1,3, Chun-Guang Ma1,3, Xiao-Yan
Zhou2,3, Xu-Dong Yao1,3
1Department of Urology, Cancer Hospital, Fudan University, Shanghai 200032, China
2Department of Pathology, Cancer Hospital, Fudan University, Shanghai 200032, China
3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Abstract
Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene
amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic
factors. Methods: Immunohistochemistry (IHC) was performed to investigate HER2 protein expression in prostate biopsy specimens from 104
Chinese metastatic prostate cancer patients. After 3_11 months of hormonal therapy, 12 patients underwent
transurethral resection of the prostate (TURP). HER2 protein expression of TURP specimens was compared with that of the
original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores
¡Ý 2+ were investigated for HER2 gene amplification status by fluorescent
in situ hybridization (FISH). Results:
Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and
2 (1.9%) cases, respectively. There was a significant association between HER2 expression and Gleason score
(P = 0.026). HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal
therapy. None of the 14 specimens with HER2 IHC
scores ¡Ý 2+ showed HER2 gene amplification. Patients with
HER2 scores ¡Ý 2+ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0
(P = 0.004) and 1+ (P = 0.034). Multivariate Cox regression analysis showed that HER2 protein expression intensity
was an independent predictor of cancer-related death
(P = 0.039).
Conclusion: An HER2 IHC score ¡Ý 2+ should be
defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might
suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual
patients after hormonal therapy. (Asian J Androl 2008 Sep; 10: 701_709)
Keywords: prostatic neoplasms; human epidermal growth factor receptor type 2; immunohistochemistry; gene amplification; prostate
cancer; prognosis
Correspondence to: Dr Ding-Wei Ye, Department of Urology, Cancer Hospital, Fudan University, Shanghai 200032, China.
Tel: +86-21-6417-5590 ext. 1807 Fax: +86-21-6443-8640
E-mail: dwye@shca.org.cn
Received 2008-04-06 Accepted 2008-06-01
DOI: 10.1111/j.1745-7262.2008.00433.x
1 Introduction
Prostate cancer is the most common cancer and the
second-leading cause of cancer related death among men
in the USA [1]. The incidence rate of prostate cancer
varies widely among countries and racial groups. In 2002,
the prostate cancer incidence rate was 15.6/100 000 in
the city of Shanghai in China [2]. Although the rate is
not currently very high in China, it has increased
dramatically over the past 2 decades as a result of economic
development and changing lifestyles [3]. Furthermore,
most newly diagnosed Chinese prostate cancer patients
are symptoma
tic and have metastatic diseases, because
screening for prostate cancer using prostate specific
antigen (PSA) and digital rectal examination is not a routine
practice in China [3].
The primary treatment for metastatic prostate
cancer is androgen deprivation therapy (ADT). Nevertheless,
resistance to ADT is a major problem worldwide in
prostate cancer treatment [4]. Currently, the mechanisms
responsible for androgen independence are not clear.
Knowledge of molecular changes caused by ADT might
lead to better understanding of the events resulting in
androgen independence [4].
Human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu or ErbB-2) is a
185-kDa transmembrane tyrosine kinase receptor and it
belongs to the epidermal growth factor receptor family
[5]. The HER2 gene is located at chromosomal 17q21
and HER2 signaling promotes cell proliferation through
the RAS_MAPK pathway and inhibits cell death through
the phosphatidylinositol 3'-kinase_AKT_mammalian
target of rapamycin pathway [5]. Preclinical studies
suggest that HER2 expression plays a role in prostate cancer
progression. Using a prostate cancer xenograft model,
Craft et al. [6] demonstrated that androgen independent
xenografts of LAPC-4 cells have higher HER2 protein
levels than androgen dependent parental LAPC-4 cells.
Forced overexpression of HER2 in androgen dependent
LNCaP cells induces androgen independent growth
in vitro and accelerates the progression to androgen
independence in castrated animals [6].
The HER2 protein expression and gene amplification
have been investigated in human prostate cancer patients.
However, the results are controversial in these studies
and there is no study including Chinese patients.
Therefore, we performed this study on Chinese metastatic prostate cancer patients to explore the relation
between HER2 status and patient outcome.
2 Materials and methods
2.1 Patients and tissue samples
The present study included materials from 104
Chinese patients who were diagnosed with metastatic
prostate cancer and treated between 2000 and 2006 at Shanghai
Cancer Hospital, Fudan University (Shanghai, China).
This study was approved by the Institutional Review
Board of the hospital. Written informed consent was
obtained from each patient before any specific
investigations were undertaken.
The diagnosis of prostate cancer was established by
prostate biopsy in each patient. Clinical data including
age, PSA level and tumor node metastasis (TNM)
staging were obtained from medical records. Metastatic
diseases were confirmed using imaging studies, including
bone scanning, computed tomography and magnetic
resonance imaging. The median age of patients was 70 years
(range: 43_90 years) and the median serum PSA level of
patients was 128.7 ng/mL (range: 10.5_6006.2) at the
time of diagnosis. All patients were treated by maximal
androgen blockade (MAB), with 44 (42.3%) patients
receiving luteinizing hormone-releasing hormone agonists
with antiandrogen agents (flutamide) and 60 (57.7%)
patients receiving bilateral orchiectomy with antiandrogen
agents (flutamide). Twelve (11.5%) patients in this study
underwent transurethral resection of the prostate (TURP)
to relieve urinary obstruction after at least 3 months of
MAB therapy. All patients included in this study were
routinely followed up according to European
Association of Urology (EAU) guidelines. The median
follow-up period was 34.5 months (range 16_94 months) for
the censored patients and 18.5 months (range:
7_57 months) for patients who died of prostate cancer.
During follow-up, 69.2% (72/104) of patients
experienced PSA progression (PSA recurrence). Although
secondary hormonal therapy (e.g. bicalutamide and ketoconazole) and chemotherapy
(docetaxel + prednisone, mitoxantrone + prednisone)
was administrated for those with androgen independent prostate cancer and hormone
refractory prostate cancer, respectively, 47 (45.2%)
patients died at the end of this study.
Specimens from the original diagnostic prostate
biopsy and the corresponding TURP were obtained. First,
the hematoxylin and eosin stained histological sections
of each specimen were reviewed and tumor grade was
determined according to the Gleason system. Then, one
representative tissue block with a high carcinoma
content was chosen for further studies.
2.2 Immunohistochemical (IHC) analysis
The IHC was performed by Envision system. The
4-μm-thick sections from the formalin fixed, paraffin
embedded representative prostate cancer tissue blocks
were mounted on aminopropyhriethoxy silane coated slides. The slides were heated to 60ºC for 2 h and
deparaffinized with xylene and rehydrated through 100%
to 85% ethanol. Endogenous peroxidase was quenched in
3% hydrogen peroxide. Antigen retrieval was performed by
soaking the slides in 0.01 mol/L (pH 6.0) citrated buffer and
heating in a 99ºC water bath for 30 min. The slides were
cooled for 20 min at room temperature and rinsed in Tris
buffered saline (TBS). The slides were incubated
overnight at room temperature with polycolonal rabbit
anti-human HER2 antibody (Code No. A0485, DakoCytomation,
Glostrup, Denmark) at 1:300 dilution in TBS. After three
sequential washes in TBS, the slides were incubated with
secondary antibody for 30 min. Then, the slides were
rinsed and incubated with 3-3'-diaminobenzidine (DAB)
for 15 min. Hematoxylin was used for counterstaining.
Paraffin sections from a breast cancer tissue block, which
were known to be positive for HER2, served as positive
controls. Omission of the primary antibody with TBS
served as negative controls.
All slides were interpreted by two experienced
pathologists in an open discussion. The pathologists were
blinded to all clinical data. HER2 staining was scored
from 0 to 3+ in accordance with the previous guidelines
for scoring the HercepTest [7_9]. A score of 0 was
assigned to no staining or faint membrane staining in
< 10% of infiltrating tumor cells. A score of 1+
indicated a faint or barely perceptible membrane staining in
> 10% of infiltrating tumor cells. A score of 2+
indicated a weak to moderate complete membrane staining
in > 10% of infiltrating tumor cells. A score of 3+ meant
strong complete membrane staining in > 10% of
infiltrating tumor cells.
2.3 Fluorescence in situ hybridization (FISH) analysis
Sections with HER2 staining scores of 2+ or 3+ were
further investigated for the HER2/neu gene amplification
status using the PathVysion HER2/neu FISH kit (Vysis,
Downers Grove, IL, USA). Sections were deparaffinized in xylene thrice for 10 min, immersed thrice with
100% ethanol, treated with pretreatment solution at 80ºC
for 30 min, digested with protease solution, and
subsequently denatured. The Vysis probe consists of two
different probes, a chromosome enumeration probe
specific for chromosome 17 (CEP) (spectrum green) and a
locus specific identifier for HER2/neu gene (spectrum
orange). Tissue sections and probes were denatured at
78ºC for 5 min and hybridized overnight at 37ºC. Tissue
sections were counterstained with 10 μL of
4,6-diamino-2-phenilindole.
Results were analyzed in fluorescent microscope
(Olympus BX51, Tokyo, Japan) using the Cytovision
software (Lecia). For each section, at least 60
non-overlapping nuclei were counted in contiguous 1 000 ×
microscopic fields. The signals per nucleus for the HER2 gene
and CEP17 were counted on a cell-to-cell basis. Nuclei
with either no signal for HER2 or CEP17, or only one
color, were not counted [7, 10]. FISH was considered
successful in each case in this study, because more than
90% of cells per case had both HER2 and CEP17 signals.
An individual case was defined as having HER2 gene
amplification when the ratio between the total number of
HER2 and CEP17 signals was 2.0 or more [7, 10].
2.4 Statistical analysis
SPSS 13.0 (SPSS, Chicago, IL, USA) and SAS 8.0 (North Califonia, USA) were used for the statistical
analysis. The Cochran_Armitage trend test was used to
test trends in patient age, tumor Gleason score and
substage of metastatic prostate cancer across HER2 protein
expression intensity. The nonparametric Kruskal_Wallis
H-test was used to analyze the difference in serum PSA
levels in patients with different HER2 protein expression.
The Mann_Whitney U-test was used to compare the
HER2 protein expression in biopsy and TURP specimens
from 12 matched pairs. The survival period was
analyzed using the Kaplan_Meier method and a survival curve
comparison between different groups was performed using the log rank test. Univariate and multivariate analysis
of risk factors predicting prostate cancer specific
survival was performed using the Cox proportional hazards
regression model. All statistical tests were two-sides and
P < 0.05 was considered statistically significant.
3 Results
3.1 HER2 protein expression by IHC analysis
In the whole study group, the HER2 staining score was
0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and
2 (1.9%) cases, respectively (Figure 1). The
Cochran_Armitage trend test determined that there was a
statistically significant trend in tumor Gleason score across
HER2 staining intensity. The tumor with a Gleason score
of 8_10 was associated with higher HER2 protein expression
(P = 0.026, Table 1). There was no significant
association between HER2 staining intensity and patient
age, serum PSA level or substage of metastatic prostate
cancer (Table 1). A total of 12 patients in this study
underwent TURP after 3_11 months of MAB therapy and
HER2 protein expression of the original diagnostic
prostate biopsy specimen was compared with the subsequent
TURP specimen in these patients (Table 2). In 4 (33.3%)
patients, the HER2 protein expression increased
intensity after MAB therapy (Table 2 and Figure 2). The
Mann_Whitney U-test did not indicate that there was a
statistically significant increase in the HER2 protein
expression intensity in our patients after a period of MAB
therapy (P = 0.059, Table 2).
3.2 HER2/neu gene amplification by FISH
We further investigated 10 biopsy specimens and 4
TURP specimens with HER2 staining scores of 2+ or 3+
for HER2/neu gene amplification status. None of the 14
specimens showed HER2 gene amplification by FISH.
3.3 Association of HER2 protein expression with cancer
specific survival
At the end of this study, 47 (45.2%) patients died of
prostate cancer. The 5-year cancer specific survival rate
was 50.2%, 29.2% and 15.0% in patients with HER2 staining scores of 0, 1+ and
¡Ý 2+, respectively (Figure 3). Patients with HER2 score
¡Ý 2+ had a significantly higher chance of dying from prostate cancer than those with
HER2 scores of 0 (P = 0.004) and 1+
(P = 0.034). However, there was no significant difference in the
cancer specific survival rate between the HER2 (score 0)
group and the HER2 (score 1+) group (P = 0.339). To
further investigate the significant prognostic factors
associated with prostate cancer specific survival the
univariate and multivariate risk factor analyses were
performed using the Cox proportional hazards regression
model (Table 3). Tumor Gleason score, substage of
metastatic prostate cancer and HER2 protein expression
were significant univariate predictors of death from
prostate cancer (Table 3). These results corresponded to the
Kaplan_Meier survival analysis curves (Figures 3_5).
However, multivariate analysis of these factors showed
that HER2 protein expression and substage of metastatic
prostate cancer were independent predictors of cancer-
related death (Table 3). They remained significant
variables in the forward and backward stepwise calculation
models.
4 Discussion
ADT has been the mainstay of treatment for metastatic and advanced prostate cancer for over 5 decades.
However, for the majority of patients, the median
duration of response is only 18_24 months [11]. Once
hormone refractory disease is documented, treatment
options are limited and the prognosis is extremely poor [11].
The mechanisms responsible for the development of
androgen independence are not yet completely understood
[4]. Recently, several experimental studies have
proposed that androgen receptor (AR) gene mutation and
amplification and alterations in growth factor activated
pathways might play important roles in the progression
to androgen independent and hormonal refractory
prostate cancer [4,12]. The results of our previous studies
indicate that there is a functional crosstalk between growth
factors and growth factor receptors of the EGF
receptor family and AR signaling pathways [12]. Dual
blockade of AR function with the anti-androgen
hydroxyflutamide and EGF receptor superfamily mediated signal
transduction with the anti-EGF receptor monoclonal
antibody C225, and the anti-HER2 receptor monoclonal
antibody trastuzumab (Herceptin) significantly enhanced
growth inhibition of the MDA PCa 2a cells [12]. Craft
et al. [6] also found HER2 to activate the AR pathway in
the absence of ligand and to synergize with low levels of
androgen to increase AR signaling in a prostate cancer
cell model. Collectively, these results strongly supported
a role for HER2 expression in the development and
progression of prostate cancer. Therefore, we designed the
current study using only Chinese metastatic prostate
cancer patients to determine the usefulness of HER2 status
as a marker for predicting the patient outcome after MAB
therapy.
The methods currently available for analyzing HER2
status in formalin-fixed paraffin embedded tissues include
protein overexpression analysis by IHC and gene
amplification analysis by FISH. HER2 protein overexpression
detected by IHC is observed in _30% of invasive breast
carcinomas, which correlates with the HER2 gene amplification detected by FISH [5]. In prostate cancer, the
situation is more complicated. Some studies have found
that the HER2 gene amplification status detected by FISH
correlates with HER2 protein expression detected by IHC
[13]. However, more and more recently published
studies have found no HER2 gene amplification in any stage of
prostate cancer, even in those with HER2 protein overexpression [7, 10, 14]. One study using the
Quantum Appligene probe technique confirms that none of
117 prostate cancer patients had true HER2 gene
amplification [15]. Therefore, in the present study we used
the economical IHC method to analyze the HER2 protein
expression in each case and FISH was used for further
investigation in those with HER2 IHC staining scores of
2+ or 3+.
In our patients, we found a correlation between the
HER2 IHC staining intensity and the tumor Gleason score,
which is consistent with previous studies [8, 16_18].
More importantly, our study suggests that in Chinese
metastatic prostate cancer patients HER2 protein
expression of the primary lesion at diagnosis influences the
patient outcome. Although only 9.6% (10/104) patients in
this study had an HER2 IHC score ¡Ý 2+, their chance of
dying from prostate cancer was significantly higher than
those with HER2 scores of 0 or 1+. The only published
report that evaluates the prognostic value of HER2
protein expression in metastatic prostate cancer patients
comes from Japan [18]. In that study, the authors
consider the HER2 score ¡Ý 1+ as protein overexpression and
they find that the 3-year period causes specific survival
rate in HER2 score ¡Ý 1+ group to be significantly lower
than that in the HER2 score 0 group [18]. From our
perspective, an HER2 IHC score 1+ should not be
considered as protein overexpression. First, HER2 is a kind
of transmembrane tyrosine kinase receptor that normally
regulates cell growth, survival, adhesion, migration,
differentiation and other cellular responses, and is expressed
at low levels in normal epithelial cells, including prostate
epithelial cells [7]. Second, in breast cancer patients, the
HER2 IHC score 1+ is considered negative for HER2 protein overexpression [5, 17]. Third, in our Chinese
metastatic prostate cancer patients, there was no
difference in the cancer specific survival rate between the HER2
score 0 group and the HER2 score 1+ group (Figure 3).
Moreover, multivariate Cox proportional hazards
regression analysis showed that HER2 protein expression
intensity was an independent predictor of prostate cancer-
related death in this study (Table 3). However, our data
suggest that the Gleason score is not an independent
prognostic factor in our Chinese metastatic prostate cancer
patients. Previous studies have also found that the
Gleason score of the primary tumor has limited
prognostic value in metastatic prostate cancer patients [19].
Therefore, to evaluate the HER2 protein expression is of
particular importance and we recommend that HER2 IHC
scores ¡Ý 2+ should be defined as HER2 protein
overexpression in prostate cancer and used as an indicator for
poor prognosis in patients with metastatic lesions.
In the present study, 12 patients underwent TURP to
relieve urinary obstruction at least 3 months after
initiation of MAB therapy. The HER2 protein expression
intensity increased in 33.3% (4/12) of TURP specimens.
Although statistical analysis did not show a significant
increase in the HER2 protein expression intensity in our
patients after a period of MAB therapy (Table 2), this
phenomenon suggested that the expression of HER2
protein might increase within some individual patients after
a period of hormonal therapy. Because these data came
from the limited 12 matched pairs, the results should be
considered as preliminary and we need to increase
patient numbers to draw definite conclusions in the future.
Previously, some researchers have also found that the
expression of HER2 is higher in prostate cancers from
patients who are treated with MAB before undergoing
surgery compared with untreated patients, whereas the
highest level of expression is found in patients who have
developed androgen independent prostate cancer [14, 16].
A recently published experiment study by Berger
et al. [20] provided an explanation for this phenomenon.
They found that the induction and activation of HER2 in
prostate cancer cells occurs in an androgen-depleted
environment or as a result of AR inactivation, promoting
survival and subsequent proliferation of ablation-resistant
prostate cancer cells [20]. Although androgen ablation
promotes G1 phase arrest and/or apoptosis of many
androgen dependent prostate cancers, a subset of cells
survives and activates and overexpresses HER2 following
androgen ablation [20]. Therefore, our study and others
provide the biochemical rationale to target HER2 in
hormone refractory prostate cancer. Trastuzumab (Herceptin,
Genentech), a humanized monoclonal antibody that binds
to the extracellular juxtamembrane domain of HER2 and
inhibits the proliferation and survival of HER2-dependent
tumors, is approved by the Food and Drug
Administration for patients with invasive breast cancers that
overexpress HER2 [5]. Clinical trails studying the
efficacy of trastuzumab in patients with metastatic hormone
refractory prostate cancer have been attempted [21]. One
study using trastuzumab as a single agent in treating
hormone refractory prostate cancer has shown relatively
low efficacy [21]. Nevertheless, given the small
number of patients in that study, further investigation is
warranted.
We did not find HER2 gene amplification in any of
the 14 specimens with HER2 IHC score ¡Ý 2+. The only
limitation of the present study was that we did not
investigate the HER2/neu gene amplification status by FISH in
HER2 IHC scores 0 and 1+ specimens for economic reasons. Theoretically, all these patients may obtain
negative results. Currently, in prostate cancer, whether gene
amplification of the HER2 locus plays a significant role
in HER2 protein overexpression is uncertain. Some
recently published studies also suggest that no HER2 gene
amplification is found at any stage of prostate cancer [7,
10, 14]. Therefore, in prostate cancer, HER2 protein
expression might be regulated mainly at the transcription
and post-translation level, and HER2 protein expression
analysis by IHC is more sensitive and more important
than gene amplification analysis by FISH for evaluation
of HER2 status in these patients.
Acknowledgement
This study was supported by grants from National
Natural Science Foundation of China (No. 30772162).
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