Annals of Diagnostic Pathology 67 (2023) 152219

Contents lists available at ScienceDirect

Annals of Diagnostic Pathology

journal homepage: www.elsevier.com/locate/anndiagpath

The prevalence and clinical significance of HER2 expression in

prostate adenocarcinoma
Fayez Estephan a, b, 1, Coen J. Lap a, b, 1, Jeff Banagan c, Martha Antonio c, Shanshan Liu d,
Guoqing Diao d, Alexandra Zara Rozalen b, Rithika Rajendran c, Steven Krasnow b,
Ramesh Subrahmanyam b, Victor E. Nava a, b, Maneesh Jain a, b, *
a
The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
b
The Edward P. Evans Precision Oncology Center of Excellence, Washington DC VA Medical Center, Washington, DC, USA
c
Institute for Clinical Research, Washington, DC, USA
d
Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, Washington, DC, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Aims: Abnormalities in HER2 are well-established oncogenic drivers and are approved therapeutic targets in
HER2 various malignancies. Prior studies evaluating HER2 expression in prostate cancer (PCa) have yielded variable
Prostate cancer results. Most of these studies used immunohistochemistry scoring systems based on breast cancer data. The goal
Immunohistochemistry
of this study was to determine the prevalence and clinical significance of HER2 expression using a scoring system
Advanced disease
that better reflects the HER2 staining pattern observed in PCa.
Methods: We randomly selected similar numbers of localized low risk (AJCC stage I), locally advanced (AJCC
stages II & III), and metastatic (AJCC stage IV) PCa patients treated at the DC VA Medical Center between 2000
and 2022. Among them, we included patients who had sufficient PCa tissue samples and clinical information
required for this analysis. Two experienced pathologists independently scored HER2 expression (Ventana
Pathway anti-HER2) according to a modified gastric cancer HER2 scoring system.
Results: Out of the 231 patients included, 85 % self-identified as Black. 58.9 % of patients expressed HER2 (1+:
35.5 %; 2+: 18.2 %; 3+: 5.2 %). Validity of the results was confirmed using the HercepTest antibody. Higher
HER2 expression was associated with a higher Gleason Score/Grade Group and advanced disease.
Conclusions: Our findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a
modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression
supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in
future PCa trials.

1. Introduction activity regulating normal cell growth, survival, and differentiation

Prostate cancer (PCa) remains a major cause of morbidity and mor­
tality in men in the United States, with an estimated 288,300 new di­
agnoses and 34,700 deaths in 2023 [1]. PCa has a significant racial
disparity as Black men historically have been disproportionately
impacted by PCa with a greater incidence, younger age at diagnosis,
more aggressive disease, and higher mortality rates [1-3].
Human Epidermal Growth Factor Receptor 2 (HER2) is a trans­
membrane glycoprotein receptor with intracellular tyrosine kinase
[4,5]. Overactivation of HER2, secondary to mutations or amplification,
and/or overexpression of the HER2 protein, occurs in various epithelial
cancers and can drive oncogenesis [6]. Importantly, the presence of
these abnormalities does not only provide prognostic information but
has also been established as a therapeutic target for malignancies of
breast, lung, and gastro-intestinal origin [7-12].
Although amplification or mutations of HER2 are rare in PCa,
expression of HER2 has been observed in a subset of patients [13-16].
Prior studies have shown HER2 to be expressed during PCa progression

* Corresponding author at: Department of Hematology and Oncology, Washington DC Veterans Affairs Medical Center, 50 Irving Street, Northwest, Washington,
DC 20422, USA.
E-mail address: maneesh.jain@va.gov (M. Jain).
1
First authors: Fayez Estephan & Coen Lap.

https://doi.org/10.1016/j.anndiagpath.2023.152219

Available online 20 October 2023

1092-9134/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
F. Estephan et al.
and have suggested that HER2-dependent signaling supports the
development of androgen independence by activating androgen recep­
tor signaling through ligand-independent mechanisms [17-20]. In
addition, several studies have specifically noted an association between
HER2 expression, even at a low level, and a poor prognosis in PCa [21-
23]. These findings suggest a functional role for HER2 in PCa.
A major study by Minner et al. [16] using tissue microarray revealed
detectable HER2 immuno-staining in approximately 20 % of cases, with
the vast majority showing 1+ or 2+ staining. However, reported rates of
HER2 expression in PCa varied considerably between different studies
[16,19-29]. The variability of prior studies indicates that the prevalence
and role of HER2 in PCa require further exploration. This discrepancy
can in part be explained by differences in methodology of HER2 quan­
titation [16,18,26,29]. Due to the lack of a standard PCa HER2 scoring
system, most studies used scoring systems validated for breast cancer,
anchored on circumferential membranous expression. However, HER2
in PCa exhibits unique immunostaining properties, including lower
levels of HER2 expression, incomplete membranous immunoreactivity,
and a high incidence of HER2 tumor heterogeneity [30-32], which may
be more similar to gastric and gastro-esophageal junction cancers.
Therefore, utilizing an upper gastro- intestinal HER2 scoring scheme
may contribute to standardizing and increasing the sensitivity of re­
ceptor detection in PCa.
In this study, our primary objective was to determine the prevalence
and clinical significance of various levels of HER2 expression in PCa in a
predominantly Black patient cohort. Consequently, we developed a
HER2 immunohistochemistry (IHC) scoring system resembling that of
gastric and gastro-esophageal cancers [32], which better accounts for
the unique staining properties of HER2 in PCa.
2. Materials and methods
2.1. Patient selection
We randomly selected an equal number (90) of localized low risk
(AJCC stage I), locally advanced (AJCC stages II & III), and metastatic
(AJCC stage IV) PCa patients treated at the Washington DC Veteran
Affairs Medical Center (DC VAMC) between 2000 and 2022. Among
them, we included patients who had adequate formalin-fixed paraffin-
embedded (FFPE) tumor tissue and clinical information needed for this
retrospective analysis which included: age at diagnosis, ethnicity, stag­
ing information, Gleason Score (GS), Grade Group (GG) and PSA level at
the time of diagnosis. All patient samples for the study were obtained
from the Department of Pathology at the DC VAMC. This study was
approved by the DC VAMC Institutional Review Board.
2.2. Tumor tissue selection
The hematoxylin and eosin-stained slides of the corresponding index
tumor (defined as the area of PCa representing the highest Gleason
Score/Grade Group in the case) were used to select FFPE tissue blocks
for IHC.
2.3. Immunohistochemistry
FFPE tissues were sliced into 4 μm-thick sections and stained for
HER2 expression using two standard platforms according to manufac­
turer instructions. For all (231 cases) we utilized the Benchmark ULTRA
IHC/ISH system (Roche Diagnostics, Indianapolis) with the Ventana
anti-HER2/neu rabbit monoclonal antibody (clone 4B5, prediluted,
program 21, CC1 and pH 8.5). PATHWAY HER2 4-in-1 human breast
cancer cell lines and a selected prostatectomy tumoral section from our
laboratory served as positive and endogenous tissue background con­
trols, respectively. In addition, the Link48 (DAKO, Santa Clara) with
HerceptTest (DAKO, prediluted and low pH) was used to assay 50
selected cases representing the entire range of reactivity noted using the
2
Annals of Diagnostic Pathology 67 (2023) 152219
aforementioned system (12 with score 0, 14 with score 1+, 13 with score
2+, and 11 with score 3+) to assess the dynamic range of signal using
another verified system [33].
2.4. Quantification of HER2 expression
In order to evaluate HER2 expression, we utilized a scoring system
(as shown in Table 1) based on the traditional gastric cancer biopsy
HER2 scoring system by Ruschoff et al. [34]. Since the expression of
HER2 in PCa is weaker and less prevalent than in gastric carcinoma only
membranous staining was considered for scoring [34] (Table 1). Tumor
reactivity was scored independently by two experienced pathologists
who were blinded to the patients' clinical information. The proportion of
tumor showing reactivity was not accounted for in the scale. When
heterogeneous staining was present, the score was determined based on
the pattern observed in the majority of tumor cells. Interobserver
agreement was above 80 %, and consensus was achieved in all cases.
Discrepancies between the two observers were resolved by consensus
obtained while using a multiheaded microscope.
2.5. Statistical analyses
Descriptive statistics are reported for patient demographics and
clinical characteristics. For continuous variables, mean and standard
deviation (SD) are reported if normally distributed; otherwise, median
and interquartile range (IQR) are reported. For categorical variables,
frequency and percentage are reported. Chi-square Tests or Fisher's
Exact Tests (when the expected cell count was <5) were used to evaluate
the association between HER2 expression and categorical variables,
including disease category, AJCC stage, age group, race/ethnicity, and
Gleason Score/Grade Group.
P-values for Fisher's Exact Tests were calculated based on Monte
Carlo simulation using 2000 replicates. Two-sample t-test was used to
evaluate the association between binary HER2 expression and age. The
Kruskal-Wallis test was used to assess the association between four-level
HER2 expression and the highest PSA before diagnosis. Among subjects
with non-zero HER2 expression, permutation tests were used to compare
the group difference in mean expression level by disease category and
race/ethnicity. To conduct the permutation test, we generated 10,000
datasets by randomly permuting HER2 expression, then fit a general
linear model for each dataset to test the difference of mean expressions
between groups, and the value of the F-test statistic was recorded.
Finally, the permutation p-value was calculated as the proportion of the
values of the F-test statistics from the 10,000 permuted datasets greater
than or equal to the observed value of the F-test statistic from the
original dataset. The statistical significance level of all the tests was set
to (0.05). All statistical analyses were performed using R Statistical
Software (version 4.2.2).
3. Results
Among the 231 patients included in our final analysis, 73 were
classified with localized low risk disease, 83 were locally advanced, and
Table 1
Modified HER2 immunohistochemistry scoring system for prostate
adenocarcinoma.
HER2 staining pattern HER2 HER2 staining
score assessment
A) No staining 0 Negative
B) Faint (barely perceptible) membranous 1+ Low positive
staining
C) Weak to moderate complete, basolateral or 2+ Moderate positive
lateral membranous staining
D) Strong complete, basolateral, or lateral 3+ Strong positive
membranous staining
F. Estephan et al. Annals of Diagnostic Pathology 67 (2023) 152219

75 were metastatic. This last group of patients included 24 patients who Table 2
had locally advanced disease at diagnosis but progressed to metastatic Presence or absence of HER2 expression based on disease category, mean age at
disease and 51 patients who presented with de novo metastatic disease. diagnosis and ethnicity (n = 231). SD Standard Deviation.
The prevalence of positive HER2 expression of any degree (1+, 2+, 3+) HER2 expression
was 58.9 % (136/231) in the tumors of the entire cohort (Fig. 1). Patients n Negative Positive p-
The vast majority (227/231) of tissue obtained was primary PCa = 231 (“0”) n = 95 (“1,2,3”) n = Value
(114 core prostate biopsy, 95 radical prostatectomies, 18 prostate chips 136
generated from transurethral resection of the prostate), and only in four Disease category 0.0001
cases, the tissue was obtained from metastatic sites (three lymph node De Novo Metastatic 51 14 (27.5) 37 (72.5)
biopsies and one lung biopsy). The positivity distribution was as follows: Cohort (%)
37 % (27/73) in the localized low risk group, 66.3 % (55/83) in the Locally Advanced with 24 7 (29.2) 17 (70.8)
Progression to Metastatic
locally advanced group, 70.8 % (17/24) in the locally advanced group Disease Cohort (%)
that progressed to metastatic disease, and 72.5 % (37/51) in the de novo Locally Advanced 83 28 (33.7) 55 (66.3)
metastatic group (p = 0.0001) (Table 2). Pairwise comparison showed a Without Progression to
statistically significant higher prevalence of HER2 expression in the Metastatic Disease
Cohort (%)
locally advanced without progression category (p = 0.0023), locally
Localized Low Risk 73 46 (63) 27 (37)
advanced with progression to metastatic disease category (p = 0.0287), Cohort (%)
and the de novo metastatic disease category (p = 0.0007) when they Age, mean years (SD) 63.5 (8.8) 62.7 (8.5) 64.0 (9.1) 0.2488
were individually compared to the localized low risk disease category. Ethnicity 0.4426
However, there was no statistically significant difference in HER2 Black (%) 197 84 (42.6) 113 (57.4)
White (%) 32 11 (34.4) 21 (65.6)
expression when the first three groups were compared against each Native Hawaiian (%) 2 0 (0) 2 (100)
other. The mean age at diagnosis was 63.5 years, and no statistical
difference in mean age at diagnosis was observed between patients with
positive and negative HER2 expression (Table 2). advanced with progression to metastatic disease category, and it was
The majority (85 %) of patients (197/231) self-identified as Black, highest at 1.73 (SD:0.66) in the de novo metastatic category (Table 3).
among them 57.4 % (113/197) showed a positive HER2 expression with A majority of patients (53.7 %) had either 1+ (35.5 %) or 2+ (18.2
a mean non-zero expression of 1.45 (SD:0.63). Among White patients, %) HER2 expression. However, (5.2 %) of patients showed HER2
65.6 % (21/32) showed a positive HER2 expression with a mean non- expression level of 3+, with half of them having de novo metastatic
zero expression of 1.57 (SD:0.75). Mean HER2 non-zero expression disease. A higher GG was associated with a higher HER2 expression (P<
was 1.49 (SD:0.66) for the entire cohort, 1.04 (SD:0.19) for the localized 0.0001). The prevalence of HER2 positive expression was 36.8 % (28/
low risk category, 1.51 (SD:0.62) for the locally advanced without 76) in patients with GG 1, whereas in patients with GG 5, it was 87.5 %
progression to metastatic disease category, 1.59 (SD:0.62) for the locally (21/24). The median PSA at the time of diagnosis was 12.75 (IQR:

Fig. 1. Representative pictures of HER2 expression in prostate adenocarcinoma. The numbers in pictures A through D represent scoring according to the modified
HER2 scoring scale. Arrows indicate individual cells stained by the Ventana HER2 antibody (scanned whole slide image (WSI), immunohistochemistry). A - No
membranous staining (score 0). B – Faint (barely perceptible) membranous staining (score 1+). C – Weak to moderate complete, basolateral, or lateral membranous
staining (score 2+). D – Strong complete, basolateral, or lateral membranous staining (score 3+).

3
F. Estephan et al. Annals of Diagnostic Pathology 67 (2023) 152219

Table 3 another FDA-approved method (HercepTest (DAKO) antibody). A se­

Mean non-zero HER2 expression level for patients with positive HER2 expres­ lection of 50 patients representing the entire range of reactivity
sion listed for each disease category and ethnicity (n = 136). SD Standard observed with the Ventana antibody (12 with score 0, 14 with score 1+,
Deviation. 13 with score 2+, and 11 with score 3+) was re-evaluated and scored
HER2 expression (Non-Zero) using the same scoring system (Table 1). All patients with positive HER2
Patients n = Mean HER2 p-value expression remained positive when HercepTest (DAKO) antibody was
136 value (SD) used. Furthermore, HercepTest was able to detect positive immunore­
Disease category 0.0004
activity of (1+) in (7/12) patients who had negative HER2 expression by
De Novo Metastatic Cohort 37 1.73 (0.73) using the Ventana antibody. While discordance of any degree between
Locally Advanced with Progression to the two IHC scores observed using these two FDA-approved antibodies
17 1.59 (0.62)
Metastatic Disease Cohort was 56 % (28/50), only one case showed a variation of 2 degrees in
Locally Advanced Without Progression
55 1.51 (0.66) HER2 IHC expression, with the rest only a variation of 1 degree (Fig. 2 A,
to Metastatic Disease Cohort
Localized Low Risk Cohort 27 1.04 (0.19) B & C).
Ethnicity 0.0525 Next-generation sequencing (NGS) data was available for 28 patients
Black 113 1.45 (0.63) with metastatic PCa at the time of the analysis, including 17 patients
White 21 1.57 (0.75) with positive HER2 expression (7 with 1+, 7 with 2+, 3 with 3+).
Native Hawaiian 2 2.5 (0.71)
However, this did not reveal the presence of HER2 mutations or
amplifications.
7.28–90.50) in patients with HER2 3+ expression and 6.70 (IQR:
4.95–12.45) in patients without HER2 expression (p-value = 0.0445, 4. Discussion
Wilcoxon rank-sum test) (Table 4).
To verify the validity of our results, we performed IHC analysis using Over the past two decades, HER2 expression in PCa has gained
considerable interest as a prognostic marker for the development of
aggressive disease and androgen blockade resistance, as well as a po­
Table 4 tential therapeutic target for HER2-directed therapies. The significant
HER2 expression level stratified by disease category, Gleason Score/Grade variation in the reported levels of HER2 expression makes it crucial to
Group and median PSA at diagnosis (n = 231). IQR Interquartile Range.
follow a reliable HER2 IHC scoring system that takes into consideration
HER2 expression potential analytical variables, similar to what is done for HER2
Overall “0” n = “1” n = “2” n = “3” n = p-value expression in breast and in upper gastrointestinal cancers.
n = 231 95 82 42 12 In this retrospective study, we evaluated HER2 expression in PCa
Disease <0.0001 using a modified HER2 scoring system modeled on the standard scoring
category system developed for gastric and gastroesophageal junction cancer.
De Novo 51 14 16 15 6 Using this modified scoring system, we observed a prevalence of HER2
Metastatic (27.5) (31.4) (29.4) (11.8)
positivity of 58.9 % in mainly primary prostate tissues of treatment
Cohort (%)
Locally 24 7 8 8 1 (4.2) naïve PCa patients. Among positive HER2 expressors, 60.2 % were found
Advanced (29.2) (33.3) (33.3) at a low level of 1+, 30.9 % of expressors had a moderate level of 2+, but
with even a strong level of 3+ was observed in 8.9 %. Importantly, higher
Progression levels of expression were associated with higher Gleason Score/Grade
to Metastatic
Disease
Group and advanced disease, consistent with prior studies that have
Cohort (%) reported HER2 to be an adverse prognostic factor in PCa.
Locally 83 28 32 18 5 (6) No amplification or mutations in HER2 were detected in the patients
Advanced (33.7) (38.6) (21.7) who had gene sequencing data, including those with positive HER2
Without
expression. This finding, although the sample size (28) is limited, is in
Progression
to Metastatic line with previous studies reporting a lack of correlation between pro­
Disease tein expression and gene amplification or mutation and suggests that
Cohort (%) HER2 expression in PCa is the result of other transcriptional processes
Localized 73 46 26 1 (1.4) 0 (0) [13-16] and highlights the importance of post-transcriptional regulation
Low Risk (63) (35.6)
Cohort (%)
in HER2 expression in PCa.
Gleason <0.0001 PCa has the most pronounced racial disparities of all cancer types in
Score/ the United States [2,3,35, 36]. The reasons for these disparities are
Grade complex and include socioeconomic inequities and genomics. It is well
Group (%)
recognized that PCa in Black men tends to present at an earlier age and
≤ 6 (Grade 76 48 27 1 (1.3) 0 (0)
Group 1) (63.2) (35.5) behaves aggressively compared to men of other ethnicities. To date, all
3+4 49 23 15 9 2 (4.1) studies that have looked at HER2 expression in PCa have been done in
(Grade (46.9) (30.6) (18.4) cohorts with predominantly White men. Because of the demographics of
Group 2) the Veteran population served by DC VAMC, our cohort is unique in that
4+3 26 5 12 8 1 (3.8)
(Grade (19.2) (46.2) (30.8)
85 % of included patients self-identified as Black. Therefore, a conclu­
Group 3) sion regarding the association between positive HER2 expression and a
8 (Grade 53 15 15 17 6 particular ethnicity is limited in this study and statistically insignificant.
Group 4) (28.3) (28.3) (32.1) (11.3) However, these findings open the door for future studies evaluating this
9 (Grade 24 3 13 7 1 (4.2)
potential association and how it may contribute to the aggressive forms
Group 5) (12.5) (54.2) (29.2)
not reported 3 1 0 (0) 0 (0) 2 of PCa observed in certain ethnicities. In a future analysis after
(33.3) (66.7) expanding our cohort, we intend to compare the racial differences in the
Median PSA at 7.50 6.70 7.68 9.40 12.75 0.0838 prevalence of HER2 expression in PCa.
diagnosis (5.25, (4.95, (5.40, (5.78, (7.28, Due to the exciting outcomes of new therapeutics targeting low
(IQR) 16.60) 12.45) 17.00) 32.90) 90.50)
levels of HER2 expression [9], we developed a scoring system with an

4
F. Estephan et al.
Fig. 2. HER2 immunohistochemistry concordance between the DAKO Herceptest and the Ventana Pathway HER2 antibodies.
(A) Breakdown of HER2 expression level for 50 cases scored using the DAKO Herceptest antibody.
(B) Breakdown of HER2 expression level for 50 cases scored using the Ventana Pathway antibody.
(C) Comparison of DAKO vs Ventana HER2 concordance.
increased sensitivity for HER2 detection. Consequently, the observed
prevalence of HER2 positivity in our study is higher than what is re­
ported in most studies that have been published to date [16,19-29]. We
used an FDA-approved antibody Ventana PATHWAY (4B5) to detect
HER2 expression. However, to further verify our findings, another FDA-
approved antibody, the DAKO HercepTest, was used in a subset of cases
representing the full range of HER2 reactivity observed using Ventana
PATHWAY (4B5). While concordance was reported in 46 % of the cases,
all the cases with positive HER2 expression using Ventana remained
positive with DAKO HercepTest. Furthermore, almost half of the cases
with negative HER2 expression using Ventana turned positive with
DAKO HercepTest, indicating a higher sensitivity with DAKO HercepT­
est [37]. These findings support the high prevalence of positive HER2
expression of any degree that we report in our study.
Patients who present with a diagnosis of de novo metastatic PCa are
usually diagnosed by a tissue biopsy of the metastatic site and do not
often undergo a biopsy of the prostate. In this study, we uniquely
analyzed samples obtained mainly from primary prostate tissue in pa­
tients with metastatic PCa. However, considering the presence of HER2
tumor heterogeneity and higher HER2 expression levels noted in
advanced disease, a discordance in HER2 status can be observed be­
tween tissue obtained from primary and metastatic sites. Likewise,
several studies in breast cancer have reported discordance between
HER2 expression observed in core biopsies and surgical specimens
[38,39]. Furthermore, the discrepancies might arise from changing
5
Annals of Diagnostic Pathology 67 (2023) 152219
status of HER2 expression in PCa as a result of androgen deprivation
[17,18]. Consequently, future studies on HER2 in PCa will need to
evaluate these discrepancies, which are beyond the scope of this study.
When the prostate tissue sample was obtained, the majority of our pa­
tients had not received any treatment.
Some limitations of this report are recognized. Patients stratified by
AJCC stage were randomly selected from a database of approximately
3000 PCa patients treated at the DC VAMC between 2000 and 2022.
However, the final inclusion of patients was constrained by the avail­
ability of clinical information and PCa FFPE tissue samples required for
this analysis. This has led to a slight imbalance in the total number of
patients in each disease category.
Another limitation is the lack of robust genomic sequencing data
available only for a subset of patients with metastatic disease when it
was ordered at the treating physician's discretion. These were included
in the database only recently when this practice became the standard of
care. However, archived FFPE tissue was limited for many patients, and
we were unable to obtain sequencing data due to the requirement of a
significant amount of tissue. We did not perform gene sequencing for the
purpose of this study and only reported the data already available at the
time of this analysis.
In our study, the pathologists selected tissue sections for IHC based
on the area of PCa representing the highest Gleason Score/Grade Group.
It is well-established that the numerical GS and grade group are major
prognostic indicators for PCa outcomes [40]. They are a component of
F. Estephan et al.
the AJCC staging system and the National Comprehensive Cancer
Network risk stratification schema. This highlights the importance of
using this approach when assessing the HER2 expression in PCa espe­
cially when considering targeted therapy in future trials.
Based on initial studies that suggested the presence of HER2
expression in PCa, clinical trials have evaluated the efficacy of HER2-
directed therapies. Trastuzumab and Pertuzumab were evaluated as
single agents in patients with hormone-refractory HER2 positive PCa,
but neither demonstrated clinical activity [41,42]. Due to the rarity of
PCa with HER2 amplification or 3+ expression, both studies included a
limited number of patients. Moreover, both monoclonal antibodies were
used as single-agents, despite pre-clinical studies demonstrating reac­
tivation of compensatory oncogenic pathways upon HER2 inhibition,
including androgen receptor signaling pathway. This suggests that
treatment with HER2 inhibitors may need to be combined with
androgen deprivation therapy or chemotherapy in PCa [17,18]. In this
regard, it is worth mentioning the recent U.S. Food and Drug Adminis­
tration (FDA) approval of fam-trastuzumab deruxtecan-nxki (T-DXd), an
antibody-drug conjugate (ADC) consisting of the humanized monoclonal
antibody trastuzumab covalently linked to the topoisomerase I inhibitor
deruxtecan for the treatment of unresectable or metastatic HER2-
positive breast cancer, HER2-low breast cancer, and locally advanced
or metastatic HER2-positive gastric cancer [9,12]. In addition, interim
results of the phase 2 trial DESTINY-PanTumor-02, a tumor-agnostic
study that included a variety of HER2-expressing solid tumors, show
that trastuzumab deruxtecan (T-DXd) has broad activity across tumor
types [43]. HER2 expression is not routinely tested across tumor types;
however, the results of this study highlight that HER2 is a compelling
target that should be evaluated routinely using scoring methods that
account for the unique characteristics of each tumor. Considering our
findings and the new generation of HER2 targeting ADCs, targeted
therapies addressing even low levels of HER2 expression should be
considered in future PCa trials.
In summary, this study shows a high prevalence of HER2 expression
in a cohort of predominantly Black men with PCa and an association
between elevated HER2 expression and advanced disease. Future studies
are necessary to further validate this modified upper gastrointestinal
tract HER2-scoring system in PCa in order to provide reliable and
reproducible prognostic data, and to evaluate HER2-directed therapy
response.
Funding
Prostate Cancer Foundation
Funding
This work was supported by the Prostate Cancer Foundation (PCF)
[grant number: 19VALO01].
Declaration of competing interest
None reported.
Acknowledgments
This work was partially presented as a poster presentation in person
at the 2023 ASCO Genitourinary Conference in San Francisco on
February 16, 2023, under the title “The Prevalence and Clinical Signif­
icance of HER2 Expression in Prostate Adenocarcinoma”. No financial
support was received from this presentation.
References
[1] Siegel RL, Miller KD, Wagle N-S, et al. Cancer statistics, 2023. CA Cancer J Clin
2023;73(1):17–48. https://doi.org/10.3322/caac.21763.
6
Annals of Diagnostic Pathology 67 (2023) 152219
[2] Awasthi S, Grass GD, Torres-Roca J, et al. Genomic testing in localized prostate
cancer can identify subsets of African Americans with aggressive disease. J Natl
Cancer Inst 2022;114(12):1656–64. https://doi.org/10.1093/jnci/djac162.
[3] Hansen M, Hamieh NM, Markt SC, et al. Racial disparities in prostate cancer:
evaluation of diet, lifestyle, family history, and screening patterns. Cancer
Epidemiol Biomark Prev 2022;31(5):982–90. https://doi.org/10.1158/1055-9965.
EPI-21-1064.
[4] Schechter AL, Hung MC, Vaidyanathan L, et al. The neu gene: an erbB-homologous
gene distinct from and unlinked to the gene encoding the EGF receptor. Science
1985;229(4717):976–8. https://doi.org/10.1126/science.2992090.
[5] Geer P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal
transduction pathways. Annu Rev Cell Biol 1994;10:251–337. https://doi.org/
10.1146/annurev.cb.10.110194.001343.
[6] Moasser MM. The oncogene HER2: its signaling and transforming functions and its
role in human cancer pathogenesis. Oncogene 2007;26(45):6469–87. https://doi.
org/10.1038/sj.onc.1210477.
[7] Von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and
trastuzumab in early HER2- positive breast cancer. N Engl J Med 2017;377:
122–31. https://doi.org/10.1056/NEJMoa1703643.
[8] Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for
HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a
double-blind, randomized, placebo-controlled, phase 3 study. Lancet Oncol 2020;
21(4):519–30. https://doi.org/10.1016/S1470-2045(19)30863-0.
[9] Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated
HER2-low advanced breast cancer. N Engl J Med 2022;387:9–20. https://doi.org/
10.1056/NEJMoa2203690.
[10] Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-
cell lung cancer. N Engl J Med 2022;386:241–51. https://doi.org/10.1056/
NEJMoa2112431.
[11] Bank YJ, van Custem E, Fevereislova A, et al. Trastuzumab in combination with
chemotherapy versus chemotherapy alone for treatment of HER2-positive
advanced gastric or gastro-esophageal junction cancer (ToGA): a phase 3, open-
label, randomized controlled trial. Lancet 2020;376(9742):687–97. https://doi.
org/10.1016/S0140-6736(10)61121-X.
[12] Shitara K, Bang Y, Iwasa S, et al. Trastuzumab deruxtecan in previously treated
HER2-positive gastric cancer. N Engl J Med 2020;382:2419–30. https://doi.org/
10.1056/NEJMoa2004413.
[13] Mark HF, Feldman D, Das S, et al. Fluorescence in situ hybridization study of
HER2/neu oncogene amplification in prostate cancer. Exp Mol Pathol 1999;66:
170–8. https://doi.org/10.1006/exmp.1999.2242.
[14] Bubendorf L, Kononen J, Koivisto P, et al. Survey of gene amplifications during
prostate cancer progression by high-througout fluoresence in situ hybridization on
tissue microarrays. Cancer Res 1999;59:803–6.
[15] Ross JS, Sheehan CE, Hayner-Buchan AM, et al. Prognostic significance of HER2/
neu gene amplification status by fluorescence in situ hybridization of prostate
carcinoma. Cancer 1997;79(11):2162–70. https://doi.org/10.1002/(sici)1097-
0142(19970601)79:11<2162::aid-cncr14>3.0.co;2-u.
[16] Minner S, Jessen B, Stiedenroth L, et al. Low-level HER2 overexpression is
associated with rapid cell proliferation and poor prognosis in prostate cancer. Clin
Cancer Res 2010;16(5):1553–60. https://doi.org/10.1158/1078-0432.CCR-09-
2546.
[17] Craft N, Shostak Y, Carey M, et al. A mechanism of hormone induced prostate
cancer through modulation of androgen receptor signaling by HER2/neu tyrosine
kinase. Nat Med 1999;5(3):280–5. https://doi.org/10.1038/6495.
[18] Signoretti S, Montironi R, Manola J, et al. Her-2-neu expression and progression
toward androgen independence in human prostate cancer. J Natl Cancer Inst 2000;
92(23):1918–25.
[19] Reese DM, Small EJ, Magrane G, et al. HER2 protein expression and gene
amplification in androgen- independent prostate cancer. Am J Clin Pathol 2001;
116)2):234–9. https://doi.org/10.1093/jnci/92.23.1918.
[20] Peixoto GA, Korkes F, Pazeto CL, et al. The influence of testosterone suppression on
HER2 immunoexpression in prostatic neoplastic tissue. Mol Clin Oncol 2021;15(3):
185. https://doi.org/10.3892/mco.2021.2347.
[21] Nishio Y, Yamada Y, Kokubo H, et al. Prognostic significance of
immunohistochemical expression of the Her-2/neu oncoprrotein in bone
metastatic prostate cancer. Urology 2006;68:110–5. https://doi.org/10.1016/j.
urology.2006.01.060.
[22] Ross JS, Nazeer T, Church K, et al. Contribution of HER-2/neu oncogene expression
to tumor grade and DNA content analysis in the prediction of prostatic carcinoma
metastasis. Cancer 1993;72(10):2020–8. https://doi.org/10.1002/1097-0142
(19931115)72:10<3020::aid-cncr2820721026>3.0.co;2-#.
[23] Ware JL, Maygarden SJ, Koontz W, et al. Immunohistochemical detection of c-
erbB-2 protein in human benign and neoplastic prostate. Hum Pathol 1991;22(3):
254–8. https://doi.org/10.1016/0046-8177(91)90159-m.
[24] Mellon K, Thompson S, Charlton RG, et al. p53, c-erbB-2 and the epidermal growth
factor receptor in the benign and malignant prostate. J Urol 1992;147(2):496–9.
https://doi.org/10.1016/s0022-5347(17)37287-7.
[25] Ibrahim GK, MacDonald JA, Kerns BJ, et al. Differential immunoreactivity of her-
2/neu oncoprotein in prostatic tissues. Surg Oncol 1992;2(6):151–5. https://doi.
org/10.1016/0960-7404(92)90028-j.
[26] Visakorpi T, Kallioniemi OP, Koivula T, et al. Expression of epidermal growth
factor receptor and ERBB2 (HER-2/Neu) oncoprotein in prostatic carcinomas. Mod
Pathol 1992;5(6):643–8.
[27] Gu K, Mes-Masson AM, Gauthier J, et al. Overexpression of her-2/neu in human
prostate cancer and benign hyperplasia. Cancer Lett 1996;99(2):185–9. https://
doi.org/10.1016/0304-3835(95)04061-7.
F. Estephan et al.
[28] Edwards J, Mukherjee R, Munro AF, et al. HER2 and COX2 expression in human
prostate cancer. Eur J Cancer 2004;40(1):50–5. https://doi.org/10.1016/j.
ejca.2003.08.010.
[29] Jorda M, Morales A, Ghorab Z, et al. Her2 expression in prostate cancer: a
comparison with mammary carcinoma. J Urol 2002;168(4 Pt 1):1412–4.
[30] Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric
cancer: results from a validation study. Histopathology 2008;52(7):797–805.
https://doi.org/10.1111/j.1365-2559.2008.03028.x.
[31] Lee S, de Boer WB, Fermoyle S, et al. Human epidermal growth factor receptor 2
testing in gastric carcinoma: issues related to heterogeneity in biopsies and
resections. Histopathology 2011;59(5):832–40. https://doi.org/10.1111/j.1365-
2559.2011.04017.x.
[32] Ruschoff J, Hanna W, Bilous M, et al. HER2 testing in gastric cancer: a practical
approach. Mod Pathol 2012;25(5):637–50. https://doi.org/10.1038/
modpathol.2011.198.
[33] Lucas E, Jabbar SB, Molberg K, et al. Comparison of Dako HercepTest and Ventana
PATHWAY anti- HER2 (4B5) tests and their correlation with fluorescent in situ
hybridization in breast carcinoma. Appl Immunohistochem Mol Morphol 2019,
Jul;27(6):403–9. https://doi.org/10.1097/PAI.0000000000000646.
[34] Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer-guideline
validation and development of standardized immunohistochemical testing.
Virchows Arch 2010, Sep;457(3):299–307. https://doi.org/10.1007/s00428-010-
0952-2.
[35] R: A Language and Environment for Statistical Computing. R foundation for
statistical computing, Vienna, Austria. https://www.R-project.org; 2022.
Annals of Diagnostic Pathology 67 (2023) 152219
[36] Lowder D, Rizwan K, McColl C, et al. Racial disparities in prostate cancer: a
complex interplay between socioeconomic inequitis and genomics. Cancer Lett
2022;531:71–82. https://doi.org/10.1016/j.canlet.2022.01.028.
[37] Ruschoff J, Friedrich M, Nagelmeier I, et al. Comparison of HercepTestTM mAb
pharmDx (Dako Omnis, GE001) with Ventana PATHWAY anti-HER-2/neu (4B5) in
breast cancer: correlation with HER2 amplification and HER2 low status. Virchows
Arch 2022;481(5):685–94. https://doi.org/10.1007/s00428-022- 03378-5.
[38] Robertson S, Ronnland C, de Boniface J, et al. Re-testing of predictive biomarkers
on surgical breast cancer specimens is clinically relevant. Breast Cancer Res Treat
2019;174(3):795–805. https://doi.org/10.1007/s10549-018-05119-2.
[39] Greer LT, Rosman M, Mylander WC, et al. Does breast tumor heterogeneity
necessitate further immunohistochemical staining on surgical specimens? Am Coll
Surg 2013;216(2):239–51. https://doi.org/10.1007/s10549-018-05119-2.
[40] Swanson GP, Trevathan S, Hammonds K, et al. Gleason score evolution and the
effect on prostate cancer outcomes. Am J Clin Pathol 2021, Apr 26;155(5):711–7.
https://doi.org/10.1093/ajcp/aqaa130.
[41] Ziada A, Barqawi A, Glode LM, et al. The use of trastuzumab in the treatment of
hormone refractory prostate cancer; phase II trial. Prostate 2004;60(4):332–7.
https://doi.org/10.1002/pros.20065.
[42] de Bono JS, Bellmunt J, Attard G, et al. Open-label phase II study evaluating the
efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naïve
patients with hormone-refractory prostate cancer. J Clin Oncol 2007;25:257–62.
https://doi.org/10.1200/JCO.2006.07.0888.
[43] Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of Trastuzumab
Deruxtecan (T-DXd) in patients with HER2-expressing solid tumors: DESTINY-
PanTumor02 (DP-02) interim results. Presented at the ASCO Annual Meeting.
2023. June 2–6, Chicago, Illinois, US.