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Clin Chem Lab Med 2011;49(1):xxx-xxx 2011 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/CCLM.2011.707
Mini Review
The human epidermal growth factor receptor 2 (HER2)
Laura J. Tafe* and Gregory J. Tsongalis
Department of Pathology, Dartmouth Medical School,
Dartmouth Hitchcock Medical Center and Norris Cotton
Cancer Center, Lebanon, NH, USA
Abstract
The declared ‘‘war on cancer’’ aimed to eradicate this disease using our knowledge of cancer cell biology to develop
novel therapeutics. One such target of these novel therapies
has been the human epidermal growth factor receptor 2
(HER2) gene. Unique in the approach to abolishing function
Q1:
In general
of this gene coded receptor, it was the first target of new
when
monoclonal antibody therapy targeting the extracellular
referring to
receptor and now also a target of small molecule drugs
gene
against the intracellular tyrosine kinase domain. In this
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alized medicine requiring companion diagnostics. In this
italics.
Please check manuscript, we review the biology and clinical applications
throughout
of HER2 as a biomarker of disease and as a therapeutic
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target.
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Keywords: •••••.
Introduction
While the field of pharmacogenomics (PGX) continues to
mature and its clinical application gains utility, one aspect of
PGX, personalized medicine, is proving to have a major
impact on the management of the cancer patient. Our
increasing knowledge base of tumor cell biology and our
ever increasing abilities to design therapeutics against various biological targets involved in different pathways has
resulted in significant advances using these novel targeted
therapies. One such biomarker, the human epidermal growth
factor receptor 2 (HER2), was the first to be targeted with a
novel humanized monoclonal antibody approach and later
with a small molecule tyrosine kinase inhibitor.
The human epidermal growth factor
receptor 2 (HER2)
The human epidermal growth factor receptor 2 (HER2) is a
proto-oncogene located on chromosome 17p11.2-12 that
Q3:
Please
supply fax
number
*Corresponding author: Laura J. Tafe, MD, Department of
Pathology, Dartmouth-Hitchcock Medical Center, One Medical
Center Drive, Lebanon, NH 03756, USA
Phone: q1-603-650-9420, E-mail: [email protected]
Received June 8, 2011; accepted August 12, 2011
encodes a 185-kd transmembrane tyrosine kinase receptor
(p185HER-2). This gene is a member of the HER gene family
which includes HER1 (epidermal growth factor receptor,
EGFR/erbB1), HER3 (erbB3) and HER4 (erbB4). Each
receptor contains an extracellular domain, a single transmembrane lipophilic domain and an intracellular tyrosine kinase
(TK) domain (Figure 1). The TK domain is non-functional
in the HER3 receptor. HER2, unlike the other members of
this family, has no identified ligand and is constitutively
active with the ability to undergo ligand-independent dimerization. Other HER proteins can preferentially heterodimerize with HER2 which leads to phosphorylation of the
tyrosine residues and activation of downstream effectors
including the mitogen activating protein kinase (MAPK),
phosphatidylinositol 3-kinase (PI3K), and signal transducers
and activators of transcription (STAT) pathways that regulate
cell proliferation, survival and other processes important in
carcinogenesis. The oncogenic activation of HER2, present
in approximately 15%–20% of all breast cancers as well as
some other cancer types (discussed later), commonly occurs
through gene amplification which results in receptor protein
overexpression (Figure 2) (1, 2). This overexpressed protein
has become the target of several novel therapies.
Targeting HER2
Currently, there are two FDA-approved targeted therapies
against HER2 that are available to treat patients with cancers
that either overexpress the HER2 protein or have an amplified HER2 gene. Such targeted therapies can be designed
against the extracellular receptor domain or the intracellular
tyrosine kinase domain. Trastuzumab (Herceptin; Genetech,
South San Francisco, CA, USA) is a recombinant humanized
monoclonal antibody which specifically targets the extracellular domain of the HER2 receptor. This was the first monoclonal antibody therapy approved for use in human cancers.
Although the exact mechanism of action of the antitumor
activity of trastuzumab is unknown, a number of mechanisms
have been proposed including: 1) activation of antibodydependent cellular cytotoxicity, 2) blockage of proteolytic
cleavage of the HER2 extracellular domain, 3) inhibition of
intracellular signal transduction, 4) inhibition of tumorinduced angiogenesis, and 5) inhibition of repair of cancer
treatment-induced DNA damage (3, 4).
More recently, lapatinib (Tykerb; GlaxoSmithKline, London,
UK), an orally available, small-molecule, reversible inhibitor
of both HER2 and EGFR tyrosine kinases (TKs) was
approved by the FDA. The use of tyrosine kinase inhibitors
(TKIs), including the selective EGFR inhibitors, gefitinib
2011/0367
Q4:
‘HER-3’
changed to
‘HER3’ to
be cinsistent,
ok?
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2 Tafe and Tsongalis: The human epidermal growth factor receptor 2 (HER2)
with several becoming FDA-cleared assays for use in clinical
testing (Table 1).
Immunohistochemistry (IHC)
Figure 1 Schematic diagram showing the extra- and intra-cellular
domains of the HER2 receptor.
(Iressa, AstraZeneca Pharmaceuticals LP, Wilmington, DE,
USA) and erlotinib (Tarceva, Genentech/OSI Pharmaceuticals, LLC, Farmingdale, NY, USA), have been used in clinical practice for various human cancers. These compounds
are all 4-anilinoquinoline derivatives, but have distinct TK
targets and mechanisms of action (5). The binding of lapatinib inhibits phosphorylation thus blocking the downstream
effects of the MAPK, PI3K and STAT pathways. In vitro,
lapatinib can effectively inhibit human tumor cell lines that
overexpress EGFR or HER2, indicating selectivity for cancers that overexpress these receptors (6).
Detecting HER2 status
An association between HER2 gene amplification and poor
prognosis in breast cancer patients was first demonstrated in
1987 (7). Subsequently, approval of trastuzamab highlighted
the need for companion diagnostics to be available in the
clinical laboratory setting. This provided more of a rationale
for the need to establish HER2 status in clinical tumor specimens prior to the initiation of therapy. Since an association
exists between p185HER-2 protein overexpression and HER2
gene amplification, quantification can be measured at either
the protein level or at the gene level. Numerous technologies
and approaches have been evaluated and described for the
detection of HER2 gene amplification and/or overexpression
Immunohistochemistry (IHC) measures expression of a target gene by utilizing antibodies specific for antigenic epitopes of a given gene product (Figure 3). Because these
assays are usually performed on tissue sections with intact
cellular architecture, their expression can be localized to a
specific cell type or specific region within the cell (i.e.,
nuclear, cytoplasmic, or membranous). A typical IHC protocol would involve application of a primary antibody
against the target protein to the tissue section on a slide. A
biotinylated secondary antibody directed against the primary
antibody species is then applied. Signal detection is performed utilizing avidin which has a very high affinity for
biotin and is conjugated to an enzyme. The presence or
absence of the target protein is determined by adding a
chromogenic substrate which produces a colorimetric reaction for which the intensity of the color is proportional to
the number of target proteins present. A number of HER2
antibodies are commercially available for IHC including the
FDA approved HercepTest (polyclonal, DAKO, Carpinteria,
CA, USA) and Pathway/Confirm (clone 4B5, monoclonal,
Ventana Medical Systems, Tucson, AZ, USA). The IHC signal is quantified and scored most commonly according to the
2007 ASCO/CAP guidelines on a scale of 0–3q based on
the membranous staining pattern, intensity and percentage of
staining (Figure 3), (8). The most commonly used testing
algorithm of HER2 status includes the use of a semiquantitative immunohistochemistry (IHC) assay to detect HER2
protein overexpression followed by fluorescence in situ
hybridization (FISH) if IHC is equivocal (2q). This scoring
system has come under intense scrutiny recently due to the
lack of precision of this technology. While IHC is a well
recognized technique and is relatively inexpensive, the drawbacks mostly stem from it being an indirect detection method
for an unstable target. It is well recognized that protein stability is affected by cold ischemic times, tissue fixation methods and length of time in fixative (9–11). Also, background
or non-specific staining can be a result of the indirect detection chemistries used.
Figure 2 Schematic diagram illustrating gene amplification which results in receptor over-expression.
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Tafe and Tsongalis: The human epidermal growth factor receptor 2 (HER2)
3
Table 1 Methods used in the assessment of HER2 status.
Detection
method
HER2 molecule
detected
Assessment
Advantage
Disadvantage
IHC
Cell membrane
protein receptor
DNA
Protein overexpression
Amplified gene
Reproducibility, heterogeneity,
endogenous enzymes, fixation, epitopes
Cost, fluorescent microscopy
Extracellular
domain (ECD)
ECD in serum
or tissue
Cell localization, ease of
use, comfort factor, cost
Cell localization, direct
detection, reproducibility, accuracy
Specimen type,
turn-around-time
FISH
ELISA
No cell localization, no detection
of heterogeneity
IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; ELISA, enzyme linked immunosorbent assay.
In situ hybridization (ISH)
Alternatively, laboratories may chose to detect gene copy
number as there has been good correlation between p185HER-2
protein overexpression and HER2 gene amplification. Fluorescence in situ hybridization (FISH) is the technique most
commonly used to quantify HER2 gene copy number or
amplification and many laboratories are now performing
FISH as their primary test for HER2 analysis. Like IHC, this
technique detects the target gene in the context of the cellular
architecture of a fixed tissue section. FISH uses a singlestranded nucleic acid probe that hybridizes to the denatured
HER2 gene locus (17q21) to form a double-stranded hybrid
between probe and target sequence. The probe is labeled with
a fluorescent dye so that direct visualization of the probe is
possible with a fluorescent microscopy. In FISH assays
where the goal is to enumerate gene copy number, a second
probe, labeled with a different fluorochrome, is used as a
comparative control, such as a centromeric enumeration
probe (CEP) for chromosome 17 (Figure 4). Amplification
status is then determined by measuring the HER2/CEP17
signal ratio (positive )2.0 and negative -2.0, according to
PathVysion FDA-approved package insert). The PathVysion
(Abbott Laboratories, Abbott Park, IL, USA) and pharmDx
(DAKO, Glostrup, Denmark) are two examples of dual colored FISH assays which have received FDA approval. A
single color assay (INFORM, Ventana Medical Systems,
Tucson, AZ, USA) used HER2 copy number/nucleus
enumeration and a separate probe assay to assess chromo-
some number. While FISH has been reported to be the more
accurate of the in situ technologies to determine HER2 status,
it is more costly than IHC and requires fluorescent microscopy capabilities. Guidelines have also been established for
HER2 FISH testing (8).
Bright-field IHC has been introduced as an alternative to
FISH. Two types are currently available, chromogenic in situ
hybridization (CISH) and enzyme metallography with silver
deposition (SISH). The main advantages of these techniques
are that the signals do not fade and the slides can be archived
and retained as part of the pathological record. In addition,
CISH and SISH do not require a fluorescent microscope and
with the use of bright-field microscopy the viewer is able to
evaluate gene status in the context of good morphology and
tumor heterogeneity is much easier to view.
CISH, similar to the IHC process, uses a chromogenically
labeled complementary DNA or RNA strand (probe) to
localize a specific DNA or RNA target sequence in a tissue
specimen (Figure 5). The CISH method can be used to evaluate gene amplification, chromosome translocation, gene
detection and chromosome enumeration. CISH utilizes peroxidase or alkaline phosphatase reactions to visualize signals
and is applicable to formalin-fixed, paraffin-embedded
(FFPE) tissues, blood and bone marrow smears, metaphase
chromosome spreads and fixed cells. The CISH signals can
be quantified using a 40X objective. Although CISH does
not permit an actual determination of gene copy number, it
has been shown to correlate well with FISH (12).
Figure 3 HER2 analysis by IHC.
Scoring is based on staining intensity and percentage of cells showing expression (0–1q, 2q, 3q). Score 0 (negative)sno membrane
staining is observed; score 1q (negative)sweak, incomplete membrane staining in any proportion of invasive tumor cells, or weak complete
membrane staining in -10% of cells; score 2q (equivocal)scomplete membrane staining that is non-uniform or weak but with obvious
circumferential distribution in )10% of invasive tumor cells, or strong complete membrane staining in no more than 30% of cells; score
3q (positive)scomplete and uniform strong membrane staining in )30% of invasive tumor cells.
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4 Tafe and Tsongalis: The human epidermal growth factor receptor 2 (HER2)
Figure 4 HER2 analysis by fluorescence in situ hybridization
(FISH).
The SPOT-Light HER2 CISH kit (Invitrogen, Carlsbad,
CA, USA) is an FDA approved, single HER2 signal assay.
The assay results can be visualized as a colored precipitate
signal and counted using a 40X objective. The assay interpretation is based on the numbers of signal dots or clusters
present in )50% of tumor cells. The CISH procedure however, is time consuming and takes nearly as long as FISH to
prepare the slides.
A dual colored CISH assay, HER2 DuoCISH (Dako,
Denmark) is also available in the USA. The signals are enumerated with a bright-field microscope similar to the method
of counting FISH signals (HER2:CEP17 ratio). This kit can
be used manually or automated on Dako Autostainer instruments. Dako has recently introduced another dual colored
CISH assay, HER2 CISH pharmDX kit, which is not available in the US.
The other alternative ISH technology is silver in situ
hybridization (SISH) which does allow for gene copy number enumeration. The INFORM HER2 SISH (Ventana,
Tucson, AZ) assay is also available in the USA. This assay
utilizes chromogenic silver deposition to detect a HER2
DNA probe on one slide and a Chromosome 17 (Chr17)
probe on a matched slide. This strategy allows HER2 status
to be determined in reference to Chr 17 so that a HER2/
Chr17 ratio can be determined using the same reported ranges as those recommended by ASCO/CAP for FISH. The
silver signals are counted and a ratio is calculated. All steps
in this assay are fully automated and can be performed on
the Benchmark series of automated strainers (Ventana,
Tucson, AZ, USA) which leads to an approximate 6 h turnaround-time. The main disadvantages of assays which
require two separate slides is the inability to know whether
signal counts are being conducted on the same cells. In addition, there is an inherent risk of sectioning through smaller
tumors when biopsy material is used for analysis.
In an attempt to overcome this, Ventana has recently introduced, and gained FDA approval for, the INFORM HER2
Dual ISH DNA Probe Cocktail, which combines ISH and
IHC staining of HER2 and Chr 17 using SISH and Alk-Phos
Red, respectively. This assay is also performed on the Benchmark instruments and is designed such that the HER2 probe
and Chr 17 reference probe are visualized on the same slide
during one automated run. High concordance rates with
FISH have been reported in multiple studies for CISH
(81%–100%) and SISH (94%–98.9%) (12–15).
Polymerase chain reaction (PCR)
Testing for HER2 gene amplification has also been performed using PCR technology (16). HER2 gene amplification is associated with mRNA and protein overexpression.
Recently, Baehner et al. reported a 97% concordance
between central FISH analysis by PathVysion and HER2
mRNA quantitative reverse-transcriptase polymerase chain
reaction (RT-PCR) by the Oncotype DX assay (17).
Lehmann-Che et al. reported a similar 97.3% overall concordance of HER2 overexpression between IHC and quantitative reverse-transcriptase PCR (Q-RT-PCR) in 466 cases.
They used TATA binding protein (an endogenous control),
to determine a cut-off ratio of )7 for HER2 overexpression
with the use of a training set of tumors that had correlative
Figure 5 Schematic diagram of chromogenic in situ hybridization (CISH). www.histalim.com/.../in-situ-hybridization.php.
Q5:
‘LehmannChe’ is
deleted here
as not
needed, ok?
Q6:
Add ‘gene’
after ‘HER2’
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Tafe and Tsongalis: The human epidermal growth factor receptor 2 (HER2)
IHC data. Of 14 cases with equivocal 2q IHC, Q-RT-PCR
was highly predictive of final HER2 status (as determined
by additional methods including FISH) in ten of the cases,
suggesting that Q-RT-PCR could be used as an alternative to
FISH in IHC equivocal cases (18). Q-RT-PCR is a fast, quantitative method that lacks intra-observer variability; however,
careful microscopic selection of tumor prior to extraction is
crucial. Quantitative PCR based assays, although compelling
will likely require a great deal more validation before they
are accepted into clinical practice.
Immunoassay
Currently, the CellSearch (Veridex LCC, Raritan, NJ, USA)
immunoassay technology is the only FDA approved technology for detecting circulating tumor cells (CTCs) in
patients with metastatic breast cancer. Ventana has developed
a CellSearch Tumor Phenotyping Reagent HER2 which can
be used in conjunction with the CTC identification technology to phenotype CTCs for HER2 expression.
However, this assay is still for research use only and the
best method of quantifying HER2 expression in CTCs is still
being determined (19–21).
HER2 in human cancer
Breast cancer
P185HER-2 overexpression is associated with a worse clinical
outcome (7) but is predictive of response to targeted therapies like trastuzumab and lapatinib. Trastuzumab was
approved by the US Food and Drug Administration (FDA)
in 1998 and is widely used as a standard therapy for patients
with HER2-positive metastatic breast cancer (22, 23); and,
as adjuvant therapy in early breast cancer combined with
chemotherapeutic agents (24). Therapy with trastuzumab
however, is not without drawbacks. It has been associated
with a small risk of cardiac toxicity in approximately 4% of
patients when combined with doxorubicin-containing protocols (25). And, although combined chemotherapy regimens
have been modified, trastuzumab is an intravenously administered drug and the cost is significant.
In 2007, the FDA approved lapatinib for use in combination with capecitabine for treatment of advanced HER2positive breast cancer in patients who had previously
received chemotherapy or trastuzumab (26). The role of
adjuvant and neoadjuvant lapatinib in early stage disease is
currently being studied by the ALTTO (Adjuvant Lapatinib
and/or Transuzumab Treatment Optimization) and the
NeoALTTO trials.
Accurate HER2 testing strategies are critical for appropriate management of breast cancer patients. In the review by
Sauter et al., they conclude that because FISH assays are less
dependent on tissue fixation and correlate better than IHC
with tumor response to trastuzumab or laptinib, FISH should
be used as the primary HER2 testing modality (27). With
approximately 200,000 women in the USA every year developing breast cancer, small discordance rates between HER2
5
assays can mean thousands of potentially inaccurate findings
which could lead to tumors misclassified as false-negative
and those patients denied trastuzumab or tumors being classified as false-positive and those women needlessly receive
the $100,000 drug.
Despite there being multiple testing methodologies available, the debate on which testing strategy establishes the
most accurate, reproducible and clinically relevant HER2
status persists. The ASCO/CAP guidelines for breast cancer
put forth in 2007 were drafted in part in response to several
studies that showed that there was huge discordance between
IHC data and FISH data observed between community
laboratories and central laboratories (27% discordant for
IHC, (28); 23% discordant for 3q IHC and 74% discordant
for 2q IHC, (29) and initial overall concordance of IHC and
FISH of 82% (30, 31), suggesting the lack of standardization
of the assays and interpretation.
The ASCO/CAP guidelines recommend HER2 testing by
either IHC or FISH with confirmatory testing for equivocal
cases (FISH for IHC equivocal and additional counting and/
or repeat if FISH equivocal). These guidelines recommend
criteria for accepting and rejecting IHC and FISH results
without maintaining that either technique is preferable,
emphasizing that there is no ‘‘gold standard’’ testing strategy.
In addition, they altered the definition of a positive result
(3q uniform intense membrane staining in )30% vs. prior
)10% of invasive tumor cells, )6 HER2 copies/nucleus, or
HER2/CEP 17 ratio )2.2) and created an equivocal FISH
category (HER2/CEP 17 ratio of 1.8–2.2 or average gene
copy number between 4.0 and 6.0). The guidelines recommend optimal validation of the tests in which positive and
negative HER2 categories are at least 95% concordant with
an alternative validated method or the same validated method
performed at another laboratory. They stress the importance
of internal quality control (QA) procedures, participation in
proficiency testing with at least 90% correct response rate
and laboratory accreditation with onsite and self inspection
(8). These guidelines do raise a number of issues that are
difficult to control, such as pre-analytical factors, e.g., variability across laboratories in tissue fixation methods and
times which impact the tissue antigenicity. Despite the adherence to and acceptance of these guidelines, some authors still
feel they are flawed. Subsequent to the publication of these
guidelines, a second manuscript was published by many of
the same authors that examined some of the false pretenses
presented in the 2007 guideline document. These differences
in the 2009 manuscript included the recommendation of
FISH testing as a more accurate methodology, the lack of
data to support an equivocal zone for FISH testing and the
lack of data to support a FISH cut-off ratio of )2.2 (27).
Another potential inherent issue with HER2 testing is
tumor HER2 heterogeneity (either protein overexpression or
amplification) which is seen in approximately 1% of tumors
(32) and is defined by CAP as more than 5% but -50% of
infiltrating tumor cells with a FISH ratio higher than 2.2 (33).
The clinical significance and implications for targeted HER2
therapy are not clearly defined (34) but ASCO/CAP guidelines recommend documenting the presence of heterogeneity
in the patient’s report (33).
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6 Tafe and Tsongalis: The human epidermal growth factor receptor 2 (HER2)
Polysomy 17 (p17) is another biological variable whose
significance is unclear and incidence is dependent on how it
is defined. According to the ASCO/CAP guidelines, polysomy is when a tumor has increased HER2 and CEP17 signals with a ratio of -1.8 (8). Downs-Kelly et al. reported
that in their patient population using a definition of CEP17
of G2.1, )2.5 or )3 would correlate with a p17 incidence
of 35.4%, 17.7% and 8%, respectively. This same group
found in a cohort of HER2 non-amplified/p17 cases (defined
as a mean CEP17 of G2.1) that most of these cases are not
associated with HER2 mRNA or protein overexpression. In
addition, they noted no correlation with tumor size, ER/PR
status, grade or lymph node status, but they did identify a
correlation with p17 and women )50 years of age (ps0.02)
(35). The report by Perez et al. on associations between
tumor characteristics and disease-free survival in the N9831
adjuvant trastuzumab trial defines p17 as G3 CEP17 signals
in more than 30% of nuclei. They found that in patients with
HER2 amplification, p17 did not predict for trastuzumab
benefit (i.e., the benefit seen in patients with HER2 amplified
tumors was not significantly different between HER2 amplified/p17 and HER2 amplified/normal 17 (ps0.36)). However, they did observe that in HER2 positive patients treated
with chemotherapy alone, those with p17 seemed to benefit
more than those with normal 17, suggesting that polysomy
may have some prognostic value for those treated with chemotherapy (36).
Recent array CGH studies have shown that complete polysomy 17 is rare and that CEP17 copy numbers )3 in dual
colored FISH assays are actually due to gains/amplification
of the centromeric region in addition to HER2 (37–39) With
co-amplification, the HER2/CEP17 ratio may be normal
masking the fact that some of these are HER2 amplified
tumors. Therefore, several authors now recommend reporting
the average number of HER2 genes per nucleus in addition
to the HER2/CEP17 ratio in these complex cases (39, 40).
Further investigation is required to clarify the importance of
these findings and to reach consensus on reporting them.
(Trastuzumab for Gastric Cancer) phase III, international,
randomized controlled trial which were recently published.
This trial enrolled 594 patients with GC/GEJ with tumors
overexpressing HER2 protein by IHC or gene amplification
by FISH and they were randomized 1:1 into chemotherapy
alone vs. chemotherapy plus trastuzumab arms. The overall
survival was clinically significant (ps0.0046) in those
receiving trastuzumab (13.8 months at trial termination; one
year follow-up, 13.1 months) vs. those treated with chemotherapy only (11.1 months at trial termination; one year follow-up, 11.7 month) (43). The tumors were evaluated at a
central laboratory by IHC (HercepTest, Dako, Denmark) and
FISH (pharmDx, Dako). They found HER2 positivity rate of
22.1% with IHC/FISH concordance of 87.3%. They used
new IHC scoring criteria which are essentially modified
HercepTest criteria that were based on a study by Hofmann
et al. that suggested differences in the staining pattern in
gastric tumors vs. breast cancers thus necessitating the modified criteria (44). Patients were eligible for the trial if their
tumor samples were either IHC 3q or FISH positive with a
HER2:CEP17 ratio G2. The results of this trial are expected
to make significant impact on clinical practice. However, this
trial did not include patients from North America and there
is still no consensus on the optimal HER2 testing strategies
in patients with gastric cancer. It is not clear if the ASCO/
CAP guidelines created for breast cancer are applicable to
GC, or if what Hofmann et al. suggest, modified criteria are
necessary. At least one study evaluating HER2 testing within
a USA cohort suggests that the ASCO/CAP guidelines are
applicable to GC/GEJ carcinoma (45). However, additional
validation studies from North America are needed to help
address these questions.
In this era of personalized medicine, the development of
targeted therapeutics has had a major impact on the treatment
of cancer patients. Paired with this is the need for accurate
and clinically relevant companion diagnostics available in
clinical laboratories.
HER2 in other human cancers
Conflict of interest statement
HER2 overexpression or amplification has been reported in
many other tumor types including, ovarian, gastric, lung,
head and neck, prostate and bladder carcinoma. Tuefferd
et al. reported that in a multicenter series of 320 patients
with advanced ovarian cancer, 6.6% of tumors had HER2
overexpression and amplification (41). In a study of 1005
patients with invasive bladder carcinoma, 5.1% had HER2
amplification (42). Clearly, there is the possibility that
patients with other cancers besides breast cancer may benefit
from HER2 targeted therapies. This potential has been perhaps been best brought to fruition to date in gastric
carcinomas.
In October 2010, trastuzumab was approved by the FDA
for use in combination with cysplatin and either capecitabine
or 5-fluorouracil in patients with metastatic gastric or gastroesophageal junction cancer (GC/GEJ) who had not previously received treatment for metastatic disease. This
approval was granted following the results of the ToGA
Authors’ conflict of interest disclosure: The authors stated that
there are no conflicts of interest regarding the publication of this
article.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
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Q7:
Ref. 40 need
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Q8:
Please
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