Diagnostics
Developing Pharmacodiagnostics* for
HER2-Positive Gastric Cancer
Jan Trøst Jørgensen, MScPharm, PhD
Director, Dx-Rx Institute External Lecturer, Department of Pharmacology and
Baunevaenget 76 Pharmacotherapy, Faculty of Pharmaceutical Sciences
DK-3480 Fredensborg, Denmark University of Copenhagen, Denmark
D etermination of the HER2 status
serves as an important predictive test
for treatment with HER2 inhibitors in breast
over-expression of the HER2 protein,
measured by immunohistochemistry (IHC),
and amplification of the HER2 gene, measured
variation in the incidence of the disease, which
to some extent has shown to be higher in the
developing countries (14). Gastric cancer is
cancer, such as the monoclonal antibody by fluorescence in situ hybridization (FISH) found more often in men than women with
trastuzumab (Herceptin®, Genentech/Roche) and chromogenic in situ hybridization(CISH) a distribution rate of approximately 2 to 1.
and the tyrosine kinase inhibitor lapatinib (1, 2). Amplifications and/or over-expression Despite some advances in the prevention and
(Tykerb®, GSK) (1, 2). The relationship between of HER2 have been reported in malignancies treatment of the disease, the 5-year survival
HER2-positivity and a positive outcome, other than breast cancer, such as ovarian, in most parts of the world still remains around
when treating with HER2 inhibitors, has been prostate, colorectal, pancreatic and 20%. Although the incidence of gastric cancer
demonstrated in a number of studies (3, 4, 5). gastric cancers (7-11). Gastric cancer, is declining, the prognosis for the disease
The HER2 protein is a 185-kDa transmembrane especially, has attracted attention recently remains poor (15). The poor survival rate is
tyrosine kinase receptor and a member of due to the encouraging results from the mainly explained by the advanced stage
the epidermal growth factor receptor (EGFR) ToGA (trastuzumab with chemotherapy of the disease at the time of diagnosis. If
family. Over-expression of HER2 has been in HER2-positive advanced Gastric screening for gastric cancer was performed
found to promote tumorigenesis and to be Cancer) trial. In this multicenter phase as is the standard practice in Japan, the
involved in the pathogenesis of several human III study HER2-positive patients with tumors could be detected at an earlier stage
cancers (6). The gene that codes for the HER2 advanced gastroesophageal and gastric and thus surgical resection performed.
protein is located on chromosome 17 and has adenocarcinoma were randomized to receive Surgical resection has shown to increase the
been found to be amplified with an increased chemotherapy, or chemotherapy plus 5-year survival to above 50% (15).
copy number in about 20-25% of women with trastuzumab (12).
breast cancer (1). Over-expression of HER2 So far, treatment of advanced gastric
and amplification of the HER2 gene in breast Gastric cancer is a major global health cancer has been palliative, and no real
cancer has been associated with a poor problem. Recent data indicates that consensuses exist in relation to the modalities
prognosis in this disease (1). 1.4 million new cases of gastroesophageal used. Various chemotherapy combination
and gastric cancer are diagnosed annually, have been tried, and it seems that the
A number of slide-based assays are and 1.1 million deaths are attributed to the combination of 5-FU/capecitabine (Xeloda®,
available for the detection of both diseases (13). There is a marked geographic Roche) and cisplatin or oxaliplatin, either
*The word “pharmacoDiagnostic®” is a registered trademark of Dako. The word has been used to describe a “pre-treatment measurement performed to aid in the
assessment of whether a patient is likely to respond to a given therapy”.
40 | Connection 2010
Figure 1. Adenocarcinoma of the stomach
stained with HercepTest™ (Dako), 3+ staining
(20×).
Figure 2. Adenocarcinoma of the stomach
stained with HER2 FISH pharmDx™ Kit (Dako),
HER2 gene amplification (HER2/CEN-17
≥2.0) (40×).
Connection 2010 | 41
Reference Type of Assay N HER2-Positive Rate
ToGA Trial (22) IHC/FISH 3,667 22.1%
Review publication (21) IHC 6,542 19.0%
Review publication (21) FISH/CISH 869 19.4%
Table 1. HER2-Positive Rate in Gastric Cancer.
alone or in combination with a third drug cancer were first described in 1986 (19, 21), calculated, the percentage of patients with
such as epirubicin (Pharmorubicin®, Pfizer) and since then a number of studies have amplification was 19.4% (21). Examples
or docetaxel (Taxotere®, Sanofi-Aventis), are confirmed these findings. In a recent review of adenocarcinoma of the stomach
the most effective combinations. In a recent publication, data on over-expression of the with over-expression of the HER2 protein
phase III study 457 patients with advanced HER2 protein from 6,542 patients comprising (IHC 3+) and amplification of the HER2 gene
gastric cancer were randomized to receive 24 independent studies were listed (21). A (HER2/CEN-17 ≥2.0) are shown in Figures 1
docetaxel, cisplatin, and 5-FU or cisplatin and rather large variation between the individual and 2, respectively.
5-FU, and the median overall survival were studies regarding the percentage of patients
9.2 months and 8.6 months, respectively (14). with HER2-positive tumors was seen From the recent ToGA trial tumor samples
Similarly in another study, 507 patients with (range 8.2-53.4%). The explanation of this from 3,667 gastric cancer patients were
advanced esophageal or gastric cancer were is presumably multifactorial, such as the successfully screened with respect to HER2
randomized to receive epirubicin, cisplatin, differences in the populations studied, but status, which is by far the largest population
and 5-FU or epirubicin, oxaliplatin, and the most important aspects are probably published until now. In this study both
capecitabine. Here the overall survival was the use of non-standardized assays and the HER2 gene amplification by FISH (HER2
marginally higher, namely 9.6 months and application of different scoring criteria for the FISH pharmDx™, Dako) and HER2 protein
11.2 months, respectively (17). With a median stained slides. When a weighted mean for the over-expression by IHC (HercepTest™,
overall survival of 8-11 months, the medical 24 studies was calculated, the percentage Dako) were measured in all patients during
needs for new effective treatment modalities of patients with HER2-positive tumors was the screening phase (22). The results from
in advanced gastric cancer are obviously 19.0%. A number of these studies also the screening part of the study showed
high. The use of the principles of stratified reported that HER2 protein over-expression that 22.1% of the patients with advanced
medicine where predictive biomarkers was associated with a poor prognosis of gastric cancer were HER2-positive either by
are combined with targeted drugs is an the disease (21). FISH or IHC (22, 23). When looking at the
approach that will probably lead to a more European and the Asian patient populations
effective treatment of patients with advanced A somewhat smaller number of studies no difference could be detected with regard
gastric cancer as has been demonstrated have investigated the amplification of the to the HER2-positivity rate. As previously
in breast cancer (2, 18). In this brief HER2 gene in patients with gastric cancer observed, the number of HER2-positive
review the background for, and the clinical measured either by FISH or CISH, and these patients were shown to be higher when the
development of, pharmacodiagnostics/ studies comprise data from a total of 869 cancer was localized to the gastroesophageal
companiondiagnostics for HER2-positive patients (21). Some variation with regard to the junction compared to when the cancer
gastroesophageal and gastric cancer will percentage of patients with amplification of was localized to the stomach (24). When
be discussed. the HER2 gene (16.0-27.1%) is seen, though the tumors were classified according to
the magnitude is much smaller than seen for the Laurén classification the intestinal type
IHC. This may be explained by the fact that showed a higher HER2-positive rate than the
The HER2 Status in Patients with the FISH and CISH assays are quantitative diffuse or mixed type (23). The HER2 results
Gastric Cancer methods compared to IHC, which use a from the ToGA trial should be regarded as
Amplification of the HER2 gene and semi-quantitative scoring system. When reliable due to the fact that the analysis were
over-expression of the HER2 protein in gastric a weighted mean for the 5 studies was performed at one single central laboratory
42 | Connection 2010
using standardized HER2 IHC and FISH
assays (25). Table 1 compares the findings
of IHC and FISH for the HER2-positive rate of
testing FISH positive was almost as high
as IHC 2+/FISH positive samples (23% vs.
26%)” (23). As indicated in the abstract this
“…HER2 has shown its
importance as target in the
gastric cancer from the ToGA trial using the is different from what has been observed
data from a recent review article (21). in breast cancer, where the best assays treatment of cancer and paves
For approximately half of the studies reported
show a concordance around 95% (30). The
population with IHC 0/1+ and FISH+ tumors
the way for a new treatment
in the literature on the HER2 status, either comprised 131 patients, which corresponded modality in patients with
”
over-expression or amplification provides to approximately 23% of the 584 patients
prognostic information (21). This is also in enrolled in the ToGA trial (12). unresectable gastric cancer.
line with what is known from breast cancer.
A recent meta-analysis, based on data At the European Cancer Organization
from 39,730 patients, showed an overall (ECCO 15)/ European Society for Medical
HER2-positive rate of 22.2% and a mean Oncology (ESMO 34) meeting in Berlin in inhibitory effect of the HER2 inhibition was
relative risk for overall survival (OS) of 2.74 (1). September 2009 an abstract/poster about demonstrated in vitro on the cultured human
the HER2 testing in the ToGA trial was gastric tumor cell line NCI-N87, and in vivo
A few studies have investigated the presented (22). This poster provided a when the same cell line was growing as
relationship between HER2 amplification more detailed explanation of how the high xenografts in nude mice (31). Subsequently,
and HER2 over-expression in gastric cancer concordance was reached despite the these studies have been repeated with
patients using FISH and IHC, and from these relative large patient population with IHC 0/1+ both trastuzumab and lapatinib using the
studies the concordance between the two and FISH+ tumors in the ToGA trial. It was NCI-N87 cell line as well as other
assays seems to be relatively high, ranging here reported that the concordance between HER2-positive gastric tumor cell lines, such as
from 86.9% to 96.4% (25, 26, 27). The results IHC and FISH was calculated based on SMU-216, 4-1ST, and MKN-45P (24, 32-35).
from these studies seem to indicate that an the screening population and not the study In these different preclinical studies
amplification of the HER2 gene results in an population. From the poster it also appeared trastuzumab and lapatinib have shown to
over-expression of the HER2 protein as is that 190 out of the 3,667 successfully tested be effective both as single agents as well as
known from breast cancer (28, 29, 30). patients had tumors that were IHC 0/1+ and in combination with the chemotherapeutic
FISH+ (22). Based on this recent data it may agents that are widely used for the treatment
Most of the studies that have investigated be concluded that the concordance between of gastric cancer, such as 5-FU, capecitabine
the relationship between HER2 amplification IHC and FISH, for the patients screened (Xeloda®, Roche), irinotecan (Camptosar®,
and HER2 over-expression in gastric cancer for the ToGA trial, is in line with what has Pfizer), cisplatin, paclitaxel (Taxol®, Bristol
are relatively small, at least compared to the previously been reported from other studies Myers Squibb), etc. In one of the in vivo
screening population from the ToGA trial that in gastric cancer (25, 26, 27), and what is studies the three-drug combination of
consists of 3,667 successfully tested patients. known from breast cancer (28, 29, 30). capecitabine, cisplatin and trastuzumab
If we look at the results available so far, the showed a remarkable tumor growth inhibitory
relationship between the gene and the protein effect in the NCI-N87 tumor xenograft model
does not seem to be so unambiguous as the Preclinical Studies (34). In fact, this drug combination is the one
results from the studies described above. In Based on the observations of over-expression that was used later in the ToGA trial, and
the abstract from the ASCO 2009 meeting it and amplification of HER2 in gastric cancer proved effective in patients with advanced
was stated that the concordance between tumors and the experiences from breast cancer gastric cancer (12). Based on these results
IHC and FISH was 87.5% (23), which is in studies, it seems rational to test the hypothesis from epidemiological studies with regard to
line with what has been reported from other of an antitumor effect of HER2 inhibition in the frequency of HER2-positivity and the
studies. However, in the abstract it has also preclinical tumor models. The first in vitro preclinical in vitro and in vivo studies, the
been mentioned that “In breast cancer most and in vivo studies were conducted in 1992 scientific rationale for initiating clinical trials
IHC 0/1+ samples are FISH negative, but in using a combination of two monoclonal with trastuzumab in HER2-positive gastric
ToGA, the frequency of IHC 0/1+ samples anti-HER2-specific antibodies. A growth cancer seem to have been well substantiated.
Connection 2010 | 43
The ToGA Trial safety and efficacy of trastuzumab combined to HER2 status showed that the survival
Except for the data from the ToGA trial, clinical with standard chemotherapy, and secondly, it benefit provided by trastuzumab seems to
documentation for the use of trastuzumab in demonstrated the predictive characteristics be dependent on the level of HER2 protein
gastric cancer patients is relatively modest. A of the HER2 IHC and FISH tests used in over-expression. The single group of patients
few case studies have been published in 2005 the study. with the greatest survival benefit was the
and 2006 where trastuzumab in combination one with a HER2 test result of IHC 3+. Here
with chemotherapy (5-FU/capecitabine For the primary endpoint the combination the median OS increased to 17.9 months for
and docetaxel) was successfully given to a of chemotherapy plus trastuzumab showed the group treated with the combination of
few patients (36, 37). Further, abstracts on to be statistically superior to chemotherapy trastuzumab and chemotherapy. The hazard
ongoing pilot/phase II studies have been alone. The median OS increased from 11.1 to ratio for this group of patients was 0.58
presented where trastuzumab is given 13.8 months (p=0.0046) with a hazard ratio (95% CI: 0.41-0.81) (12). The results of the
either as monotherapy or in combination of 0.74 (95% CI: 0.60-0.91). The secondary subgroup analysis for the different IHC scores
chemotherapy (cisplatin, docetaxel), but no endpoints, both ORR and PFS, also showed are shown in Figure 3.
final results from these studies have been superiority in favor of the combined treatment
reported yet (38-40). with chemotherapy and trastuzumab (12). Based on the information from the
A subgroup analysis performed looking subgroup analysis, an explorative analysis
The ToGA trial is, so far, the only well-controlled at the effect of the combined treatment of was performed on a sub-population of the
published study with a HER2 inhibitor in trastuzumab plus chemotherapy, with respect originally included patients. This population
advanced gastric cancer. The study was
conducted in 24 countries, which included the
following parts of the world: Asia, Australia,
Europe, Central and South America, and
20
South Africa (12). The trial was designed as OS (Months)
an open labeled, randomized multicenter 18
phase III study in HER2-positive patients
with advanced gastroesophageal and gastric 16
adenocarcinoma. HER2-positivity was defined
as being either IHC positive (3+) or positive 14
by HER2 FISH (HER2/CEN-17 ≥2.0). The IHC
testing was performed using the HercepTest™ 12
(Dako) with slightly modified scoring criteria
as described in the publication by Hofmann, 10
C
et al. (25). The FISH testing was performed
using the HER2 FISH pharmDx™ Kit (Dako). 8 C+T
After enrollment in the study the patients were
6
randomized to receive chemotherapy (5-FU or
capecitabine and cisplatin) or chemotherapy
4
plus trastuzumab. In total, 584 patients
were randomized. Trastuzumab was given
2
as a loading dose of 8 mg/kg followed by
6 mg/kg every third week until progression of 0
the disease. The primary endpoint in the study
IHC0/FISH+ IHC1+/FISH+ IHC2+/FISH+ IHC3+/FISH+
was overall survival (OS), and the secondary (n=61) (n=70) (n=159) (n=256)
endpoints included, among others, overall
response rate (ORR) and progression free
survival (PFS) (12). The aim of the ToGA trial Figure 3. Median Overall Survival (OS) in months for the four individual HER2 IHC scores for two treatment
served two purposes; firstly, it showed the groups; namely the chemotherapy group (C) and the chemotherapy plus trastuzumab group (C+T) (12).
44 | Connection 2010
comprised the patients who were IHC 3+ than normally observed in breast cancer. Conclusion
positive or IHC 2+ positive and FISH positive. A A relatively high number of HER2 FISH The data from the ToGA trial should be
total of 446 patients fulfilled these criteria, and positive cases were found among the IHC 0 considered encouraging and a major step
the median OS for the group of patients who and IHC 1+ tumors (22, 23). forward in the treatment of advanced gastric
had received chemotherapy plus trastuzumab cancer. Again, HER2 has shown its importance
increased to 16.0 months compared to 11.8 In December 2009, the European as target in the treatment of cancer and
months for the patients on chemotherapy Medicines Agency’s (EMEA) Committee paves the way for a new treatment modality
alone. The hazard ratio for this analysis on Human Medicinal Products (CHMP) in patients with unresectable gastric cancer.
was 0.65 (95% CI: 0.51-0.83). The median gave a positive opinion for extending the Hopefully, this will open up for a development
follow-up for all the patients in the ToGA trial indication of Herceptin ®, Genentech/ parallel to what has been seen in breast cancer
was reported to be 17.1 months (12). Roche to include treatment of patients with treatment where the principles of stratified
HER2-positive metastatic adenocarcinoma of medicine have been practiced for years (42).
Concerning the predictive properties of the the stomach or gastro-esophageal junction The key driver in a more individualized and
two HER2 assays, both the subgroup and based on the results from the ToGA trial. effective cancer treatment, including gastric
the explorative analysis showed that the IHC With respect to the treatment selection, the cancer, is molecular diagnostics, and we
test should be used as the primary test CHMP stated in the “approval letter” that will hopefully see an increasing number of
for selection of patients for treatment with Herceptin® should only be used in patients drug-diagnostic combinations being
trastuzumab. As shown in Figure 3, the effect with metastatic gastric cancer whose tumors introduced in the years to come (18, 43).
of trastuzumab seems to be dependent on have HER2 over-expression as defined by Based on the encouraging results from the
the degree of over-expression of the HER2 IHC 2+ and a confirmatory FISH+ result, or ToGA trial, it is now expected that routine
protein, with the best median OS in the group IHC 3+ as determined by an accurate and HER2 testing of all patients with advanced
of patients that were IHC 3+. Further, when validated assay (41). This again emphasizes gastric cancer will be performed worldwide.
looking at the HER2 test results from the ToGA the fact that IHC should be regarded as the
trial only, but not the screening population, the “primary” test for the selection of gastric
agreement between over-expression of the cancer patients who may be considered
HER2 protein and amplification of the gene is potential candidates for treatment with
found to be somewhat lower in gastric cancer trastuzumab.
Glossary 3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of 10. Safran H, Steinhoff M, Mangray S, et al.
chemotherapy plus a monoclonal antibody against HER2 Over-expression of the HER2/neu oncogene in
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