HER-2 Overexpression in Gastric and Gastroaesophageal Cancer: A Different
Disease among Gastric Adenocarcinoma Subtypes
C Caglevic1, J Anabalon2, S Panay2, B Tudela3, C Gallardo4, M Mahave4 , V Hornig5 and J Gallard6
1 Department of Medical Oncology, Universidad del Desarrollo, Chile
2Department of Medical Oncolgy, Fundacion Arturo Lopez Perez, Chile
3 Radiotherapy Resident, Universidad de Valparaiso, Chile
4 Medical Oncologist, Fundación Arturo López Pérez, Chile
5 Medical Oncologist, Hospital Base San Jose Osorno, Chile
6 Medical Oncologist, Clinica Indisa, Chile
Submission: September 13, 2018; Published: October 09, 2018
*Corresponding author: Christian Caglevic, Medical Oncologist, Medical Oncology Service, Department of Medical Oncology, Clinica Alemana Santiago, Av. Vitacura 5951, Vitacura, Santiago, Chile, Email: firstname.lastname@example.orgemail@example.com
How to cite this article: C Caglevic, J Anabalon, S Panay, B Tudela, C Gallardo, M Mahave , V Hornig, J Gallard. HER-2 Overexpression in Gastric and
Gastroaesophageal Cancer: A Different Disease among Gastric Adenocarcinoma Subtypes. Adv Res Gastroentero Hepatol. 2018; 11(2): 555809.DOI: 10.19080/ARGH.2018.11.555809.
Gastric cancer and gastroesophageal junction adenocarcinoma is a common malignancy worldwide, in particular in Japan and in the Pacific coast of Latin America. Unless early diagnosis is performed, this disease carries a bad prognosis with a high mortality rate regardless of the use of standard treatments. A subgroup of this patients, probably close to a 20 percent, carry HER 2 mutations that result in HER 2 overepression. Targeted treatment to block HER 2 in the first line of treatment in the metastatic setting has resulted in positive outcomes when adding trastuzumab to standard chemotherapy, nonetheless no other HER 2 targeted treatments have reported benefit in this malignancy. Clinical trials are currently ongoing to evaluate the benefit of HER 2 blockade as perioperative treatment for patients that overexpress HER 2.
Gastric adenocarcinoma is currently one of the most frequent malignancies worldwide, becoming the fifth place in incidence and third place in mortality among solid tumors . The geographical distribution of this disease is variable, being most common in countries with worse water quality and deficient food storage .
In the Pacific coast of South America, mainly in countries like Chile and Peru, probably due to a high prevalence of pathogenic Helicobacter Pylori subtypes, gastric cancer is a serious public health problem that involves a higher mortality when compared with developed countries of North America and Europe . In high income countries, gastric cancer incidence has decreased during the last decades due to an important impact in environment that overlaps the genetic predisposition for this malignancy [4,5].
Despite its high frequency, gastric adenocarcinoma, unfortunately, is often diagnosed at late stages, when curative surgery cannot be performed due to the presence of unresectable tumors or to metastatic disease. First steps of this malignancy are often asymptomatic or give mild and non- specific symptoms such as abdominal discomfort, anemia, weight loss, anorexia and others, which can delay the correct and opportune diagnosis .
This issue has been well considered in countries such as Japan, where gastric cancer screening has become a powerful tool in order to improve early diagnosis providing real options of curative treatments and therefore diminishing mortality [7,8].
Regarding to non-metastatic locally advanced disease, different approaches to improve overall survival have been done. Despite that improving results have been achieved, several patients treated with a curative attempt will have disease recurrence and will die for this malignancy, including patients that underwent perioperative chemotherapy, post-operative radio-chemotherapy or adjuvant chemotherapy [9-11].
For metastatic gastric cancer the expected median overall survival is less than 1 year [12,13]. Since 1990´s decade clinical trials have shown overall survival benefit when palliative chemotherapy has been compared with best supportive care [13,14]. Combining different cytotoxic chemotherapy agents has shown improving results in overall survival and higher response rates when compared with single agent chemotherapy, however these results are modest and adding a third drug does not really improve results but increases toxicity [15-19].
By recent years, thanks to a better comprehension of the
molecular heterogeneity and of the pathways that are involved in
gastric carcinogenesis, research has focused in new approaches
such as targeted therapy . Human Epidermal Growth Factor
Receptor 2 (HER 2), also known as Cerb-2 o ERBB2, is a protooncogene
located in chromosome 17 q21 that codes for this
transmembrane protein that enhances a tyrosine kinase activity,
conducting cell growth and differentiation . HER 2 is an
independent ligand that can be activated by mutations or due to
overexpression of the receptor . First discovered in breast
cancer tumors, HER 2 mutations were found to have a worse
prognosis of the disease when compared with patients that not
carried such mutations [22,23]. Slamon et al.  shown that
trastuzumab, a humanized IgG1 monoclonal antibody, when
added to adjuvant chemotherapy regimen (doxorubicin plus
cyclophosphamide follow by docetaxel), in Her 2 overexpressed
patients, had an enormous impact in overall survival when
comparing the chemotherapy regimen without adding the
monoclonal antibody (HR 0.63; p<0.001) and also the arm that
received trastuzumab had benefit in disease free survival (HR 0.64;
p<0,001) when compared with the control arm. Positive results
were also achieved in HER 2 overexpressed breast cancer patients
that underwent neoadjuvant treatment , and in metastatic
disease when adding trastuzumab to chemotherapy or when
including a double anti HER 2 blockade using also pertuzumab,
other antibody that targets HER 2 overexpressed tumors [26,27].
Since recently, HER 2 mutations have been identified in several
other solid tumors including ovarian cancer, prostatic cancer, lung
cancer, colorectal cancer, gastric and gastroesophageal cancer as
Among gastric and gastroesophageal junction cancer patients,
HER 2 overexpression has been found in different proportions
depending of reports, therefore this incidence fluctuates between
4 to 53%, with a median of incidence of 17,9% [28-30]. In Chile,
where gastric cancer is a highly prevalent malignancy, HER 2
overexpression has been reported in the 11.9% of the patients.
These findings have been reported mainly in the intestinal variety
of adenocarcinoma but not in diffuse subtype patients .
Looking forward improving survival in metastatic gastric
cancer patients that overexpress HER 2, clinical trials have been
ToGA Trial was a phase III clinical trial for the first line of
treatment of advanced gastric and gastroesophageal junction
adenocarcinomas (unresectable locally advanced, recurrent and
metastatic), restricted to patients with HER 2 overexpression
in their tumors, that compared chemotherapy combination
(fluoropyrimidine and cisplatin doublet) with or without adding
trastuzumab . This was a multicenter, open-label, randomized
trial. From a total of 3807 patients that consented for participating
in this study, only 810 overexpressed HER 2 (22%), and finally a total
of 584 patients from Asia, America and Europe, with measurable
and non-measurable disease were randomized and treated. HER 2
expression of the tumors was assessed using different criteria as
used for breast carcinoma, based on a different staining pattern
of immunohistochemistry, which was also validated with FISH by
Hofmann, including patients with HER 2 +++ in IHC or based on
HER2:CEP17 ratio of at least 2 or greater .
Its primary endpoint was overall survival, showing a
statistically and clinically relevant difference, with a mean overall
survival of 13.8 months (95% CI: 12-16) in those patients who
received chemotherapy plus trastuzumab combination and
11.1 months (95% CI: 12-16) in those patients who received
chemotherapy without the monoclonal antibody, with a hazard
ratio of 0.74 (95% CI; 0.6-0.91 p=0.046). Secondary endpoints
such as progression free survival, time to progression, duration
of response and overall response rate were also higher in the
trastuzumab plus chemotherapy combination group when
compared with the control arm. In a post-hoc analysis, the effect
on overall survival was greater on patients with higher levels of
HER-2 expression (IHC 3+, IHC 2+ and FISH positive), achieving a
median overall survival of 16 months versus 11 months in those
with lower HER-2 expression (HER 2 1+- HER 2 negatives but
FISH +). There were no differences in adverse effects between the
control arm and study treatment arm, except for grade 3 infusion
reactions that were higher in the trastuzumab group.
After these findings, the predictive value of HER 2 level was
explored by Gomez-Martin and cols., by studying 90 patients
with advanced gastric adenocarcinoma in the first-line treatment
including trastuzumab, with regards of the HER2/CEP17 ratio
and HER2 gene copies number (GCN), calculating a HER2/CEP17
ratio of 4.7 and GCN of 9.4 as the optimal cutoff levels for defining
sensitivity to trastuzumab .
From a pharmacological point of view, there were differences
in the calculated plasmatic clearance of trastuzumab between
patients with HER-2 positive breast and gastric cancer, being
higher on the latter, suggesting that a higher dose of trastuzumab
would be more effective. This question was explored on a phase
3btrial (HELOISE, Hoffmann-La Roche) in the first line of treatment
for gastric and gastroesophageal metastatic patients with HER
2 overexpression, that compared standard chemotherapy with
two different doses of trastuzumab (loading dose of 8 mg/kg for
both groups followed by 6 mg/kg intravenously every 3 weeks for
control arm or 10 mg/kg intravenously every 3 weeks for the study
arm). This trial was terminated because of futility demonstrated
on a preplanned interim analysis .
Assuming the positive results previously achieved with trastuzumab,
other strategies to block the HER 2 pathway were studied.
The use of lapatinib, a small-molecule tyrosine kinase dual
inhibitor of EGFR and HER 2, was explored in the phase III TRIO-
013/LOGiC trial, that compared chemotherapy (capecitabine plus
oxaliplatin) with or without lapatinib in untreated patients with
advanced or metastatic gastric, esophageal or gastroesophageal
adenocarcinoma with HER 2-amplification assessed by FISH or, if
not available, by immunohistochemistry (IHC 3+). Unfortunately,
this trial failed to show benefit in overall survival and in progression free survival when adding lapatinib in the study population.
Nevertheless, in a preplanned subgroup analysis, the trial showed
increased overall survival in Asiatic and in 60 years old or younger
patients. Toxicity was higher in the lapatinib arm, principally more
diarrhea grade 3 and higher was reported .
Looking forward enhancing HER 2 blockade, currently there
is an ongoing phase III trial, JACOB, that compares the same
study arm treatment used in ToGA trial (5FU or capecitabine,
cisplatin and trastuzumab) with the addition of pertuzumab as
a first line treatment for metastatic gastric and gastroesophageal
gastric cancer that overexpresses HER 2. The primay end point
of this study is to evaluate overall survival. Results have not been
published yet .
Considering the positive results of the ToGA trial, the next
question to address is to evaluate if the addition of HER-2 targeted
therapy in the perioperative setting can improve the outcomes
in resectable - HER2 overexpressed gastric adenocarcinoma
or allowing that unresectable disease to become potentially
resectable in case of response. To answer this issue currently there
are two ongoing clinical trials. INNOVATION trial is a randomized
phase II collaborative study between EORTC and the Korean
Cancer Study Group, comparing perioperative chemotherapy with
fluoropyrimidine, cisplatin and trastuzumab, with or without
the use of pertuzumab. Its primary endpoint is to evaluate and
compare pathological complete response among study arms .
The other study, TRIGGER trial, is a randomized phase II trial, that
compared perioperative chemotherapy with S-1 and cisplatin,
with or without trastuzumab. Its primary endpoint is overall
Despite that there is not data yet the supports the use of HER
2 blockade in the perioperative setting, case reports have been
published, most of them from Asiatic patients and centers [40-47]
The role of HER2 blockade in the metastatic second-line
treatment scenario has been explored using two different agents:
lapatinib, an oral tyrosine-kinase inhibitor of HER-1 and HER-2
intracellular domains, and ado-trastuzumab-emtansine (TDM-1),
a monoclonal antibody conjugated of trastuzumab and emtansine,
a cytotoxic microtubule binding agent. Both have shown activity
on HER2 positive breast cancer beyond the first line of treatment
in metastatic disease [48-52].
The TyTAN trial was an open-label multicenter phase III
trial, including Asiatic patients, who had progressed after prior
chemotherapy. It compared weekly paclitaxel with paclitaxel plus
lapatinib. There was no difference on overall survival, progression
free survival or time to progression, showing effect only on
overall response rate, which is of little clinical significance. In a
subgroup analysis, there was benefit on overall survival in the
IHC 3+ subgroup (median overall survival 5.6m vs 4.2m; HR, 0.59;
95% CI, 0.37 to 0.93; P 0.0176) and in Chinese population, when
compared with Japanese, in median overall survival (9.7 m v 7.6
months; P 0.0351) and median progression free survival (7.2m v
4.7 months ;P 0.0077) .
The GATSBY trial was an open-label phase 2-3 international
multicenter study, that included advanced HER-2 positive gastric
cancer who had progressed after a first-line therapy. It compared
TDM-1 with taxane monotherapy (paclitaxel or docetaxel).
The primary end point was overall survival with no significant
differences between arms .
Both TyTAN and GATSBY raise the question about the different
role of HER-2 in the gastric adenocarcinoma biology, in contrast to
breast cancer, where sequential and/or additive blockade of HER-
2 signaling have some efficacy.
Gastric and gastroesophageal adenocarcinoma is a frequent
malignancy that has an intrinsic bad prognosis unless its diagnosis
was done in very early stages. HER 2 overexpression in tumor cells
represent a worse prognosis, nevertheless blocking HER 2 has
been demonstrated to be useful in the metastatic setting.
As an example, here, we report the case of a 65 years old
man that in 2014 consulted due to dysphagia and loss of weight.
Upper endoscopy found a subcardial tumor with compromise
of the gastroesophageal junction. Its biopsy reported a gastric
adenocarcinoma moderately differentiated. Baseline PET CT
demonstrated multiple widespread disease beyond the primary
tumor, metastasis was shown in lymph nodes, adrenal, lungs, liver
and in several bones. After palliative radiotherapy to bone lesions
to diminish bone pain, cytotoxic chemotherapy with FOLFOX
regimen was started by June 2014. During cycle 4 of this regimen
HER 2 was informed by IHC as highly overexpressed, then after
trastuzumab was added with a loading dose of 8 mg/kg followed
by 4 mg/kg every two weeks. After cycle number 22 of FOLFOX
due to periferic neuropathy regimen was changed to 5FU/
Leucovorin plus trastuzumab every two weeks. After completing
a total of 35 cycles of chemotherapy (including both FOLFOX and
5FU/LV regimens) and after achieving complete response patient
has undergone continue treatment with trastuzumab 6 mg/kg
every 3 weeks maintaining complete response. By date 62 cycles
of trastuzumab have been administered without toxicity and with
evident benefit (radiological and quality of life) (Figure 1).
This case is an example because molecular profile, specifically
HER 2, should be always be considered in the study of metastatic
and or unresectable gastric cancer patients, and the use of trastuzumab
in these cases should be mandatory unless contraindicated.
Despite the positive results of other HER 2 targeted treatment
in the metastatic setting of breast cancer, no other targeted HER 2
blockades has shown real efficacy in gastric or gastroesophageal
adenocarcinoma with HER 2 overexpression.
Clinical trials that are currently ongoing probably will answer
if adding HER 2 blockades to perioperative and postoperative
treatment in HER 2 overexpressed gastric and gastroesophageal
junction adenocarcinomas will improve overall survival of these
Authors have not received funds neither any type of sponsorship
and have not any conflict of interest regarding this manuscript.
Dr C. Caglevic discloses: Speaker: BMS – MSD- Boehringer Ingelheim – Tecnofarma- ROCHE. Advisory and Consulting: BMS
- MSD– Boehringer Ingelheim – Lilly – Astra Zeneca – Bayer. Investigator:
MSD – BMS – Boehringer Ingelheim – Bayer- Roche- Astra
Zeneca – Astellas- Advaxis. Travelling and educational grants:
MSD – Boehringer Ingelheim, Dr C. Gallardo discloses: Travelling
grants: MSD- Roche – Novartis – Eli Lilly. Advisory board: Eli Lilly