METHODS
We retrospectively analyzed the records of 49 gastric cancer patients treated with curative intent between
April 2012 and January 2017; we also assessed the impact of HER2 status on prognosis and treatment
outcomes.
RESULTS
During a median follow-up period of 14.6 months (range, 4.0?56.97 months), two patients (4%) had local
recurrence and 21 patients (43%) developed distant metastasis. We found no statistically significant difference
in metastasis frequency rates between HER2 negative (?) and positive (+) patients. The median
overall survival (OS) and disease-free survival (DFS) for the whole group were 24.9 and 24.2 months,
respectively. Although there was no significant difference in OS and DFS according to HER2 status, there
was a negative trend in OS (p=0.451) and DFS (p=0.633) in HER2 (+) patients.
CONCLUSION
Although our study did not demonstrate any statistically significant importance of HER2 status in gastric
cancer patients treated with postoperative chemoradiotherapy, the median OS of 13 months in HER2
(+) patients and 24.9 months for HER2 (?) patients warranted randomized trials with larger cohorts.
Keywords: Chemoradiotherapy; gastric cancer; HER2; radiotherapy
Targeted therapies are commonly used for other
cancer types such as breast cancer.[
In this study, we retrospectively analyzed gastric
cancer patients treated with postoperative chemoradiotherapy.
We divided patients into two groups according
to their HER2 status to determine whether HER2 positivity
has any prognostic or predictive importance in
these patients both for local control and survival.
All patients underwent routine initial clinical staging before operation, including a detailed physical examination, endoscopic examination, complete blood count, blood chemistry test, and computerized tomography of the abdomen. We staged the patients according to the American Joint Committee on Cancer 7th Edition 2010.
The patients were treated according to the clinical protocol described in the INT-0116 trial. Chemotherapy regimen consisted of 5-fluorouracil (425 mg/ m2 per day) and leucovorin (20 mg/m2 per day) or Capecitabine (825 mg/m2, B.I.D, per day) administered for five days. After the first cycle of chemotherapy, patients were treated with a combination of 3-dimensional conformal or intensity-modulated external beam radiotherapy. Clinical tumor volume included the tumor bed, regional lymph nodes, and safety margins for planning the tumor volume. A total dose of 45 Gy (1.8 Gy per fraction, per day) was delivered using 18 MV photons for five days. Nine patients (16%) were treated with radiation up to 50.4 Gy because of positive surgical margins. The second and third cycles of chemotherapy were administered along with radiotherapy. After radiotherapy, patients were treated with two cycles of adjuvant chemotherapy in the same regimen.
HER2 Analysis
Tissue specimens were evaluated using immunohistochemistry
or FISH, where appropriate, for HER2 gene
amplification status. In FISH assay, average HER2 gene
copy numbers and average chromosome 17 centromeres
were evaluated by counting the numbers of signals
for at least 50 interphases. The ASCO/CAP scoring
criteria was used: ratios<1.8 or HER2 signals<4 were
reported as non-amplified; ratios of 1.8?2.2 or HER2
signals between 4 and 6 were reported as borderline
amplification; and ratios>2.2 or HER2 signals>6 were
reported as amplified.
Clinical Follow-up
The clinical follow-up of patients was performed every
three months for two years and every six months after
two years up to five years. Recurrence or metastasis
was defined as biopsy-proven recurrence or documentation
of disease progression on serial imaging studies.
Failure patterns were described in two main groups as
local recurrence or distant metastasis.
Statistical analysis
The time to event was calculated as the time interval
from the date of surgery to the date of the first finding
on clinical or imaging examination that suggested
disease recurrence. Overall survival (OS) and diseasefree
survival (DFS) were calculated using the Kaplan?
Meier method. The survival curves of subgroups were
compared using two-sided log-rank tests. All p values
were two-tailed, and p<0.05 was considered statistically
significant.
Local Recurrences and Distant Metastasis
During a median follow-up period of 14.6 (range, 4.0?
56.97) months, two patients (4%) had local recurrence
and 21 patients (43%) developed distant metastasis.
Local recurrence was observed in two patients (4%) in
the HER2 (?) group, but not in the HER2 (+) group.
We could not perform statistical analysis between the groups for local recurrence rates due to low event rates. Distant metastasis was observed in 17 patients (35%) with HER2 (?) and four patients (8%) with HER2 (+). There was no statistically significant difference in metastasis frequency rates.
Survival
The median OS and DFS for the whole group were 24.9
(12.9?36.9) months and 24.2 months, respectively. The
median OS for HER2 (?) and (+) patients were 24.9
(range, 19.2?30.7) months and 13.0 (range, 5.0?21.0)
months, respectively. Although HER2 (?) patients had
a numerically better median OS, this difference did not
have statistical significance (p=0.451). There was also
no statistically significant difference in DFS between
HER2 (+) and (?) patients (p=0.633; Fig.
In univariate analysis, gender (male vs. female), Tstage (T1-2 vs. T3-4), and surgery (total vs. subtotal) did not show any significant difference for both OS and DFS. N-stage (N0-1 vs. N2-3) was predictive for DFS (p=0.005), and dissection status (D1 vs. D2) was statistically significantly favoring D2 for OS (p=0.038).
In the era of molecular oncology, targeted therapies
have become more interesting. One of these therapies
is trastuzumab, which is an anti-HER2 monoclonal antibody.[
In our study, the incidence of HER2 positivity was
16%. Although our cohort was relatively small and
could not represent the whole population, the incidence
was consistent with results of previous studies.
Moreover, adenocarcinoma was the only histology in
the HER2 (+) patients, and majority of the patients
were male. We did not acquire any data about male
predominance or adenocarcinoma histology association
with HER2 (+) gastric cancer. Therefore, it is hard
to say whether these findings are incidental or related
to the disease.
A similar study, the INT-0116 clinical trial, retrospectively
focused on the available tissue specimens for
HER2 gene amplification and investigated the relation
between HER2 expression and outcomes. They concluded
that there was a significant interaction between
HER2 amplification and treatment with respect to both
DFS (p=0.020) and OS (p=0.034). Patients whose tumors
had HER2 gene amplification had shorter DFS
and OS (13 and 16 months, respectively) compared
with the patients whose tumors lacked HER2 gene amplification
(34 and 44 months; p=0.026 and 0.025, respectively).
The analysis of HER2 (+) patients indicated
no significant difference between treatment regimens.
Here the absence of benefit from adjuvant chemoradiotherapy
should be interpreted with caution in view of
the small patient sample [28 HER2 (+) patients]. The
same study found no significant difference in OS or
DFS based on HER2 amplification status among patients
who only underwent surgery. Therefore, they
concluded that HER2 may not be an insufficient prognostic
marker of poor outcome in the absence of treatment.[
18]
The MAGIC trial evaluated 415 specimens for
HER2 status. The systemic treatment regimen consisted
of anthracycline-based chemotherapy. HER2 status
was not a prognostic factor in this study and did not
have any predictive value for screening the treatment
response to anthracycline-based chemotherapy.[19]
Likewise, the ACTS-GC study did not demonstrate
any influence of HER2 expression/amplification on the
prognosis of gastric cancer patients.[
A systematic analysis of data from Danish literature
performed with 42 publications and over 12000
patients concluded that HER2 had a potential role as
a negative prognostic factor in gastric cancer. In addition,
they reported that HER2 overexpression and/or
amplification may be a molecular abnormality linked
to this disease development.[
In addition to the abovementioned studies, Li et
al.[
Our study has some limitations. First, as with any
retrospective study, unpredictable biases may have influenced
our results. Second, the limited cohort size
makes it difficult to generalize the results to whole
population. Nevertheless, we had a homogenous group
of gastric cancer patients treated with the same protocol,
and our study may help evaluate the prognostic
significance of molecular therapies in the presence of
conventional chemoradiotherapy protocols.
Disclosures
Ethics Committee Approval: This study was conducted inaccordance
with local ethical rules.
Peer-review: Externally peer-reviewed.
Conflict of Interest: None declared.
Authorship contributions: Concept - O.C.G, A.Y; Design
- O.C.G, A.Y; Supervision - A.Y; Materials - M.K, Z.B, E.C; Data collection &/or processing - Z.B, E.C, E.Ç; Analysis
and/or interpretation - E.C, Z.B; Literature search - M.K;
Writing - O.C.G, A.Y; Critical review - O.C.G, M.K, Z.B,
E.C, E.Ç, A.Y
