Introduction
Trastuzumab was the first molecular-targeted agent
approved in Japan for the treatment of unresectable or recurrent
advanced-stage gastric cancer, with its efficacy established by the
trastuzumab for gastric cancer (ToGA) trial (1). Since then, the development of
molecular-targeted therapies and immune checkpoint inhibitors has
continued to advance, leading to the approval of several new
agents, including ramucirumab [based on the RAINBOW trial (2) and REGARD trial (3)], nivolumab [ATTRACTION-2 trial (4)], pembrolizumab [KEYNOTE-158 trial
(5)], trastuzumab deruxtecan
[DESTINY-Gastric01 trial (6)], and
more recently, the zolbetuximab [SPOTLIGHT trial (7) and GLOW trial (8)]. As a result, therapeutic options for
advanced-stage gastric cancer have steadily expanded.
According to the ‘Guidelines for Biomarker Testing,
2nd Edition’ published by the Japanese Gastric Cancer Association
(9), the evaluation of human
epidermal growth factor receptor 2 (HER2), programmed death-ligand
1 (PD-L1), microsatellite instability/mismatch repair and CLDN18.2
is recommended as essential biomarkers. Among these, HER2 testing
is positioned as the starting point of the biomarker-based
treatment cascade. HER2 positivity is observed in ~15-20% of all
gastric cancers and is more frequently observed in differentiated
adenocarcinomas, proximal gastric cancers and gastroeophageal
junction (GEJ) cancers (10).
However, the intratumoral heterogeneity of HER2 expression remains
a clinical challenge, with factors, such as sampling location,
specimen processing and interobserver variability in pathological
assessment known to influence diagnostic accuracy. The present
study reports a case in which a patient diagnosed as having a HER2
score of 0 on the surgical specimen developed liver metastasis 27
months following surgery. Although treatment with nivolumab plus
the oxaliplatin + leucovorin + 5-fluorouracil regimen (mFOLFOX6)
was initiated, the response was considered insufficient after two
cycles. At that time, HER2 was re-evaluated using a different
section of the resected specimen, which revealed a score of 2+ with
fluorescence in situ hybridization (FISH) positivity. This
finding prompted a switch to trastuzumab plus mFOLFOX6, resulting
in tumor shrinkage.
Case report
A 79-year-old man presented to Kashiwa Kousei
General Hospital (Kashiwa, Japan) with epigastric pain. An upper
gastrointestinal endoscopy revealed a type 3 lesion at the cardia
(Fig. 1A), and a biopsy confirmed a
diagnosis of moderately differentiated adenocarcinoma (tub2). The
levels of serum tumor markers were elevated, with the levels of
carcinoembryonic antigen (CEA) at 27.7 ng/ml and carbohydrate
antigen 19-9 (CA19-9) at 2,164 U/ml. A contrast-enhanced abdominal
computed tomography (CT) scan demonstrated gastric wall thickening
with central depression at the cardia and multiple enlarged lymph
nodes adjacent to the primary tumor (Fig. 1B). Lymph node enlargement was
confined to the regional lymph nodes, with no para-aortic
lymphadenopathy and no evidence of distant metastasis to the liver,
lungs, or other organs.
 | Figure 1Upper gastrointestinal endoscopic
findings, macroscopic finding of the resected stomach and
pathological findings, and contrast-enhanced CT scan prior to
surgery. (A) Upper gastrointestinal endoscopy illustrating a type 3
lesion at the cardia, accompanied by minimal esophageal
involvement. (B) Contrast enhanced abdominal CT scan illustrating
gastric wall thickening with central depression at the cardia and
multiple enlarged lymph nodes adjacent to the primary tumor, which
are highlighted within the yellow circle. (C) Macroscopic
examination of the resected stomach demonstrating a type 3 tumor
measuring 60x50 mm, and histopathological analysis revealed well-
to moderately differentiated tubular adenocarcinoma, classified as
pT3, pN2 (4/60), Ly1b, V1a, with negative proximal and distal
margins (pPM0, pDM0). The biomarker analysis showed HER2 score of
0, pMMR, CLDN18.2-negative, and PD-L1 (28-8) CPS >5, as
described in the text. CT, computed tomography. |
Based on the 15th edition of the Japanese
Classification of Gastric Carcinoma (11), the clinical diagnosis was cT4aN1M0,
stage III. The patient underwent robot-assisted total gastrectomy
with D2 plus lower mediastinal lymph node dissection and Roux-en-Y
reconstruction. Due to esophageal invasion, the esophagus was
transected 20 mm above the tumor, and esophagojejunostomy was
performed within the lower mediastinum. The duration of the surgery
was 511 min, and blood loss was 200 g. The post-operative course
was uneventful, with no anastomotic leakage or pancreatic fistula;
oral intake was initiated on post-operative day (POD) 6, and the
patient was discharged on POD 20. A final pathological examination
revealed well- to moderately differentiated adenocarcinoma, type 3,
pT3N2M0, stage IIIA. The details are illustrated in Fig. 1C.
The levels of tumor markers normalized
post-operatively, with the levels of CEA at 4.1 ng/ml and CA19-9 at
28 U/ml. Post-operatively, adjuvant chemotherapy with docetaxel
plus S-1 at 60% of the standard dose was administered every 3 weeks
for nine cycles, followed by S-1 monotherapy at a 60% dose.
At 12 months following surgery, gallbladder wall
thickening was detected, and laparoscopic cholecystectomy was
performed as malignancy could not be excluded. A pathological
analysis revealed adenomyomatosis with chronic cholecystitis. Due
to declining physical strength, chemotherapy was discontinued
thereafter, and the patient was followed without treatment.
From 18 months post-operatively, the levels of CEA
and CA19-9 gradually increased. At 25 months, the CEA level was
15.5 ng/ml and the CA19-9 level was 441 U/ml. A contrast-enhanced
CT scan revealed a newly appeared 15-mm low-density area in segment
8 of the liver, raising suspicion of liver metastasis (Fig. 2A). PET-CT was subsequently performed,
but no abnormal uptake was observed, and a definitive diagnosis of
liver metastasis could not be established. At 27 months, the CEA
level increased to 20.6 ng/ml and the CA19-9 level to 572 U/ml. An
MRI revealed an enlarged 21x19 mm round lesion in segment 8 of the
liver, exhibiting low signal intensity on T1-weighted imaging and
mildly high signal on T2-weighted imaging, leading to a diagnosis
of liver metastasis from gastric cancer (Fig. 2B). Metastatic lesions were not
detected in any organs other than the liver.
The biomarkers of the carcinoma cells were analyzed
by immunohistochemistry (IHC) using 4-µm-thick paraffin sections,
composed of well-differentiated adenocarcinoma (Fig. 3A, No. 1). The paraffin sections were
stained with hematoxylin and eosin (H&E). The paraffin sections
were deparaffinized, stained with hematoxylin (Muto Pure Chemicals)
for 6.5 min at room temperature and eosin (Muto Pure Chemicals) for
1.5 min at room temperature. HER2 was immunostained by Ventana
BenchMark GX (Roche Diagnostics) using PATHWAY anti-HER-2/neu (4B5)
rabbit monoclonal primary antibody (cat. no. 518-107918;
prediluted; Roche Diagnostics) and ultraView Universal DAB
Detection kit (cat. no. 518-109431; Roche Diagnostics), containing
DAB Inhibitor, HRP multimer (prediluted), DAB chromogen, DAB
H2O2 and DAB Copper and counterstained with
Hematoxylin II and Bluing reagent (Roche Diagnostics) according to
the standard clinical protocol. The primary antibody was incubated
37˚C for 16 min. The H&E- and immune-stained sections were
examined under a blight-field microscope Axioscope 5 (Zeiss). The
expression of HER2 was scored according to Japanese Guidelines for
HER2 Testing in Breast Cancer/Gastric Cancer, 2nd Edition (12). The expression of HER2 was not found
in carcinoma cells, and the score was diagnosed as 0 (Fig. 3B). IHC of PD-L1 was immunostained by
Autostainer Link 48 (Agilent Technologies Japan, Ltd., Tokyo,
Japan) using PD-L1 IHC 28-8 pharmDx kit (cat. no. SK00521-5J;
Agilent Technologies, Inc.), containing EnVision FLEX target
retrieval solution low pH, peroxidase blocking reagent, monoclonal
rabbit anti-PD-L1 (clone 28-8; prediluted), linker (anti-rabbit)
and visualization reagent-HRP DAB+ substrate buffer, DAB+
chromogen, DAB enhancer and counterstained with EnVision FLEX
hematoxylin (Agilent Technologies Japan, Ltd) according to the
standard clinical protocol. The primary antibody was incubated at
room temperature for 30 min. The combined positive score (CPS) of
PD-L1 was calculated as the number of PD-L1-positive cells
including tumor cells, lymphocytes and macrophages divided by the
number of tumor cells x100. The CPS was estimated >5. Therefore,
nivolumab (100%) plus mFOLFOX6 (60%) was initiated and administered
every 2 weeks. After two cycles, the level of CEA exhibited a
slight decrease from 28.6 ng/ml at the initiation of chemotherapy
to 27.4 ng/ml, whereas the level of CA19-9 markedly increased from
881 to 1,312 U/ml. Although the assessment was made shortly
following the initiation of chemotherapy, the response to
nivolumab-based treatment was considered insufficient, prompting
the re-evaluation of the HER2 status. Re-evaluation was performed
on the section, which was located close to the section for the
initial evaluation and composed of well-differentiated
adenocarcinoma (Fig. 3A, No. 2). IHC
of HER2 was performed by Ventana BenchMark GX (Roche Diagnostics)
using prediluted primary antibody PATHWAY anti-HER-2/neu (4B5)
rabbit monoclonal primary antibody (cat. no. 518-107918;
prediluted; Roche Diagnostics) and ultraView Universal DAB
Detection kit (cat. no. 518-109431; Roche Diagnostics) and
counterstained with Hematoxylin II and Bluing Reagent (Roche
Diagnostics) according to the standard clinical protocol. The
primary antibody was incubated 37˚C for 16 min. The moderate
membranous expression of HER2 was noted in ~10% of carcinoma cells,
and the expression of HER2 was scored as 2+ (Fig. 3C). FISH was performed using the
PathVysion HER2 DNA Probe kit (Abott Japan LLC) according with
standard clinical protocol, and the numbers of HER2 and CEP17 were
counted under a fluorescence microscope Olympus BX-63 (EVIDENT;
Olympus Corp.) according to Japanese Guidelines for HER2 Testing in
Breast Cancer/Gastric Cancer, 2nd Edition (12). The HER2/CEP17 ratio was calculated as
3.9, indicating the amplification of the ERBB2 gene. Based on these
findings, the patient received three courses of a
nivolumab-containing regimen, after which the treatment was
switched to trastuzumab (100%) plus mFOLFOX6 (60%) regimen
administered every 3 weeks. After one cycle, the levels of tumor
markers decreased (CEA, 19.3 ng/ml; and CA19-9, 1,061 U/ml); after
two cycles, these levels further declined (CEA, 12.9 ng/ml; and
CA19-9, 569 U/ml). The overall trend of CEA and CA19-9 throughout
the clinical course is presented in Fig.
4. A contrast-enhanced CT scan at 31 months revealed that the
segment 8 liver metastasis had decreased to 13 mm (Fig. 2C), representing a 38% reduction
compared with the MRI performed at 27 months. Although this does
not constitute a formal RECIST assessment as the measurements were
obtained using different imaging modalities, the degree of
shrinkage corresponds to a partial response. Due to a decline in
physical strength, the mFOLFOX6 dose was reduced to 50% from the
fifth cycle onward, with administration performed every 4 weeks.
The disease remained dormant through the ninth cycle (37 months
post-operatively), with the level of CEA at 17.1 ng/ml and that of
CA19-9 at 544 U/ml. At the tenth cycle (38 months
post-operatively), the levels of tumor markers again showed an
upward trend (CEA, 24.1 ng/ml; CA19-9, 582 U/ml). A
contrast-enhanced CT scan revealed that the metastatic lesion in
liver segment 8 had enlarged to 23 mm; therefore, second-line
therapy with ramucirumab (100%) plus paclitaxel (60%) was
administered every 2 weeks at 39 months post-operatively, and
treatment is ongoing.
Discussion
Advances in systemic chemotherapy for unresectable
or recurrent advanced-stage gastric cancer have highlighted the
increasing importance of biomarker testing. In particular,
biomarkers that function as companion diagnostics, such as HER2,
PD-L1 and CLDN18.2 play a critical role in determining eligibility
for specific therapeutic regimens. According to the additional
analyses of the ToGA trial (10),
the overall HER2-positive rate in gastric and GEJ cancers was
22.1%, with a notably higher rate of 32.2% in GEJ cancers.
Furthermore, HER2-positivity was significantly more common in
intestinal-type tumors than in diffuse-type tumors (31.8 vs.
6.1%).
HER2 heterogeneity has long been recognized as a
clinically relevant issue. A nationwide Japanese survey evaluating
HER2 and PD-L1 testing revealed substantial inter-institutional
variability in HER2 scoring (13).
According to this report, differences in tissue fixation methods
and the time interval prior to fixation were identified as
potential contributing factors. Notably, prolonged fixation was
associated with an increased proportion of HER2 cases with a score
of 0 or 1 and a decreased proportion of cases with a score of 3.
Similar variability was also reported for PD-L1 expression,
suggesting that pre-analytical factors and institutional practices
significantly influence biomarker assessment.
The extent to which HER2 expression can be detected
upon retesting is of particular clinical interest. The GASTHER1
trial investigated the utility of repeat biopsies in initially
HER2-negative advanced-stage gastric cancer (14). That study reported a rescued
HER2-positive rate of 8.7% following re-biopsy of the primary
tumor. Notably, the likelihood of conversion to HER2 positivity
increased with higher initial IHC scores (0 → 6.7%, 1 → 15.4%, 2 →
25%) (14). These findings suggest
that HER2 expression may evolve over time or differ across tumor
sites. However, in Japan, repeated biomarker testing is not
routinely reimbursed under the national health insurance system,
limiting the feasibility of systematic retesting in clinical
practice. As regards the case described herein, it was decided to
re-evaluate the HER2 status using a different section of the
gastrectomy specimen as the tumor was a differentiated
adenocarcinoma located at the gastroesophageal junction, where HER2
positivity is more common, and as the patient exhibited early
biochemical progression within 1 month of initiating
nivolumab-based first-line therapy. The re-evaluated section was
processed using the same fixation method and assessed by the same
pathologist as in the initial evaluation.
The GASTHER1 trial also reported that among patients
whose primary tumors were HER2-negative, the rescued HER2-positive
rate was highest in liver metastases (17.2%), which was 5.88-fold
higher than in other metastatic sites (14). This observation suggests that
metastatic lesions may harbor higher HER2 expression than the
primary tumor. In the case presented herein as well, it is possible
that HER2 expression was higher in the liver metastasis than in the
primary lesion. However, a needle biopsy for HER2 testing of the
liver metastasis was not performed due to the risk of peritoneal
dissemination and bleeding from the punctured liver.
Although no standardized treatment guidelines exist
for hepatic metastases from gastric cancer, several clinical
studies have explored the role of hepatectomy and perioperative
chemotherapy (15,16). In the case described herein,
following four cycles of trastuzumab plus mFOLFOX6, the liver
metastasis had decreased in size and remained solitary in segment
8. Although hepatectomy was considered, partial resection of
segment 8 is not minimally invasive even when performed
laparoscopically. Given the advanced age of the patient and his
declining physical strength, surgical intervention was deferred in
favor of continued systemic therapy.
Chemotherapy in elderly patients requires careful
consideration of the dosage and treatment intensity. The GO2 Phase
3 trial demonstrated that reduced-dose capecitabine + oxaliplatin
(0.8x and 0.6x) was non-inferior to standard dosing in 514 elderly
or frail patients with gastroesophageal cancer, supporting the use
of dose-attenuated chemotherapy to maintain disease control while
preserving QOL (17). In the case in
the present study, chemotherapy was initiated at 60% of the
standard dose, and from the fifth cycle onward, the dosing interval
was extended to every 4 weeks to accommodate the reduced physical
reserve of the patient. Despite these adjustments, the patient
maintained disease stability for 6 months through the ninth cycle,
achieving outcomes comparable to the median progression-free
survival of 6.7 months reported in the ToGA trial, indicating that
the reduced dosing was appropriate.
The present case report describes a case in which a
tumor initially classified as HER2-negative was reclassified as
HER20-positive upon re-evaluation of a different area of the same
resected specimen, leading to a favorable response to
trastuzumab-based chemotherapy. In gastric cancer, where the
intratumoral heterogeneity of HER2 expression is frequently
observed, repeat HER2 testing based on tumor location and
histopathological features may help identify latent HER2-positive
cases even among those initially judged to be negative. Such
re-evaluation efforts have the potential to more accurately
identify patients who may benefit from HER2-targeted therapy and
ultimately improve the therapeutic efficacy of chemotherapy for
unresectable or recurrent disease.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
SU performed appropriate blood tests and imaging
examinations for the patient and analyzed the clinical course.
Based on the pathological findings and biomarker results, SU
proposed the treatment strategy for this case. The final treatment
plan was determined and implemented in consultation with KI, RS and
TS, who jointly managed the patient. RW was responsible for the
final diagnosis of the pathological and biomarker examinations and
contributed to this report by providing pathological images and
explanations of the findings. SU drafted the manuscript. A ll
authors have read and approved the final manuscript. Each author
agrees to be accountable for all aspects of the study. IK and RS
confirm the authenticity of all the raw data.
Ethics approval and consent to
participate
For the present study, written informed consent for
publication was obtained from the patient, and the protocol was
submitted to and approved by the Ethics Committee of Kashiwa Kousei
General Hospital (approval no. 25033).
Patient consent for publication
Written informed consent was obtained from the
patient for the publication of the present case report and any
accompanying images.
Competing interests
The authors declare that they have no competing
interests.
Use of artificial intelligence tools
During the preparation of this work, AI tools were
used to improve the readability and language of the manuscript or
to generate images, and subsequently, the authors revised and
edited the content produced by the AI tools as necessary, taking
full responsibility for the ultimate content of the present
manuscript.
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