Correlation of HER2 Expression in Gastric Carcinoma with Clinicopathological Parameters in the Omani Population

By Asim Qureshi¹, Hana Al Julandana², Sara Al Barkhati³, Ahmed Al Ghaithi², Asem Shalaby^1,3

Affiliations

1. Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
2. College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
3. Department of Pathology, College of Medicine, Mansoura University, Mansoura, Egypt

doi: 10.29271/jcpsp.2025.07.929

ABSTRACT
This retrospective study was conducted to determine the relation between human epidermal growth factor receptor 2 (HER2) expression and the clinicopathological and prognostic characteristics of gastric cancer (GC) patients treated at the Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman. It included 49 patients diagnosed with GC and treated between 2018 and 2021. The positivity rate for HER2 was 24.4%, but no significant correlation was found between HER2 expression and tumour histological grade (p = 0.577), presence of metastasis (p = 0.935), or histopathological type (p = 0.531). Furthermore, there was no statistically significant difference in survival rates between patients who received Herceptin (immune-targeted therapy also known as trastuzumab) and those who did not, despite having positive HER2 expression (p = 0.826). No significant correlation was observed between the examined parameters and HER2 expression status.

Key Words: Gastric cancer, HER2, Clinical, Pathological parameters.

The treatment of advanced gastric cancer (GC) continues to be challenging in clinical practice, and the primary treatment option is combination chemotherapy. The use of targeted therapy as an adjuvant to chemotherapy has been documented to significantly enhance the overall survival (OS) of cancer patients. One such molecular target that has been studied is human epidermal growth factor receptor 2 (HER2). The HER2/neu gene, also known as c-erbB2, expresses a 185 kDa transmembrane glycoprotein (HER2/neu, also known as p185^HER2/neu) that is overexpressed in 15–30% of breast cancers¹ and other cancers. HER2 expression has been found in many other solid organ tumours, including breast cancer, colorectal cancer, lung cancer, ovarian cancer, and GC.¹ Additionally, extensive research has been conducted on the correlation of HER2 overexpression with various factors such as age, gender, tumour stage, tumour grade, and prognosis.¹

Trastuzumab (also known as Herceptin) is a cancer-targeted medicine used in the treatment of advanced gastric cancer in patients who test positive for the HER2 receptor.
 

Hence, knowing the significance of targeted therapy in the modern era, specifically the study aims to evaluate HER2 expression in GC and to see its relationship with the tumour's clinicopathological parameters. It also explores the prognostic role of HER2 in GC patients.²

A study was conducted on GC patients treated and monitored at the Sultan Qaboos University Hospital, Muscat, Oman, between 2018 and 2021. The study collected various parameters from the electronic medical records of participating patients using the TackCare system. These parameters included the patient's age, gender, pathology findings (including morphology, histological grade, and subtype), HER2 status, imaging findings on distant metastases, and survival status (including the date of diagnosis and death).

Immunohistochemistry (IHC) was primarily used to detect the HER2 status, HER2 neu clone 4BS (Ventana), and the inconclusive cases were later re-assessed with ISH. HER2 overexpression was defined as (3+) or (2+) in the IHC staining pattern, and positive ISH was scored according to a testing algorithm. Patients who were positive for HER2 neu received Herceptin therapy. The TNM system (7^th Edition AJCC) was used for tumour M staging, while Lauren's histologic classification system was used for tumour subtyping.

HER2 status, positive or negative, was recorded along with morphological differentiation, and the histological grade was also documented. The study was approved by the Medical Research and Ethics Committee (MREC) of the College of Medicine and Health Sciences.

Table I: Table association of HER2 status with clinicopathological parameters. The chi-square was performed to correlate IHC results and HER2 final status with clinico-pathological parameters.

Parameters	Overall n = 49 (%)	HER2 positive n = 12 (%)	HER2 negative n = 37 (%)	p-value Chi-square test
Gender        Male        Female	- 31 (63.2) 18 (36.7)	- 5 (41.6) 7 (58.3)	- 26 (70.2) 11 (29.7)	- 0.196 (Insignificant)
Age group (years)        ≤40        40–60        ≥60	- 7 (14.3) 15 (30.6) 27 (55.1)	- 1 (8.3) 2 (16.6) 9 (75)	- 6 (16.2) 13 (35.1) 18 (48.6)	0.615   (Insignificant) -
Histological grade differentiation        Well        Moderately        Poorly	- - 0 (0) 22 (44.9) 27 (55.1)	- - 0 (0) 8 (66.7) 4 (33.3)	- - 0 (0) 14 (37.8) 23 (62.2)	0.577 - (Insignificant)
Histological type        Intestinal        Diffuse        Mixed        NA	- 17 (34.7) 21 (42.9) 4 (8.2) 7 (14.3)	- 7 (58.3) 3 (25) 0 (0) 2 (16.6)	- 10 (20.4) 18 (36.7) 4 (8.2) 5 (10.2)	- 0.531 (Insignificant)
M Staging (clinical)        M0        M1	- 21 (42.9) 28 (57.1)	- 5 (41.7) 7 (58.3)	- 16 (43.2) 21 (56.8)	0.935 (Insignificant)

Figure 1: Photomicrographs of HER2 IHC showing: (A) Negative score 0 (B) Negative score 1+ (C) Equivocal score 2+ (D) Positive score 3+.

This study was conducted on patients who had GC and were treated and monitored at the Sultan Qaboos University Hospital. All patients suffering from gastric adenocarcinoma (both genders) were included. Patients who suffered a second malignancy were excluded from the study.

SPSS version 25 was used to analyse the data. Quantitative data were expressed as mean ± standard deviation and range. Qualitative variables were expressed as counts and percent-ages. The chi-square was performed to correlate IHC results and HER2 final status with clinicopathological parameters.

All tests were two-tailed, and a p-value <0.05 was considered statistically significant. The Kaplan–Meier test was used to calculate the survival rate, and statistical analysis was performed using the log-rank test.

This study involved 49 patients with a median age of 60 years (range 31–101 years). All these patients underwent gastric biopsy for cancer diagnosis. Among them, 31 (63.2%) were males and the other 18 (36.7%) were females. IHC analysis showed that 24.4% (n = 12) of cases tested positive for HER2 overexpression, with majority (83%) having a score of 3+. Only the cases with a 2+ score (2 out of 12) were retested by in situ hybridisation (ISH). Histological subtyping revealed that 42.9% of the tumours were diffused, followed by the intestinal type (34.7%), and 8.2% were classified as mixed. Examples of different IHC results are shown in Figure 1.

There was no significant correlation between HER2 positivity and gender or age group. However, the rate of HER2 positivity was higher in females (58.3%). The maximum number of HER2-positive tumours was found in individuals over 60 years old.

HER2 positivity was not statistically associated with the histological grade of the tumour (p = 0.577). No HER2 positivity was observed in well-differentiated tumours. Additionally, HER2 expression was associated with the intestinal type (58%). However, no significant association was observed between HER2 expression and tumour Lauren subtype (p = 0.531).

Out of the total, 58.3% of M1 metastasis cases showed positive HER2 test results, while only 41.7% of stage M0 cases tested positive (p = 0.935, Table I).

The study found no statistically significant association between HER2 expression status (p-value = 0.826) and patient survival. The mean survival time was 20.84 months (range: 7~33 months) in HER2 positive patients (who received Herceptin treatment), compared to 26.9 months (range: 4~50 months) in negative patients (who did not receive Herceptin).

An analysis of 49 cases of GC found that the rate of HER2 positivity was 24.4%, which falls within the range of 4.4-53.4% reported in various populations.³ However, the variation in HER2 positivity rates between countries and populations could be due to specific parameters on which HER2 positivity has been correlated.

This suggests that HER2 positivity may not be a reliable prog-nostic factor for these parameters.

The analysis also showed no statistically significant association between HER2 expression status (p = 0.826) and patient survival. However, some studies have indicated that HER2-positive patients have a longer median overall survival than HER2-negative patients.^3-5 Despite these findings, the relation-ship between HER2 positivity, prognostic parameters, and survival remains controversial.

This controversy could be due to genetic differences, sample size variations, and the methodology used to investigate HER2 status.^5,6 Nonetheless, the primary limitation of this study was its relatively small sample size.

In conclusion, this study demonstrated a HER2 positive gastric cancer frequency of about 24% among the Omani patients with no significant statistical difference between the two groups of patients (HER2 positive and negative) in parameters such as age, gender, histological type, differentiation grade, and presence of distant metastasis and survival. Thus, this study strongly suggests the need for further studies defining the role of HER2 expression in gastric adenocarcinoma in Omani patients using a large sample size. Overall, the findings of this study may help clinicians make/modify guidelines for GC in the Omani population.

COMPETING  INTEREST:
The authors declared no conflict of interest.

AUTHORS’  CONTRIBUTION:
AQ: Original idea and script writing.
HAJ, SAB, AAG: Compiling data and write-up.
AS: Overall supervision and finalisation of the manuscript.
All authors approved the final version of the manuscript to be published.

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