Introduction

Human epidermal growth factor receptor 2 (HER2) is a well-known oncogene with established roles in various cancers, including breast cancer [1]. The recently defined HER2-low-positive breast cancer subtype is characterized by an immunohistochemistry (IHC) score of 1 + or 2 + in cases negative for HER2 by in situ hybridization (ISH) [2]. A previous report reported significantly longer survival in patients with HER2-low-positive breast cancer than in those with HER2-null breast cancer [2]. Recent advances in cancer therapy highlight the significance of anti-HER2 therapies not only for patients with breast cancer exhibiting classic HER2 positivity (IHC score of 3 + or 2 + with positive ISH) but also for those with low HER2 expression levels [3,4,5,6]. These developments have paved the way for studies exploring the role of HER2 in other cancers including gastric cancer [7]. HER2 involvement in gastric cancer, although less prevalent compared to breast cancer, presents a potential avenue for novel treatment strategies, especially in patients with HER2-positive gastric cancer [7]. Nevertheless, the clinical significance of low HER2 expression in gastric cancer remains unclear. A previous study on early-stage gastric cancer reported that low HER2 expression was associated with age, histologic differentiation, tumor location, and the Ki-67 index but not with disease-free or overall survival [8].

Drawing on these recent developments in breast cancer subtypes, the present study aimed to investigate the clinical and molecular characteristics of gastric cancer with low HER2 expression with the aim to elucidate the association of HER2 expression level with overall prognosis in patients with gastric cancer. The findings will be instrumental in identifying new gastric cancer subtypes, akin to the further refinement of breast cancer cases as HER2-low-positive and HER2-null subtypes, thereby enabling the development of better tailored and effective treatment strategies.

Materials and methods

This retrospective study included 129 patients with HER2-nonamplified gastric cancer who were treated in Iwate prefectural Iwai Hospital, between 2013 and 2019. In all cases, the HER2 status was evaluated by board-certified pathologists. Patient characteristics and outcomes obtained from their medical records were retrospectively reviewed. In the present study, the terms used to define breast cancer subtypes were adopted to categorize cases as HER2­-null (IHC score of 0) and HER2-­low­-positive (IHC score of 1 + or 2 + with negative ISH). The study protocol was approved by the Ethics Committee of Iwate prefectural Iwai Hospital (approval no. R6–26). Informed consent was obtained from all participants.

Statistical analysis

All statistical analyses were performed using JMP Pro version 17. Data were compared using Student’s t test or Fisher’s exact test. The Kaplan–Meier method was used to estimate survival curves, and the Cox proportional hazards model was used for univariate and multivariate analyses. The multivariate analysis included clinicopathological features with a P value of < 0.05 in the univariate analysis [9]. P value of < 0.05 denoted statistical significance.

Results

Low HER2 expression was detected in 33 of the 129 patients (26%) included in this study (Fig. 1). The clinicopathological characteristics between those with low HER2 expression (HER2-low group) and no expression (HER2-null) showed no significance (Table 1). The Kaplan–Meier analysis revealed that overall survival was significantly longer in patients with HER2-low cancer than in those with HER2-null cancer (P = 0.01; Fig. 2). Among patients with stage III cancer, overall survival was significantly longer in those with HER2-low cancer than in those with HER2-null cancer (P = 0.03; Fig. 3). However, significant differences in overall survival were not observed between these groups among patients with stage I–II cancer. Moreover, among patients receiving adjuvant chemotherapy, overall survival was significantly longer in those with HER2-low cancer than in those with HER2-null cancer (P = 0.04; Fig. 4). In the multivariate Cox regression analysis, the HER2-null status was associated with worse overall survival (multivariate hazard ratio 3.01, 95% confidence interval 1.18–7.65; P = 0.02) (Table 2).

Fig. 1
figure 1

Representative images of cases evaluated for human epidermal growth factor receptor 2 (HER2) expression by immunohistochemical (IHC) staining. Cases with IHC scores of 2+ (A), 1+ (B), and 0 (null) (C) are shown

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Table 1 Human epidermal growth factor receptor 2 (HER2) status in gastric cancer and clinicopathologic features
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Fig. 2
figure 2

Kaplan–Meier curves of survival in patients with gastric cancer categorized according to the HER2 status, showing the significantly better prognosis in patients with low HER2 expression (P = 0.01). *P < 0.05

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Fig. 3
figure 3

Kaplan–Meier curves of survival in patients with gastric cancer categorized according to the HER2 status and the stage of their cancer. Among patients with stage III cancer, overall survival was significantly longer in those with HER2-low cancer than in those with HER2-null cancer (P = 0.03). *P < 0.05

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Fig. 4
figure 4

Kaplan–Meier curves of survival in patients with gastric cancer, sorted based on their HER2 status and whether they received adjuvant chemotherapy. Among patients with adjuvant chemotherapy, overall survival was significantly longer in those with HER2-low cancer than in those with HER2-null cancer (P = 0.04). *P < 0.05

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Table 2 Univariate and multivariate analysis of patient survival
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Discussion

Our analyses of clinical and molecular characteristics of gastric cancers with low HER2 expression identified low HER2 expression in 26% of the patients with HER2-nonamplified gastric cancer included in the study. Notably, the Kaplan–Meier analysis revealed that overall survival was significantly longer in patients with HER2-low gastric cancer than in those with HER2-null gastric cancer, a finding supported by multivariate Cox regression analysis.

A novel aspect of our study is the identification of a distinct subtype of gastric cancer characterized by low HER2 expression, reflecting the HER2-low-positive subtype that has been recently defined in breast cancer [2]. The present study’s findings provide new insights into the prognostic significance of low HER2 expression in gastric cancer, which is a relatively underexplored area.

Our analyses revealed that low HER2 expression was associated with significantly improved overall survival especially in patients with stage III gastric cancer and in those who received adjuvant chemotherapy, which suggested that low HER2 expression reflects less aggressive tumor biology or unique response to adjuvant chemotherapy.

Moreover, the positive impact of adjuvant chemotherapy on survival outcomes observed in the HER2-low group suggested an interaction between HER2 expression level and chemotherapy efficacy, which might be attributed to the distinct HER2-associated biologic pathways that alter tumor response to chemotherapy.

Better prognosis was reported in patients with HER2-low breast cancer compared to those with HER2-null breast cancer [2]. Lower Ki-67 index in HER2-low breast cancer indicated less tumor aggressiveness, lower histologic grade, activated inflammatory immune response, and higher rate for hormone receptor positivity [2]. However, using HER2 status alone as a predictor of prognosis is uncommon [1,2,3,4,5,6, 10]. Previous studies have investigated the crosstalk between hormone-receptor and HER2 signaling pathways, typically categorizing groups based on their status for hormone and HER2 receptors [2, 10]. Extrapolating the mechanisms of favorable prognosis associated with low HER2 expression in breast cancer to patients with gastric cancer might not be straightforward; studies on breast cancer should be considered only as a reference [11].

The HER2 signaling pathway plays a major role in tumor cell proliferation and is associated with poor prognosis [2, 10]. However, the relationship between HER2 status and prognosis in gastric cancer remains unestablished by clinical studies [11,12,13,14,15]. Immunohistochemical studies reveal that regions of high differentiation within gastric cancer lesions are more likely to express HER2 and immunopositivity for HER2 exhibits greater heterogeneity in gastric cancer than in breast cancer [12, 13].

In contrast to previous studies that did not find a significant association between HER2-low expression and survival outcomes in early-stage gastric cancer, our analyses indicated a clear survival advantage in the HER2-low group compared to the HER2-null group [8]. This discrepancy can be attributed to differences in study populations, methodologies, and tumor biology. For example, the present study included a relatively low number of patients with advanced cancer and well-differentiated tumor [8]. Additionally, differences in tissue processing might have contributed to the observed heterogeneity and immunoreactivity [11, 13]. Although, the present study was limited by the single-center, small-scale design and mechanisms underlying our findings remain speculative as parameters such as the Ki-67 index and the presence and extent of tumor-infiltrating lymphocytes, which are parameters investigated in previous studies, were not evaluated [2]. Furthermore, in this study, it cannot be completely ruled out that the histological type acted as a confounding factor, specifically that the predominance of well-differentiated adenocarcinoma in the HER2-low group may have contributed to their observed better prognosis. Therefore, future studies should evaluate the impact of HER2 expression on prognosis in specific histologic gastric cancer types. In the present study, the small number of cases precluded such analyses. Further investigation is warranted to understand the mechanisms underlying our findings.

The improved survival in the HER2-low group suggests that low HER2 expression is associated with less aggressive tumor phenotype or it indicates the involvement of a distinct biological pathway in gastric cancer. Similar HER2’s established role in breast cancer our findings also underscore the potential of HER2 as a biomarker for the stratification of patients with gastric cancer. The present study’s findings will potentially open new avenues for targeted therapies in gastric cancer, similar to the success of anti-HER2 therapies in breast cancer.

A major study limitation is the study design and the relatively small sample size, which may limit the generalizability of our findings. Additionally, the study focuses solely on HER2 expression without exploring other molecular characteristics that might influence prognosis or therapeutic response. Furthermore, in the clinical practice of breast cancer in Japan, retesting using companion diagnostic agents is required for the diagnosis of HER2 low. However, this study only retrospectively reviewed past histopathological reports.

In conclusion, the present study findings highlight the prognostic significance of low HER2 expression in gastric cancer and are a significant step forward in the understanding of gastric cancer biology, suggesting its potential utility in reclassifying these patients for improved tailored therapeutic strategies and outcomes. However, these findings warrant validation in future studies, in addition to exploring the molecular mechanisms of low HER2 expression in gastric cancer.