Prognostic significance of low HER2 expression in gastric cancer: a retrospective, single-center analysis

doi:10.21203/rs.3.rs-3919401/v1

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Prognostic significance of low HER2 expression in gastric cancer: a retrospective, single-center analysis

https://doi.org/10.21203/rs.3.rs-3919401/v1

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published 02 Sep, 2024

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Introduction: Mutated human epidermal growth factor receptor 2 (HER2) is an oncogene with critical pathogenic roles in breast cancer. HER2-low-positive breast cancer is a recently described subtype. We aimed to explore the clinical and molecular characteristics of gastric cancer with low HER2expression, drawing on recent developments in breast cancer subtypes.

Material and methods: This retrospective study involved 135 patients with HER2-non-amplified gastric cancer treated in Iwate Prefectural Iwai Hospital from 2013 to 2018. HER2 evaluation was performed per the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines, and tumors were classified as HER2-null or low-positive based on immunohistochemistry score 0 or 1+ or 2+ with HER2 negativity in situ hybridization, respectively. Statistical analyses, including Kaplan–Meier analyses and Cox proportional hazards model were conducted.

Results:Low HER2 expression was present in 25% (34/135) of the patients. Clinicopathological characteristics were not significantly different between the HER2-low and null groups. Kaplan–Meier analysis of overall survival was significantly longer in the HER2-low group than in the HER2-null group (P = 0.01). In multivariate Cox regression analysis, HER2-null status was associated with worse survival (hazard ratio 2.92; 95% confidence interval 1.24–6.86; and P = 0.01).

Conclusion: This study highlights the prognostic importance of low HER2 expression in gastric cancer, similar to that observed in HER2-low-positive breast cancer, and suggests reclassification of gastric cancer to improve personalized treatment. Future studies should elucidate the molecular underpinnings of low HER2 expression in gastric cancer to guide novel therapeutic strategies and improve outcomes.

gastric cancer

human epidermal growth factor receptor 2

prognosis

biomarker

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 ^3–6. 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.

This was a retrospective study including 135 patients with HER2-nonamplified gastric cancer who were treated in Iwate prefectural Iwai Hospital, between 2013 and 2018. In all cases, the HER2 status was evaluated by board-certified pathologists according to the American Society of Clinical Oncology/College of American Pathologists guidelines 2013. 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 HER2null (IHC score of 0) and HER2lowpositive (IHC score of 1 + or 2 + with negative ISH). The study protocol was approved by the Ethics Committee of Iwai Hospital (approval no. Iwa6 1003). 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.

Low HER2 expression was detected in 34 of the 135 patients (25%) 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). In the multivariate Cox regression analysis, the HER2-null status was associated with worse overall survival (multivariate hazard ratio 2.92, 95% confidence interval 1.24–6.86; P = 0.01) (Table 2).

Table 1

Human epidermal growth factor receptor 2 (*HER2*) status in gastric cancer and clinicopathologic features
Clinicopathologic feature	HER2-low (N = 34)		HER2-null (N = 101)		P value
Age (years)†	70.6	(9.4)	68.0	(9.8)	0.16
Gender
Male	22	(65)	73	(72)	0.40
Female	12	(35)	28	(28)
Surgical procedure
Distal gastrectomy	16	(47)	53	(52)	0.10
Total gastrectomy	16	(47)	48	(48)
Pylorus-preserving gastrectomy	2	(6)	0	(0)
Tumor location
Upper	10	(29)	26	(26)	0.56
Middle	15	(44)	38	(37)
Lower	9	(27)	37	(37)
Histologic grade
Well/moderately differentiated	10	(29)	22	(22)	0.36
Poorly differentiated	24	(71)	79	(78)
Tumor depth
T1–2	17	(50)	39	(39)	0.31
T3–4	17	(50)	62	(61)
Lymph node metastasis
Negative	17	(50)	51	(50)	1.00
Positive	17	(50)	50	(50)
*P < 0.05 by Student’s t test for age, time, and laboratory findings and by Fisher’s exact test for other parameters. Values in parentheses are percentages unless indicated otherwise; † mean ± standard deviation

Table 2

Univariate and multivariate analysis of patient survival
	Univariate analysis		Multivariate analysis
Covariates	HR (95% CI)	P value	HR (95% CI)	P value
Age (≥ 65 vs. <65 years)	1.67 (0.91–3.05)	0.10
Sex (male vs. female)	1.08 (0.59–2.01)	0.79
Histologic type (poorly vs. well/moderately differentiated)	1.17 (0.62–2.20)	0.63
Tumor depth (T3–4 vs. T1–2)	4.36 (2.12–8.97)	< 0.001**	2.66 (1.19–5.94)	0.02*
Lymph node metastasis (positive vs. negative)	3.79 (2.02–7.14)	< 0.001**	2.49 (1.23–5.01)	0.01*
HER2 status (null vs. low)	2.98 (1.27–7.00)	0.01*	2.92 (1.24–6.86)	0.01*
Multivariate analysis included clinicopathological features with a P value of < 0.05 in univariate analysis.
P < 0.05, *P < 0.01

Our analyses of clinical and molecular characteristics of gastric cancers with low HER2 expression identified low HER2 expression in 25% 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.

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.

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.

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.

HER2

human epidermal growth factor receptor 2

IHC

immunohistochemistry

ISH

in situ hybridization

Ethics approval and consent to participate:

The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution and it conforms to the provisions of the Declaration of Helsinki. Committee of Iwai hospital, Approval No. Iwa6 1003. Consent to participate was obtained from all the study participants.

Consent for publication:

Consent to publish was obtained from all the study participants.

Competing interests:

The authors declare no competing interests for this article.

Funding:

None.

Author Contribution

YG: conceptualization, methodology, formal analysis, investigation, data curation, resources, writing—original draft. YN: conceptualization, methodology, formal analysis, investigation, data curation, writing—original draft. YO: conceptualization, methodology, investigation, resources, writing—review and editing. TO: investigation, writing—review and editing. KH: investigation, writing—review and editing. KS: investigation, writing—review and editing. TK: conceptualization, methodology, formal analysis, investigation, data curation, writing—review and editing. KK: investigation, writing—review and editing. TA: writing—review and editing, supervision. KS: conceptualization, methodology, investigation, resources, writing—review and editing, supervision. All authors have read and approved the final version of the manuscript.

Acknowledgments:

We thank Enago (www.enago.jp) for the English language review.

Availability of data and materials:

The datasets analyzed during the current study are available from the corresponding author.

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No competing interests reported.

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You are reading this latest preprint version

Prognostic significance of low HER2 expression in gastric cancer: a retrospective, single-center analysis

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