
==== Front
Ther Adv Med Oncol
Ther Adv Med Oncol
TAM
sptam
Therapeutic Advances in Medical Oncology
1758-8340
1758-8359
SAGE Publications Sage UK: London, England

10.1177/17588359241271913
10.1177_17588359241271913
Meta-Analysis
HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis
https://orcid.org/0000-0002-7673-9157
Cheng Ji Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
Conceptualization Data curation Formal analysis Funding acquisition Investigation Methodology Writing – original draft Writing – review & editing
Cai Ming Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Conceptualization Data curation Formal analysis Funding acquisition
Wang Guobin Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Formal analysis Funding acquisition Writing – original draft Writing – review & editing
Tao Kaixiong Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Conceptualization Data curation Formal analysis
jicheng1@hust.edu.cn
5 9 2024
2024
16 175883592412719133 12 2023
2 7 2024
© The Author(s), 2024
2024
SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Background:

Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics.

Objectives:

To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study.

Design:

Meta-analysis.

Data sources and methods:

Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle–Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4.

Results:

Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality (n = 31). Regarding resectable cases (n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32–1.85, p < 0.00001). For HER2-positive patients with advanced gastric cancer (n = 10), HER2 overexpression was also an unfavorable survival indicator (HR 1.70, 95%CI 1.23–2.35, p = 0.001). Potential heterogeneous studies had been eliminated while outcomes remained stable by sensitivity analysis. Subgroup analysis suggested HER2-positive patients had a poorer prognosis in both East Asian (resectable: HR 1.56; advanced: HR 1.32) and non-East Asian countries (HR 1.58; HR 3.27).

Conclusion:

As a novel survival biomarker in gastric cancer, HER2 overexpression indicates unfavorable prognosis among both resectable and advanced patients, irrespective of East Asian or non-East Asian populations.

Trial registration:

PROSPERO (CRD42020168051).

gastric cancer
HER2
meta-analysis
survival
systematic review
Natural Science Foundation of Hubei Province https://doi.org/10.13039/501100003819 2024AFB673 cover-dateJanuary-December 2024
typesetterts1
==== Body
pmcIntroduction

Gastric cancer is currently the fifth most frequent and fourth most lethal malignancy globally. It is estimated that over 1 million gastric cancer cases occurred in 2020, with nearly 770,000 deaths at the same time.1,2 Although therapeutic signs of progress have been achieved in recent years, survival biomarkers for gastric cancer patients remain in scarcity.3,4

Currently, the anti-HER2 monoclonal antibody trastuzumab has been recommended as the first-line option against advanced gastric cancer together with platinum-based chemotherapy.5,6 Nevertheless, unlike breast cancer, the prognostic significance of HER2 overexpression in gastric cancer remains controversial. Several cohort studies hinted that the positivity of HER2 was directly linked to poorer survival,7,8 while others reported that HER2 overexpression was not an independent prognostic indicator among gastric cancer patients.9–11 Meanwhile, inconsistent conclusions could also be observed among previously published meta-analyses in this field (Supplemental Materials). By exploring the methodological designs of previous primary studies and meta-analyses in detail, they evidently had heterogeneous standards regarding HER2 evaluation and incomparable clinical features, which might explain those less harmonious conclusions concerning prognostic values of HER2 expression.

HER2 is one of the most important and commonly examined biomarkers among gastric cancer patients, hence the importance of clarifying its prognostic value. We performed a systematic review and meta-analysis to clarify the survival significance of HER2 overexpression in gastric cancer, with an emphasis on methodology to limit the pooling of data across homogeneous populations.

Methods

Guidelines and registration

Design, calculation, and drafting of our systematic review and meta-analysis were in accordance with standards in PRISMA Checklist 12 (Supplemental Materials) and Cochrane Handbook. Each step was conducted by two individuals in our group (J.C. and M.C.). Any discrepancy was settled by the third investigator (G.W. and K.T.). We registered our systematic review and meta-analysis in PROSPERO (CRD42020168051).

Search strategy

PubMed, Web of Science, Cochrane Library as well as Embase were carefully searched. Meanwhile, ASCO and ESMO Meeting Library were also examined, together with the reference lists of previously published meta-analyses. Our search procedures began on September 3rd until November 12th of 2022, covering records published from January 1966 to November 2022. The title and abstract of each retrieved record were checked first, followed by full-text assessment if necessary. The entire search strategy was listed in Supplemental Materials.

Selection criteria

Studies that met all the following requirements were eligible for inclusion (PICOS framework):

Participant: Patients from eligible studies should be diagnosed with previously untreated resectable or advanced (unresectable, recurrent, or metastatic) gastric cancer (including gastroesophageal junction cancer) from a generalized community without specific selection of pathological, histological, or clinical features. Studies involving patients with synchronous malignancies other than gastric cancer were not permitted. Overall, this was a traditional meta-analysis based on study-level data extraction; therefore, only studies with patients fulfilling the abovementioned criteria were considered.

Intervention: For resectable gastric cancer, all surgeries should be of curative intent. Both perioperative and adjuvant treatments were permitted. For advanced gastric cancer, previous gastrectomy was permitted, irrespective of curative or palliative operations. Either chemotherapy alone or chemotherapy with targeted treatments was qualified.

Comparator: The HER2-positive group was regarded as the experimental group while the HER2-negative counterpart acted as a control. Standards for examining and scoring HER2 expression were strictly in accordance with NCCN guidelines without any exception. 6 Briefly speaking, after immunohistochemical (IHC) grading of surgical or biopsy specimens into 0, 1+, 2+, or 3+, IHC2+ was further examined by in situ hybridization (ISH) methods. Only those with IHC3+ or IHC2+/ISH+ were regarded as HER2 positive and therefore we only included studies with this definition in their methods. Studies using evaluation standards from ToGA trial 5 were therefore also ineligible. In both HER2 positive and negative groups, no comparisons between other targeted markers were allowed.

Outcome: Overall survival data (hazard ratio (HR) or Kaplan–Meier curves) were mandatory. Overall survival data for combined cases from both resectable and advanced gastric cancer without subgroup analysis were not allowed. In addition, to perform a more specific analysis, overall survival data should be separately provided if advanced-stage HER2-positive patients had mixed treatment regimens containing either chemotherapy plus targeted treatments (except for those targeting HER2) or chemotherapy alone. For those studies reported that a mixture of advanced and resectable patients, we only included them if they reported separate survival outcomes.

Study design: Cohort studies reported from January 1966 to November 2022 without language limitations.

Studies were excluded due to the following criteria:

For resectable gastric cancer, the overall follow-up time was less than 3 years.

Quality assessment

The Newcastle–Ottawa Scale was applied to assess the methodological quality of eligible studies. Details of assessment standards of the Newcastle–Ottawa Scale are listed in Supplemental Materials (eTable 1). The full score of each study was 9, while studies with scores equal to or more than 6 were regarded as high-quality studies.

Data extraction and endpoints

Electronic sheets were used to collect original data from the included studies. Baseline clinical features and overall survival data were extracted from the main text or Supplemental Materials. HR results of overall survival from multivariate (in priority) and univariate analysis were both extracted. Meanwhile, Kaplan–Meier curves were applied for survival data extraction if necessary, in accordance with suggestions by Tierney et al. 13 Moreover, for results that were estimated from Kaplan–Meier curves, we also used the p value provided by original studies to test and adjust the outcomes. Overall survival was the primary and only endpoint in our meta-analysis since it was the main survival indicator for gastric cancer patients.

Statistical analysis

Reviewer Manager 5.4 was the statistical platform for our pooled analysis. HR and its 95% confidence interval were used as effect size for pooled analysis of overall survival data. A significant difference was achieved when the pooled confidence interval for HR did not include 1.0, which could also be demonstrated by p < 0.05. According to the Cochrane Handbook, I2 was utilized as an indicator of heterogeneity. A fixed-effects model was suitable for calculations with low heterogeneity (I2 < 50%) while a random-effects model was more reliable for pooled analysis with high heterogeneity. Using STATA 14.0, publication bias was analyzed for pooled analysis with at least 10 studies inside. A symmetrical funnel plot indicated a low risk of publication bias. Several methods were used for performing sensitivity analyses in our meta-analysis, including interchanging between random-effects and fixed-effects models, eliminating low-quality studies (those scored below 6 by the Newcastle–Ottawa Scale) and extra small sample-size studies (<100), since those studies might have less statistical power. Studies based on East Asian and non-East Asian populations were further analyzed by subgroup analysis.

Results

Baseline characteristics

A total of 8408 records were retrieved from electronic databases, among which 32 studies were eligible for our systematic review and meta-analysis with a total population of 9945 patients (Figure 1). Details of search strategies are listed in Supplemental Materials while reasons for each ineligible study by full-text assessments are displayed in eTable 2 (Supplemental Materials). Twenty-two studies were included for resectable gastric cancer analysis, containing an overall 8125 patients (ranging from 75 to 1148 by each study). Most of the included studies were conducted by East Asian countries (n = 18). All studies had a median age of over 60.0 and a male-dominant sex ratio. The majority of included studies shared comparable composition of tumor locations, Lauren classifications, and TNM stages without specific selection. All studies had at least 3 years of follow-up for resectable cases, and most of them reported a 3-year overall survival rate in the HER2-negative group to be at least 60.0% (Table 1). Ten studies were eligible for advanced gastric cancer analysis, with a total population of 1820 patients (ranging from 32 to 321 in each study). The majority of studies originated from East Asian countries (n = 7). The median age of included studies ranged from 53.0 to 67.0, all with a male-dominant sex ratio. Most of the included patients had well performance status (ECOG 0–2) and metastatic lesions. All studies were followed up for at least 12.0 months while the median survival time of the HER2-negative group in most studies had also surpassed 12.0 months (Table 2). None of the included studies reported mixed stages of patients.

Figure 1. Selection flow chart.

The list of eight meta-analyses was embedded in Supplemental Materials.

Table 1. Baseline features of included studies (resectable).

Study	Date of diagnosis	Country	Group	Sample size	Median age (years)	Sex (M/F)	Location (G/J)	Lauren (I/D/M)	TNM (I/II/III/IV)	Follow-up (months)	3-Year overall survival rate (%)	5-Year overall survival rate (%)	Overall survival (HR)	
Byeon et al. (2017) 14	01/2004–12/2004	South Korea	HER2 (+)	32	NA	25/7	NA	19/13	16/16	Max 60.0	55.0	52.0	1.28 (95%CI 0.71–2.31)	
HER2 (−)	281	198/83	111/170	134/147	62.6	57.1	
Chen et al. (2021) 15	01/2001–11/2002	China	HER2 (+)	23	67.5	17/6	20/3	NA	25/22/48/18	Max 100.0	87.3	83.0	1.49 (95%CI 0.38–5.84)	
HER2 (−)	90	66/24	85/5	73.0	66.1	
Cho et al. (2017) 7	03/2008–10/2013	South Korea	HER2 (+)	32	61.7	238/146	NA	NA	0/17/15/0	26.0; Max 60.0	60.0	NA	2.39 (95%CI 1.18–4.83) a	
HER2 (−)	352	0/176/174/0	82.1	
Fisher et al. (2014) 16	05/2000–06/2011	United States	HER2 (+)	21	60.9	10/11	19/2	NA	5/6/10/0	19.2; Max 120.0	52.8	35.3	0.74 (95%CI 0.36–1.55)	
HER2 (−)	90	61.8	50/40	76/14	19/26/45/0	41.6	30.0	
Fusco et al. (2013) 17	1996–2005	Italy	HER2 (+)	37	NA	NA	34/3	30/7	NA	40.6; Max 93.7	21.7	0.0	1.82 (95%CI 1.19–2.79)	
HER2 (−)	255	228/27	155/100	54.6	29.7	
Gu et al. (2015) 18	12/2006–10/2008	China	HER2 (+)	10	61.0	10/0	8/2	NA	2/0/8/0	49.5 (2.2–87.8)	40.1	30.0	2.49 (95%CI 0.98–6.35)	
HER2 (−)	82	49/33	66/16	13/32/37/0	62.6	51.2	
Jiang et al. (2015) 19	2002–2004	China	HER2 (+)	27	60.0	18/9	NA	26/0/1	3/6/18/0	64.0 (1.0–108.0)	37.2	27.3	1.76 (95%CI 1.05–2.94)	
HER2 (−)	200	139/61	118/49/33	43/53/105/0	56.3	42.8	
Katai et al. (2014) 20	01/1980–01/2010	Japan	HER2 (+)	38	NA	35/3	0/38	NA	5/8/24/1	76.8 (2.4–248.4)	65.7	48.5	1.40 (95%CI 0.81–2.41)	
HER2 (−)	170	139/31	0/170	37/34/82/17	71.8	61.2	
Kataoka et al. (2013) 21	01/2001–12/2007	Japan	HER2 (+)	25	71.2	23/2	NA	21/0/4	5/11/9/0	Max 120.0	62.1	52.9	1.50 (95%CI 0.78–2.87)	
HER2 (−)	188	66.2	120/68	73/93/22	45/66/81/6	76.4	66.5	
Kurokawa et al. (2015) 22	2000–2006	Japan	HER2 (+)	180	67.5	133/47	NA	142/38/0	79/30/35/36	62.0; Max 108.0	61.3	56.1	1.96 (95%CI 1.51–2.55)	
HER2 (−)	968	67.0	657/311	478/490/0	403/225/228/112	75.5	69.2	
Lago et al. (2020) 23	01/2007–06/2014	Spain	HER2 (+)	14	69.0	11/3	NA	14/0	NA	54.0	45.0	45.0	2.38 (95%CI 1.08–5.24) a	
HER2 (−)	92	57/35	63/29	69.9	66.1	
Li et al. (2021) 24	01/2013–04/2015	China	HER2 (+)	115	NA	90/25	27/88	105/1/9	12/45/58/0	62.2 (1.0–107.0)	65.8	39.1	3.33 (95%CI 2.35–4.72)	
HER2 (−)	1006	812/194	351/655	445/269/192	123/408/466/9	91.8	53.4	
Lian et al. (2022) 25	01/2010–12/2015	China	HER2 (+)	13	NA	63/12	52/23	40/35/0	8/29/30/8	48.0 (1.0–123.0)	39.4	25.5	2.26 (95%CI 0.88–5.80)	
HER2 (−)	62	72.0	57.1	
Lv et al. (2014) 26	01/2007–01/2009	China	HER2 (+)	24	NA	18/6	NA	16/3/5	9/15/0	45.3 (9.0–60.0)	31.4	NA	1.66 (95%CI 0.90–3.05)	
HER2 (−)	105	79/26	89/6/10	17/88/0	60.0	
Nagatsuma et al. (2015) 27	01/2003–07/2007	Japan	HER2 (+)	112	66.0	90/22	109/3	NA	52/28/22/10	60.1 (0.1–126.0)	87.0	82.2	0.84 (95%CI 0.51–1.40)	
HER2 (−)	838	63.0	544/294	808/30	477/171/133/57	82.3	78.1	
Sheng et al. (2013) 10	2008	China	HER2 (+)	91	NA	NA	NA	NA	NA	26.0 (2.0–45.0)	63.0	NA	1.04 (95%CI 0.66–1.66)	
HER2 (−)	635	65.0	
Shi et al. (2017) 28	12/2012–06/2013	China	HER2 (+)	39	61.0	167/72	198/41	104/135/0	39/78/102/20	33.0 (19.0–42.0)	54.9	NA	1.46 (95%CI 0.92–2.32)	
HER2 (−)	200	67.2	
Tang et al. (2015) 29	2007–2010	China	HER2 (+)	21	NA	16/5	NA	9/12	5/14/2	Max 48.4	51.6	NA	0.82 (95%CI 0.29–2.33)	
HER2 (−)	100	69/31	15/83	31/47/22	55.0	
Terashima et al. (2012) 30	10/2001–12/2004	Japan	HER2 (+)	113	NA	565/264	NA	NA	0/372/457/0	Max 60.0	75.1	64.5	1.05 (95%CI 0.73–1.51)	
HER2 (−)	716	78.5	68.3	
Wei et al. (2020) 31	10/2013–12/2014	China	HER2 (+)	55	NA	45/10	27/28	NA	11/18/26/0	Max 60.0	47.0	43.2	1.52 (95%CI 0.90–2.57)	
HER2 (−)	140	103/37	66/74	20/31/89/0	56.0	48.6	
Wiegand et al. (2014) 32	2001–2011	Canada	HER2 (+)	30	67.9	21/9	NA	27/1/2	NA	Max 110.0	30.0	NA	1.73 (95%CI 1.03–2.89)	
HER2 (−)	223	65.2	159/64	132/56/35	60.3	
Xu et al. (2018) 33	2006–2009	China	HER2 (+)	36	NA	25/11	NA	27/6/3	27/9	Max 90.0	68.9	44.9	1.60 (95%CI 1.08–2.37)	
HER2 (−)	244	147/97	63/108/73	144/100	79.3	61.1	
The underlined number in “Lauren (I/D/M)” represented the combined amount of both diffuse and mixed type, while in “TNM (I/II/III/IV),” it represented the combined number of either stage 1/2 or 3/4.

a This HR of “HER2 (+) versus HER2 (−)” was transformed from the original result of “HER2 (−) versus HER2 (+)” in the study.

G/J, gastric/junctional; HR, hazard ratio; I/D/M, intestinal/diffuse/mixed; M/F, male/female; NA, not available.

Table 2. Baseline features of included studies (advanced).

Study	Date of diagnosis	Country	Group	Sample size	Median age (years)	Sex (M/F)	ECOG (0/1/2)	Location (G/J)	Lauren (I/D/M)	Metastasis (Y/N)	Previous gastrectomy (Y/N)	Follow-up (months)	Chemotherapy only (C)	
Median survival time (months)	Overall survival (HR)	
Dai et al. (2013) 34	10/2004–03/2012	China	HER2 (+)	37	53.0	135/84	NA	158/61	NA	37/0	51/168	20.0; Max 57.0	9.0 (95%CI 4.6–13.4)	1.37 (95%CI 1.01–1.86)	
HER2 (−)	182	182/0	13.1 (95%CI 11.3–15.0)	
Fuse et al. (2016) 35	01/2006–03/2010	Japan	HER2 (+)	43	NA	34/9	33/10	40/3	NA	NA	10/33	58.4; Max 70.0	11.7 (95%CI 7.4–16.0)	1.09 (95%CI 0.78–1.51)	
HER2 (−)	250	167/83	170/80	223/27	90/160	13.7 (95%CI 12.4–14.9)	
Haffner et al. (2021) 36	05/2014–01/2018	Germany	HER2 (+)	69 (60 Patients receiving HER2-targeted treatment were excluded)	65.6	55/14	57/10	21/48	NA	69/0	14/55	Max 80.0	NA	2.96 (95%CI 1.17–7.49)	
HER2 (−)	270 (65 Patients receiving HER2-targeted treatment were excluded)	184/86	244/21	141/124	269/0	109/161	
Honma et al. (2014) 37	04/2007–03/2011	Japan	HER2 (+)	7	66.0	6/1	7/0	NA	NA	7/0	2/5	12.0 (0.8–42.4)	13.6 (95%CI 0.8–44.7)	2.18 (95%CI 0.71–6.67) a	
HER2 (−)	70	66.0	55/15	69/1	70/0	10/60	12.9 (95%CI 8.3–17.5)	
Huemer et al. (2020) 38	05/2011–08/2018	Austria	HER2 (+)	38 (28 Patients receiving HER2-targeted treatment were excluded)	66.0	26/12	NA	18/19	29/3/1	NA	12/26	NA	6.9 (95%CI 4.0–9.8)	6.47 (95%CI 2.77–15.11)	
HER2 (−)	145 (15 Patients receiving HER2-targeted treatment were excluded)	67.0	98/47	75/58	57/57/9	62/83	12.0 (95%CI 10.5–14.1)	
Jiang et al. (2017) 39	01/2012–06/2015	China	HER2 (+)	35 (28 Patients receiving HER2-targeted treatment were excluded)	NA	27/8	All 0–2	29/6	12/6	35/0	29/5	9.8 (2.4–36.2)	10.5 (95%CI 2.7–18.3)	0.91 (95%CI 0.18–4.56)	
HER2 (−)	59	44/15	47/12	8/12	59/0	44/15	8.7 (95%CI 7.7–12.7)	
Junior et al. (2016) 40	01/2011–05/2015	Brazil	HER2 (+)	5	58.0	4/1	0/5/0	5/0	3/2	5/0	0/5	Max 32.0	14.8	1.53 (95%CI 0.50–4.66)	
HER2 (−)	27	54.0	17/10	2/17/8	21/6	11/16	27/0	0/27	16.9	
Lee et al. (2017) 41	01/2011–12/2012	South Korea	HER2 (+)	32 (21 Patients receiving HER2-targeted treatment were excluded)	61.6	28/4	NA	NA	NA	31/1	6/26	Max 43.0	5.0 (95%CI 0.4–9.5)	1.80 (95%CI 0.73–4.47)	
HER2 (−)	149	60.4	110/39	141/8	37/112	9.6 (95%CI 7.8–11.4)	
Qiu et al. (2014) 42	01/2010–12/2012	China	HER2 (+)	98 (51 Patients receiving HER2-targeted treatment were excluded)	58.0	71/27	All 0–2	70/28	58/32/8	87/11	22/76	13.5 (5.0–18.6)	11.3	1.97 (95%CI 1.13–3.45)	
HER2 (−)	251	56.0	189/62	185/66	63/172/16	225/26	60/191	14.4	
Shitara et al. (2013) 11	04/2005–08/2011	Japan	HER2 (+)	58 (43 Patients receiving HER2-targeted treatment were excluded)	65.5	40/18	30/23/5	45/13	42/16/0	58/0	24/34	38.9; Max 60.0	13.5 (95%CI 3.6–not reached)	1.05 (95%CI 0.52–2.11)	
HER2 (−)	306	64.0	196/110	123/149/34	278/28	99/217/0	306/0	146/160	13.9 (95%CI 12.7–16.1)	
The underlined number in “ECOG (0/1/2)” represented the combined amount of either 0/1or 1/2, while in “Lauren (I/D/M),” it represented the combined amount of both diffuse and mixed type.

a This HR of “HER2 (+) versus HER2 (−)” was transformed from the original result of “HER2 (−) versus HER2 (+)” in the study.

G/J, gastric/junctional; HR, hazard ratio; I/D/M, intestinal/diffuse/mixed; M/F, male/female; NA, not available; Y/N, yes/no.

Quality assessment

Concerning resectable cases, all, except one, studies were high quality (at least scored 6) based on the Newcastle–Ottawa Scale, including 11 studies scored 7, 10 studies scored 6, and 1 study scored 5. By further analyzing the results in each category, most studies had full marks in terms of “Outcome,” while some of them obtained relatively low scores concerning “Comparability.” Moreover, since all eligible studies were retrospectively analyzed, none of them reached full scores regarding “Selection” (Figure 2 and eTable 3 in Supplemental Materials).

Figure 2. Quality assessment of eligible studies by the Newcastle–Ottawa Scale.

All studies with advanced-stage patients were high quality based on the Newcastle-Ottawa Scale, including two studies scored 8, five studies scored 7, and three studies scored 6. Via further analyzing the scores in each category, the majority of studies had full marks regarding “Outcome,” while some of them received relatively low scores concerning “Comparability.” Only two prospective studies received full scores concerning “Selection” (Figure 2 and eTable 4 in Supplemental Materials).

Overall survival (resectable)

By pooling 22 studies together, HER2-positive groups had a significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32–1.85, p < 0.00001). The overall heterogeneity index was I2 = 53% (Figure 3). The risk of publication bias among all included studies was relatively low based on the symmetry of the funnel plot (eFigure 1 in Supplemental Materials).

Figure 3. Forest plot of pooled analysis on resectable gastric cancer patients.

Since the heterogeneity level could not be neglected, we conducted comprehensive sensitivity analyses to test the stability of outcomes. Results from all four methods of sensitivity analyses confirmed that the overall pooled outcome was stable (eTable 5 in Supplemental Materials). Moreover, the leave-one-out method confirmed that Li et al. 24 might be the biggest source of heterogeneity since eliminating Li et al. 24 could lower the overall heterogeneity level to I2 = 25% (HR 1.48, 95%CI 1.29–1.70, p < 0.00001) (eTable 5 in Supplemental Materials).

In subgroup analysis based on geographical difference, patients with HER2 positivity also had significantly worse survival than those with HER2-negative expression, irrespective of studies from East Asian (n = 18, HR 1.56, 95%CI 1.29–1.89, p < 0.00001) or non-East Asian countries (n = 4, HR 1.58, 95%CI 1.06–2.36, p = 0.03).

Overall survival (advanced)

For HER2-positive patients receiving chemotherapy only (n = 10), HER2 overexpression was also an unfavorable prognostic indicator (HR 1.70, 95%CI 1.23–2.35, p = 0.001). The overall heterogeneity level was I2 = 56% (Figure 4). The risk of publication bias among eligible studies was not high due to the symmetry of the funnel plot (eFigure 2 in Supplemental Materials).

Figure 4. Forest plot of pooled analysis on advanced gastric cancer patients and sensitivity analysis.

Upper portion: Pooled outcome of advanced-stage patients treated by chemotherapy only; Middle portion: The leave-one-out method of sensitivity analysis by eliminating one study with major heterogeneity; Lower portion: Sensitivity analysis by eliminating studies based on non-East Asian population.

Since the heterogeneity level could not be ignored, we performed comprehensive sensitivity analyses to examine the stability of outcomes. Results from all three methods of sensitivity analyses verified the stability of the overall pooled outcome (eTable 6 in Supplemental Materials). Among all eligible studies, Huemer et al. 38 might be the primary source of heterogeneity by the leave-one-out method since excluding it could help reduce heterogeneity to I2 = 1% (HR 1.37, 95%CI 1.14–1.65, p = 0.0008) (eTable 6 in Supplemental Materials).

Subgroup analysis based on geographical difference suggested that HER2-positive patients had significantly poorer prognosis than HER2-negative counterparts, irrespective of studies from East Asian (n = 7, HR 1.32, 95%CI 1.09–1.60, p = 0.004) or non-East Asian countries (n = 3, HR 3.27, 95%CI 1.46–7.34, p = 0.004).

Discussion

Although HER2 is a vital therapeutic target and routinely detected among gastric cancer patients, its prognostic value remains controversial. Previously published meta-analyses reported inconsistent conclusions on this topic. To be specific, six meta-analyses concluded that HER2 positivity was associated with a poorer prognosis, while two found it irrelevant to survival expectancy (eTable 7 in Supplemental Materials). However, none of these meta-analyses were based on consistent HER2 evaluation standards across included studies, let alone in accordance with the HER2 evaluation system recommended by NCCN guidelines. 6 Moreover, baseline comparability and methodological quality were poorly controlled among most of these meta-analyses, which resulted in high heterogeneity and lowered the credibility of them to become clinically available (eTable 7 in Supplemental Materials).

Learning lessons from previous meta-analyses, we conducted this systematic review and meta-analysis by strictly maintaining homogeneity across included studies and subsequent calculations. All studies must strictly conform with HER2 evaluation standards recommended by NCCN guidelines 6 without any exception. Meanwhile, since resectable and advanced cases were quite different in terms of clinical features and therapeutic reactions, they were separately investigated in our pooled analysis to lower heterogeneity and highlight clinical specificity. Regarding resectable gastric cancer, we confirmed that HER2 positivity was significantly associated with a worse prognosis compared to HER2-negative expression. We then conducted comprehensive sensitivity analyses to test the stability of outcomes as well as find out potential sources of heterogeneity. Regardless of the calculation model, methodological quality, or sample size, pooled results remained stable. Therefore, all our results consistently proved that HER2 was a novel survival biomarker for resectable gastric cancer under current HER2 evaluation standards. From the perspective of each included study, most of them reported either statistical significance or an insignificant tendency of unfavorable survival by HER2 overexpression. And that is why a meta-analysis could lead to clear and significant results here by elevating statistical power. Only three studies reported favorable survival tendency (HR < 1) of HER2 overexpression without statistical significance.14–16 However, they were either with very small sample sizes or unbalanced levels of TNM stages, which were therefore removed by sensitivity analyses without affecting outcome stability. This could also hint that heterogeneous results among other meta-analyses or original studies might be indeed due to their inconsistent standards of HER2 status and incomparable clinical features.

Regarding advanced gastric cancer, since anti-HER2 trastuzumab had been recommended for HER2-positive patients, 6 we only compared survival data of HER2-positive and HER2-negative groups treated by chemotherapy only or chemotherapy plus targeted treatments (except for those targeting HER2), to eliminate impacts from therapeutic interventions. As a result, HER2 overexpression was also a negative indicator of survival among advanced-stage patients. Leave-one-out method of sensitivity analyses indicated that Huemer et al. 38 might be the major source of heterogeneity since the elimination of which significantly lowered the heterogeneity level to I2 = 1%. Moreover, after excluding another two non-East Asian countries-based studies (Haffner et al. 36 and Junior et al. 40 ), the heterogeneity level further reduced to I2 = 0% while the pooled outcome remained stable. This hinted that geographical disparity might have a significant impact on heterogeneity level. Furthermore, like resectable cases, both East Asian and non-East Asian countries subgroups reported similar outcomes that HER2 overexpression was linked to worse survival among advanced-stage patients. This might implicate the potential of global accessibility of our conclusions. All these pooled results seemed consistent with findings of cellular mechanisms, where HER2 overexpression led to activation of multiple downstream proliferative pathways, such as MAPK and PI3K/Akt signaling, 43 making it easier to explain its unfavorable prognostic impacts.

Although our systematic review and meta-analysis was rigorously designed and performed, some limitations were still inevitable. First, the number of included studies and overall population could be more, especially for advanced cases, which could help us to perform more subgroup analyses and sensitivity analyses so that pooled results could be more clinically meaningful and specific. Second, due to lacking original data from the included studies, we could only provide an overall survival analysis. We hoped that more studies could be provided in the future concerning more survival endpoints such as disease-free survival or progression-free survival.

Conclusion

Taken together, based on rigorous approaches and analyses, our study made the first credible pooled evidence suggesting that as a novel survival biomarker in gastric cancer, overexpression of HER2 indicates unfavorable survival outcomes among both resectable and advanced patients, irrespective of East Asian or non-East Asian population. We hypothesized that anti-HER2 therapy may also be a promising option among resectable cases in the future with improved global access.

Supplemental Material

sj-docx-1-tam-10.1177_17588359241271913 – Supplemental material for HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis

Supplemental material, sj-docx-1-tam-10.1177_17588359241271913 for HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis by Ji Cheng, Ming Cai, Guobin Wang and Kaixiong Tao in Therapeutic Advances in Medical Oncology

sj-pdf-2-tam-10.1177_17588359241271913 – Supplemental material for HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis

Supplemental material, sj-pdf-2-tam-10.1177_17588359241271913 for HER2 becomes a novel survival biomarker for gastric cancer patients: a pooled analysis by Ji Cheng, Ming Cai, Guobin Wang and Kaixiong Tao in Therapeutic Advances in Medical Oncology

We thank all members in our department for offering clinical and methodological suggestions.

Declarations

ORCID iD: Ji Cheng https://orcid.org/0000-0002-7673-9157

Supplemental material: Supplemental material for this article is available online.

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contributions: Ji Cheng: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Writing – original draft; Writing – review & editing.

Ming Cai: Conceptualization; Data curation; Formal analysis; Funding acquisition.

Guobin Wang: Formal analysis; Funding acquisition; Writing – original draft; Writing – review & editing.

Kaixiong Tao: Conceptualization; Data curation; Formal analysis.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This meta-analysis was funded by the Natural Science Foundation of Hubei (2024AFB673) to Ji Cheng.

The authors declare that there is no conflict of interest.

Availability of data and materials: Not applicable.
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References

1 Sung H Ferlay J Siegel RL , et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 : 209–249.33538338
2 Siegel RL Miller KD Fuchs HE , et al . Cancer statistics, 2022. CA Cancer J Clin 2022; 72 : 7–33.35020204
3 Smyth EC Nilsson M Grabsch HI , et al . Gastric cancer. Lancet 2020; 396 : 635–648.32861308
4 Yeoh KG Tan P. Mapping the genomic diaspora of gastric cancer. Nat Rev Cancer 2022; 22 : 71–84.34702982
5 Bang YJ Van Cutsem E Feyereislova A , et al . Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376 : 687–697.20728210
6 National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Gastric cancer, version 3, https://www.nccn.org (2022, accessed June 2022).
7 Cho JH Lim JY Cho JY. Survival analysis based on human epidermal growth factor 2 status in stage II–III gastric cancer. World J Gastroenterol 2017; 23 : 7407–7414.29151694
8 Kato S Okamura R Baumgartner JM , et al . Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction, and gastric adenocarcinoma. Clin Cancer Res 2018; 24 : 6248–6256.30348637
9 Janjigian YY Werner D Pauligk C , et al . Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis. Ann Oncol 2012; 23 : 2656–2662.22689179
10 Sheng WQ Huang D Ying JM , et al . HER2 status in gastric cancers: a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance. Ann Oncol 2013; 24 : 2360–2364.23788757
11 Shitara K Yatabe Y Matsuo K , et al . Prognosis of patients with advanced gastric cancer by HER2 status and trastuzumab treatment. Gastric Cancer 2013; 16 : 261–267.22797858
12 Page MJ McKenzie JE Bossuyt PM , et al . The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372 : n71.33782057
13 Tierney JF Stewart LA Ghersi D , et al . Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8 : 16.17555582
14 Byeon SJ Lee HS Kim MA , et al . Expression of the ERBB family of ligands and receptors in gastric cancer. Pathobiology 2017; 84 : 210–217.28399526
15 Chen L Wang L Li X , et al . Clinic-pathological characteristics and prognostic value of PD-L1 and HER2 in gastric cancer. DNA Cell Biol 2021; 40 : 405–413.33605797
16 Fisher SB Fisher KE Squires MH 3rd , et al . HER2 in resected gastric cancer: is there prognostic value? J Surg Oncol 2014; 109 : 61–66.24122802
17 Fusco N Rocco EG Del Conte C , et al . HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions. Mod Pathol 2013; 26 : 816–824.23348899
18 Gu J Zheng L Zhang L , et al . TFF3 and HER2 expression and their correlation with survival in gastric cancer. Tumour Biol 2015; 36 : 3001–3007.25514872
19 Jiang W Jin Z Zhou F , et al . High co-expression of Sp1 and HER-2 is correlated with poor prognosis of gastric cancer patients. Surg Oncol 2015; 24 : 220–225.26096373
20 Katai H Ishida M Yamashita H , et al . HER2 expression in carcinomas of the true cardia (Siewert type II esophagogastric junction carcinoma). World J Surg 2014; 38 : 426–430.24114368
21 Kataoka Y Okabe H Yoshizawa A , et al . HER2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer 2013; 16 : 84–93.22410801
22 Kurokawa Y Matsuura N Kimura Y , et al . Multicenter large-scale study of prognostic impact of HER2 expression in patients with resectable gastric cancer. Gastric Cancer 2015; 18 : 691–697.25224659
23 Lago NM Villar MV Ponte RV , et al . Impact of HER2 status in resected gastric or gastroesophageal junction adenocarcinoma in a Western population. Ecancermedicalscience 2020; 14 : 1020.32256703
24 Li F Meng G Tan B , et al . Relationship between HER2 expression and tumor interstitial angiogenesis in primary gastric cancer and its effect on prognosis. Pathol Res Pract 2021; 217 : 153280.33253925
25 Lian J Zhang G Zhang Y , et al . PD-L1 and HER2 expression in gastric adenocarcinoma and their prognostic significance. Dig Liver Dis 2022; 54 : 1419–1427.35123909
26 Lv J Yao YS Zhou F , et al . Prognosis significance of HER2 status and TACC1 expression in patients with gastric carcinoma. Med Oncol 2014; 31 : 280.25297519
27 Nagatsuma AK Aizawa M Kuwata T , et al . Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer 2015; 18 : 227–238.24626858
28 Shi HZ Wang YN Huang XH , et al . Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer. World J Gastroenterol 2017; 23 : 1836–1842.28348489
29 Tang D Liu CY Shen D , et al . Assessment and prognostic analysis of EGFR, HER2, and HER3 protein expression in surgically resected gastric adenocarcinomas. Onco Targets Ther 2015; 8 : 7–14.25565860
30 Terashima M Kitada K Ochiai A , et al . Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin Cancer Res 2012; 18 : 5992–6000.22977193
31 Wei Z Huang L Zhang X , et al . Expression and significance of Her2 and Ki-67 in gastric adenocarcinoma without distant metastasis: a cohort study. BMC Gastroenterol 2020; 20 : 343.33059614
32 Wiegand KC Sy K Kalloger SE , et al . ARID1A/BAF250a as a prognostic marker for gastric carcinoma: a study of 2 cohorts. Hum Pathol 2014; 45 : 1258–1268.24767857
33 Xu B Huang C Yang X , et al . Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer. Oncol Lett 2018; 15 : 5185–5192.29552156
34 Dai SQ An X Wang F , et al . Serum HER 2 extracellular domain level is correlated with tissue HER 2 status in metastatic gastric or gastro-oesophageal junction adenocarcinoma. PLoS One 2013; 8 : e63458.
35 Fuse N Kuboki Y Kuwata T , et al . Prognostic impact of HER2, EGFR, and c-MET status on overall survival of advanced gastric cancer patients. Gastric Cancer 2016; 19 : 183–191.25682441
36 Haffner I Schierle K Raimundez E , et al . HER2 expression, test deviations, and their impact on survival in metastatic gastric cancer: results from the prospective multicenter VARIANZ study. J Clin Oncol 2021; 39 : 1468–1478.33764808
37 Honma Y Shimada Y Takashima A , et al . Efficacy of S-1 plus cisplatin combination chemotherapy in patients with HER2-positive advanced gastric cancer. Int J Clin Oncol 2014; 19 : 863–870.24218279
38 Huemer F Weiss L Regitnig P , et al . Local and central evaluation of HER2 positivity and clinical outcome in advanced gastric and gastroesophageal cancer—results from the AGMT GASTRIC-5 registry. J Clin Med 2020; 9 : 935.32235305
39 Jiang H Li Q Yu S , et al . Impact of HER2 expression on outcome in gastric cancer patients with liver metastasis. Clin Transl Oncol 2017; 19 : 197–203.27324991
40 Junior PN Neto RA Forones NM. Her2 expression as a prognostic factor in metastatic gastric cancer. Arq Gastroenterol 2016; 53 : 62–67.27305410
41 Lee JS Kim SH Im SA , et al . Human epidermal growth factor receptor 2 expression in unresectable gastric cancers: relationship with CT characteristics. Korean J Radiol 2017; 18 : 809–820.28860898
42 Qiu MZ Li Q Wang ZQ , et al . HER2-positive patients receiving trastuzumab treatment have a comparable prognosis with HER2-negative advanced gastric cancer patients: a prospective cohort observation. Int J Cancer 2014; 134 : 2468–2477.24155030
43 Adam-Artigues A Arenas EJ Martinez-Sabadell A , et al . Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Sci Adv 2022; 8 : eabk2746.
