Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study

Gao, Xintao; Zhao, Lulu; Zhang, Nannan; Han, Wei; Liu, Kun; Yan, Junya; Chen, Ling; Pan, Yan; Li, Renlong; Li, Wenjiao; Zhang, Haohao; Li, Hongwei; Wang, Shibo; Gao, Xiaoliang; Niu, Penghui; Wang, Wanqing; Ji, Gang; Zhao, Qingchuan; Lu, Yuanyuan; Li, Zengshan; Shang, Lei; Liang, Han; Wu, Kaichun; Deng, Jingyu; Chen, Yingtai; Nie, Yongzhan

doi:10.1097/js9.0000000000000370

Cited by 7 publications

(4 citation statements)

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“…involved 5622 consecutive stage II/III GC patients and observed that HER2 overexpression was independently associated with a lower 5‐year OS in stage II, but not in stage III GC. 43 These findings together revealed that the impacts of HER2 amplification and PD‐L1 expression on prognosis in patients with GC remains controversial and should be re‐considered under different circumstances (e.g., clinical, pathological stage, genomic, transcriptomic, and immune landscapes).…”

Section: Discussionmentioning

confidence: 96%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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BackgroundAnti‐PD1/PD‐L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first‐line therapy for HER2 overexpression‐positive advanced gastric cancers (GC), suggesting that HER2 and PD‐L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD‐L1 expression.Patients and MethodsNext‐generation targeted sequencing and PD‐L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD‐L1 expression were analyzed.ResultsThe most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy‐six (10%) patients were HER2 amplification, and 291 (40%) had positive PD‐L1 expression. Classifying the total population based on HER2 amplification and PD‐L1 expression level, 735 patients were divided into four subgroups: HER2+/PD‐L1+ (4.5%), HER2+/PD‐L1− (5.9%), HER2−/PD‐L1+ (35.1%), and HER2−/PD‐L1− (54.5%). The HER2+/PD‐L1− and HER2+/PD‐L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD‐L1− subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2−/PD‐L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD‐L1− subgroup had the highest TMB level and HER2−/PD‐L1+ subgroup had the highest proportion of patients with microsatellite instability‐high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD‐L1 expression and therapeutic genomic alterations, but no impact on the prognosis.ConclusionThe combination of HER2 amplification and PD‐L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

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Section: Discussionmentioning

confidence: 96%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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“…According to previous studies, low levels of HER2 expression account for 40% to 60% of all GC patients[ 14 ]. In a study involving patients with stage III GC, Gao et al [ 15 ] reported that the prognosis of patients with an HER2 score of 1 or 2+ was significantly better than that of patients with an HER2 score of 0 or 3+. In addition, most previous studies focused on the relationship between HER2 and tumor cell growth and apoptosis; relatively few studies have been conducted on the role of HER2 with respect to the immune cycle of tumors and the role of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

Ma,

Ou,

Yang

et al. 2024

World J Clin Oncol

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BACKGROUND Although treatment options for gastric cancer (GC) continue to advance, the overall prognosis for patients with GC remains poor. At present, the predictors of treatment efficacy remain controversial except for high microsatellite instability. AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2 (HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital, Chinese Academy of Medical Sciences between November 2020 and October 2022. All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment. RESULTS As of July 1, 2023, the objective response rate was 61.9%, and the disease control rate was 96.8%. The median progression-free survival (mPFS) for all patients was 6.3 months. The median overall survival was not achieved. Survival analysis showed that patients with a combined positive score (CPS) ≥ 1 exhibited an extended trend in progression-free survival (PFS) when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment. PFS exhibited a trend for prolongation as the expression level of HER2 increased. Based on PFS, we divided patients into two groups: A treatment group with excellent efficacy and a treatment group with poor efficacy. The mPFS of the excellent efficacy group was 8 months, with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery. The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery. Using good/poor efficacy as the endpoint of our study, univariate analysis revealed that both CPS score (P = 0.004) and HER2 expression level (P = 0.015) were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC (AGC). Finally, multivariate analysis confirmed that CPS score was a significant influencing factor. CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

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“…The clinical information of the internal populations was drawn from the Xijing Hospital of Digestive Diseases Gastric Cancer Database (XJHDDGCD). 17 , 18 This database contains prospectively collected clinicopathologic data, biological specimens, and follow‐up information on patients who were admitted to Xijing Hospital. Tissue samples from gastric cancer patients eligible for inclusion can be randomly selected for this study.…”

Section: Methodsmentioning

confidence: 99%

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

Gao,

Han,

Chen

et al. 2023

Cancer Medicine

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BackgroundBetter predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil‐based adjuvant chemotherapy benefits.MethodsCDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193).ResultsIn the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2‐negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2‐negative and CDX2‐positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5‐year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery‐only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts.ConclusionsNegative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

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Impact of HER2 on prognosis and benefit from adjuvant chemotherapy in stage II/III gastric cancer patients: a multicenter observational study

Cited by 7 publications

References 50 publications

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer

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