Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer

Abstract

BackgroundPD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC.MethodsBetween January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism.ResultsWe retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2.ConclusionHER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.

Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

“…A significant prognostic value of ERBB2 CN, TMB and genomic alterations associated with HER2 signaling could not be confirmed in this cohort. PD-L1 expression has been found to co-occur with HER2-positivity in 25-85% of GC/GEJ patients [21][22][23]32]. With 47.3% of HER2+/PD-L1+ patients, our result falls within the reported range.…”

“…In the study by Lian et al, combined HER2 and PD-L1 positivity was associated with improved overall survival in resectable GC [22]. In contrast, Lv et al showed that HER2+/PD-L1+ GC patients had inferior survival compared with HER2-/PD-L1patients [32]. The authors speculated that immunotherapy would be less suitable for HER2positive GC, which is controversial since the first interim analysis of the KEYNOTE-811 demonstrated an increased response rate of HER2-positive mGC/mGEJC patients to trastuzumab and pembrolizumab combined with chemotherapy [21].…”

Multimodal MRI for Estimating Her-2 Gene Expression in Endometrial Cancer

“…Yang et al [14] found more tumor infiltration lymphocytes (TILs) in Her-2-positive regions of breast cancer tumor cells than in Her-2-negative expression regions. In this study, we found that Her-2 positive patients tended to have lower differentiation and higher tumor grade, which may be related to the high expression of CD4+ T cells as well as the relatively low expression of CD8+ T cells in the tumor stroma of the Her-2 positive group [16]. Furthermore, Yang et al [17,18] have confirmed that Her-2 positivity is usually indicative of EC with high proliferation and low differentiation.…”

HER2 Prognostic Significance and Therapeutic Implications in Gastric Cardia Adenocarcinoma: Insights from Multi-Omics Profiling

“…Given the widespread use of immune checkpoint blockade therapies in gastrointestinal tumors [23][24][25]57 , we sought to determine whether there were distinct immune inhibitory checkpoints among three HER2 groups. To achieve this, we compared the RNA expression levels of key immune inhibitory and stimulatory checkpoint genes, along with their paired ligands and receptors 58 , between tumor and NAT in each HER2 group (Figure 5E).…”

“…Currently, HER2 targeted therapy has become a vital treatment option for certain types of gastroesophageal cancers, including esophageal Adenocarcinoma (EAC), GCA, GNCA, and stomach adenocarcinoma (STAD), particularly in advanced or metastatic cases 20, 23,24 . Anti-HER2 targeted therapies have improved survival outcomes in advanced gastroesophageal cancer patients with HER2 overexpression [23][24][25] . However, the relatively low prevalence (less than 30%) of HER2-positive cases poses challenges [26][27][28] , particularly for HER2-negative patients.…”