Genetic and immune microenvironment characterization of HER2‐positive gastric cancer: Their association with response to trastuzumab‐based treatment

Abstract

Background We aimed to determine the molecular and immune microenvironment characteristics of HER2‐positive gastric cancer (GC) related to the patient's response to first‐line trastuzumab‐based treatment. Methods Eighty‐three cases of HER2‐positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post‐treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor‐infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression‐free survival (PFS) analysis was performed. Results Group 1 showed frequent amplification of G1/S cell cycle checkpoint‐related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune‐related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle‐related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune‐related including high density of CD3−CD57+ NK cells and PD‐L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). Conclusion HER2‐positive GC with favorable response to trastuzumab were characterized by cell cycle‐related gene alterations and increased CD3−CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2‐positive GC.

Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers

“… 10 ). Amplification/overexpression of cyclin E has been proposed as a mechanism of resistance to HER2-targeted therapies, which has been demonstrated by a worse clinical benefit from trastuzumab in HER2/cyclin E-positive breast cancers ( 9 ), and poorer prognosis in gastric cancer ( 21 ) However, a recent report has suggested cyclin E amplification is associated with better progression-free survival in HER2-positive gastric cancer ( 38 ). Therefore, further study is needed to determine the effect of cyclin E amplification on the antitumor activity HER2-targeted therapies in the clinic, especially in the context of T-DXd treatment.…”

HER2+ advanced gastric cancer: Current state and opportunities (Review)

“…Overexpression of HER2 confers a heightened malignant phenotype to the tumor ( 5 ). Specifically, activated HER2 promotes GC cell proliferation and survival by regulating the expression of cycle-related proteins such as SKP2 and p27/Cdk2 ( 8 - 10 ). The overexpression of HER2 enhances vascular endothelial growth factor (VEGF) production and angiogenesis to accelerate tumor growth and metastasis ( 11 , 12 ).…”