Dataset Information

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

ABSTRACT: Human epidermal growth factor receptor 2 (HER2)⁺ gastric cancer (GC) is a distinct subtype of GC, accounting for 10‑20% of all cases of GC. Although the development of the anti‑HER2 monoclonal antibody trastuzumab has markedly improved response rates and prognosis of patients with HER2⁺ advanced GC (AGC), drug resistance remains a considerable challenge. Therefore, dynamic monitoring of HER2 expression levels can facilitate the identification of patients who may benefit from targeted therapy. Besides trastuzumab, DS‑8201 and RC48 have been applied in the treatment of HER2⁺ AGC, and several novel anti‑HER2 therapies are undergoing preclinical/clinical trials. At present, combination immunotherapy with anti‑HER2 agents is used as the first‑line treatment of this disease subtype. New promising approaches such as chimeric antigen receptor T‑cell immunotherapy and cancer vaccines are also being investigated for their potential to improve clinical outcomes. The current review provides new insights that will guide the future application of anti‑HER2 therapy by summarizing research progress on targeted therapy drugs for HER2⁺ AGC and combination treatments.

SUBMITTER: Hu HH

PROVIDER: S-EPMC10901538 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Hu Hui-Hui HH Wang Sai-Qi SQ Zhao Huichen H Chen Zhe-Sheng ZS Shi Xiaojing X Chen Xiao-Bing XB

International journal of oncology 20240223 4

Human epidermal growth factor receptor 2 (HER2)+ gastric cancer (GC) is a distinct subtype of GC, accounting for 10‑20% of all cases of GC. Although the development of the anti‑HER2 monoclonal antibody trastuzumab has markedly improved response rates and prognosis of patients with HER2+ advanced GC (AGC), drug resistance remains a considerable challenge. Therefore, dynamic monitoring of HER2 expression levels can facilitate the identification of patients who may benefit fro ...[more]

PMID: 38391024

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Project description:BackgroundHER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab.Patients and methodsForty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed.ResultsConcurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS.ConclusionOur results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab.Implications for practiceThis article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.

Dataset Information

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

Publications

HER2<sup>+</sup> advanced gastric cancer: Current state and opportunities (Review).

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