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Updated: Feb 11, 2026

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Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive

Asunción Díaz-Serrano1, Barbara Angulo2, Carolina Dominguez2

  • 1Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain cgomezm@seom.org asundiazserrano@gmail.com.

The Oncologist
|April 28, 2018
PubMed
Abstract

Insights

Activation of the PI3K pathway predicts poor outcomes in HER2-positive advanced gastric cancer treated with trastuzumab. This finding offers a potential biomarker for resistance to HER2-targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • HER2-positive advanced gastric cancer (AGC) is treated with trastuzumab, but resistance mechanisms are unknown.
  • Upregulation of the PI3K pathway and tyrosine kinase receptor (TKR) alterations are implicated in resistance in other cancers.

Purpose of the Study:

  • To molecularly characterize HER2-positive AGC.
  • To investigate PI3K/Akt/mTOR pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers for trastuzumab resistance.

Main Methods:

  • Analyzed 42 HER2-positive GC samples from patients receiving first-line trastuzumab-based chemotherapy.
  • Performed DNA sequencing, PTEN and MET immunohistochemistry.

Main Results:

  • Concurrent genetic alterations found in 97.1% of samples.
  • PI3K/Akt/mTOR pathway activation in 52.4%; TKR GCN gains in 38.1%.
  • PI3K/Akt/mTOR activation negatively impacted overall survival (OS) and progression-free survival (PFS).

Conclusions:

  • PI3K pathway activation is a potential predictive marker for worse outcomes in HER2-positive AGC.
  • TKR GCN gains may also influence survival benefits from trastuzumab.
  • Detailed molecular profiling of AGC provides insights into resistance mechanisms.
Keywords:
Gastric cancerHER2Next‐generation sequencingPI3KTrastuzumabTyrosine kinase receptors

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