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Development of an Immunohistochemical Assay to Detect the Ataxia-Telangiectasia Mutated (ATM) Protein in Gastric

Rachel M Miller1, Chinedu Nworu1, Laurel McKee1

  • 1Ventana Medical Systems Inc., a Member of the Roche Group, Tucson, AZ.

Applied Immunohistochemistry & Molecular Morphology : AIMM
|June 18, 2019
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) deficiency may predict better overall survival in gastric cancer patients treated with olaparib and paclitaxel. An ATM immunohistochemical assay showed reproducibility but requires further clinical validation for companion diagnostic use.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biomarker Development

Background:

  • Ataxia-telangiectasia mutated (ATM) is crucial for DNA damage response and a potential biomarker for gastric cancer.
  • Previous studies suggested a potential survival benefit in ATM-negative gastric cancer patients receiving olaparib plus paclitaxel.

Purpose of the Study:

  • To develop and validate an ATM immunohistochemical (IHC) assay for identifying gastric carcinoma patients who may benefit from targeted therapies.
  • To assess the utility of the ATM (Y170) assay in a Phase III clinical trial.

Main Methods:

  • Development and optimization of the VENTANA ATM (Y170) assay using an anti-ATM antibody on a BenchMark ULTRA instrument.
  • Characterization of assay performance including sensitivity, specificity, robustness, and reproducibility.
  • Definition of a scoring algorithm with a <25% tumor cell nuclei staining cutoff for ATM-deficiency.

Main Results:

  • The ATM (Y170) assay met predefined acceptance criteria and demonstrated reproducibility.
  • The assay is suitable for investigational use in evaluating gastric carcinoma samples for ATM-deficiency.
  • The Phase III GOLD trial did not meet its primary endpoint, suggesting but not proving ATM IHC utility.

Conclusions:

  • The developed ATM (Y170) IHC assay is reproducible and suitable for investigational use in gastric cancer.
  • Further clinical validation is required to establish the ATM (Y170) assay's utility as a companion diagnostic.
  • The study did not definitively demonstrate that ATM assessment can guide olaparib plus paclitaxel treatment decisions in gastric carcinoma.

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