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A Genomic Alteration in GATA3 Affects Treatment Responses With a CDK4/6 Inhibitor Collaborating With p18INK4C

Xiao Huang1, Sooryanarayana Varambally2, Sarah A Anderson2

  • 1Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama; Now with Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|July 18, 2025
PubMed

Insights

GATA3 gene mutations predict better response to cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) therapy in breast cancer. Nuclear p18 protein expression may also indicate treatment success.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are effective for hormone receptor-positive, human epidermal growth receptor 2-negative breast cancer.
  • Tumor resistance to CDK4/6i is a significant clinical challenge, necessitating the identification of predictive biomarkers.
  • Current understanding of resistance mechanisms lacks validated predictive markers for clinical application.

Purpose of the Study:

  • To investigate tumor molecular profiling in advanced breast cancer patients treated with CDK4/6i.
  • To identify potential molecular markers that predict response to CDK4/6i therapy.
  • To explore the underlying mechanisms associated with treatment response and resistance.

Main Methods:

  • Analysis of tumor molecular profiles from 42 patients with advanced breast carcinoma undergoing CDK4/6i therapy.
  • Genomic analysis to identify gene mutations, focusing on GATA-binding protein 3 (GATA3).
  • Assessment of nuclear p18 protein expression as a potential biomarker.

Main Results:

  • Tumors with GATA-binding protein 3 (GATA3) gene mutations, particularly frameshift variants, demonstrated a significantly better response to CDK4/6i therapy.
  • Nuclear expression of p18, an INK family protein, was positively correlated with both GATA3 mutations and improved CDK4/6i treatment outcomes.
  • These findings suggest a potential interplay between GATA3 mutation status and p18 expression in predicting therapeutic efficacy.

Conclusions:

  • GATA-binding protein 3 (GATA3) gene mutation may serve as a predictive marker for CDK4/6i therapy response in breast carcinoma.
  • The combined evaluation of GATA3 mutation and nuclear p18 protein expression could offer valuable insights for personalized treatment strategies.
  • Further research is warranted to validate these findings and elucidate the precise molecular mechanisms involved in CDK4/6i resistance.
Keywords:
CDK4/6 inhibitorGATA3 mutationadvanced breast carcinomap18 immunohistochemistry

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