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Genomic hallmarks of endocrine therapy resistance in ER/PR+HER2- breast tumours

Arnab Ghosh1,2, Rohan Chaubal3, Chitrarpita Das1

  • 1Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics (BRIC-NIBMG), Kalyani, India.

Communications Biology
|February 10, 2025
PubMed

Insights

Genomic analysis reveals a three-gene signature (PIK3CA-ESR1-TP53) and impaired DNA repair pathways are linked to endocrine therapy resistance in estrogen receptor-positive, HER2-negative breast cancer.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Estrogen receptor/progesterone receptor-positive, HER2-negative (ER/PR+HER2-) breast tumors are the most common subtype.
  • Endocrine therapy is effective, but resistance and recurrence remain significant challenges, impacting patient survival.
  • The genomic basis for endocrine therapy resistance in ER/PR+HER2- breast cancer is not fully understood.

Purpose of the Study:

  • To investigate the genomic underpinnings of endocrine therapy resistance in ER/PR+HER2- breast cancer.
  • To compare whole genome sequencing data from resistant and sensitive patient cohorts.
  • To identify genomic markers associated with treatment failure and disease recurrence.

Main Methods:

  • Whole genome sequencing (WGS) of tumor and normal tissue samples.
  • Comparative analysis of WGS data from endocrine-therapy resistant and sensitive ER/PR+HER2- breast cancer patients.
  • Identification of genomic signatures and pathway alterations associated with resistance.

Main Results:

  • A significant three-gene resistance signature (PIK3CA-ESR1-TP53) was identified.
  • Impaired DNA double-strand break repair and homologous recombination pathways were associated with resistance.
  • Increased genome instability, including copy-number alterations and structural variations, marked endocrine treatment resistance.

Conclusions:

  • Genomic landscape analysis can predict endocrine therapy resistance in ER/PR+HER2- breast tumors.
  • Findings suggest potential for repurposing PARP inhibitors for endocrine therapy-resistant breast cancer.
  • Understanding resistance mechanisms can guide therapeutic strategies and improve patient outcomes.

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