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BRCA1-methylated triple negative breast cancers previously exposed to neoadjuvant chemotherapy form RAD51 foci and

Carolina Velazquez1, Esin Orhan1, Imene Tabet1

  • 1Institut de Recherche en Cancérologie de Montpellier, IRCM U1194, Montpellier University, INSERM, ICM, CNRS, Montpellier, France.

Frontiers in Oncology
|April 3, 2023
PubMed
Abstract

Insights

Triple-Negative-Breast-Cancer (TNBC) with BRCA1 promoter methylation may not be homologous recombination deficient (HRD) after chemotherapy. The BRCA1 and RAD51 foci assay is crucial for verifying HRD status in these patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Approximately 15% of Triple-Negative-Breast-Cancer (TNBC) exhibit BRCA1 promoter methylation, suggesting Homologous Recombination Deficiency (HRD).
  • BRCA1-methylated (BRCA1-Me) TNBC are candidates for PARP-inhibitors or platinum-based therapies.
  • Concerns exist regarding the actual HRD status and potential chemotherapy resistance in BRCA1-Me TNBC.

Purpose of the Study:

  • To investigate the sensitivity of BRCA1-methylated TNBC models to olaparib and carboplatin.
  • To assess the homologous recombination deficiency (HRD) status in patient-derived xenografts (PDX) and cell lines.
  • To explore HR restoration mechanisms associated with olaparib resistance.

Main Methods:

  • Evaluated olaparib and carboplatin sensitivity in 8 TNBC PDX models, including BRCA1-methylated, BRCA1-mutated, and BRCA1-wild type.
  • Assessed HRD status using genomic signatures and BRCA1/RAD51 nuclear foci assays.
  • Studied HR restoration in BRCA1-deficient cell lines and their resistant subclones.

Main Results:

  • Three NACT-exposed BRCA1-Me PDX models showed poor response to olaparib, similar to BRCA1-WT PDX.
  • Treatment-naïve BRCA1-deficient PDX (1 BRCA1-Me, 2 BRCA1-mutated) responded to olaparib.
  • Olaparib-responsive PDX were negative for BRCA1/RAD51 foci, while non-responsive PDX were positive for RAD51 foci, indicating HRD in responsive and HR proficiency in non-responsive models.
  • Olaparib-resistant cell lines exhibited increased RAD51 foci, suggesting HR restoration.

Conclusions:

  • The HRD status of BRCA1-methylated TNBC, particularly after chemotherapy exposure, warrants careful evaluation.
  • The BRCA1 and RAD51 foci assay is a valuable tool for verifying HRD status in BRCA1-methylated TNBC.
Keywords:
BRCA1 methylationHRD (homologous recombination deficiency)RAD51TNBCnuclear foci

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