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A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

Marta Castroviejo-Bermejo1, Cristina Cruz1,2,3, Alba Llop-Guevara1

  • 1Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

EMBO Molecular Medicine
|November 1, 2018
PubMed

Insights

A new RAD51 score accurately identifies homologous recombination deficiency (HRD) in breast cancer (BC) patients, predicting sensitivity to Poly(ADP-ribose) polymerase inhibitors (PARPi). This functional biomarker expands PARPi therapy beyond BRCA1/2 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) show efficacy in cancers with homologous recombination DNA repair (HRR) defects, notably BRCA1/2-mutated tumors.
  • Identifying additional HRR-deficient tumors is crucial for expanding PARPi therapeutic applications.
  • Current predictive tests may not fully capture functional HRR deficiency across diverse cancer types.

Purpose of the Study:

  • To evaluate the efficacy of the PARPi olaparib in patient-derived breast cancer xenografts (PDXs).
  • To investigate mechanisms of PARPi sensitivity and resistance.
  • To assess the predictive capacity of a RAD51-based biomarker compared to genomic tests for identifying HRR-deficient tumors.

Main Methods:

  • Utilized patient-derived tumor xenografts (PDXs) from breast cancer patients.
  • Conducted exome sequencing, BRCA1 promoter methylation analysis, and RAD51 immunostaining.
  • Compared RAD51 and homologous recombination deficiency (HRD) scores in independent PDX panels and clinical samples.

Main Results:

  • The RAD51 score effectively distinguished PARPi sensitivity from resistance in breast cancer PDXs.
  • RAD51 scoring outperformed genomic tests in predicting PARPi response.
  • All tested PALB2-related hereditary breast cancer samples were classified as HRR-deficient using the RAD51 score.

Conclusions:

  • The functional RAD51 biomarker accurately identifies PARPi-sensitive breast cancer.
  • This assay broadens the eligible patient population for PARPi therapy beyond those with BRCA1/2 mutations.
  • RAD51 immunostaining offers a feasible method for identifying HRR deficiency in clinical settings.
Keywords:
BRCA1PALB2PARP inhibitorsRAD51homologous recombination

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