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

Marta Castroviejo-Bermejo,Judit Grueso,Alba Llop‐Guevara,Alejandra Bruna,Vicente Peg,Sandra Bonache,Jacques Simard,José Baselga,Jean‐Yves Masson,Graham Dellaire,Jos Jonkers,Violeta Serra,Stefano Cairo,Alejandro Moles‐Fernández,Carlos Caldas,Paolo Nuciforo,Cristina Viaplana,Guillermo Villacampa,Cristina Saura,Sara Gutiérrez‐Enríquez,Cristina Cruz,Javier Cortés,Olivier Déas,Mandy Ducy,Patricia Gómez,Benedetta Pellegrino,Marta Guzmán,Olga Rodríguez,Rodrigo Dienstmann,Yasir H Ibrahim ,Albert Gris-Oliver,Xavier Serres-Créixams,Jean-Gabriel Judde,J Carl Barrett ,Mark J O’connor ,María Vidal ,Orland Dı́ez ,Judith Balmañà ,Isabel T Rubio

doi:10.15252/emmm.201809172

Abstract

Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers.

Highlights

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers
Olaparib antitumor activity in a non-germline BRCA1/2 (gBRCA) breast cancer (BC) patient-derived tumor xenograft (PDX) panel distinguishes a subset of tumors highly sensitive to PARP inhibitors (PARPi)
Our results show that RAD51 foci in PDX tumor samples correlated with PARPi response, while BRCA1 promoter hypermethylation, BRCA1 expression, BRCA1 foci, or HRR gene mutations did not fully correlate with PARPi response

Summary

Introduction

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2-related cancers. We evaluated the activity of the PARPi olaparib in patient-derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. All PALB2-related tumors were classified as HRR-deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi-sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2-related cancers

Methods

Results

Conclusion