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

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

doi:https://doi.org/10.15252/emmm.201809172

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

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

Research output: Contribution to journal › Article › Research

98 Citations (Scopus)

Abstract

© 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.

Original language	English
Article number	e9172
Journal	EMBO Molecular Medicine
Volume	10
DOIs	https://doi.org/10.15252/emmm.201809172
Publication status	Published - 1 Dec 2018

Keywords

BRCA1
PALB2
PARP inhibitors
RAD51
homologous recombination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.15252/emmm.201809172

https://ddd.uab.cat/record/253701

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Castroviejo-Bermejo, M., Cruz, C., Llop-Guevara, A., Gutiérrez-Enríquez, S., Ducy, M., Ibrahim, Y. H., Gris-Oliver, A., Pellegrino, B., Bruna, A., Guzmán, M., Rodríguez, O., Grueso, J., Bonache, S., Moles-Fernández, A., Villacampa, G., Viaplana, C., Gómez, P., Vidal, M., Peg, V., ... Serra, V. (2018). A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Molecular Medicine, 10, [e9172]. https://doi.org/10.15252/emmm.201809172

Castroviejo-Bermejo, Marta ; Cruz, Cristina ; Llop-Guevara, Alba ; Gutiérrez-Enríquez, Sara ; Ducy, Mandy ; Ibrahim, Yasir Hussein ; Gris-Oliver, Albert ; Pellegrino, Benedetta ; Bruna, Alejandra ; Guzmán, Marta ; Rodríguez, Olga ; Grueso, Judit ; Bonache, Sandra ; Moles-Fernández, Alejandro ; Villacampa, Guillermo ; Viaplana, Cristina ; Gómez, Patricia ; Vidal, Marc ; Peg, Vicente ; Serres-Créixams, Xavier ; Dellaire, Graham ; Simard, Jacques ; Nuciforo, Paolo ; Rubio, Isabel T. ; Dientsmann, Rodrigo ; Barrett, J. Carl ; Caldas, Carlos ; Baselga, José ; Saura, Cristina ; Cortés, Javier ; Déas, Olivier ; Jonkers, Jos ; Masson, Jean Yves ; Cairo, Stefano ; Judde, Jean Gabriel ; O'Connor, Mark J. ; Díez, Orland ; Balmaña, Judith ; Serra, Violeta. / A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. In: EMBO Molecular Medicine. 2018 ; Vol. 10.

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title = "A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation",

abstract = "{\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.",

keywords = "BRCA1, PALB2, PARP inhibitors, RAD51, homologous recombination",

author = "Marta Castroviejo-Bermejo and Cristina Cruz and Alba Llop-Guevara and Sara Guti{\'e}rrez-Enr{\'i}quez and Mandy Ducy and Ibrahim, {Yasir Hussein} and Albert Gris-Oliver and Benedetta Pellegrino and Alejandra Bruna and Marta Guzm{\'a}n and Olga Rodr{\'i}guez and Judit Grueso and Sandra Bonache and Alejandro Moles-Fern{\'a}ndez and Guillermo Villacampa and Cristina Viaplana and Patricia G{\'o}mez and Marc Vidal and Vicente Peg and Xavier Serres-Cr{\'e}ixams and Graham Dellaire and Jacques Simard and Paolo Nuciforo and Rubio, {Isabel T.} and Rodrigo Dientsmann and Barrett, {J. Carl} and Carlos Caldas and Jos{\'e} Baselga and Cristina Saura and Javier Cort{\'e}s and Olivier D{\'e}as and Jos Jonkers and Masson, {Jean Yves} and Stefano Cairo and Judde, {Jean Gabriel} and O'Connor, {Mark J.} and Orland D{\'i}ez and Judith Balma{\~n}a and Violeta Serra",

year = "2018",

month = dec,

day = "1",

doi = "https://doi.org/10.15252/emmm.201809172",

language = "English",

volume = "10",

}

Castroviejo-Bermejo, M, Cruz, C, Llop-Guevara, A, Gutiérrez-Enríquez, S, Ducy, M, Ibrahim, YH, Gris-Oliver, A, Pellegrino, B, Bruna, A, Guzmán, M, Rodríguez, O, Grueso, J, Bonache, S, Moles-Fernández, A, Villacampa, G, Viaplana, C, Gómez, P, Vidal, M, Peg, V , Serres-Créixams, X, Dellaire, G, Simard, J, Nuciforo, P, Rubio, IT, Dientsmann, R, Barrett, JC, Caldas, C, Baselga, J, Saura, C, Cortés, J, Déas, O, Jonkers, J, Masson, JY, Cairo, S, Judde, JG, O'Connor, MJ, Díez, O, Balmaña, J & Serra, V 2018, 'A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation', EMBO Molecular Medicine, vol. 10, e9172. https://doi.org/10.15252/emmm.201809172

A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. / Castroviejo-Bermejo, Marta; Cruz, Cristina; Llop-Guevara, Alba; Gutiérrez-Enríquez, Sara; Ducy, Mandy; Ibrahim, Yasir Hussein; Gris-Oliver, Albert; Pellegrino, Benedetta; Bruna, Alejandra; Guzmán, Marta; Rodríguez, Olga; Grueso, Judit; Bonache, Sandra; Moles-Fernández, Alejandro; Villacampa, Guillermo; Viaplana, Cristina; Gómez, Patricia; Vidal, Marc; Peg, Vicente ; Serres-Créixams, Xavier; Dellaire, Graham; Simard, Jacques; Nuciforo, Paolo; Rubio, Isabel T.; Dientsmann, Rodrigo; Barrett, J. Carl; Caldas, Carlos; Baselga, José; Saura, Cristina; Cortés, Javier; Déas, Olivier; Jonkers, Jos; Masson, Jean Yves; Cairo, Stefano; Judde, Jean Gabriel; O'Connor, Mark J.; Díez, Orland; Balmaña, Judith; Serra, Violeta.

In: EMBO Molecular Medicine, Vol. 10, e9172, 01.12.2018.

Research output: Contribution to journal › Article › Research

TY - JOUR

T1 - A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation

AU - Castroviejo-Bermejo, Marta

AU - Cruz, Cristina

AU - Llop-Guevara, Alba

AU - Gutiérrez-Enríquez, Sara

AU - Ducy, Mandy

AU - Ibrahim, Yasir Hussein

AU - Gris-Oliver, Albert

AU - Pellegrino, Benedetta

AU - Bruna, Alejandra

AU - Guzmán, Marta

AU - Rodríguez, Olga

AU - Grueso, Judit

AU - Bonache, Sandra

AU - Moles-Fernández, Alejandro

AU - Villacampa, Guillermo

AU - Viaplana, Cristina

AU - Gómez, Patricia

AU - Vidal, Marc

AU - Peg, Vicente

AU - Serres-Créixams, Xavier

AU - Dellaire, Graham

AU - Simard, Jacques

AU - Nuciforo, Paolo

AU - Rubio, Isabel T.

AU - Dientsmann, Rodrigo

AU - Barrett, J. Carl

AU - Caldas, Carlos

AU - Baselga, José

AU - Saura, Cristina

AU - Cortés, Javier

AU - Déas, Olivier

AU - Jonkers, Jos

AU - Masson, Jean Yves

AU - Cairo, Stefano

AU - Judde, Jean Gabriel

AU - O'Connor, Mark J.

AU - Díez, Orland

AU - Balmaña, Judith

AU - Serra, Violeta

PY - 2018/12/1

Y1 - 2018/12/1

N2 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.

AB - © 2018 The Authors. Published under the terms of the CC BY 4.0 license 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.

KW - BRCA1

KW - PALB2

KW - PARP inhibitors

KW - RAD51

KW - homologous recombination

U2 - https://doi.org/10.15252/emmm.201809172

DO - https://doi.org/10.15252/emmm.201809172

M3 - Article

C2 - 30377213

VL - 10

M1 - e9172

ER -

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

Abstract

Keywords

UN SDGs

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