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: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

Medicine

Research output: Contribution to journal › Article › peer-review

204 Citations (Scopus)

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.

Original language	English
Article number	e9172
Journal	EMBO Molecular Medicine
Volume	10
Issue number	12
DOIs	https://doi.org/10.15252/emmm.201809172
Publication status	Published - Dec 2018

Bibliographical note

Funding Information:
The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d’Hebron Hospital; Pilar Antón, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Amélie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balmaña, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/ 01711 and PI16/01218 to S. Gutiérrez-Enríquez], by a TRANSCAN-2 [AC15/ 00063 to V.Serra], the Asociación Española Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien à des initiatives internationales de recherche et d’innovation (SIIRI) du Ministère de l’Économie, de l’Innovation et des Exportations du Québec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the “Tumor Biomarkers Collaboration” supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociación Espa-ñola Contra el Cáncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Gutiérrez-Enríquez [CP10/ 00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN).

Funding Information:
The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d'Hebron Hospital; Pilar Ant?n, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Am?lie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balma?a, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/01711 and PI16/01218 to S. Guti?rrez-Enr?quez], by a TRANSCAN-2 [AC15/00063 to V.Serra], the Asociaci?n Espa?ola Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien ? des initiatives internationales de recherche et d'innovation (SIIRI) du Minist?re de l??conomie, de l'Innovation et des Exportations du Qu?bec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the ?Tumor Biomarkers Collaboration? supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociaci?n Espa?ola Contra el C?ncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Guti?rrez-Enr?quez [CP10/00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN).

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

ASJC Scopus Subject Areas

Molecular Medicine

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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

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10.15252/emmm.201809172

Cite this

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(12), Article e9172. https://doi.org/10.15252/emmm.201809172

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, no. 12, e9172. https://doi.org/10.15252/emmm.201809172

@article{052787aaeccb41acbdbaaf49c87b62d3,

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

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.",

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",

note = "Funding Information: The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d{\textquoteright}Hebron Hospital; Pilar Ant{\'o}n, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Am{\'e}lie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balma{\~n}a, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/ 01711 and PI16/01218 to S. Guti{\'e}rrez-Enr{\'i}quez], by a TRANSCAN-2 [AC15/ 00063 to V.Serra], the Asociaci{\'o}n Espa{\~n}ola Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien {\`a} des initiatives internationales de recherche et d{\textquoteright}innovation (SIIRI) du Minist{\`e}re de l{\textquoteright}{\'E}conomie, de l{\textquoteright}Innovation et des Exportations du Qu{\'e}bec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the “Tumor Biomarkers Collaboration” supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociaci{\'o}n Espa-{\~n}ola Contra el C{\'a}ncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Guti{\'e}rrez-Enr{\'i}quez [CP10/ 00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). Funding Information: The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d'Hebron Hospital; Pilar Ant?n, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Am?lie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balma?a, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/01711 and PI16/01218 to S. Guti?rrez-Enr?quez], by a TRANSCAN-2 [AC15/00063 to V.Serra], the Asociaci?n Espa?ola Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien ? des initiatives internationales de recherche et d'innovation (SIIRI) du Minist?re de l??conomie, de l'Innovation et des Exportations du Qu?bec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the ?Tumor Biomarkers Collaboration? supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociaci?n Espa?ola Contra el C?ncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Guti?rrez-Enr?quez [CP10/00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). Publisher Copyright: {\textcopyright} 2018 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2018",

month = dec,

doi = "10.15252/emmm.201809172",

language = "English",

volume = "10",

journal = "EMBO Molecular Medicine",

issn = "1757-4676",

publisher = "Wiley-Blackwell",

number = "12",

}

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

N1 - Funding Information: The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d’Hebron Hospital; Pilar Antón, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Amélie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balmaña, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/ 01711 and PI16/01218 to S. Gutiérrez-Enríquez], by a TRANSCAN-2 [AC15/ 00063 to V.Serra], the Asociación Española Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien à des initiatives internationales de recherche et d’innovation (SIIRI) du Ministère de l’Économie, de l’Innovation et des Exportations du Québec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the “Tumor Biomarkers Collaboration” supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociación Espa-ñola Contra el Cáncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Gutiérrez-Enríquez [CP10/ 00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). Funding Information: The authors thank Dr. Geoffrey Shapiro, Dr. Peter Bouwman, Dr. Neil Johnson, Dr. Josep V. Forment, the Molecular Pathology Group at VHIO, the Breast Cancer and Melanoma Group at VHIO, Dr. Felip Vilardell Villellas, and Laura Duran-Lozano for helpful discussions. The Breast Surgical Unit from Vall d'Hebron Hospital; Pilar Ant?n, Maite Calvo, Patricia Cozar from the Experimental Therapeutics Group at VHIO; Brian Dougherty, Zhongwu Lai, and Ambar Ahmed from AstraZeneca and Am?lie Rodrigue and Yan Coulombe from Masson laboratory have provided technical support. The authors acknowledge the Cellex Foundation for providing research facilities and equipment. This Research Project was also supported by ESMO with the aid of a grant from Roche. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or Roche. This research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [FIS PI17/01080 to V. Serra, FIS PI12-02606 to J. Balma?a, FIS PI12/02585 and PI15-00355 to O. Diez, FIS PI13/01711 and PI16/01218 to S. Guti?rrez-Enr?quez], by a TRANSCAN-2 [AC15/00063 to V.Serra], the Asociaci?n Espa?ola Contra el Cancer (AECC) [LABAE16020PORTT to V.Serra], the Catalan Agency AGAUR [2017 SGR 540 coordinator V. Serra], the Canadian Institutes of Health Research (CIHR) [Foundation grant to J.-Y. Masson], and the Programme de soutien ? des initiatives internationales de recherche et d'innovation (SIIRI) du Minist?re de l??conomie, de l'Innovation et des Exportations du Qu?bec [to J.-Y. Masson and J. Simard, PSR-SIIRI-949]. We acknowledge the ?Tumor Biomarkers Collaboration? supported by the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation, the GHD-Pink program, the FERO Foundation, and the Orozco Family for supporting this study [to V. Serra and J. Baselga]. M. Castroviejo-Bermejo is awarded with a Junta Provincial de Barcelona, Asociaci?n Espa?ola Contra el C?ncer (AECC) fellowship. C. Cruz [AIOC15152806CRUZ] and S. Bonache are recipients of AECC fellowships. A. Llop-Guevara is awarded with a PERIS fellowship from the Departament de Salut, Generalitat de Catalunya [SLT002/16/00477]. V. Serra [CP14/00228] and S. Guti?rrez-Enr?quez [CP10/00617] are supported by the Miguel Servet Program (ISCIII). J.-Y. Masson is a FRQS chair in genome stability, and J. Simard is a Canada Research Chair in Oncogenetics. The xenograft program in the Caldas laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). Publisher Copyright: © 2018 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2018/12

Y1 - 2018/12

N2 - 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 - 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.

UR - http://www.scopus.com/inward/record.url?scp=85055668699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055668699&partnerID=8YFLogxK

U2 - 10.15252/emmm.201809172

DO - 10.15252/emmm.201809172

M3 - Article

C2 - 30377213

AN - SCOPUS:85055668699

SN - 1757-4676

VL - 10

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

M1 - e9172

ER -

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

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