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

被引：200

作者：

Castroviejo-Bermejo, Marta ^{[1
]}

Cruz, Cristina ^{[1
,2
,3
]}

Llop-Guevara, Alba ^{[1
]}

Gutierrez-Enriquez, Sara ^{[4
]}

Ducy, Mandy ^{[5
,6
,7
]}

Hussein Ibrahim, Yasir ^{[1
]}

Gris-Oliver, Albert ^{[1
]}

Pellegrino, Benedetta ^{[1
,8
]}

Bruna, Alejandra ^{[9
,10
]}

Guzman, Marta ^{[1
]}

Rodriguez, Olga ^{[1
]}

Grueso, Judit ^{[1
]}

Bonache, Sandra ^{[4
]}

Moles-Fernandez, Alejandro ^{[4
]}

Villacampa, Guillermo ^{[11
]}

Viaplana, Cristina ^{[11
]}

Gomez, Patricia ^{[3
,12
]}

Vidal, Marc ^{[3
,12
]}

Peg, Vicente ^{[13
,14
]}

Serres-Creixams, Xavier ^{[15
]}

Dellaire, Graham ^{[16
]}

Simard, Jacques ^{[7
]}

Nuciforo, Paolo ^{[14
,17
]}

Rubio, Isabel T. ^{[14
,18
]}

Dientsmann, Rodrigo ^{[11
]}

Barrett, J. Carl ^{[19
]}

Caldas, Carlos ^{[9
,10
,20
]}

Baselga, Jose ^{[21
,22
]}

Saura, Cristina ^{[3
,12
]}

Cortes, Javier ^{[14
,23
,24
]}

Deas, Olivier ^{[25
]}

Jonkers, Jos ^{[26
]}

Masson, Jean-Yves ^{[5
,6
]}

Cairo, Stefano ^{[25
]}

Judde, Jean-Gabriel ^{[25
]}

O'Connor, Mark J. ^{[27
]}

Diez, Orland ^{[4
,28
]}

Balmana, Judith ^{[2
,3
]}

Serra, Violeta ^{[1
,14
]}

机构：

[1] Vall dHebron Inst Oncol, Expt Therapeut Grp, Barcelona, Spain

[2] Vall dHebron Inst Oncol, High Risk & Familial Canc Grp, Barcelona, Spain

[3] Univ Autonoma Barcelona, Dept Med Oncol, Hosp Vall dHebron, Barcelona, Spain

[4] Vall dHebron Inst Oncol, Oncogenet Grp, Barcelona, Spain

[5] CHU Quebec Res Ctr, Genome Stabil Lab, Quebec City, PQ, Canada

[6] Laval Univ, Dept Mol Biol, Med Biochem & Pathol, Canc Res Ctr, Quebec City, PQ, Canada

[7] Univ Laval, Genom Ctr, CHUL, Res Ctr,CHU Quebec, Quebec City, PQ, Canada

[8] Univ Hosp Parma, Dept Med Oncol, Parma, Italy

[9] Univ Cambridge, Canc Res UK Cambridge Inst, Li Ka Shing Ctr, Cambridge, England

[10] Univ Cambridge, Dept Oncol, Li Ka Shing Ctr, Cambridge, England

[11] Vall dHebron Inst Oncol, Oncol Data Sci, OdysSey Grp, Barcelona, Spain

[12] Vall dHebron Inst Oncol, Breast Canc & Melanoma Grp, Barcelona, Spain

[13] Vall dHebron Univ Hosp, Pathol Dept, Barcelona, Spain

[14] Inst Salud Carlos III, CIBERONC, Madrid, Spain

[15] Univ Autonoma Barcelona, Dept Radiol, Hosp Vall dHebron, Barcelona, Spain

[16] Dalhousie Univ, Dept Pathol, Halifax, NS, Canada

[17] Vall dHebron Inst Oncol, Mol Oncol Grp, Barcelona, Spain

[18] Univ Autonoma Barcelona, Breast Surg Unit, Breast Canc Ctr, Hosp Vall dHebron, Barcelona, Spain

[19] AstraZeneca, Waltham, MA USA

[20] Cambridge Canc Ctr, Canc Res UK CRUK, Breast Canc Programme, Cambridge, England

[21] Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10021 USA

[22] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[23] Ramon y Cajal Univ Hosp, Dept Oncol, Madrid, Spain

[24] Vall dHebron Inst Oncol, Barcelona, Spain

[25] XenTech, Evry, France

[26] Netherlands Canc Inst, Div Mol Pathol & Canc Genom, Amsterdam, Netherlands

[27] AstraZeneca, Oncol Innovat Med & Early Clin Dev Biotech, Cambridge, England

[28] Univ Autonoma Barcelona, Hosp Vall dHebron, Clin & Mol Genet Area, Barcelona, Spain

来源：

EMBO MOLECULAR MEDICINE | 2018年 / 10卷 / 12期

基金：

加拿大健康研究院;

关键词：

BRCA1; homologous recombination; PALB2; PARP inhibitors; RAD51; HOMOLOGOUS RECOMBINATION REPAIR; BREAST-CANCER; DNA-REPAIR; POLY(ADP-RIBOSE) POLYMERASE; MAINTENANCE THERAPY; SYNTHETIC LETHALITY; OVARIAN-CARCINOMA; FORK STABILITY; MUTANT-CELLS; DOUBLE-BLIND;

D O I：

10.15252/emmm.201809172

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16

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