Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification.

Autor:	Pellegrino B; Department of Medicine and Surgery, University of Parma, Italy.; Medical Oncology and Breast Unit, University Hospital of Parma, Italy., Herencia-Ropero A; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain., Llop-Guevara A; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Pedretti F; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain., Moles-Fernández A; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Viaplana C; Oncology Data Science Group (ODysSey Group), Vall d'Hebron Institute of Oncology, Barcelona, Spain., Villacampa G; Oncology Data Science Group (ODysSey Group), Vall d'Hebron Institute of Oncology, Barcelona, Spain., Guzmán M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Rodríguez O; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Grueso J; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Jiménez J; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Arenas EJ; Growth Factors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; CIBERONC, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Degasperi A; Academic Department of Medical Genetics, University of Cambridge, Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.; MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom., Dias JML; Academic Department of Medical Genetics, University of Cambridge, Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.; MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom., Forment JV; Oncology iMED, AstraZeneca, Cambridge, United Kingdom., O'Connor MJ; DDR Biology Group, Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Déas O; XenTech, Evry, France., Cairo S; XenTech, Evry, France., Zhou Y; TESARO: A GSK company, Waltham, Massachusetts., Musolino A; Department of Medicine and Surgery, University of Parma, Italy.; Medical Oncology and Breast Unit, University Hospital of Parma, Italy., Caldas C; Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.; Breast Cancer Programme, Cancer Research UK (CRUK) Cambridge Cancer Centre, Cambridge, United Kingdom., Nik-Zainal S; Academic Department of Medical Genetics, University of Cambridge, Addenbrooke's Treatment Centre, Cambridge Biomedical Campus, Cambridge, United Kingdom.; MRC Cancer Unit, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom., Clarke RB; Manchester Breast Centre, Division of Cancer Sciences, University of Manchester, Oglesby Cancer Research Building, Manchester, United Kingdom., Nuciforo P; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Díez O; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Area of Clinical and Molecular Genetics, Vall d'Hebron University Hospital, Barcelona, Spain., Serres-Créixams X; Department of Radiology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain., Peg V; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain., Espinosa-Bravo M; Breast Surgical Unit, Breast Cancer Center, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain., Macarulla T; Gastrointestinal and Endocrine Tumors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain., Oaknin A; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.; Gynecological Malignancies Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Mateo J; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.; Prostate Cancer Translational Research Group, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain., Arribas J; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain.; Growth Factors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; CIBERONC, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Dienstmann R; Oncology Data Science Group (ODysSey Group), Vall d'Hebron Institute of Oncology, Barcelona, Spain., Bellet M; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.; Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Oliveira M; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.; Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Saura C; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.; Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Gutiérrez-Enríquez S; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Balmaña J; Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Department of Medical Oncology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain., Serra V; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; CIBERONC, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Apr 15; Vol. 82 (8), pp. 1646-1657.
DOI:	10.1158/0008-5472.CAN-21-2409
Abstrakt:	PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously established a test to detect RAD51 nuclear foci. Here, we aimed to validate the RAD51 score cut off and compare the performance of this test to other HRR deficiency (HRD) detection methods. Laboratory models from BRCA1/BRCA2-associated breast cancer, HGSOC, and PaC were developed and evaluated for their response to PARPi and cisplatin. HRD in these models and patient samples was evaluated by DNA sequencing of HRR genes, genomic HRD tests, and RAD51 foci detection. We established patient-derived xenograft models from breast cancer (n = 103), HGSOC (n = 4), and PaC (n = 2) that recapitulated patient HRD status and treatment response. The RAD51 test showed higher accuracy than HRR gene mutations and genomic HRD analysis for predicting PARPi response (95%, 67%, and 71%, respectively). RAD51 detection captured dynamic changes in HRR status upon acquisition of PARPi resistance. The accuracy of the RAD51 test was similar to HRR gene mutations for predicting platinum response. The predefined RAD51 score cut off was validated, and the high predictive value of the RAD51 test in preclinical models was confirmed. These results collectively support pursuing clinical assessment of the RAD51 test in patient samples from randomized trials testing PARPi or platinum-based therapies. Significance: This work demonstrates the high accuracy of a histopathology-based test based on the detection of RAD51 nuclear foci in predicting response to PARPi and cisplatin. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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