A Llop-Guevara1, S Loibl2, G Villacampa1, V Vladimirova2, A Schneeweiss3, T Karn4, D-M Zahm5, A Herencia-Ropero1, P Jank6, M van Mackelenbergh7, P A Fasching8, F Marmé9, E Stickeler10, C Schem11, R Dienstmann1, S Florian12, V Nekljudova2, J Balmaña1, E Hahnen13, C Denkert6, V Serra14. 1. Vall d'Hebron Institute of Oncology, Barcelona, Spain. 2. GBG, Medicine and Research, Neu-Isenburg, Germany. 3. Nationales Centrum für Tumorerkrankungen, Universitätsklinikum und Deutsches Krebsforschungszentrum, Heidelberg, Germany. 4. Goethe University Hospital, Frankfurt, Germany. 5. SRH Wald-Klinikum Gera, Gera, Germany. 6. Institut für Pathologie, UKGM Marburg, Philipps-Universität Marburg, Marburg, Germany. 7. Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Kiel, Germany. 8. Universitätsklinikum Erlangen, Erlangen, Germany. 9. Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Mannheim, Germany. 10. Klinik für Gynäkologie, Uniklinik RWTH Aachen, Aachen, Germany. 11. Mammazentrum Hamburg, Hamburg, Germany. 12. Institut für Pathologie, Charité - Universitätsmedizin Berlin, Berlin, Germany. 13. Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany. 14. Vall d'Hebron Institute of Oncology, Barcelona, Spain. Electronic address: vserra@vhio.net.
Abstract
BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.
BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.
Authors: Benedetta Pellegrino; Andrea Herencia-Ropero; Alba Llop-Guevara; Flaminia Pedretti; Alejandro Moles-Fernández; Cristina Viaplana; Guillermo Villacampa; Marta Guzmán; Olga Rodríguez; Judit Grueso; Jose Jiménez; Enrique J Arenas; Andrea Degasperi; João M L Dias; Josep V Forment; Mark J O'Connor; Olivier Déas; Stefano Cairo; Yinghui Zhou; Antonino Musolino; Carlos Caldas; Serena Nik-Zainal; Robert B Clarke; Paolo Nuciforo; Orland Díez; Xavier Serres-Créixams; Vicente Peg; Martín Espinosa-Bravo; Teresa Macarulla; Ana Oaknin; Joaquin Mateo; Joaquín Arribas; Rodrigo Dienstmann; Meritxell Bellet; Mafalda Oliveira; Cristina Saura; Sara Gutiérrez-Enríquez; Judith Balmaña; Violeta Serra Journal: Cancer Res Date: 2022-04-15 Impact factor: 13.312
Authors: Titia G Meijer; Luan Nguyen; Arne Van Hoeck; Anieta M Sieuwerts; Nicole S Verkaik; Marjolijn M Ladan; Kirsten Ruigrok-Ritstier; Carolien H M van Deurzen; Harmen J G van de Werken; Esther H Lips; Sabine C Linn; Yasin Memari; Helen Davies; Serena Nik-Zainal; Roland Kanaar; John W M Martens; Edwin Cuppen; Agnes Jager; Dik C van Gent Journal: Oncogene Date: 2022-06-03 Impact factor: 8.756
Authors: Diego Gomez-Puerto; Alba Llop-Guevara; Mara Cruellas; Sara Torres-Esquius; Javier De La Torre; Vicente Peg; Judith Balmaña; Isabel Pimentel Journal: Front Oncol Date: 2022-09-14 Impact factor: 5.738