TY - JOUR
T1 - Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests
AU - Meijer, Titia G
AU - Nguyen, Luan
AU - Van Hoeck, Arne
AU - Sieuwerts, Anieta M
AU - Verkaik, Nicole S
AU - Ladan, Marjolijn M
AU - Ruigrok-Ritstier, Kirsten
AU - van Deurzen, Carolien H M
AU - van de Werken, Harmen J G
AU - Lips, Esther H
AU - Linn, Sabine C
AU - Memari, Yasin
AU - Davies, Helen
AU - Nik-Zainal, Serena
AU - Kanaar, Roland
AU - Martens, John W M
AU - Cuppen, Edwin
AU - Jager, Agnes
AU - van Gent, Dik C
N1 - Funding Information:
The authors thank many colleagues from the departments of Molecular Genetics, Medical Oncology and Pathology at Erasmus MC as well as from the Maasstad hospital, who contributed to the collection of patient material. We thank Dorine den Toom for her assistance with the DNA isolations. This publication has been made possible partly by the data that the Hartwig Medical Foundation and CPCT have made available to the study (data request no. DR-026).
Funding Information:
DCvG, AJ, and RK have received funding from the Dutch Cancer Society (Alpe d’Huzes grant number EMCR 2014-7048 and grant number EMCR 2008-4045). This work is part of the Oncode Institute which is partly financed by the Dutch Cancer Society and was funded by the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research (NWO).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/6/24
Y1 - 2022/6/24
N2 - Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation. The REpair CAPacity (RECAP) test is a functional method to select HRD tumors based on their inability to form RAD51 foci. We investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests. An HRD enriched cohort (n = 71; 52 primary and 19 metastatic BCs) selected based on the RECAP test (26 RECAP-HRD; 37%), was subjected to DNA-based HRD tests (i.e., Classifier of HOmologous Recombination Deficiency (CHORD) and BRCA1/2-like classifier). Whole genome sequencing (WGS) was carried out for 38 primary and 19 metastatic BCs. The RECAP test identified all bi-allelic BRCA deficient samples (n = 15) in this cohort. RECAP status partially correlated with DNA-based HRD test outcomes (70% concordance for both RECAP-CHORD and RECAP-BRCA1/2-like classifier). RECAP selected additional samples unable to form RAD51 foci, suggesting that this functional assay identified deficiencies in other DNA repair genes, which could also result in PARP-inhibitor sensitivity. Direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making.
AB - Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation. The REpair CAPacity (RECAP) test is a functional method to select HRD tumors based on their inability to form RAD51 foci. We investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests. An HRD enriched cohort (n = 71; 52 primary and 19 metastatic BCs) selected based on the RECAP test (26 RECAP-HRD; 37%), was subjected to DNA-based HRD tests (i.e., Classifier of HOmologous Recombination Deficiency (CHORD) and BRCA1/2-like classifier). Whole genome sequencing (WGS) was carried out for 38 primary and 19 metastatic BCs. The RECAP test identified all bi-allelic BRCA deficient samples (n = 15) in this cohort. RECAP status partially correlated with DNA-based HRD test outcomes (70% concordance for both RECAP-CHORD and RECAP-BRCA1/2-like classifier). RECAP selected additional samples unable to form RAD51 foci, suggesting that this functional assay identified deficiencies in other DNA repair genes, which could also result in PARP-inhibitor sensitivity. Direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making.
KW - Antineoplastic Agents/therapeutic use
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Breast Neoplasms/diagnosis
KW - DNA
KW - Female
KW - Homologous Recombination/genetics
KW - Humans
KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
KW - Poly(ADP-ribose) Polymerases/genetics
KW - Recombinational DNA Repair/genetics
UR - https://www.scopus.com/pages/publications/85131307244
U2 - 10.1038/s41388-022-02363-1
DO - 10.1038/s41388-022-02363-1
M3 - Article
C2 - 35662281
SN - 0950-9232
VL - 41
SP - 3498
EP - 3506
JO - Oncogene
JF - Oncogene
IS - 26
ER -