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
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.
UR - http://www.scopus.com/inward/record.url?scp=85131307244&partnerID=8YFLogxK
U2 - 10.1038/s41388-022-02363-1
DO - 10.1038/s41388-022-02363-1
M3 - Article
C2 - 35662281
AN - SCOPUS:85131307244
SN - 0950-9232
VL - 41
SP - 3498
EP - 3506
JO - Oncogene
JF - Oncogene
IS - 26
ER -