Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects

Publication Date:
2018-12-15
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1836399105018953728
autor Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
beschreibung Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts ( P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2 -deficient and BRCA1/2 -proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
citation_standardnr 6369715
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-12-15
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/24/6277?rss=1
search_space articles
shingle_author_1 Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
shingle_author_2 Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
shingle_author_3 Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
shingle_author_4 Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
shingle_catch_all_1 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts ( P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2 -deficient and BRCA1/2 -proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts ( P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2 -deficient and BRCA1/2 -proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts ( P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2 -deficient and BRCA1/2 -proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
Purpose: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double-strand break (DSB) repair and high sensitivity to PARP inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In this study, we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancer tissue: the recombination REpair CAPacity (RECAP) test. Experimental Design: Fresh samples of 170 primary breast cancer were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor-infiltrating lymphocytes (TIL), and microsatellite instability (MSI). Results: RECAP was completed successfully in 148 of 170 samples (87%). Twenty-four tumors showed HRD (16%), whereas six tumors were HR intermediate (HRi; 4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas seven HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts ( P = 0.023) compared with HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in breast cancer (1%; P = 0.017). Conclusions: RECAP is a robust functional HR assay detecting both BRCA1/2 -deficient and BRCA1/2 -proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.
Meijer, T. G., Verkaik, N. S., Sieuwerts, A. M., van Riet, J., Naipal, K. A. T., van Deurzen, C. H. M., den Bakker, M. A., Sleddens, H. F. B. M., Dubbink, H.-J., den Toom, T. D., Dinjens, W. N. M., Lips, E., Nederlof, P. M., Smid, M., van de Werken, H. J. G., Kanaar, R., Martens, J. W. M., Jager, A., van Gent, D. C.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
shingle_title_2 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
shingle_title_3 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
shingle_title_4 Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
timestamp 2025-06-30T23:37:40.373Z
titel Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
titel_suche Functional Ex Vivo Assay Reveals Homologous Recombination Deficiency in Breast Cancer Beyond BRCA Gene Defects
topic WW-YZ
uid ipn_articles_6369715