Functional Ex Vivo Assay to Select Homologous Recombination-Deficient Breast Tumors for PARP Inhibitor Treatment
| Autor: | Roland Kanaar, Mark J. O'Connor, Carolien H.M. van Deurzen, Agnes Jager, Harry Vrieling, Dik C. van Gent, Matty Meijers, John W.M. Martens, Anieta M. Sieuwerts, Maaike P.G. Vreeswijk, Kishan A. T. Naipal, Jan H.J. Hoeijmakers, Johan P. de Winter, Nicole S. Verkaik, Petra ter Brugge, Najim Ameziane, Jos Jonkers |
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| Přispěvatelé: | Human genetics, CCA - Innovative therapy, Molecular Genetics, Pathology, Pulmonary Medicine, Medical Oncology |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Genes BRCA2 Genes BRCA1 RAD51 Fluorescent Antibody Technique Antineoplastic Agents Breast Neoplasms Poly(ADP-ribose) Polymerase Inhibitors Biology Gene mutation Poly (ADP-Ribose) Polymerase Inhibitor Mice Breast cancer SDG 3 - Good Health and Well-being medicine Animals Humans Enzyme Inhibitors Homologous Recombination skin and connective tissue diseases Cancer medicine.disease Xenograft Model Antitumor Assays Molecular biology Oncology PARP inhibitor Cancer research Biological Assay Female Rad51 Recombinase Homologous recombination Ex vivo |
| Zdroj: | Naipal, K A T, Verkaik, N S, Ameziane, N, van Deurzen, C H M, ter Brugge, P, Meijers, M, Sieuwerts, A M, Martens, J W, O'Connor, M J, Vrieling, H, Hoeijmakers, J H J, Jonkers, J, Kanaar, R, de Winter, J P, Vreeswijk, M P, Jager, A & van Gent, D C 2014, ' Functional Ex Vivo Assay to Select Homologous Recombination-Deficient Breast Tumors for PARP Inhibitor Treatment ', Clinical Cancer Research, vol. 20, no. 18, pp. 4816-4826 . https://doi.org/10.1158/1078-0432.CCR-14-0571 Clinical Cancer Research, 20(18), 4816-4826. American Association for Cancer Research Inc. Clinical Cancer Research, 20(18), 4816-4826 |
| ISSN: | 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-14-0571 |
| Popis: | Purpose: Poly(ADP-ribose) polymerase (PARP) inhibitors are promising targeted treatment options for hereditary breast tumors with a homologous recombination (HR) deficiency caused by BRCA1 or BRCA2 mutations. However, the functional consequence of BRCA gene mutations is not always known and tumors can be HR deficient for other reasons than BRCA gene mutations. Therefore, we aimed to develop a functional test to determine HR activity in tumor samples to facilitate selection of patients eligible for PARP inhibitor treatment. Experimental design: We obtained 54 fresh primary breast tumor samples from patients undergoing surgery. We determined their HR capacity by studying the formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51 IRIF formation were subjected to genetic and epigenetic analysis. Results: Five of 45 primary breast tumors with sufficient numbers of proliferating tumor cells were RAD51 IRIF formation deficient (11%, 95% CI, 5%–24%). This HR defect was significantly associated with triple-negative breast cancer (OR, 57; 95% CI, 3.9–825; P = 0.003). Two of five HR-deficient tumors were not caused by mutations in the BRCA genes, but by BRCA1 promoter hypermethylation. Conclusion: The functional RAD51 IRIF assay faithfully identifies HR-deficient tumors and has clear advantages over gene sequencing. It is a relatively easy assay that can be performed on biopsy material, making it a powerful tool to select patients with an HR-deficient cancer for PARP inhibitor treatment in the clinic. Clin Cancer Res; 20(18); 4816–26. ©2014 AACR. |
| Databáze: | OpenAIRE |
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