Functional Ex vivo assay to select homologous recombination-deficient breast tumors for PARP inhibitor treatment

Kishan A.T. Naipal, Nicole S. Verkaik, Najim Ameziane, Carolien H.M. Van Deurzen, Petra Ter Brugge, Matty Meijers, Anieta M. Sieuwerts, John W. Martens, Mark J. O'Connor, Harry Vrieling, Jan H.J. Hoeijmakers, Jos Jonkers, Roland Kanaar, Johan P. De Winter, Maaike P. Vreeswijk, Agnes Jager, Dik C. Van Gent

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130 Citaten (Scopus)

Samenvatting

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).Twoof 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.

Originele taal-2Engels
Pagina's (van-tot)4816-4826
Aantal pagina's11
TijdschriftClinical Cancer Research
Volume20
Nummer van het tijdschrift18
DOI's
StatusGepubliceerd - 15 sep. 2014
Extern gepubliceerdJa

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