Format

Send to

Choose Destination
See comment in PubMed Commons below
Clin Cancer Res. 2014 Sep 15;20(18):4816-26. doi: 10.1158/1078-0432.CCR-14-0571. Epub 2014 Jun 24.

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

Author information

1
Department of Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
2
Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
3
Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
4
Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Department of Toxicogenetics, Leiden University Medical Center, Leiden, the Netherlands.
6
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.
7
AstraZeneca, iMed Oncology, Macclesfield, Cheshire, United Kingdom.
8
Department of Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands. Cancer Genomics Center Netherlands, Erasmus University Medical Center, Rotterdam, the Netherlands. Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands.
9
Department of Toxicogenetics, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
10
Department of Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands. d.vangent@erasmusmc.nl.

Abstract

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.

PMID:
24963051
DOI:
10.1158/1078-0432.CCR-14-0571
[Indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire
    Loading ...
    Support Center