Abstract 5483: Implications of the type of <i>BRCA1</i> germline mutation in the treatment of patients with hereditary breast cancer

Abstract Carrying an inherited mutation in BRCA1 or BRCA2 genes significantly increases individual´s lifetime risk to develop breast or ovarian cancer. However, there are considerable differences in disease manifestation among mutation carriers, suggesting the existence of other factors which could modify the risk of cancer development. Since BRCA1 is an important component of DNA repair, BRCA1-deficient cells have to rely on other members of the DNA repair machinery. This makes them sensitive to drugs which target specific repair pathways, such as inhibitors of poly (ADP-ribose) polymerase (PARP). Several PARP inhibitors are currently being tested in preclinical or clinical trials, either as a monotherapy or in combination with chemo- or radiotherapy. Taking into account the promising results in patients with germline mutation in BRCA1 or BRCA2 genes, we aimed to investigate which BRCA1 mutation carriers, depending on the mutation type, might benefit from treatment with PARP inhibitors the most. In addition, we were also interested in identifying markers of sensitivity/resistance to PARP inhibitors. We have used lymphoblastoid cell lines (LCLs) derived from lymphocytes of healthy women heterozygous for different BRCA1 mutations and healthy women from the same families with no mutation. In total, 23 LCLs were characterized according to their DNA repair capacity, growth rate, gene/miRNA expression and sensitivity to PARP inhibitors. Our preliminary results have shown significantly higher sensitivity to PARP inhibitor olaparib in cells harbouring missense mutation in comparison to cells with truncating or no mutation. The ongoing functional studies on these BRCA1 missense variants indicate that these mutations could act in a dominant negative manner. Importantly, the observed differences in sensitivity to olaparib among mutation carriers could be also relevant for recently proposed use of PARP inhibitors as prophylactic agent for mutation carriers. Our ongoing work may help us to better understand the mechanisms of action of PARP inhibitors and lead to improvement of therapeutic strategies for BRCA1-associated cancers with extension to other tumors. Citation Format: Tereza Vaclova, Nicholas T. Woods, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Alvaro N.A. Monteiro, Javier Benítez, Ana Osorio. Implications of the type of BRCA1 germline mutation in the treatment of patients with hereditary breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5483. doi:10.1158/1538-7445.AM2014-5483