Abstract 2425: Exploiting DNA repair defects in breast cancer

Abstract

Abstract One of the hallmarks of cancer is genetic instability. Many chemotherapeutic strategies make use of DNA damaging agents, that preferentially target dividing cells. Recently, DNA repair defects have been identified in many different types of tumors, suggesting that the effectiveness of such treatments may be modulated by the precise genetic make-up of the tumor; defects in specific DNA repair pathways can be used as the Achilles' Heel of the tumor. An important new concept is synthetic lethality, the observation that combinations of mutations can be lethal, while both single mutations are viable. In selected tumors, the specific DNA repair defect can be targeted in such a way that the tumor cells can be killed without causing severe side effect on normal tissues. The combination of PARP inhibitors and homologous recombination (HR) deficient hereditary breast cancer is on its way to the clinic and more combinations are currently in the preclinical phase. Selection of breast cancer patients for targeted treatment with PARP inhibitors requires a validated test to identify HR deficient tumors. For this purpose, we have assessed ionizing radiation induced RAD51 foci (IRIF) after ex vivo irradiation of individual breast tumor slices as a marker for HR defects. We validated this approach in known HR- deficient tumors, where we found a severe defect in RAD51 IRIF formation. Subsequently, we used this assay to identify a subgroup of HR deficient primary breast cancers. Out of 42 tumors, we found five HR deficient breast cancers, caused by two distinct modes of BRCA gene inactivation, mutations and promoter hypermethylation. HR deficiency was significantly associated with high grade, triple-negative breast cancer (TNBC). A large fraction of TNBC showed HR defects, suggesting that PARP inhibitors may be particularly promising for this group of tumors that currently have a poor prognosis. We conclude that the RAD51 IRIF assay is a powerful tool to select patients with HR-deficient primary breast cancers eligible for PARP-inhibitor treatment in the clinic. These approaches may change cancer medicine in a fundamental way, from a one-size-fits-all concept to an individualized treatment strategy based on the functional molecular make-up of the tumor for each patient. Citation Format: Kishan A.T. Naipal, Nicole S. Verkaik, Petra ter Brugge, Najim Ameziane, Carolien H.M. van Deurzen, John W. Martens, Johan P. de Winter, Jos Jonkers, Maaike P. Vreeswijk, Agnes Jager, Jan Hoeijmakers, Roland Kanaar, Dik C. van Gent. Exploiting DNA repair defects in 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 2425. doi:10.1158/1538-7445.AM2014-2425