Abstract A42: The treatment of sporadic breast cancer with Poly(ADP-ribose) polymerase (PARP1) inhibitors (AZD2281, ABT888, AG14361) as single agents and in combination with chemotherapy

Introduction: It has been shown that poly(ADP-ribose) polymerase (PARP1) inhibitors may be useful in the treatment of BRCA1 and 2 hereditary breast cancers due to their deficiency in homologous repair. Many sporadic breast cancers may also be deficient in homologous repair due to deficiency's in RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CH1, CHK2, FANCD2, FANCA, FANC or a down regulation of BRCA. Methods: Human breast cancer cell lines representative of basal, Her2/neu, luminal A and luminal B subtypes were treated with PARP1 inhibitors alone or in combination with standard chemotherapeutic agents (alkylating, topoisomerase inhibitors, anti-metabolites, anti-mitotics and/or DNA intercalators) for 72 hours. IC50 values were determined by standard dose response curves of the PARP1) inhibitors (AZD2281, ABT888, AG14361), standard chemotherapeutic agents alone and in combination with each other. PARP1 inhibitor pharmacodynamic, PARP1 activity assays and the quantification of molecular markers from the apoptotic, DNA repair and mitotic pathways were also performed and correlated with IC50 values. Results: There was no statistical difference in the IC50 of PARP1 inhibitors for BRCA1, non-BRCA1 triple negative or luminal human breast cancer tissue. Significant enhancement of chemotherapeutic cytotoxicity by PARP1 inhibitors was observed in not only hereditary (BRCA1 & BRCA2) breast cancer but, in sporadic breast cancer also. The results suggest that many sporadic breast cancers are deficient in homologous recombination and their ability to preserve DNA and chromosomal fidelity. Conclusion: PARP1 inhibitors in combination with chemotherapy may be effective in treating sporadic breast cancer. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A42