Abstract #5494: Pre-clinical evaluation of single-agent activity of the PARP inhibitor olaparib (AZD2281) in homologous recombination deficient triple-negative breast cancer

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO The oral PARP inhibitor olaparib (AZD2281, KU-0059436) has been shown to have single agent clinical activity in tumours from patients with hereditary BRCA mutations (Fong et al ., 2008). The BRCA genes play key roles in homologous recombination (HR) repair of DNA double strand breaks (DSBs) and BRCA dysfunction is associated with an increased incidence of breast and ovarian cancers. In addition to BRCA, RNAi-mediated gene expression knockdown of other components of the HR DNA damage response pathway such as ATM, ATR and CHK2 has been shown to cause sensitivity to PARP inhibition pre-clinically (McCabe et al ., 2006). These data suggest broader clinical potential of PARP inhibitors in other tumours that may be homologous recombination deficient (HRD). Triple negative (TN) breast cancers represent a distinct clinical subgroup and are defined as ER, PR and HER-2 receptor negative. TN tumours are associated with increased aggressiveness and decreased recurrence-free survival (Reis-filho et al ., 2008). Microarray profiling studies have shown most TN breast cancers cluster in the basal-like gene expression sub-type (Perou et al ., 2000; Sorlie et al ., 2001) and those with hereditary BRCA1 mutations are typically both TN and Basal-like, suggesting an association with HRD within these sub-types. We have undertaken pre-clinical studies to assess the sensitivity of breast cancer cell lines to olaparib and better define the link between TN and HRD status. 2D-clonogenic survival assays were performed with single agent olaparib on a panel of 25 breast cancer cell lines. TN cell lines were found to be twice as likely to be sensitive to olaparib than ER+, PR+ or HER-2+ cell lines (44% vs. 22%) with the majority of sensitive cell lines being TN or basal-like. Genetic BRCA mutations only accounted for 33% of sensitive cell lines indicating HRD through loss of other factors may be driving olaparib sensitivity. HRD status was determined by baseline gene expression analysis of key HR genes and low expression was found in all highly sensitive cell lines but not in resistant cells. HRD status was confirmed in several cell lines through the inability to form Rad51 HR repair foci or impaired phosphorylation of DNA damage markers. Olaparib sensitivity was then determined in vivo using xenograft models and single agent olaparib was found to cause marked tumour growth inhibition only in cell lines with HRD. In summary, olaparib demonstrates enhanced pre-clinical activity in TN breast cancer cell lines and therefore support the further assessment in TN breast cancer clinical trials. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5494.