55IN - Targeting DNA Repair Deficiency in Ovarian and Endometrial Cancers

Abstract

ABSTRACT The key repair deficiency in cancer cells which has led to recent therapeutic innovation is homologous recombination deficiency (HRD), which is a defining feature of those cancers, particularly ovarian and breast, arising in patients with germ line BRCA mutations. Poly ADP ribose polymerase (PARP) inhibitors take advantage of HRD, through tumour specific synthetic lethality to provide clear clinical efficacy as single agents with an excellent toxicity profile in patients with these diseases. Response rates of 30%-60% have been documented according to prior platinum sensitivity. Their application has subsequently been broadened into patient with recurrent high grade serous ovarian cancer and platinum-sensitive disease, but who are not know to have germ line BRCA mutations. In these cases a clear benefit was seen with the PARP inhibitor olaparib in a randomised maintenance therapy trial in terms of progression-free survival (but not overall survival). A similar benefit in PFS was seen in a second maintenance trial in which olaparib was also combined with carboplatin - paclitaxel in the chemotherapy phase of treatment. Several PARP inhibitors are now in active development in ovarian cancer and the focus is increasingly moving to their application in germ line BRCA associated disease where the extent of benefit of these agents may after all be the greatest. As regards gynaecological cancers in general, the other disease of interest is endometrial cancer, in which in vitro data have also indicated substantial potential for PARP inhibitors. In endometrial cancer cell lines, HRD has also been noted and thought likely to relate to the characteristic PTEN loss seen in this disease (particularly Type I) rather than BRCA dysfunction. Clinical trials with PARP inhibitors are therefore awaited with interest. References Banerjee S & Kaye SB; PARP inhibitors in BRCA gene-mutated ovarian cancer and beyond. Current Oncology Reports - 13: 442-449, 2011. Disclosure The author has declared no conflicts of interest.