Abstract IA14: Exploiting the translational and functional opportunities for homologous recombination deficiency

Abstract

Abstract Cancer is a disease of DNA, and the processes by which cells repair DNA damage are critical, not only in causing the disease but also in determining how the cancer cell will respond to treatment. Of the six major pathways by which DNA damage is repaired, homologous recombination (HR) is perhaps the best studied in ovarian cancer. This pathway is responsible for repairing double strand breaks and uses at least forty proteins, including both BRCA1 and BRCA2. We have shown that 50% of high grade serous cancers are defective in homologous recombination and this group are more likely to be sensitive to platinum chemotherapy and have a better prognosis than tumours which are competent for the pathway. As may be expected, this group also includes all the tumours occurring in women with germline mutations of BRCA1 and BRCA2. HR status has also been suggested to be predictive of response to PARP inhibitors and it is proposed that this is an example of synthetic lethality in which inactivation of one pathway is not harmful to a cell but inhibition of two (one by the PARP inhibitor and the other the underlying HR defectiveness) will render the cell non viable. We have confirmed in a large panel of ovarian cancer primary cultures and cell lines that HR defectiveness is indeed a very strong predictor of ex vivo drug sensitivity with positive and negative predictive values close to 100%. These data provide the basis for developing biomarker directed therapy for PARP inhibitors and provide a rationale for increasing the indication for these drugs to tumours other than those caused by germline mutations. Challenges still exist however and current work is seeking to investigate the interplay of the different DNA damage repair pathways and how these may be used to further refine the biomarkers currently available. Citation Format: Richard John Edmondson. Exploiting the translational and functional opportunities for homologous recombination deficiency. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA14.