Introduction: We developed a functional assay and showed that 50% epithelial ovarian cancers (EOCs) are homologous recombination (HR) deficient (HRD) and are sensitive to PARP inhibition . HRD patients showed improved clinical platinum sensitivity (53.8% vs 16.7%), survival (12 month OS- 41.7% vs 11.5%) and optimal cytoreduction (80% vs. 62%) rates compared to HR competent (HRC) tumours which are less responsive and represent an unmet clinical need. Recently, HIPEC (hyperthermic intraperitoneal chemotherapy) has been shown to improve survival in ovarian cancer; we hypothesize that HRC tumours would benefit from primary surgery and targeted HIPEC as a strategy to improve outcome.
Methods: HRC cell lines (VC8-B2, UWB1.29+BRCA1, A2780) and HRD cell lines (VC8, UW) were used. RAD51 foci, a marker of HRR, and gamma H2AX foci, a marker of DNA damage, were measured by immune-fluorescence microscopy after treatment with heat at 39 degree C/42 degree C and HSP90 inhibitors (17-AAG and NVP-AUY922). Effect on the levels of RAD51, BRCA1 and BRCA2 protein was assessed by Western Blot (WB). Sensitivity to the PARPi (rucaparib and olaparib), in combination with a HSP90 inhibitor and in hyperthermic conditions was measured using clonogenic assays.
Results: HSP90 inhibition and incubation at 39 degree C both resulted in a modest sensitization to rucaparib. 1 hr incubation at 42degree C caused total cell death but at 39 degree C, viability was 25% and sensitised V-C8 B2 cells, but not V-C8 cells to rucaparib. HSP90 inhibitors reduced RAD51 foci formation in a concentration-dependent manner and levels of RAD51 protein in WB.
In a separate set of experiments (Helen Bryant, University of Sheffield, UK), heat at 42 degree C sensitized UW+B1 (BRCA 1 competent) cells to olaparib (PARP inhibitor) but UW cells (BRCA1 deficient) all died. WB showed that 42 degree C degrades BRCA2 but not BRCA1.
Conclusions: Personalized surgical and chemotherapeutic strategies may be developed for HR stratified EOCs. Primary surgery may be the preferred approach in HRC due to poor chemoresponse and resources should be optimized to achieve complete cytoreduction anticipating difficult resection. Intra-operative hyperthermic treatment and selective HR inhibitors (HSP90) may improve subsequent chemoresponse in HRC. Pre-clinical studies on patient tissues and after HIPEC procedures are proposed in ongoing studies to consolidate our hypothesis.
1. Epithelial ovarian cancer: HR assay to stratify as HRD and HRC
2. HRC: Primary surgery+ HIPEC
Adjuvant selective HR inhibitors based on expression of HR proteins/ interaction with other pathways + platinum/ PARPi
Benefit: Survival, improved chemoresponse. Also quality of life and time by averting inappropriate use of NACT in poor chemo-responders
3. HRD: NACT or primary surgery, role for PARPi in either setting
In select cases with good chemoresponse to NACT, may consider limited surgery or delayed surgery at recurrence ±HIPEC; assess HR status again and targeted chemotherapy
Benefit- Quality of life, limited extent of surgery/ delayed surgery without compromising survival as expected to be good chemo-responders
1. Mukhopadhyay A, et al. Clinicopathological features of homologous recombination deficient epithelial ovarian cancers: sensitivity to PARP inhibitors, platinum and survival. Cancer Research 2012;72: 5675
Citation Format: Asima Mukhopadhyay, Ganyi Abdulrahman, Eliza Davison, Elizabeth Matheson, Yvette Drew, Nicola Curtin. Improving outcome in homologous recombination competent epithelial ovarian cancer: Hyperthemia and surgeon's perspective [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A05.