Abstract A05: Improving outcome in homologous recombination competent epithelial ovarian cancer: Hyperthemia and surgeon's perspective
Bibliographic record
Abstract
Abstract 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 [1]. 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 References: 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".