Ovarian Cancer Markers of Response to Neoadjuvant Chemotherapy

2014 ◽  
Vol 36 (14) ◽  
pp. 21 ◽  
Author(s):  
&NA;
2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6080-6080
Author(s):  
Mary M Mullen ◽  
Elena Lomonosova ◽  
Michael Driscoll Toboni ◽  
Hollie M Noia ◽  
Danny Wilke ◽  
...  

6080 Background: Less than 10% of patients with high grade serous ovarian cancer (HGSC) have a complete pathologic response to neoadjuvant chemotherapy. We aimed to identify a biomarker predictive of response to neoadjuvant chemotherapy and to determine if GAS6/AXL inhibition with AVB500 (AVB) could increase platinum response. Methods: AVB was supplied by Aravive Biologics. HGSC tumor samples were obtained pre- and post-neoadjuvant chemotherapy. GAS6 expression was measured by tissue immunohistochemistry (IHC) and serum ELISA. Four HGSC cell lines were used for all experiments. Immunofluorescent (IF) assays targeting ɣH2AX for DNA damage, RAD51, BRCA1, and BRCA2 for homologous recombination (HR) and 53BP1 for non-homologous end joining (NHEJ) were performed. Flow cytometry was used to evaluate RPA binding. DNA fiber assays were performed. In vitro clonogenic assays were done on chemoresistant ovarian tumor cells treated with carboplatin (carbo) +/- AVB and olaparib +/- AVB. Synergy assays were analyzed using Combenefit software. Mouse models were used to evaluate the combination of carboplatin + AVB and olaparib + AVB on tumor burden. Results: Patients with high pretreatment tumor GAS6 IHC expression ( > 85%) or serum GAS6 concentrations ( > 25ng/mL) were more likely to have a poor response to neoadjuvant chemotherapy than those with low GAS6 (P = 0.002). Additionally, high GAS6 concentration was associated with decreased overall survival (24.4 months versus undefined, P = 0.009). Carbo + AVB resulted in decreased clonogenic colonies compared to carbo alone (p < 0.05). In vivo tumor mouse models treated with chemotherapy + AVB had significantly less tumor burden than those treated with chemotherapy alone (50mg vs 357mg, P = 0.003). We identified an induction in HR deficiency by a decrease in RAD51, BRCA1, and BRCA2 foci and RPA binding in cells treated with carbo + AVB compared to carbo (P < 0.05). There was increase in ɣH2AX and 53BP1 foci as well as replication fork slowing in tumor cells treated with carboplatin + AVB (P < 0.01). We also AVB and carboplatin were synergistic. Olaparib + AVB resulted in decreased clonogenic colonies (P < 0.05) and decreased tumor burden in mouse models (76mg vs 171mg, P = 0.03) compared to olaparib alone. Conclusions: GAS6 is a potential biomarker predictive of poor response to neoadjuvant chemotherapy in HGSC. Inhibition of this GAS6/AXL pathway with AVB improves sensitivity to traditional neoadjuvant chemotherapy by inducing a homologous recombination deficiency.


Author(s):  
Ra�l Garc�a-V�zquez ◽  
Dolores Gallardo Rinc�n ◽  
Erika Ruiz-Garc�a ◽  
Abelardo Meneses Garc�a ◽  
Olga Hern�ndez De La Cruz ◽  
...  

2019 ◽  
Vol 29 (6) ◽  
pp. 1064-1071
Author(s):  
Camilla Nero ◽  
Anna Fagotti ◽  
Gian Franco Zannoni ◽  
Eleonora Palluzzi ◽  
Giovanni Scambia ◽  
...  

BackgroundGrowing evidence supports the role of neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. Currently, there is no shared histopathologic scoring system to assess pathologic response in the specimens obtained at interval surgery after neoadjuvant chemotherapy This review aims to summarize the literature on pathologic response, focusing on proposed scoring systems.MethodsThe systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, focusing on the definition of pathologic response, its prognostic value, possible predictors, and future implications. Eighteen manuscripts focusing on pathologic response in epithelial ovarian cancer were selected for analysis.ResultsOverall, eight histopathologic scoring systems to evaluate pathologic response have been proposed. There are currently no available markers (serum, radiological, genomic) to select which patients could achieve the highest benefit from neoadjuvant chemotherapy experiencing a complete pathologic response. A three-tier scoring system (CRS) based on omental assessment and which classifies the response to neoadjuvant chemotherapy has been validated in external cohorts of epithelial ovarian cancer. This scoring system demonstrated adequate interobserver reproducibility. Data is limited on the pathologic complete response rate changes according to chemotherapy regimen.ConclusionsA histopathologic scoring system endowed with prognostic value could be helpful in personalizing the treatment decision in patients with epithelial ovarian cancer.


2018 ◽  
Vol 28 (9) ◽  
pp. 1706-1713 ◽  
Author(s):  
Francesco Raspagliesi ◽  
Giorgio Bogani ◽  
Laura Matteucci ◽  
Jvan Casarin ◽  
Ilaria Sabatucci ◽  
...  

ObjectiveThe aim of the study was to evaluate outcomes of patients with unresectable advanced ovarian cancer experiencing complete response (CR) to neoadjuvant chemotherapy.MethodsData of consecutive patients undergoing neoadjuvant chemotherapy plus interval debulking surgery (IDS) were retrospectively reviewed in 4 Italian centers. Using a propensity-matching algorithm, we compared data of patients achieving CR with neoadjuvant chemotherapy (no macroscopic either microscopic residual disease (RD) at the time of IDS) with patients achieving partial response (PR). This latter group was stratified by the presence of RD (RD = 0 vs RD > 0).ResultsOverall, 193 had IDS after neoadjuvant chemotherapy: 25 (13%), 81 (41.9%), and 74 (38.3%) patients had CR, PR with RD of 0, and PR with RD of more than 0, respectively. In addition, 13 (6.7%) patients had no macroscopic disease detected at DS but just microscopic disease at pathological examination. For the study purpose, 25 patients achieving CR were matched (1:2) with 50 patients having PR and RD of 0 and 50 patients having PR and RD of more than 0. As the result of propensity matching, baseline characteristics were similar between groups. Comparing survival outcomes of patients having CR and PR with RD of 0, we observed that type of response to chemotherapy did not influence disease-free (hazard ratio = 1.53 [95% confidence interval = 0.88–2.66], P = 0.127) and overall (hazard ratio = 1.74 [95% confidence interval = 0.76–4.01], P = 0.189) survivals. Patients achieving CR experienced significantly better disease-free survival (P = 0.004) and a trend toward better overall survival (P = 0.06) than patients achieving PR with RD of more than 0 at IDS.ConclusionsComplete cytoreduction might mitigate the difference in response to neoadjuvant chemotherapy. The presence of RD at IDS is associated with worse survival outcomes.


2011 ◽  
Vol 105 (2) ◽  
pp. 200-205 ◽  
Author(s):  
Yusuf Yildirim ◽  
Ibrahim Egemen Ertas ◽  
Askin Dogan ◽  
Ozge Elmastas Gultekin ◽  
Emre Gultekin

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