Advanced Ovarian Clear Cell Carcinoma Research Articles

Abstract B056: The unconfounded effect of bevacizumab on advanced ovarian clear cell carcinoma: a systematic review, traditional meta-analysis, and network meta-analysis

Abstract Background Ovarian clear cell carcinoma (OCCC) accounts for 5-20% of all epithelail ovarian cancers, and is associated high recurrence rate and chemoresistance. There are some new therapies available in recent years, including bevacizumab, an anti-VEGF monoclonal antibody, and the poly ADP-ribose polymerase (PARP) inhibitors. Previous research and current support the use of both medication in OCCC. However, most of the studies reported results for all subtypes collectively in which OCCC only accounted for a small proportion of the study cohort. Besides, dislike the high-grade serous subtype, only around 10% of OCCC respond to poly ADP-ribose polymerase (PARP) inhibitor. In the subgroup analysis from ICON7, Bevacizumab had limited role in OCCC patients, in which OCCC of any stage were included. On the other hand, another 2 multi-center studies evaluated Bevacizumab as the front-line or salvage therapy revealed positive results. However, the results could be biased due to unadjusted confounders. Objective: To find the real effect of Bevacizumab on advanced stage OCCC. Materials and Methods: A systematic review via searching the Pubmed with "ovarian clear cell carcinoma" and "bevacizumab" was performed. Any comparative study met the inclusion criteria. The data were extracted, evaluated and classified by their combination of potential confounders. Primary data from National Taiwan University Hospital (NTUH) Database were collected and incorporated into the traditional meta-analysis, and the network meta-analysis. The potential confounders for analysis include "residual tumor", "FIGO stage", and "functional status". Results: There were 3 retrospective studies, including one single-center study from Japan (N=28), one multi-center study from Japan (N=145), and one multi-center study from Korea (N=138). There were 64 patients identified from NTUH database between 2011 and 2020. By traditional meta-analysis, it revealed Bevacizumab is associated with improved progression-free survival (HR 0.62, 95% C.I. 0.44 - 0.87, common effect model, I2= 50%). After adjusted for confonders and analyzed by network meta-analysis, however, only "no residual tumor" is associated with improved progression-free survival (HR 0.37, 95% C.I. 0.14 - 0.97). The role of Bevacizumab on OCCC is limited (HR 1.20, 95% C.I. 0.51 - 2.83). Conclusion: By adjusting for possible confounders in published studies, it reveals that Bevacizumab may not improve progression-free survival in advanced-stage OCCC from a network meta-analysis. Citation Format: Fisher Kuan-Ju Huang. The unconfounded effect of bevacizumab on advanced ovarian clear cell carcinoma: a systematic review, traditional meta-analysis, and network meta-analysis [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B056.

The Significance of Radiotherapy in Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis.

To assess the response rate and survival effect of adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) during ovarian clear cell carcinoma (OCCC). We searched Web of Science, PubMed,Cochrane library electronic databases, Clinical Trials, WanFang Data and Chinese National Knowledge Infrastructure (CNKI)up to October2022. We also searched registers of clinical trials, abstracts of scientific meetings and reference listsof included studies. We identifieda total of4259patients from 14studies metthe inclusion criteria. The pooled response rate of residual tumors for RT/CRT was 80.0%, the pooled 5-year progression-free survival (PFS) ratio during RT/CRT group was 61.0%, and the pooled 5-year overall survival (OS) ratio during RT/CRT group was 68.0%; heterogeneity tests demonstrated significant difference between studies (I2 >50%). Cumulative results suggested adjuvant RT/CRT improved 5-year PFS ratio of OCCC patients (OR: 0.51 (95% CI: 0.42-.88), I2 = 22%, P = .009), had no impact on 5-year OS ratio (OR: 0.52 (95% CI: 0.19-1.44), I2 = 87%, P = .21); meta-regression of studies before and after 2000 found consistent results. Sub-analysis observed that adjuvant RT/CRT had no impact on 5-year OS ratio of early-stage (stage I + II) OCCC patients (OR: 0.67 (95% CI: 0.25-1.83), I2 = 85%, P = .44), but might improve 5-year OS ratio of advanced and recurrent OCCC patients (OR: 0.13(95% CI: 0.04-.44), P = .001). This analysis suggested that adjuvant RT/CRT might improve oncologic outcomes of OCCC, especially for advanced and recurrent cases. Due to the inherent selective biases of retrospective studies enrolled in the meta-analysis, more convincing evidences based on prospective randomized controlled trials (RCTs) are urgently needed.

Abstract 5185: First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination

Abstract Background: The development of chimeric antigen receptor (CAR) T cell therapy has introduced an effective strategy to guide and promote the immune response. Also, gene-engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be directed against target tumor antigen. However, these autologous applications are limited by toxicities, restricted trafficking and infiltration into tumor, suboptimal persistence, and exhausted status of immune cells that may cause manufacturing failure. One approach to overcome those limitations is the development of “off-the-shelf” iPS-cell sources. The iCAR-ILC-N101 is an allogeneic human leukocyte antigen (HLA)-homozygous induced pluripotent stem cell (iPSC)-derived anti-glypican-3 (GPC3) CAR-expressing innate lymphoid cells/natural killer cell (ILC/NK), which has both antigen-specific and NK activating receptor-mediated cytotoxicity. The iCAR-ILC-N101 is produced from the established iPSC strain QHJI01s04, and there is theoretically no risk of developing graft-versus host disease because the product dose not have T cell receptor. The product has a relevant living period in the body, thereby has little concern about residual toxicity and reduces systemic side effects by topical treatment. GPC3 is a cancer-specific membranous protein that is expressed in hepatoblastoma, hepatocellular carcinoma and ovarian clear cell carcinoma (OCCC) but is not expressed in normal tissue. OCCC is a relatively rare malignancy and is associated with poor prognosis. Intraperitoneal administration of iCAR-ILC-N101 is expected to show antitumor activity for OCCC patients with peritoneal dissemination that express GPC3 and reduce systemic side effects, thereby ensuring safety and improving therapeutic efficacy. Preclinical study showed that intraperitoneal injection of iCAR-ILC-N101 for GPC3-positive ovarian tumor-bearing immunodeficient mouse model showed suppressed tumor growth. Method: This is a first-in human phase 1 study to evaluate safety, toxicity and efficacy of the iCAR-ILC-N101 in patients with GPC3-positive advanced or recurrent OCCC harboring peritoneal dissemination. Major inclusion criteria include histologically diagnosed GPC3-positive advanced or recurrent OCCC with peritoneal dissemination who are resistant to standard therapy and have matched HLA-A24 or B52. The study includes 3 cohorts (cohort -1, 0.5x106 cells/kg; cohort 1, 1x106 cells/kg; cohort 2, 3x106 cells/kg) and starts with cohort 1. The iCAR-ILC-N101 is administered intraperitoneally once a week for 4 weeks; for the first patient in each cohort, patient is observed for 14 days for safety evaluation after the first administration and then receive iCAR-ILC-N101 on day15 and 22. Enrollment initiated in July 2021 and one patient was enrolled. No dose-limiting toxicity was observed. Clinical trial registry number: jRCT2033200431 Citation Format: Kenichi Harano, Shin Kaneko, Tetsuya Nakatsura, Junichiro Yuda, Nozomu Fuse, Akihiro Sato, Reiko Watanabe, Genichiro Ishii, Toru Mukohara, Hiroshi Tanabe, Yukiko Ishiguro, Hideki Furuya, Masashi Wakabayashi, Miki Fukutani, Manami Shimomura, Tatsuki Ueda, Shoichi Iriguchi, Ayako Kumagai, Kengo Nakagoshi, Aki Sasaki, Toshihiko Doi. First in human trial of off-the shelf iPS derived anti-GPC3 NK cells for recurrent ovarian clear cell carcinoma with peritoneal dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5185.

Abstract 5173: Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient

Abstract Intrinsic intra-tumor heterogeneity (ITH) has been linked to worse patient outcomes. The development of spatial profiling technology has enabled the deciphering of ITH with multiple analysis readouts. Advanced ovarian clear cell carcinoma (OCCC), known to harbor ITH, is chemoresistant, poor prognostic, and possesses distinct molecular and histological characteristics. However, detailed spatial information of the nature of ITH within OCCC remains unclear. Here, we utilized the NanoString Digital spatial profiling (DSP) GeoMx platform to perform multiplex protein expression analysis on tumor samples of primary and colonic metastatic sites from one advanced OCCC patient. The spatial resolution revealed the existence of an epithelial-mesenchymal (EM) gradient within the metastatic tumor but not the primary tumor, and similar EM gradient was not observed within the primary tumor. The EM gradient exhibited a distinct pattern from the periphery to the core of the metastatic tumor. Compared to tumor cells at the primary site, there was an intermediate zone in between the tumor periphery and the tumor core in the colonic metastasis with differential expression patterns of pan-cytokeratin (PanCK), fibronectin (FN), smooth muscle actin (SMA), neural cell adhesion molecule (NCAM), integrin alpha X (ITGAX), and Ki-67. Our study provides the first spatially resolved in situ evidence of intermediate or hybrid EM states within the tumor samples of similar morphology. This not only demonstrates the promising applications of spatial profiling in precision medicine but also provides an unprecedented view of the EM gradient during the progression of cancer such as OCCC. Citation Format: Duncan Y.T. Wang, Tuan Zea Tan, Ya-Ting Tai, Jieru Ye, Wei-Chou Lin, Lin-Hung Wei, Ruby Y. J. Huang. Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5173.

Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis.

5502 Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. Bevacizumab (Bev) was approved in November 2013 in Japan and became incorporated in the treatment of advanced ovarian cancer. However, the efficacy of Bev against ACCC remain unknown. We investigated the survival outcomes for ACCC, following first-line chemotherapy with or without Bev. Methods: Patients diagnosed with ACCC at seven institutions between 2008 and 2018 were enrolled in this study. Patients underwent cytoreductive surgery and taxane-carboplatin chemotherapy (78: triweekly regimen; 30: weekly regimen; 25: dose-dense regimen; 12: others) with or without concurrent and maintenance Bev (15 mg/kg/3 weeks). We compared the progression-free survival (PFS) and overall survival (OS) before (group A, n = 102) and after (group B, n = 43) Bev approval, using Kaplan–Meier method and Cox regression model. We excluded patients with poor performance status (PS) in group A, and patients who did not receive Bev due to poor PS or thrombosis in group B. Results: There was no significant difference between two groups in terms of age (p = 0.135) and initial CA125 level (p = 0.674). Thirteen (13%) and 11 (26%) patients had stage IV disease (p = 0.058) and 2 (3%) and 7 (16%) patients were of poor PS (PS ≥2) (p = 0.004) in group A and B, respectively (p = 0.058). More patients (29/43, 67%) in group B were achieved complete resection than in A group (52/102, 51%) (p = 0.068). The median cycle of Bev in B group was 16 (interquartile range: 6-21). The median follow-up time was 36 months. The median PFS increased from 12.5months in A group to 29.7 months in B group (log-rank test: p = 0.023, Wilcoxon test: p = 0.006). The median OS increased from 34.7 months in A group to 51.4 months in B group (log-rank test: p = 0.085, Wilcoxon test: p = 0.027). Multivariate analysis revealed that Bev use (Hazard ratio (HR): 0.54, p = 0.011; HR: 0.54, p = 0.019), PS <2 (HR: 0.33, p = 0.013; HR: 0.29, p = 0.006) and completeness of resection (HR: 0.38, p < 0.001; HR: 0.37, p <0.001) were independent prognostic factors for PFS and OS. Conclusions: Incorporating Bev in first-line chemotherapy may improve PFS in patients with ACCC. [Table: see text]

Bevacizumab in First-Line Chemotherapy Improves Progression-Free Survival for Advanced Ovarian Clear Cell Carcinoma.

Simple SummaryWe investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab for ovarian cancer in Japan to evaluate the efficacy of bevacizumab for advanced clear cell carcinoma. We investigated 28 consecutive patients diagnosed with clear cell carcinoma (stages III/IV) at our hospital between 2008 and 2018. Bevacizumab was administered for treatment after approval in Japan in November 2013. Progression-free survival was compared between 10 patients treated before bevacizumab approval (2008–2013,) and 18 patients treated after Bev approval (2014–2018) for first-line chemotherapy. The median progression-free survival increased from 12.0 months before bevacizumab approval to 29.8 months after bevacizumab approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), bevacizumab administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for progression-free survival. Bevacizumab incorporated into first-line chemotherapy might improve progression-free survival in patients with advanced clear cell carcinoma. (1) Background: We investigated survival outcomes following first-line chemotherapy before and after approval of bevacizumab (Bev) for ovarian cancer in Japan to evaluate the efficacy of Bev for advanced clear cell carcinoma (CCC). (2) Methods: We investigated 28 consecutive patients diagnosed with CCC (stages III/IV) at our hospital between 2008 and 2018. Bev was administered for treatment of advanced CCC after approval in Japan in November 2013. Progression-free survival (PFS) was compared between 10 patients treated before Bev approval (2008–2013, Bev- group) and 18 patients treated after Bev approval (2014–2018, Bev+ group) for first-line chemotherapy. (3) Results: No intergroup difference was observed in patient characteristics. The rate of completeness of resection was higher in the Bev − group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev + group received ≥ 21 cycles of Bev. The median PFS increased from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis showed that performance status (p = 0.049), Bev administration (p = 0.023) and completeness of resection (p = 0.023) were independent prognostic factors for PFS. (4) Conclusions: Bev incorporated into first-line chemotherapy might improve PFS in patients with advanced CCC. We hope that our findings will be confirmed in adequate clinical trials.

Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40mg/kg, i.p. injection weekly); G5: PTX (20mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2weeks. The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Residual Tumor Diameter Predicts Progression After Primary Debulking Surgery of Ovarian Clear Cell Carcinoma (OCCC): Clinicopathologic Study of Stage II-IV OCCC Patients from a Single Institution

IntroductionOvarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer characterized by highly aggressive and poor prognosis. However, it is unclear what factors are associated with OCCC recurrence and death. The study aimed to evaluate whether residual tumor diameter after primary debulking surgery, or other clinicopathological features play roles in predicting survival outcome in stage II–IV OCCC patients.Material and MethodsWe present a retrospective study of OCCC patients with stage II–IV in our department from 2010 to 2015. Kaplan–Meier method was used to draw a survival curve. Survival analysis was performed using Log-rank test for univariate analysis and COX proportional risk regression model for multivariate analysis.ResultsIn this cohort of 78 patients who underwent primary debulking surgery, 47 patients had disease recurrence and 32 cases died. On univariate analysis, FIGO stage, residual tumor diameter and ascites were significant predictors of 3-year PFS (P values<0.05) and OS (P values<0.05). On multivariate analysis, the residual tumor diameter was an independent prognostic factor for 3-year PFS and OS (P values<0.05). The outcomes of patients in residual-free group were significantly better than those in the residual tumor diameter 0–1cm and >1cm group (PFS: P=0.000, OS: P=0.001), but there was no significant difference in prognosis between 0–1cm and > 1cm group (P values >0.05). Greater residual tumor diameter predicted progression on cox analysis in patients with stage III, but not for patients with stage IV.ConclusionResidual tumor diameter is prognostic after surgery for OCCC. Achieving no residual disease will significantly improve the prognosis in advanced OCCC patients.

Expression of the chrXq27.3 miRNA cluster in recurrent ovarian clear cell carcinoma and its impact on cisplatin resistance

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer and exhibits dismal prognosis due to chemoresistance. Moreover, only few effective therapeutic options exist for patients with recurrent OCCC, and an understanding of its molecular characteristics is essential for the development of novel therapeutic approaches. In the present study, we investigated unique MicroRNAs (miRNA) profiles in recurrent/metastatic OCCC and the role of miRNAs in cisplatin resistance. Comprehensive miRNA sequencing revealed that expression of several miRNAs, including miR-508-3p, miR-509-3p, miR-509-3-5p, and miR-514a-3p was remarkably less in recurrent cancer tissues when compared with that in paired primary cancer tissues. These miRNAs are located in the chrXq27.3 region on the genome. Moreover, its expression was negative in omental metastases in two patients with advanced OCCC. In vitro analyses revealed that overexpression of miR-509-3p and miR-509-3-5p reversed cisplatin resistance and yes-associated protein 1 (YAP1) was partially responsible for the resistance. Immunohistochemistry revealed that YAP1 expression was inversely correlated with the chrXq27.3 miRNA cluster expression. In conclusion, these findings suggest that alteration of the chrXq27.3 miRNA cluster could play a critical role in chemoresistance and miRNAs in the cluster and their target genes can be potential therapeutic targets.

Hypoxia-inducible Factor-1α Suppression in Ovarian Clear-cell Carcinoma Cells by Silibinin Administration.

Advanced ovarian clear-cell carcinoma (CCC) fails to respond to standard chemotherapy, and has a poor prognosis. Since hypoxia-inducible factor-1 (HIF-1) stimulates various genes involved in cancer, we aimed to examine the efficacy of silibinin, an active component of milk thistle belonging to Asteraceae, in suppressing HIF-1 activity, and elucidate the underlying mechanism in human CCC cell lines. Human ovarian CCC cell lines HAC-2, OVISE, and RMG-1 were treated with 500 μM silibinin for 4 h under normoxic and hypoxic conditions. Using DNA microarray, we analysed genes whose expression modulated more than 2-fold in response to hypoxia, whereas HIF-1α expression was measured using ELISA. Silibinin treatment decreased HIF-1α protein in all cell lines, and eIF4E2 and RPS6 mRNA in HAC-2 and RMG-1 cells. Silibinin suppressed HIF-1α protein under hypoxic conditions in CCC cell lines and could be a potential anti-cancer drug.

Is There a Survival Benefit for Patients with Advanced Ovarian Clear Cell Carcinoma Who Complete More Than 6 Cycles of Postoperative Chemotherapy?

PurposeTo provide a reference for clinicians, whether patients with advanced ovarian clear cell carcinoma (OCCC) require chemotherapy (CT) for more than 6 cycles after tumor debulking.Patients and MethodsA retrospective review was performed on 85 women diagnosed and treated for advanced OCCC. Outcomes of patients who underwent >6 vs ≤6 cycles of CT were analyzed based on clinicopathological factors.ResultsAmong the 85 patients with advanced OCCC, 47 patients underwent ≤6 cycles of CT, and 38 patients underwent CT for over 6 cycles. Out of these, 49 patients had disease recurrence, and 35 died. The 2-year progression-free survival (PFS) for patients in the two groups was 51.5% and 42.2% (P＞0.05), respectively. The 2-year overall survival (OS) was 59.7% and 64.5%, respectively (P＞0.05), and the difference was not statistically significant. Multivariate analysis showed that residual tumor diameter was an independent risk factor for prognosis (PFS and OS). We divided the patients into three groups according to residual tumor diameter as 0 (R0), ≤1cm (R1), and >1cm (R2). The prognosis of R0 was better than R1 and R2. Further studies found that patients who received postoperative adjuvant chemotherapy for over 6 cycles showed no difference in improved prognosis, regardless of residual tumor diameter.ConclusionPatients with advanced OCCC who received more than 6 courses of adjuvant chemotherapy after surgery did not show improved prognosis. The residual tumor diameter is an independent indicator of prognosis in patients with advanced OCCC. Complete staging improves the prognosis of patients compared to the ideal or non-ideal cytoreductive surgery.

Targeting an autocrine IL-6-SPINK1 signaling axis to suppress metastatic spread in ovarian clear cell carcinoma.

A major clinical challenge of ovarian cancer is the development of malignant ascites accompanied by widespread peritoneal metastasis. In ovarian clear cell carcinoma (OCCC), a challenging subtype of ovarian cancer, this problem is compounded by near-universal primary chemoresistance; patients with advanced stage OCCC thus lack effective therapies and face extremely poor survival rates. Here we show that tumor cell expressed serine protease inhibitor Kazal type 1 (SPINK1) is a key driver of OCCC progression and metastasis. Using cell culture models of human OCCC, we find that shRNA silencing of SPINK1 sensitizes tumor cells to anoikis and inhibits proliferation. Knockdown of SPINK1 in OCCC cells also profoundly suppresses peritoneal metastasis in mouse implantation models of human OCCC. We next identify a novel autocrine signaling axis in OCCC cells whereby tumor cell-produced interleukin-6 (IL-6) regulates SPINK1 expression to stimulate a common protumorigenic gene expression pattern leading to anoikis resistance and proliferation of OCCC cells. We further demonstrate that this signaling pathway can be successfully interrupted with the IL-6Rα inhibitor tocilizumab, sensitizing cells to anoikis in vitro and reducing metastasis in vivo. These results suggest that clinical trials of IL-6 pathway inhibitors in OCCC may be warranted, and that SPINK1 might offer a candidate predictive biomarker in this population.

834P A phase II study of gemcitabine, cisplatin, and bevacizumab for first recurrent and refractory ovarian clear-cell carcinoma (KCOG-G1601 trial)

Patients with advanced ovarian clear-cell carcinoma (OCC) have poor prognosis in the absence of an effective standard treatment. The response rate of chemotherapy for relapsed OCC is <10%. Gemcitabine and cisplatin are reported to have a synergic effect on ovarian cancer. Evidence indicates that addition of bevacizumab to a chemotherapy regimen improves progression-free survival. We conducted a multi institutional phase II trial in Japan to examine the efficacy and safety of a gemcitabine, cisplatin, and bevacizumab combination (GPB) therapy for OCC.

Effect of bevacizumab in first-line chemotherapy on progression-free survival in advanced ovarian clear cell carcinoma.

e18086 Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. To evaluate the efficacy of bevacizumab (Bev) for ACCC, we investigated the survival outcome of first-line treatment before and after the approval of Bev for ovarian cancer treatment in November 2013 in Japan. Methods: We recruited 28 consecutive patients diagnosed with ACCC at our institution between 2007 and 2018. We performed cytoreductive surgery and administered paclitaxel-carboplatin chemotherapy (paclitaxel: 80 mg/m2 + carboplatin area under the curve 2.0–3.0 mg/mL/min, weekly without break) as first-line chemotherapy. Bev (15 mg/kg/3 weeks) was also administered after its approval. We compared progression-free survival (PFS) between Bev+ group (n = 18) and Bev- group (n = 10) using the Kaplan–Meier method and a Cox regression model. Results: Patients characteristics were similar between the Bev- and Bev+ groups. The median age was 54 years and 53 in the Bev- and Bev+ groups (p = 0.810), respectively. Three (30%) and 4 (22%) patients in the Bev- and Bev+ groups had stage IV disease (p = 0.674), respectively. The performance status (PS) was ≥2 in 1(10%) and 5 (28%) patients in the Bev- and Bev+ groups (p = 0.375), respectively. Peritoneal cancer index was 5.5 and 5.5 in the in Bev- and Bev+ groups (p = 0.727), respectively. Primary debulking surgery was performed in 10 (100%) and 11 (61%) patients in the Bev- and in Bev+ groups, respectively. Surgical complexity score was 9 and 9 in the Bev- and in Bev+ groups (p = 0.700), respectively. Completeness of resection was higher in the Bev- group (9/10, 90%) than in the Bev+ group (15/18, 83%) (p = 0.044). Eleven (61%) patients in the Bev+ group received ≥21 cycles of Bev. The median PFS increases from 12.0 months before Bev approval to 29.8 months after Bev approval (Wilcoxon test, p = 0.026). Multivariate analysis revealed that Bev use (p = 0.005) and PS &lt; 2 (p = 0.035) were independent prognostic factors for PFS; however, completeness of resection was not a prognostic factor (p = 0.052). Conclusions: Bev in first-line chemotherapy improves the survival outcome of ACCC. [Table: see text]

The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis.

Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients’ survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls.

The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma.

ObjectiveThe impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked.MethodsBetween 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB–IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors.ResultsThe median follow-up duration of all surviving women was 52.8 (1.6–184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633–2.187; p=0.615).ConclusionsThis study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction.

TGF-β-mediated LEFTY/Akt/GSK-3β/Snail axis modulates epithelial-mesenchymal transition and cancer stem cell properties in ovarian clear cell carcinomas.

Advanced ovarian clear cell carcinoma (OCCCa) shows poor prognosis with chemoresistance, which is associated with epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The left-right determination factor (LEFTY), a novel member of the TGF-β superfamily, is a marker of stemness. Here we focused on the functional roles of LEFTY in OCCCas. OCCCa cell lines that were cultured in STK2, a serum-free medium for mesenchymal stem cells, or treated with TGF-β1 underwent morphological changes toward an EMT appearance, along with increased expression of LEFTY and Snail. The cells also showed CSC properties, as demonstrated by increases in the aldehyde dehydrogenase (ALDH)1high activity population, number of spheroid formation, and expression of several CSC markers. Inhibition of LEFTY expression induced decreases in the number of spindle-shaped cells and CSC features, while cells stably overexpressing LEFTY exhibited enhancement of such EMT/CSC properties. Finally, treatment of cells with TGF-β1 led to increased LEFTY expression and activation of Akt, which subsequently induced inactivation of GSK-3β, while inhibition of GSK-3β resulted in increased expression of both LEFTY and Snail. In clinical samples, LEFTY expression showed a tendency for positive associations with expression of vimentin, as well as Sox2 and ALDH1, in OCCCas with epithelial-like morphology, indicating a possible relationship between LEFTY and the epithelial-mesenchymal hybrid stage of the tumors. In conclusion, TGF-β-mediated LEFTY/Akt/GSK-3β/Snail axis may contribute to the establishment and maintenance of phenotypic characteristics of OCCCas through modulation of EMT/CSC properties.

Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma.

Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. Signal transducer and activator of transcription 3(STAT3) expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of human umbilical vein endothelial cells capillary-like structures and invasion at both 5 and 10 µM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.

Abstract 1179: EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas that overexpress class III β-tubulin

Abstract OBJECTIVES: Advanced ovarian clear cell carcinoma (OCCC) is associated with a survival disadvantage relative to ovarian serous carcinoma following platinum/taxane-based chemotherapy and optimal cytoreduction. Prostaglandin E2 (PGE2) contributes to disease progression through modulation of several G-protein coupled receptors (EP1-4) [Fig.1a]. The addition of upstream COX inhibition to platinum/taxane-based chemotherapy in the first-line phase II setting in ovarian cancer has been disappointing,a possibly due to compensatory upregulation of COX isoenzymes and negation of protective effects of EP1. Selective antagonism of EP4 may therefore pose a more rational strategy than global COX inhibition. Paclitaxel administration has been shown to upregulate components of the COX pathway.b Class III β-tubulin is a marker for paclitaxel resistance and is widely overexpressed in OCCC. The purpose of this study is to demonstrate that EP4 inhibition may overcome paclitaxel resistance in OCCC that overexpress class III β-tubulin. METHODS: Expression of EP4 receptor and class III β-tubulin was quantified using immunohistochemistry and Western blot in solid tissues and cell lines. Standard metabolic growth and migration assays were employed to test the effects of drug treatment (paclitaxel and EP4 inhibitors RQ-15986/AH-23848) with and without EP4 silencing using siRNA. RESULTS: OCCC overexpress class III β-tubulin/EP4 relative to normal ovary [Fig. 1b/c]. EP4 staining intensity was 2+ in 100% OCCC using an ovarian cancer tissue microarray (62 cores, 13% OCCC); this rate was only 26-56% among other histologies. EP4 inhibition reduces growth of paclitaxel-resistant cells [Fig. 1d]. Likewise, treatment with EP inhibitors [Fig.1 e-top] and silencing of EP4 resulted in reduced migration [Fig.1 e-bottom]. CONCLUSIONS: Selective antagonism of PGE2 through EP4 receptor inhibition may represent a powerful targeted therapy for paclitaxel-resistant OCCC. Further study including simultaneous treatment (EP4 inhibitor+paclitaxel) and larger samples sizes is required. REFERENCES: a Reyners et al. A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, fallopian tube or primary peritoneal carcinomas: the DoCaCel study. Ann Oncol 2012; 23:2986-902. b Moos et al. Effects of taxol/taxotere on gene expression in macrophages: induction of the PGH synthetase-2 isoenzyme. J Immunol 1999;162:476-73. Citation Format: Dana M. Roque, Danielle Meir-Levi, Gautam G. Rao, Paul Staats, Amy Fulton, Jocelyn Reader. EP4 receptor antagonism in paclitaxel-resistant ovarian clear cell carcinomas that overexpress class III β-tubulin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1179. doi:10.1158/1538-7445.AM2017-1179

The potential of gemcitabine, cisplatin, and bevacizumab combination therapy for patients with ovarian clear cell carcinoma.

e17065 Background: Patients with advanced ovarian clear cell carcinoma (OCC) have poor prognosis, and response rate of chemotherapy for relapsed OCC is less than 10%. The effective standard treatment has not been established yet. The synergic effect between gemcitabine and cisplatin in ovarian cancer patients has been reported. And bevacizumab added on chemotherapy has some evidences of progression-free survival improvement at primary, platinum sensitive relapse and platinum resistant relapse situation than chemotherapy only. Therefore, we conducted a retrospective charts review to examine the safety and efficacy of gemcitabine, cisplatin, and bevacizumab combination (GPB) therapy in OCC patients treated in our hospital. Methods: Intravenous gemcitabine (1,000 mg/m2, day 1, 15), cisplatin (40 mg/m2, day 1, 15), and bevacizumab (15 mg/kg, day 1) were administrated every 28 days. This combination therapy was continued until disease progression or appearance of intolerable toxicity. This retrospective study was approved by our institutional ethics board. Results: Eight patients were treated with this GPB therapy in our institution between April 2013 and August 2015. Six patients received this therapy due to presence of relapse, and 2 patients were administered GPB as post-operative adjuvant therapy. Four patients were not treated with bevacizumab due to their medical conditions. The median treatment cycle was 5.5 (range: 1-15). Six patients were evaluable and their responses were partial response (PR) 1, stable disease (SD) 2, and progressive disease (PD) 3. The overall response rate was 13% and the disease control rate was 50%. Four patients needed dose reduction or treatment delay. Grade 3 adverse events observed were anemia (25%), nausea (13%), and elevation of G-GTP (13%). Conclusions: GPB therapy is feasible and moderately effective for patients with OCC. We are currently conducting the prospective multi-institutional phase II trial (UMIN 000023097) and expect that GPB therapy will be used as the standard treatment regimen for OCC, in future.