High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo

Yuji Ikeda,Sho Sato,Akira Yabuno,Daisuke Shintani,Aiko Ogasawara,Maiko Miwa,Makda Zewde,Takashi Miyamoto,Keiichi Fujiwara,Yusuke Nakamura,Kosei Hasegawa 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.6

Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attentionas a therapeutic target in various types of cancers. In this study, we aimed to evaluate theprognostic significance of MELK expression in ovarian cancer using clinical samples, andassessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derivedovarian cancer cells as well as cell lines. Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed bywestern blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients byquantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluatedusing freshly-isolated primary ovarian cancer cells including spheroid formation condition. Results: MELK mRNA expression was significantly higher in ovarian cancer than in normalovaries (p<0.001), and high MELK mRNA expression was observed in patients with advancedstage, positive ascites cytology and residual tumor size. Patients with high MELK mRNAexpression showed shorter progression-free survival (p=0.001). Expression of MELK wasalso confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitoryconcentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167showed significant growth inhibitory effect against patient-derived ovarian cancer cells,regardless of their tumor locations, histologic subtypes and stages. Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic targetfor ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may bean effective approach to treat ovarian cancer patients.

Incidence and treatment outcomes of ovarian carcinosarcoma from the national cancer registry of Korea

하형인,김지현,임지원,송용중,원영주,임명철 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.1

Objective: To investigate the incidence and sur vival outcomes of ovarian carcinosarcoma inKorea between 1999 and 2018. Methods: Patients diagnosed with ovarian carcinosarcoma between 1999 and 2018 wereidentified from the Korea Central Cancer Registr y (KCCR) and their information wascollected. Age-standardized incidence rates (ASRs), annual percent changes (APC), andrelative sur vival rates of ovarian carcinosarcoma were calculated and compared to those ofepithelial ovarian cancer. Results: According to the KCCR, 458 cases of ovarian carcinosarcoma were detected, andaccounted for 1.5% (458/30,679) of all epithelial ovarian cancers in Korea between 1999 and2018. The ASR of ovarian carcinosarcoma between 1999 and 2018 was 0.064 per 100,000women. The incidence rate of ovarian carcinosarcoma increased during the study period,with an ASR of 0.029 per 100,000 in 1999 and 0.073 per 100,000 in 2018. The APC of ovariancarcinosarcoma during 1999–2018 was 5.86 (p<0.001). The median overall sur vival (OS) ofpatients with ovarian carcinosarcoma was 39 months, and the 5-year OS rate was 42.5%. Among ovarian carcinosarcomas, patients with localized stages showed better clinicaloutcomes than those with regional or distant stages (5-year OS, 60.8%, 57.9%, and 32.8%,respectively; p<0.001). In addition, younger (<50 years) patients showed better OS than older(≥50 years) patients (5-year OS, 52.6% vs. 40.2%; p<0.001). Conclusion: Our nationwide registr y-based study demonstrated that the incidence of ovariancarcinosarcoma increased from 1999 to 2018 in Korea. Patients with advanced-stage diseaseand older age (≥50 years) had poorer sur vival outcomes.

Study of upfront surgery versus neoadjuvant chemotherapy followed by interval debulking surgery for patients with stage IIIC and IV ovarian cancer, SGOG SUNNY (SOC-2) trial concept

Rong Jiang,Jianqing Zhu,김재원,Jihong Liu,Kazuyoshi Kato,김희승,Yuqin Zhang,Ping Zhang,Tao Zhu,Daisuke Aoki,Aijun Yu,Xiaojun Chen,Xipeng Wang,Ding Zhu,Wei Zhang,Huixun Jia,Ting-Yan Shi,Wen Gao,Sheng Yin,Yan 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.5

Background: Two randomized phase III trials (EORTC55971 and CHORUS) showed similarprogression-free and overall survival in primary or interval debulking surgery in ovariancancer, however both studies had limitations with lower rate of complete resection and lack ofsurgical qualifications for participating centers. There is no consensus on whether neoadjuvantchemotherapy followed by interval debulking surgery (NACT-IDS) could be a preferred approachin the management of advanced epithelial ovarian cancer (EOC) in the clinical practice. Methods: The Asian SUNNY study is an open-label, multicenter, randomized controlled,phase III trial to compare the effect of primary debulking surgery (PDS) to NACT-IDS instages IIIC and IV EOC, fallopian tube cancer (FTC) or primary peritoneal carcinoma (PPC). The hypothesis is that PDS enhances the survivorship when compared with NACT-IDS inadvanced ovarian cancer. The primary objective is to clarify the role of PDS and NACT-IDS inthe treatment of advanced ovarian cancer. Surgical quality assures include at least 50% of nogross residual (NGR) in PDS group in all centers and participating centers should be nationalcancer centers or designed ovarian cancer section or those with the experience participatingsurgical trials of ovarian cancer. Any participating center should be monitored evaluatingthe proportions of NGR by a training set. The aim of the surgery in both arms is maximalcytoreduction. Tumor burden of the disease is evaluated by diagnostic laparoscopy orpositron emission tomography/computed tomography scan. Patients assigned to PDS groupwill undergo upfront maximal cytoreductive surgery within 3 weeks after biopsy, followed by6 cycles of standard adjuvant chemotherapy. Patients assigned to NACT group will undergo 3cycles of NACT-IDS, and subsequently 3 cycles of adjuvant chemotherapy. The maximal timeinterval between IDS and the initiation of adjuvant chemotherapy is 8 weeks. Major inclusioncriteria are pathologic confirmed stage IIIC and IV EOC, FTC or PPC; ECOG performancestatus of 0 to 2; ASA score of 1 to 2. Major exclusion criteria are non-epithelial tumors as wellas borderline tumors; low-grade carcinoma; mucinous ovarian cancer. The sample size is 456subjects. Primary endpoint is overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT02859038

Predictors of postoperative pancreatic fistula after splenectomy with or without distal pancreatectomy performed as a component of cytoreductive surgery for advanced ovarian cancer

Kyoko Nishikimi,Shinichi Tate,Ayumu Matsuoka,Satoyo Otsuka,Makio Shozu 대한부인종양학회 2022 Journal of Gynecologic Oncology Vol.33 No.3

Objective: Splenectomy with or without distal pancreatectomy is occasionally performed during cytoreductive surgery for advanced ovarian cancer. We investigated pre-, intra-, postoperative risk factors and predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in patients who underwent cytoreductive surgery for advanced ovarian cancer. Methods: We investigated 165 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma categorized as stage III/IV disease, who underwent splenectomy with or without distal pancreatectomy as a component of cytoreductive surgery performed as initial treatment at Chiba University Hospital. Patient characteristics, clinical factors, and surgical outcomes were compared between those with and without CR-POPF. Results: CR-POPF occurred in 20 patients (12%). There were no significant intergroup differences in the characteristics between patients with CR-POPF and patients without CR-POPF except for operative time, intraoperative blood loss, amylase (AMY) levels in drain fluid on postoperative day (POD)1 and POD3, and pancreatic stump thickness. Multivariate analysis showed that the POD3 drain fluid AMY level was the only significant risk factor and predictor of CR-POPF in patients who underwent cytoreductive surgery for advanced ovarian cancer. The receiver operating characteristic curve of the POD3 drain fluid AMY level, which predicted development of CR-POPF showed an area under the curve of 0.77, and the optimal cut-off value of AMY was 808 U/L. A pancreatic fistula did not occur in patients with POD3 drain fluid AMY levels <130 U/L. Conclusion: The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

Peritoneal dissemination of high- grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

Ikuo Konishi,Kaoru Abiko,Takuma Hayashi,Koji Yamanoi,Ryusuke Murakami,Ken Yamaguchi,Junzo Hamanishi,Tsukasa Baba,Noriomi Matsumura,Masaki Mandai,Kyoto Study Group for Ovarian Cancer Research 대한부인종양학회 2022 Journal of Gynecologic Oncology Vol.33 No.5

Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

The impact of interval between primary cytoreductive surgery with bowel resection and initiation of adjuvant chemotherapy on survival of women with advanced ovarian cancer: a multicenter cohort study

Yoo-Young Lee,Soyoun Rachel Kim,Alexandra Kollara,Theodore Brown,Taymaa May 대한부인종양학회 2022 Journal of Gynecologic Oncology Vol.33 No.6

Objective: Our aim was to determine if the time interval between bowel resection and initiation of adjuvant chemotherapy impacts survival in advanced ovarian cancers. Methods: This was a retrospective cohort study using data from two cancer centers, Princess Margaret Cancer Centre in Toronto, Ontario, Canada and Samsung Comprehensive Cancer Center in Seoul, South Korea. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV ovarian cancer that underwent large bowel resection during primary cytoreductive surgery (PCS) were included. Results: Ninety-one women were eligible of which the majority (90.1%) were diagnosed with high-grade serous cancer. The median interval from PCS to chemotherapy for all patients was 21 days (7–86 days). Patients were stratified into 3 groups: 1) Interval ≤14 days, 32 (35.2%) patients; 2) Interval between 15–28 days, 27 (29.6%) patients; and 3) Interval between29–90 days, 32 (35.2%) patients. Surgical procedures and postoperative outcomes were similar between groups. Multivariate analysis indicated that PCS to chemotherapy interval of 2–4 weeks, younger age, and completion of 4 or more adjuvant chemotherapy cycles were independent prognostic factors of favorable overall survival. Conclusion: Initiation of adjuvant chemotherapy between 2 to 4 weeks after PCS with bowel resection may improve survival outcomes in women with advanced ovarian cancer by maximizing the benefit of PCS plus adjuvant chemotherapy.

Clinical and molecular biomarkers predicting response to PARP inhibitors in ovarian cancer

Takahiro Nozaki,Ikuko Sakamoto,Keiko Kagami,Kenji Amemiya,Yosuke Hirotsu,Hitoshi Mochizuki,Masao Omata 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.4

Objective: To determine the useful biomarker for predicting the effects of poly-(ADP ribose)-polymerase (PARP) inhibitors in Japanese patients with ovarian cancer. Methods: We collected clinical information and performed molecular biological analysis on42 patients with ovarian, fallopian tube, and primar y peritoneal carcinomas who receivedPARP inhibitors. Results: Among the analyzed patients with ovarian cancer, 23.8% had germline BRCAmutation (gBRCAm), 42.9% had homologous recombination repair-related gene mutation(HRRm), and 61.1% had a genomic instability score (GIS) of ≥42. Patients with HRRm hada significantly longer progression-free sur vival (PFS) than those without HRRm (medianPFS 35.6 vs. 7.9 months; p=0.009), with a particularly marked increase in PFS in patientswith gBRCAm (median PFS 42.3 months). Similarly, among patients with recurrent ovariancancer, those with HRRm had a longer PFS than those without HRRm (median PFS 42.3 vs. 7.7 months; p=0.040). Multivariate Cox proportional hazards regression analysis found thatperformance status and gBRCAm status were independent factors associated with prolongedPFS with PARP inhibitors. In recurrent ovarian cancer, multivariate regression analysisidentified platinum-free inter val (PFI) in addition to performance status as a significantpredictor of PFS. On the contrar y, no significant association was obser ved between PFS and aGIS of ≥42 used in clinical practice. Conclusion: We found that HRRm can be a useful biomarker for predicting the effects ofPARP inhibitors in treating ovarian cancer and that the PFI can also be useful in recurrentovarian cancer.

Clinical guidelines for ovarian cancer: the Korean Society of Gynecologic Oncology guidelines

이방현,장석준,권병수,손주혁,임명철,김윤환,이신화,최철훈 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.1

Since the latest practice guidelines for ovarian cancer were developed by the Korean Society ofGynecologic Oncology (KSGO) in 2021, many studies have examined the efficacy and safetyof various treatments for epithelial ovarian cancer (EOC). Therefore, the need to developrecommendations for EOC treatments has been raised. This study searched the literatureusing 4 key items and the Population, Inter vention, Comparison, and Outcome: the efficacyand safety of poly-ADP ribose polymerase inhibitors in newly diagnosed advanced EOC; theefficacy and safety of intraperitoneal plus intravenous chemotherapy in optimally debulkedadvanced EOC; the efficacy and safety of secondar y cytoreductive surger y in platinum-sensitive recurrent ovarian cancer; and the efficacy and safety of the addition of bevacizumabto platinum-based chemotherapy in first platinum-sensitive recurrent EOC patients whoreceived prior bevacizumab. The evidence for these recommendations, according to eachkey question, was evaluated using a systematic review and meta-analysis. The committee ofovarian cancer of the KSGO developed updated guidelines for treatments of EOC.

SURF4 maintains stem-like properties via BIRC3 in ovarian cancer cells

Yongfang Yue,Lili Xia,Shanshan Xu,Conghui Wang,Xinyu Wang,Weiguo Lu,Xing Xie 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.4

Objective: As cancer stem cells (CSCs) are considered as the origin of tumor development,recurrence, and drug resistance, we aimed to explore the mechanism related to modulatingstemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. Methods: In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AOand A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-likeproperties was evaluated by sphere-forming assays, re-differentiation assays, quantitativereal-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assaysand in vivo xenograft experiments. The downstream molecule participating in SURF4maintaining stemness was screened by RNA-sequencing and identified by the experiments ofgene function. Results: SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced theexpression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability,and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs. SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combinedimmunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showedthe similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-likeproperties abolished by SURF4 knockdown. Conclusion: Our findings suggest that SURF4 possesses the ability to maintain stemness ofOCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy forovarian cancer.

First-line bevacizumab plus chemotherapy in Chinese patients with stage III/IV epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer: a phase III randomized controlled trial

Xiaohua Wu,Jihong Liu,Ruifang An,Rutie Yin,Yu Zhang,Huaijun Zhou,Aiqin He,Li Wang,Jieqing Zhang,Ziling Liu 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.5

Objective: First-line bevacizumab plus carboplatin and paclitaxel (CP) is approved for stage III/IV ovarian cancer treatment following initial surgical resection, based on global phase III GOG-0218 and ICON7 trials. This study evaluated the efficacy and safety of bevacizumab + CP as first-line ovarian cancer therapy in Chinese patients. Methods: Patients with newly diagnosed, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian, fallopian tube, or primary peritoneal cancer post-primary surgery were randomized 1:1 to receive 6 cycles of CP with bevacizumab/placebo, followed by bevacizumab/placebo maintenance until unacceptable toxicity or disease progression. Primary endpoint was investigator-assessed progression-free survival (PFS). Stratification factors were FIGO stage and debulking status (stage III optimally debulked vs stage III suboptimally debulked vs stage IV) and Eastern Cooperative Oncology Group performance status (0 vs 1 or 2). Results: Of randomized patients, 51 received bevacizumab + CP and 49 received placebo + CP. Median PFS was 22.6 months with bevacizumab + CP (95% confidence interval [CI]=18.6, not estimable) and 12.3 months (95% CI=9.5, 15.0) with placebo + CP (stratified hazard ratio=0.30; 95% CI=0.17, 0.53). Treatment-related grade 3/4 adverse events occurred in 46 of 49 (94%) patients receiving bevacizumab + CP, and 34 of 50 (68%) receiving placebo + CP. Conclusion: Bevacizumab + CP showed clinically meaningful improvement in PFS vs placebo + CP, consistent with GOG-0218 results. Safety data were aligned with the known bevacizumab safety profile. These results support first-line bevacizumab + CP therapy in Chinese patients with ovarian cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03635489