Recurrence Of Epithelial Ovarian Cancer Research Articles

Abstract 5606: The role of KMT2C in the homologous recombination repair in epithelial ovarian cancer

Abstract Background: Epithelial ovarian cancer (EOC) with homologous recombination (HR) deficiency is susceptible to PARP inhibitor therapy due to synthetic lethality. Identification of the patient population for PARP inhibitor therapy is imperative to reduce recurrence of EOC and improve the survival outcomes of patients. Current biomarkers for PARP inhibitor therapy consist of an array of genes involved in the HR repair pathway in EOC, including BRCA1, BRCA2 and PALB2. Through TCGA analysis, we found that the lysine (K)-specific methyltransferase 2C (KMT2C) gene is mutated in 10.3% of all EOC patients and considerably enriched in BRCA1 mutated EOC patients. However, the role of KMT2C in HR repair and PARP inhibitor sensitivity of EOC remains largely undefined. Methods: BRCA2-mutated PEO1 and BRCA2-wild type PEO1-NR cells were transfected with KMT2C siRNA and assayed for KMT2C protein expression by western blotting. DR-GFP (HR) and EJ5-GFP (NHEJ)-SKOV3 cell lines were co-transfected with the ISceI-expressing plasmid pCBA-ISceI and KMT2C siRNA. GFP-positive cells were analyzed by flow cytometry. SKOV3 cells were transfected with KMT2C siRNA and the expression of BRCA2 and Rad51 mRNA was determined using quantitative RT-PCR analysis. Results: siRNA-mediated knockdown of KMT2C resulted in marked down-regulation of KMT2C protein in PEO1 and PEO1-NR cells. KMT2C knockdown caused a significant decrease in ISceI-induced HR activity in DR-GFP-SKOV3 cells (p < 0.05). In contrast, KMT2C knockdown had no effects on ISceI-induced NHEJ activity in EJ5-GFP-SKOV3 cells. As a control, Rad51 knockdown caused complete suppression of HR activity and had no effects on NHEJ activity. Furthermore, quantitative RT-PCR analysis of key HR genes showed that KMT2C knockdown resulted in a moderate but significant down-regulation of BRCA2 (p < 0.05) and Rad51 (p < 0.01) expression in SKOV3 cells. Conclusion: Our results suggest that KMT2C partakes in the HR repair pathway in EOC. However, the contribution of KMT2C to HR activity is not rate-limiting. Based on the known function of KMT2C in histone modification, we speculate that KMT2C serves to positively regulate the transcription of HR genes and therefore promote HR activity. Future investigation into the exact roles of KMT2C in HR repair, etiology of EOC, and diagnostic biomarkers for the PARP inhibitor sensitivity of EOC is warranted. Citation Format: Mirielle C. Ma, Z. Ping Lin, Elena S. Ratner. The role of KMT2C in the homologous recombination repair in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5606.

ZSWIM4 inhibition improves chemosensitivity in epithelial ovarian cancer cells by suppressing intracellular glycine biosynthesis

BackgroundZinc finger SWIM-type containing 4 (ZSWIM4) induces drug resistance in breast cancer cells. However, its role in epithelial ovarian cancer (EOC) remains unknown. In this study, we aimed to investigate the clinical significance of ZSWIM4 expression in EOC and develop new clinical therapeutic strategies for EOC.MethodsZSWIM4 expression in control and EOC tumor tissues was examined using immunohistochemistry. Lentiviral transduction, Cell Counting Kit-8 assay, tumorsphere formation assay, flow cytometry, western blotting, and animal xenograft model were used to assess the role of ZSWIM4 in chemotherapy. Cleavage Under Targets and Tagmentation (CUT&Tag) assays, chromatin immunoprecipitation assays, and luciferase reporter assays were used to confirm FOXK1-mediated upregulation of ZSWIM4 expression. The mechanism by which ZSWIM4 inhibition improves chemosensitivity was evaluated using RNA-sequencing. A ZSWIM4-targeting inhibitor was explored by virtual screening and surface plasmon resonance analysis. Patient-derived organoid (PDO) models were constructed from EOC tumor tissues with ZSWIM4 expression.ResultsZSWIM4 was overexpressed in EOC tumor tissues and impaired patient prognoses. Its expression correlated positively with EOC recurrence. ZSWIM4 expression was upregulated following carboplatin treatment, which, in turn, contributed to chemoresistance. Silencing ZSWIM4 expression sensitized EOC cells to carboplatin treatment in vitro and in vivo. FOXK1 could bind to the GTAAACA sequence of the ZSWIM4 promoter region to upregulate ZSWIM4 transcriptional activity and FOXK1 expression increased following carboplatin treatment, leading to an increase in ZSWIM4 expression. Mechanistically, ZSWIM4 knockdown downregulated the expression of several rate-limiting enzymes involved in glycine synthesis, causing a decrease in intracellular glycine levels, thus enhancing intracellular reactive oxygen species production induced by carboplatin treatment. Compound IPN60090 directly bound to ZSWIM4 protein and exerted a significant chemosensitizing effect in both EOC cells and PDO models.ConclusionsZSWIM4 inhibition enhanced EOC cell chemosensitivity by ameliorating intracellular glycine metabolism reprogramming, thus providing a new potential therapeutic strategy for EOC.

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI

ObjectiveTo determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a...

The role of minimally invasive surgery in epithelial ovarian cancer treatment: a narrative review.

The aim of this narrative review is to summarize the available evidence on the use of minimal invasive surgery (MIS) in the management of epithelial ovarian cancer (EOC). MIS is currently performed to stage and treat EOC at different stage of presentation. We will evaluate risks and benefits of minimally invasive surgery for early stage EOC treatment, then potential advantages provided by staging laparoscopy in identifying patients suitable for primary cytoreductive surgery (PDS) will be discussed. Finally we will investigate the growing role of MIS in the treatment of advanced EOC after neoadjuvant chemotherapy (NACT) and in the treatment of EOC recurrence. An electronic database search was performed on PubMed, Medline, and Google Scholar for relevant studies up to December 2022. LPS represents a feasible surgical procedure for the staging and treatment in early, advanced and EOC relapse in selected patients treated in high-volume oncological centers by surgeons with adequate experience in advanced surgical procedures. Despite the increasing use of MIS over the last few years, randomized clinical trials are still needed to prove its effectiveness.

NF-κB Signaling Modulates miR-452-5p and miR-335-5p Expression to Functionally Decrease Epithelial Ovarian Cancer Progression in Tumor-Initiating Cells.

Epithelial ovarian cancer (EOC) remains the fifth leading cause of cancer-related death in women worldwide, partly due to the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that promote disease relapse. We previously described a role for the NF-κB pathway in promoting TIC chemoresistance and survival through NF-κB transcription factors (TFs) RelA and RelB, which regulate genes important for the inflammatory response and those associated with cancer, including microRNAs (miRNAs). We hypothesized that NF-κB signaling differentially regulates miRNA expression through RelA and RelB to support TIC persistence. Inducible shRNA was stably expressed in OV90 cells to knockdown RELA or RELB; miR-seq analyses identified differentially expressed miRNAs hsa-miR-452-5p and hsa-miR-335-5p in cells grown in TIC versus adherent conditions. We validated the miR-seq findings via qPCR in TIC or adherent conditions with RELA or RELB knocked-down. We confirmed decreased expression of hsa-miR-452-5p when either RELA or RELB were depleted and increased expression of hsa-miR-335-5p when RELA was depleted. Either inhibiting miR-452-5p or mimicking miR-335-5p functionally decreased the stem-like potential of the TICs. These results highlight a novel role of NF-κB TFs in modulating miRNA expression in EOC cells, thus opening a better understanding toward preventing recurrence of EOC.

Factors Associated With Recurrence Of Epithelial Ovarian Cancer In RSUP Dr. Kariadi Semarang

Introductions: Epithelial ovarian cancer accounts for 90% of all ovarian malignancies. More than 70% of patients will experience a relapse even after receiving operative therapy and chemotherapy. There are several prognostic factors that influence the recurrence of ovarian cancer. In Indonesia, especially at Dr. Kariadi Hospital, Semarang, the data as mentioned above is still very limited.objective: Knowing the disease-free survival rate, optimizing surgery and factors related to the incidence of recurrence in epithelial ovarian cancer patients at Dr. Kariadi Hospital SemarangMethods: This study is a retrospective cohort study with survival analysis. Data were collected through medical records, with the study population are patients with a diagnosis of epithelial ovarian cancer who were treated at Dr. Kariadi Hospital Semarang in period January 2018-December 2019. Furthermore, patients who had been remission were observed for signs of disease recurrence for 2 years period.Results: There were 361 patients with epithelial ovarian cancer who underwent primary treatment at Dr. Kariadi Hospital, Semarang in 2018-2019. Furthermore, there were observations of recurrence in 148 patients who achieved remission. Of these 76 patients (51.4%) experienced recurrence, while 72 patients not relapse. From 148 epithelial ovarian cancer patients who underwent cytoreduction surgery at Dr. Kariadi Hospital, Semarang, 113 patients (76.4%) achieved optimal operation with a residu less than 2 cm, while 35 patients (23.6%) were not optimal with a residu more than 2 cm. FIGO stage (HR 2.44) and tumor residu (HR 2.15) were shown to be significant factors associated with the recurrence of epithelial ovarian cancer.Conclusion: Overall disease-free survival in epithelial ovarian cancer at Dr. Kariadi Semarang were 74.8% (6 months), 57.1% (1 year), 42.5% (18 months), and 37.4% (2 years). Tumor residual factors and FIGO stage were shown to be significant prognostic factors influencing the recurrence of epithelial ovarian cancer.

Tumor-Bowel Fistula as a Rare Form of Recurrent Ovarian Cancer-Imaging and Treatment: Preliminary Report.

The aim of this pilot study was to evaluate the value of imaging techniques, including computed tomography (CT) and magnetic resonance imaging (MRI), in the diagnosis of a tumor-bowel fistula as a rare form of epithelial ovarian cancer (EOC) relapse. We also performed an initial assessment of the effectiveness of the treatment of this form of relapse. The study group consisted of eight patients with suspected platinum-sensitive recurrence in the form of a tumor/bowel fistula. All patients finished their first line of chemotherapy and subsequently showed complete remission for 6 months or more. To qualify patients for further treatment, CT and MRI were performed, which suggested the presence of a fistula between the recurrent tumor and intestine. DESKTOP study criteria were used to qualify patients for secondary cytoreduction. Second-line chemotherapy was given after secondary debulking. In all patients, fistulas formed between the tumor and large bowel. On CT, the fistulas were indirectly visible. In all cases, the fistula was visible on MR images, which showed hypointensity on the T2 and T1 post-contrast sequences but did not show restricted diffusion on the diffusion-weighted imaging (DWI) sequence. Patients who were qualified for the study underwent secondary debulking with bowel resection. In all eight cases, the fistula between the tumor and surrounding organs was confirmed. During surgery, seven intestinal anastomoses and one colostomy were performed. No residual macroscopic tumor remained in seven cases (resection R0-87.5%). The progression-free survival (PFS) was 8.4-22.6 months (median 13.4). In the group with cytoreduction R0, the median PFS was 15.5 months (12-22). In patients with suspected EOC recurrence with clinically suspected fistula, CT scan is not sufficient. In CT, the presence of a fistula is suspected based on indirect symptoms. MRI, as a method with much greater tissue resolution, confirms the diagnosis. In addition, MRI can identify the point of the tumor/bowel junction. This is especially true with a large infiltration covering several intestinal parts. Bowel resection with simultaneous anastomosis is a good and safe solution for these patients. However, appropriate qualification for the procedure is necessary, which will allow for surgery without residual macroscopic disease (R0 surgery). Due to the small number of cases, our results cannot be generalized. We treat them as a hypothesis that can be verified in a larger study.

Correlation of Fibroblast Activation Protein Expression and Incidence of Epithelial Ovarian Cancer Recurrence

Background : Ovarian cancer is one of women death causes and almost diagnosed at advanced stage which related to high recurrence rate therefore accurate biomarker is needed to predict recurrence rate.
 Aim: This research purpose to determine correlation of fibroblast activation protein (FAP) expression and epithelial ovarian cancer recurrence at H. Adam Malik Hospital Medan.
 Methods: This research is an analytic observational study with case control approach that will be carried out starting in May 2022 until number of samples is met. Immunohistochemical assessment for FAP expression uses Allred score because this system is simplest and has good sensitivity and specificity. The preparations were interpreted by two anatomical pathologists. The correlation between variables was carried out by chi square statistical test with 95% confidence interval and p < 0.05 was considered significant.
 Results: The analysis results using Chi Square test showed that there was a significant relationship between tissue FAP expression and ovarian cancer recurrence (p = 0.004). The OR value obtained was 7.429 (95% CI = 1.778 – 31.040), which means patients with tissue FAP expression (+) had risk of recurrent ovarian cancer 7.429 times greater than patients with tissue FAP expression (-).
 Conclusion : There is a statistically significant correlation between FAP expression and epithelial ovarian cancer recurrence.

Value of the risk of ovarian malignancy algorithm index in predicting the recurrence of epithelial ovarian cancer.

Aim: This study aimed to assess the predictive and diagnostic value of the risk of ovarian malignancy algorithm (ROMA) index for epithelial ovarian cancer (EOC) recurrence. Materials & methods: The clinical features and follow-up data of 159 EOC cases were studied. The ROMA indexwas calculated by serum CA125 andHE4 levels withmenopausal status. Recurrence-free survival was evaluated for an end point. Results: The ROMA was strongly associated with clinical characteristics. The ROMAindexabove the cutoff value (34.71%) was significantly associated with recurrence-free survival. The ROMA indexhad a significantly higher sensitivity (90.59%) than CA125 (84.71%) and HE4 (80.80%) for recurrence diagnosis, and its optimal cutoff value was 17.07%. Conclusion: The primary ROMA index is a predictive factor in EOC recurrence and has better performance in the diagnosis of EOC recurrence.

CDC50A might be a novel biomarker of epithelial ovarian cancer-initiating cells

BackgroundThe aim of this work was to screen and validate biomarkers of ovarian cancer-initiating cells to detect the mechanisms of recurrence of epithelial ovarian cancer (EOC).MethodsStably labelled the amino acid in side population (SP) cells of epithelial ovarian cancer which were rich in cancer-initiating cells and non-SP cells with isotope in culture and differentially expressed cellular membrane proteins in SP cells were identified through proteomics technology. The new candidate biomarker was screened and validated through RT-PCR and western blot. Both in cell lines and primary EOC, cancer-initiating biofunctions of CDC50A positive cells were validated. Moreover, the characteristics of mesenchymal transition (EMT) was also detected and the correlation between the biomarker and clinical prognosis was observed.ResultsThrough proteomics technology, candidate protein CDC50A was screened, and its significantly differential expression in SP cells was validated. CDC50A-positive cells from cell lines and primary ovarian cancer tissues were validated to show characteristics of cancer-initiating cells both in vitro and in vivo, including sphere-forming, self-renewal, differentiation, tumor metastasis and tumorigenicity in mice. The relationship between CDC50A-positive cells from primary tissues and tumour metastasis was confirmed based on their mesenchymal transition characteristics. Among 16 high-grade ovarian serous cancer patients, a high ratio of CDC50A-positive cells in primary tumours was correlated with a shorter platinum-free interval (p = 0.031, HR 0.260, 95% CI 0.77 ~ 0.885).ConclusionCDC50A could be used to screen ovarian cancer-initiating cells and might be a new target to resolve tumour development in EOC patients.

Reproductive and oncological outcomes of fertility-sparing surgery in patients with stage I epithelial ovarian cancer: A systematic review and meta-analysis.

Objective:We meta-analyzed available evidence on fertility, survival, and cancer recurrence in patients with stage I epithelial ovarian cancer (EOC) after fertility-sparing surgery (FSS).Methods:We systematically reviewed PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to identify studies reporting reproductive and oncological outcomes of patients with stage I EOC who underwent FSS. Random-effects models were used to calculate pooled rates of disease outcomes, along with 95% confidence intervals (CIs). Subgroup and sensitivity analyses were conducted to identify sources of heterogeneity in the data.Results:We included 23 observational retrospective studies involving 1126 patients. The pooled pregnancy rate was 30% (95% CI, 0.26–0.34), while the pooled natural conception rate was 26% (95% CI, 0.20–0.33). The pooled live birth rate was 27% (95% CI, 0.22–0.32). The pooled rate of EOC recurrence was 12% (95% CI, 0.09–0.14), which did not differ significantly from the rate among patients who underwent radical surgery (odds ratio, 0.77; 95% CI, 0.45–1.33).Conclusions:FSS is associated with good oncological outcomes but less than satisfactory reproductive outcomes. All in all, the procedure appears to be a safe alternative to radical surgery for EOC patients who want to preserve fertility.

Timing of recurrence and overall survival in epithelial ovarian cancer: A 10-year retrospective review

Background: The timing of recurrence of epithelial ovarian cancer (EOC) after a standard primary treatment is an important indicator of the degree of response of the tumour to treatment. It, however, remains unclear if the timing of recurrence will predict survival outcomes. Aim: This study explored the impact of timing of recurrence after an initial response to standard primary treatment on the overall survival (OS) of patients with EOC. Methods: Data was extracted from the records of patients who underwent standard primary treatment and follow-up after EOC diagnosis between January 2011 and December 2020. The Kaplan-Meier survival estimates and Cox proportional hazards model adjusted for covariates were used for analyses. Results: The risks of recurrence of EOC increased steadily with increasing time from the start of primary treatment from 13.6% in 6-months to 71.0% after 12-months. In the final multivariate analyses, recurrence within 6 months of treatment was a significant independent predictor of poor OS in EOC patients (hazard ratio=7.23, 95%CI: 3.87–13.51, P<0.01). Conclusion: Our study suggests that recurrence within 6-months is an important prognostic predictor of poor OS in EOC. Early tumour recurrence may be a useful surrogate of OS and thus this information should be considered in the design of future tailored randomized controlled trials. Future strategies to improve OS in EOC patients should focus on identifying effective measures to prevent early tumour recurrence.

Effectiveness of oral etoposide in recurrent or refractory epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer

The aim of treatment in recurrent or refractory epithelial ovarian cancer is palliation. In a patient with platinum-resistant status, several chemotherapy regimens have been reported with similar response rates. Among these agents, the oral etoposide holds an advantage of the route of administration and management in the out-patient setting. This retrospective study was conducted to evaluate the effectiveness of oral etoposide. Data of patients with recurrent or refractory epithelial ovarian, primary peritoneal and fallopian tube cancer who received oral etoposide treatment in Ramathibodi Hospital, Mahidol University from January 1997 to December 2017 were collected. Progression-free survival (PFS) and overall survival (OS) were primary and secondary outcomes, respectively. The oral etoposide at a dose of 50 mg/m2 was prescribed. Sixty-six records were analysed. Median OS and median PFS were 8.3 months (95% confidence interval (CI): 6.8, 10.4) and 3.1 months (95%CI: 2.3, 3.9), respectively. Other factors including age, body mass index (BMI), histopathology subtype, primary treatment, result of the primary surgery, platinum status, site and size of recurrent cancer, treatment after discontinuation of oral etoposide and the line of chemotherapy regimen were not associated with the prognosis. The initial cancer stage was the only independent poor prognostic factor. The main toxicity was neutropenia. Impact Statement What is already known on this subject? After the recurrence of epithelial ovarian cancer, peritoneal cancer or fallopian tube cancer, the aim of treatment in this setting is palliation with accentuating on symptomatic control and enhancing the quality of life. According to previous clinical trials, the chemotherapy regimens which were considered as a second-line or beyond the second-line therapy have been reported with similar response rates. Among these agents, the oral etoposide could be administrated by oral route. There were several articles reported the effectiveness of oral etoposide in different dosage. What do the results of this study add? This study adds that administration of oral etoposide at a dose of 50 mg/m2 showed fairish oncologic outcomes with manageable toxicity. What are the implications of these findings for clinical practice and/ or further research? The results will provide evidence that the oral etoposide can be considerate as a choice of palliative chemotherapy because of an advantage of the route of administration and management in the out-patient setting.

Involvement of Cancer Stem Cells in Chemoresistant Relapse of Epithelial Ovarian Cancer Identified by Transcriptome Analysis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite the initial resection and chemotherapeutic treatment, relapse is common, which leads to poor survival rates in patients. A primary cause of recurrence is the persistence of ovarian cancer stem cells (OCSCs) with high tumorigenicity and chemoresistance. To achieve a better therapeutic response in EOC relapse, the mechanisms underlying acquired chemoresistance associated with relapse-initiating OCSCs need to be studied. Transcriptomes of both chemosensitive primary and chemoresistant relapse EOC samples were obtained from ICGC OV-AU dataset for differential expression analysis. The upregulated genes were further studied using KEGG and GO analysis. Significantly increased expression of eighteen CSC-related genes was found in chemoresistant relapse EOC groups. Upregulation of the expression in four hub genes including WNT3A, SMAD3, KLF4, and PAX6 was verified in chemoresistant relapse samples via immunohistochemistry staining, which confirmed the existence and enrichment of OCSCs in chemoresistant relapse EOC. KEGG and GO enrichment analysis in microarray expression datasets of isolated OCSCs indicated that quiescent state, increased ability of drug efflux, and enhanced response to DNA damage may have caused the chemoresistance in relapse EOC patients. These findings demonstrated a correlation between OCSCs and acquired chemoresistance and illustrated potential underlying mechanisms of OCSC-initiated relapse in EOC patients. Meanwhile, the differentially expressed genes in OCSCs may serve as novel preventive or therapeutic targets against EOC recurrence in the future.

Disulfiram Transcends ALDH Inhibitory Activity When Targeting Ovarian Cancer Tumor-Initiating Cells.

Epithelial ovarian cancer (EOC) is a global health burden and remains the fifth leading cause of cancer related death in women worldwide with the poorest five-year survival rate of the gynecological malignancies. EOC recurrence is considered to be driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs). We previously showed that disulfiram, an ALDH inhibitor, effectively targeted TICs compared to adherent EOC cells in terms of viability, spheroid formation, oxidative stress and also prevented relapse in an in vivo model of EOC. In this study we sought to determine whether specific targeting of ALDH isoenzyme ALDH1A1 would provide similar benefit to broader pathway inhibition by disulfiram. NCT-505 and NCT-506 are isoenzyme-specific ALDH1A1 inhibitors whose activity was compared to the effects of disulfiram. Following treatment with both the NCTs and disulfiram, the viability of TICs versus adherent cells, sphere formation, and cell death in our in vitro relapse model were measured and compared in EOC cell lines. We found that disulfiram decreased the viability of TICs significantly more effectively versus adherent cells, while no consistent trend was observed when the cells were treated with the NCTs. Disulfiram also affected the expression of proteins associated with NFκB signaling. Comparison of disulfiram to the direct targeting of ALDH1A1 with the NCTs suggests that the broader cellular effects of disulfiram are more suitable as a therapeutic to eradicate TICs from tumors and prevent EOC relapse. In addition to providing insight into a fitting treatment for TICs, the comparison of disulfiram to NCT-505 and -506 has increased our understanding of the mechanism of action of disulfiram. Further elucidation of the mechanism of disulfiram has the potential to reveal additional targets to treat EOC TICs and prevent disease recurrence.

Hubungan antara Ekspresi Heat Shock Protein-70 (HSP70) dengan Skor Risk of Ovarian Cancer Relapse (ROVAR) pada Pasien Kanker Ovarium Epitelial yang Dilakukan Operasi dan Dilanjutkan dengan Kemoterapi

Background: Ovarian cancer is one of the leading causes of death in gynecological malignancies which occupies the third place in the world. One of largest challenge in epithelial ovarian cancer therapy is resistance to chemotherapy. Increased of Heat Shock Protein-70 (HSP70) expression associated with the progressivity of tumor cells growth through the resistance process against chemotherapy, whereas Risk Of Ovarian Cancer Relapse (ROVAR) score is a tool that used to predict the ovarian cancer recurrence risk in patient who underwent surgery followed by chemotherapy.Objective: This study is aimed to evaluate the correlation between HSP70 expression and ROVAR score in patient with epithelial ovarian cancer who underwent first line therapy. Method: This is a retrospective cohort study that involve 42 subjects with epithelial ovarian cancer who had been through surgery (optimal or suboptimal surgery) followed by chemotherapy. Immunohistochemical staining of pre chemotherapy paraffin blocks was performed using HSP70 antibody and recurrence risk was calculated using ROVAR scores after surgery followed by chemotherapy. The external variables evaluated were age, parity, Body Mass Index (BMI), menopause history, and surgical type. Data analysis used Chi Square test, spearman test, and logistic regression analysis.Result and Discussion: Of the total 42 subjects who met the inclusion criteria, most found in advanced stage with the age mean is 54,3 years old. In the ROVAR score measurement, in high risk category is found about 32(76.19%), while in the medium risk and low risk category is 10 (23.81%). On the other hand, strong HSP70 expression was found in 36(85,71%), moderate HSP70 expression in 6(14,39%), and weak HSP70 expression was not found. Based on Spearman's correlative test, there was a positive, very strong, and significant correlation between the expression of HSP70 and risk allocation according to ROVAR score (r=0.717, p=0.000). As well as in multivariate analysis, HSP70 expression had a statistically and clinically significant relationship with ROVAR score (p=0.017; RR 2.710; 95% CI 0.366-5.054) which strong HSP70 expression was 2.71 times more likely to have a high risk of recurrence according to ROVAR score.Conclusion: There is a positive, very strong, and significantly meaning between HSP70 expression and ROVAR score. Increased in HSP70 expression may lead to increased recurrence risk according to ROVAR score. Both could be used to predict recurrence in epithelial ovarian cancer post first line therapy.Keywords: Epithelial ovarian cancer, HSP70, ROVAR score, recurrence.

Single-cell RNA-seq recognized the initiator of epithelial ovarian cancer recurrence.

Epithelial ovarian cancers (EOCs) are sensitive to chemotherapy but will ultimately relapse and develop drug resistance. The origin of EOC recurrence has been elusive due to intra-tumor heterogeneity. Here we performed single-cell RNA sequencing (scRNA-seq) in 13,369 cells from primary, untreated peritoneal metastasis, and relapse tumors. We used time-resolved analysis to chart the developmental sequence of cells from the metastatic tumors, then traced the earliest replanting cells back to the primary tumors. We discovered seven distinct subpopulations in primary tumors where the CYR61+ "stress" subpopulation was identified as the relapse-initiators. Furthermore, a subpopulation of RGS5+ cancer-associated fibroblasts (CAFs) was found to strongly support tumor metastasis. The combined CYR61/RGS5 expression scores significantly correlated with the relapse-free-survival of EOC patients and can be used as predictors of EOC recurrence. Our study provides insights into the mechanism of EOC recurrence and presents CYR61+ relapse-initiating cells as potential therapeutic targets to prevent EOC relapse.

Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth.

Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients' prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

Predicting Factors Affecting the First Recurrence of Epithelial Ovarian Cancer Using Random Survival Forest

Predicting survival time has many Effective implications in life quality management for the remainder of the patient's life. Also, survival data are highly variable and make accurate predictions difficult or impossible. Random Survival Forest by repeated tree construction on Bootstrap samples and averaging on the results of these trees reduce the prediction error and cause further generalization of these results. In this retrospective study, the records of 141 patients with epithelial ovarian cancer who were referred to the oncology and radiotherapy ward of Imam Hossein Hospital in Tehran from 2007 to 2018 were used. Random Survival Forest was fitted to the data to investigate the key factors affecting the first recurrence of epithelial ovarian cancer. The mean age of the patients in our study was 52 (23-82) years and the median time to the first recurrence in these was 17 (0.5-127) months, respectively. According to RSF results, using variable importance criterion (VIMP) metastatic tumor with relative importance 2.665 and also using minimal (MD) by depth 2.349, tumor stage with relative importance 1.993 and depth 2.678, and maximum platelet count with relative importance 2.132 and depth 2.683 were the most important variables affecting in the first recurrence of Epithelial Ovarian Cancer. One of the disadvantages of classical methods is the inappropriate fitting of many variables and the need for specific assumptions. More advanced methods such as RSF without the need for any specific assumptions with less prediction error can well explain event variations when exposed to high-dimensional data.

Prognostic implications of tumour-infiltrating lymphocytes for recurrence in epithelial ovarian cancer.

The recurrence of patients with epithelial ovarian cancer (EOC) is largely attributed to tumour cells escaping from the surveillance of immune cells. However, to date there is a lack of studies that have systematically evaluated the associations between the infiltration fraction of immune cells and the recurrence risk of EOC. Based on the micro-ribonucleic acid (microRNA) expression profiles of 441 EOC patients, we constructed a microRNA-based panel with recurrence prediction potential using non-negative matrix factorization consensus clustering. Then, we evaluated the association between recurrence risk and infiltration proportions among 10immune cell types by CIBERSORT and a multivariable Cox regression model. As a result, we identified a 72-microRNA-based panel that could stratify patients into high and low risk of recurrence. The infiltration of plasma cells and M1 macrophages was consistently significantly associated with the risk of recurrence in patients with EOC. Plasma cells were significantly associated with a decreased risk of relapse [hazard ratio (HR)=0.58, p=0.006), while M1 macrophages were associated with an increased risk of relapse (HR=1.59, p=0.003). Therefore, the 72-microRNA-based panel, M1 macrophages and plasma cells may hold potential to serve as recurrence predictors of EOC patients in clinical practice.