Prognosis Of Epithelial Ovarian Cancer Research Articles

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRmvHRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

The impact of laterality on the incidence and prognosis of epithelial ovarian cancer

IntroductionEpithelial ovarian cancer (EOC) is the most prevalent type of ovarian cancer, yet the impact of ovarian laterality has received limited attention. Materials and methodsWe conducted a comprehensive investigation into the impact of laterality (left-right and bilateral-unilateral) on EOC incidence and prognosis, focusing on distinct subtypes. Binomial tests and Pearson's χ2 tests were employed to compare occurrence rates among laterality groups. Cox regression analyses were used to create a proportional hazards model for tumor prognosis. Nomograms were developed and validated, including internal validation via bootstrapping. ResultsOur study encompassed 20,790 EOC patients, revealing disparities in incidence and prognosis between unilateral and bilateral cases. Unilateral tumor development was notably predominant in clear cell, endometrioid, brenner, and mucinous subtypes, while bilateral involvement was more frequent in serous ovarian cancer. Laterality differences, reflecting disparities between the left and right sides, were chiefly evident in the incidence rates across various stages and in the prognosis of specific subtypes. Notably, mucinous ovarian cancer exhibited significantly better prognosis on the right side compared to the left (right tumors: HR = 0.745, p = 0.015, CI: 0.587–0.945). ConclusionThese findings emphasize the importance of considering ovarian laterality —both left-right and bilateral-unilateral aspects —as a critical factor influencing EOC incidence and prognosis, necessitating attention in clinical practice.

Association of homologous recombination repair mutation defined with a 15-gene panel with the prognosis of epithelial ovarian cancer: A Chinese multicenter retrospective study.

e17556 Background: There was no consensus regarding the optimal homologous recombination repair (HRR) gene panel to predict prognosis of epithelial ovarian cancer (EOC). Methods: The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centres were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and progression-free survival (PFS) with 15-gene panel mutation status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRR mutations (HRRm), among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. Patients who received PARP inhibitors (PARPis) were 29.1% (37/127) and 50.5% (46/91) in the HRR wild-type (HRRwt) group and HRRm group at IIIC-IV stages, respectively. A prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. In univariate analysis, significant predictors of relapse included nonresidual status (HR, 0.62; 95% CI, 0.39-0.98; P = 0.0287), 15-gene panel mutation (HR, 0.42; 95% CI, 0.28-0.64; P = 0.0001), platinum sensitivity (HR, 0.07; 95% CI, 0.02-0.22; P < 0.001) and maintenance therapy (PARPi) (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0028) (Figure 5). In multivariate Cox analysis, nonresidual (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046), 15-gene panel mutation (HR, 0.49; 95% CI, 0.28-0.88; P = 0.016) and platinum sensitivity (HR, 0.02; 95% CI, 0.01-0.05; P < 0.001) remained independent prognostic factors. Conclusions: This study provides evidence that HRRm with a 15-gene panel can predict the prognosis of EOC, among which only BRCA1/2 mutations contribute to prognosis prediction. [Table: see text]

Association of low Angiomotin-p130 and high YAP1 nuclear expression with adverse prognosis in epithelial ovarian cancer.

The aim of our study was to examine the association of Angiomotin (Amot-p130) and Yes-associated protein 1 (YAP1) expressions and their prognostic significance in epithelial ovarian cancer (EOC). A total of 100 primary EOC samples were obtained for immunohistochemical analysis of Amot-p130 and YAP1 expressions. Correlation analysis was performed between Amot-p130 or YAP1 and clinical factors. The overall survival time was calculated. Low Amot-p130 and high YAP1 nuclear expression were identified in 34 and 56 of 100 EOC tissues, respectively. Both low Amot-p130 and high YAP1 nuclear expression were associated with advanced tumor stage, high-grade carcinoma, and non-response to chemotherapy (p<0.05). They were also associated with shorter overall survival time (p<0.05) by log-rank test. A marker of low Amot-p130 and high YAP1 expression was associated with high-grade ovarian carcinoma, late-stage disease, non-response to chemotherapy, and shorter overall survival time (p<0.05). Low Amot-p130 and high YAP1 nuclear expression can provide additional prognostic information for patients with EOC. A marker of low Amot-p130 and high YAP1 expression may be a potent predictor of poor prognosis in patients with epithelial ovarian cancer.

Identification of PDZD11 as a Potential Biomarker Associated with Immune Infiltration for Diagnosis and Prognosis in Epithelial Ovarian Cancer.

Evidence has indicated that PDZD11 is involved in regulating adherens junction. However, the distinct effect of its aberrant expression on epithelial ovarian cancer (EOC) awaits clarification. In this study, public databases (Gene Expression Omnibus, The Cancer Genome Atlas, and The Genotype-Tissue Expression), online analysis tools (Kaplan-Meier plotter and TIMER), and data analysis methods (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and the CIBERSORT algorithm) were fully utilized to analyze the differential expression, diagnostic efficiency, prognostic significance, potential function, and correlation with immune infiltration of PDZD11. The differential expression of PDZD11 was tested by immunohistochemistry in EOC tissues (78 cases) and control tissues (37 cases). Our results indicate that PDZD11 was remarkably overexpressed in EOC, which was associated with advanced cancer stages, no lymphatic metastasis status, and poor prognosis. Moreover, PDZD11 played a role in cell adhesion, cell proliferation, and immune responses. Also, PDZD11 was significantly related to the abundances of infiltrating immune cells in EOC, including neutrophils, macrophages, dendritic cells, CD8+ T cells, and CD4+ T cells, and its expression was positively co-expressed with well-known immune checkpoints, including TIGIT, TIM3, LAG3, CTLA4, and PD-1. These results suggest that PDZD11 could be a potential diagnostic and prognostic biomarker associated with immune infiltration in EOC, and our findings might help elucidate the function of PDZD11 in carcinogenesis.

CX3CR1 is a potential biomarker of immune microenvironment and prognosis in epithelial ovarian cancer.

Immunotherapy is less efficient for epithelial ovarian cancer and lacks ideal biomarkers to select the best beneficiaries for immunotherapy. CX3CR1 as chemokine receptor mainly expressed on immune cell membranes, and combined with its unique ligand CX3CL1, mediates tissue chemotaxis and adhesion of immune cells. However, the immune functional and prognostic value of CX3CR1 in epithelial ovarian cancer has not been clarified. A comprehensive retrospective analysis was performed by using the online database to identify the underlying immunological mechanisms and prognostic value of CX3CR1. The Human Protein Atlas, gene expression profiling interactive analysis, and TISIDB (an integrated repository portal for tumor-immune system interactions) database showed that CX3CR1 expressed higher in epithelial ovarian cancer than that in normal ovarian tissue. Four hundred twenty-two cases from Gene Expression Profiling Interactive Analysis and 1656 cases from Kaplan-Meier plotter database showed higher expression of CX3CR1 (above median) was associated with unfavorable overall survival. TIMER, UALCAN, and TISIDB database were applied to validate CX3CR1 negative impact on overall survival. In addition, correlation analysis showed that the expression level of CX3CR1 was positive association with infiltrating levels of B cells (R = 0.31, P = 3.10e-12), CD8+ T cells (R = 0.26, P = 7.93e-09), CD4+ T cells (R = 0.11, P = 1.41e-02), macrophages (R = 0.32, P = 4.29e-13), dendritic cells (R = 0.27, P = 2.98e-09), and neutrophil (R = 0.25, P = 3.25e-08) in epithelial ovarian cancer. Therefore, CX3CR1 involved in reshaping the immune microenvironment for epithelial ovarian cancer and maybe a potential immunotherapy target and prognostic marker for ovarian cancer.

Predicting epithelial ovarian cancer prognosis: correlation of posttreatment 18F-fluorodeoxyglucose positron emission tomography-computed tomography metabolic parameters, serum carbohydrate antigen, and human epididymis protein levels with overall survival.

Identifying reliable prognostic indicators can aid in improving patient care. The aim of this study was to establish the association of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) whole-body metabolic parameters, serum carbohydrate antigen 125 (CA125), and human epididymis protein 4 (HE4) with overall survival (OS) in patients with epithelial ovarian cancer (EOC) after surgery combined with platinum-based chemotherapy. From May 2014 to May 2019, a total of 79 patients with EOC who underwent posttreatment 18F-FDG PET/CT in the First Affiliated Hospital of Chongqing Medical University were included. Clinical data and laboratory indicators were obtained. The whole-body maximum standardized uptake value (WBSUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) were measured and calculated on 18F-FDG PET/CT. The follow-up was conducted until February 2023, and the endpoint was death from any cause. Pearson correlation analysis, Kaplan-Meier, and Cox proportional regression were used in this study. The PET-positive (PET-P) patients had significantly decreased OS based on either Kaplan-Meier survival analysis (P<0.001) or univariate Cox regression analysis [hazard ratio (HR) =40.177, 95% confidence interval (CI): 2.690-600.134; P=0.007]. "Ln" is a logarithmic transformation with a base of "e" (natural logarithm). LnWBMTV, lnWBTLG, and therapy after PET were independent predictors of OS in a cohort of 63 PET-P patients. The difference in OS between groups sorted by the median WBMTV (4.16; P<0.001) and WBTLG (14.71; P<0.001) was statistically significant. There were statistically significant differences in CA125 and HE4 levels between patients in the PET-P and PET-negative (PET-N) groups (P<0.001). In the PET-P patient cohort, serum HE4 levels were substantially correlated with WBMTV and WBTLG. Kaplan-Meier survival analysis suggested a reduction in OS after treatment in patients with EOC positive for CA125, HE4, and PET (P<0.001). Post-PET/CT treatment strategy, WBMTV, and WBTLG demonstrated significant prognostic utility in predicting posttreatment OS in patients with EOC. Patients who tested positive for both tumor markers CA125 and HE4 and had a positive PET scan demonstrated a significantly poorer prognosis in terms of posttreatment OS.

Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy.

Introduction: High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadliest subtype of epithelial ovarian cancer (EOC), killing over 140,000 people annually. Morbidity and mortality are compounded by a lack of screening methods, and recurrence is common. Plasminogen-activator-inhibitor 1 (PAI-1, the protein product of SERPIN E1) is involved in hemostasis, extracellular matrix (ECM) remodeling, and tumor cell migration and invasion. Overexpression is associated with poor prognosis in EOC. Platelets significantly increase PAI-1 in cancer cells in vitro, and may contribute to the hematogenous metastasis of circulating tumor cells (CTCs). CTCs are viable tumor cells that intravasate and travel through the circulation-often aided by platelets - with the potential to form secondary metastases. Here, we provide evidence that PAI-1 is central to the platelet-cancer cell interactome, and plays a role in the metastatic cascade. Methods: SK-OV-3 cells where PAI-1 had been silenced, treated with healthy donor platelets, and treated with platelet-conditioned medium were used as an in vitro model of metastatic EOC. Gene expression analysis was performed using RNA-Seq data from untreated cells and cells treated with PAI-1 siRNA or negative control, each with and without platelets. Four cohorts of banked patient plasma samples (n = 239) were assayed for PAI-1 by ELISA. Treatment-naïve (TN) whole blood (WB) samples were evaluated for CTCs in conjunction with PAI-1 evaluation in matched plasma. Results and discussion: Significant phenotypic changes occurring when PAI-1 was silenced and when platelets were added to cells were reflected by RNA-seq data, with PAI-1 observed to be central to molecular mechanisms of EOC metastasis. Increased proliferation was observed in cells treated with platelets. Plasma PAI-1 significantly correlated with advanced disease in a TN cohort, and was significantly reduced in a neoadjuvant chemotherapy (NACT) cohort. PAI-1 demonstrated a trend towards significance in overall survival (OS) in the late-stage TN cohort, and correlation between PAI-1 and neutrophils in this cohort was significant. 72.7% (16/22) of TN patients with plasma PAI-1 levels higher than OS cutoff were CTC-positive. These data support a central role for PAI-1 in EOC metastasis, and highlight PAI-1's potential as a biomarker, prognostic indicator, or gauge of treatment response in HGSOC.

Simultaneous detection of CA-125 and mesothelin by gold nanoparticles in surface plasmon resonance

The early-stage diagnosis and monitoring of disease evolution is still one of the most challenging tasks in the field of cancer research. Several research have been driven toward the discovery of new cancer biomarkers as well as to the development of biosensors able to detect these biomarkers with high specificity and sensitivity. Many types of cancer have been detected at an advanced stage and, in particular, epithelial ovarian cancer (EOC) has a high incidence of diagnosis in the metastatic stage. This cancer is considered as the most aggressive type of gynecological cancer with a 5-year survival and until now, no specific biomarkers have been identified. Nevertheless, some studies have indicated that mesothelin, a protein overexpressed by tumour cells in the ovary, interacts with the CA-125 biomarker present in the blood system accelerating the metastatic process. Therefore, the simultaneous presence of CA-125 and mesothelin in the blood during the evolution of EOC could be used to diagnose this disease before the metastasis. Therefore, with this motivation, this work aimed at the development of a biosensor capable of simultaneously detecting mesothelin and CA-125 at low concentrations. A biosensor based on the surface plasmon resonance imaging (SPRi) technique was developed and gold nanoparticles (AuNPs) were used in order to enhance the sensitivity. The study analysed successive injections of the biomarkers CA-125 and mesothelin, both in solution (analytical range of 9–120 nM). The limits of detection were obtained for CA-125 and mesothelin, being of 3.03 nM and 13.62 nM, respectively. The biosensor detected mesothelin at a concentration close to the cutoff point for EOC (3 nM) and was able to detect the biomarker CA-125 at 9 nM. Furthermore, the biosensor interacted preferentially and simultaneously with the biomarkers CA-125 and mesothelin incubated in fetal bovine serum. Finally, the use of AuNPs increased the sensor signal for CA-125 detection compared to its direct detection and showed greater selectivity for both biomarkers. Therefore, the biosensor has important characteristics that allow testing with real samples. In a future project, it could be applied in the research of diagnosis and prognosis of EOC.

Deciphering tumor immune microenvironment differences between high-grade serous and endometrioid ovarian cancer to investigate their potential in indicating immunotherapy response

BackgroundOvarian cancer is a significant public health concern with a poor prognosis for epithelial ovarian cancer. To explore the potential of immunotherapy in treating epithelial ovarian cancer, we investigated the immune microenvironments of 52 patients with epithelial ovarian cancer, including 43 with high-grade serous ovarian cancer and 9 with endometrioid ovarian cancer.ResultsFresh tumor tissue was analyzed for genetic mutations and various parameters related to immune evasion and infiltration. The mean stromal score (stromal cell infiltration) in high-grade serous ovarian cancer was higher than in endometrioid ovarian cancer. The infiltration of CD8 T cells and exhausted CD8 T cells were found to be more extensive in high-grade serous ovarian cancer. Tumor Immune Dysfunction and Exclusion scores, T cell exclusion scores, and cancer-associated fibroblasts (CAF) scores were also higher in the high-grade serous ovarian cancer group, suggesting that the number of cytotoxic lymphocytes in the tumor microenvironment of high-grade serous ovarian cancer is likely lower compared to endometrioid ovarian cancer.ConclusionsThe high mean stromal score and more extensive infiltration and exhaustion of CD8 T cells in high-grade serous ovarian cancer indicate that high-grade serous ovarian cancer exhibits a higher level of cytotoxic T cell infiltration, yet these T cells tend to be in a dysfunctional state. Higher Tumor Immune Dysfunction and Exclusion scores, T cell exclusion scores, and CAF scores in high-grade serous ovarian cancers suggest that immune escape is more likely to occur in high-grade serous ovarian cancer, thus endometrioid ovarian cancer may be more conducive to immunotherapy. Therefore, it is crucial to design immunotherapy clinical trials for ovarian cancer to distinguish between high-grade serous and endometrioid ovarian cancer from the outset. This distinction will help optimize treatment strategies and improve outcomes for patients with different subtypes.

Prognostic significance of TM4SF1 and DDR1 expression in epithelial ovarian cancer.

Transmembrane 4 L6 family member 1 (TM4SF1) and discoidin domain receptor 1 (DDR1) are expressed in numerous types of cancer, but their expression in epithelial ovarian cancer and the association between their expression and patient prognosis are unclear. The present study aimed to explore the expression of TM4SF1 and DDR1 and their relationship with prognosis in epithelial ovarian cancer. Firstly, the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) platforms were used to compare the expression levels of TM4SF1 and DDR1 in ovarian cancer and normal ovarian tissue, and Kaplan-Meier plotter was used to analyze the association between gene expression and patient prognosis. The proteins interacting with TM4SF1 and DDR1 were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways was conducted for the interacting proteins. Furthermore, immunohistochemical staining was performed to detect the expression of TM4SF1 and DDR1 protein in epithelial ovarian cancer tissue and to analyze the association between expression and prognosis. The Oncomine and GEPIA analyses showed that the expression levels of TM4SF1 and DDR1 were significantly higher in epithelial ovarian cancer than in normal ovarian tissue, and the analysis of clinical samples revealed that TM4SF1 and DDR1 were coexpressed in some cases. STRING analysis indicated that the TM4SF1 and DDR1 proteins interact with each other. The overall survival and progression-free survival of patients whose epithelial ovarian cancer coexpressed TM4SF1 and DDR1 were significantly shorter than those of patients lacking TM4SF1 and DDR1 coexpression. Multivariate analysis indicated that TM4SF1 and DDR1 protein coexpression was an independent prognostic factor. In summary, TM4SF1 and DDR1 proteins were coexpressed in some epithelial ovarian cancer tissues and appear to be adverse prognostic factors for epithelial ovarian cancer. In addition, TM4SF1 and DDR1 may have an interactive or mutual regulatory mechanism.

Hormone Receptors and Epithelial Ovarian Cancer: Recent Advances in Biology and Treatment Options.

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.

A retrospective analysis for investigating the relationship between FIGO stage IVA/IVB and cytoreductive surgery with prognosis in epithelial ovarian cancer.

To investigate the effect of primary debulking surgery (PDS), NACT followed by interval debulking surgery (NACT-IDS), and chemotherapy alone on the prognosis of FIGO stage IV epithelial ovarian cancer (EOC) with different metastatic patterns. We retrospectively analyzed 133 cases of FIGO stage IV EOC with pleural effusion (stage IVA), parenchymal metastases (stage IVB), or extra-abdominal lymph node metastases (stage IVB) at our Hospital between January 2014 and July 2021. Among 133 cases with stage IV disease, 16.5% (n=22) presented with pleural effusion, 46.6% (n=62) with parenchymal metastases, and 36.9% (n=49) with extra-abdominal lymph node metastases. Regardless of the metastatic patterns, the 90.2% (n=120) of cases who underwent PDS/NACT-IDS exhibited a significantly superior overall survival (OS) compared to the 9.8% cases (n=13) who received chemotherapy alone (32 vs 17 months, p=0.000). The cohort was further stratified into 58 cases (48.3%) with R0, 41 cases (34.2%) with R1, and 21 cases (17.5%) with R2. The median OS of cases with R0 was significantly better than that of cases with R1/R2 (74 vs 27 months, p=0.000). There was no significant difference in median OS between PDS and NACT-IDS (43 vs 31 months, p=0.676), as well as between FIGO IVA and IVB (35 vs 31 months, p=0.582). Additionally, the metastatic patterns and the number of neoadjuvant chemotherapy cycles (≤4 or >4) did not demonstrate any prognostic significance for median OS (p=0.820 and 33 vs 26 months, p=0.280, respectively). Regardless of FIGO IVA and IVB stages or metastatic patterns, patients diagnosed with stage IV EOC may benefit from cytoreductive surgery with abdominal R0, compared with chemotherapy alone.

Long Noncoding RNA SNHG15 Serves as an Oncogene and Predicts Poor Prognosis in Epithelial Ovarian Cancer [Retraction

[This retracts the article DOI: 10.2147/OTT.S182657.].

VGLL3 expression is associated with macrophage infiltration and predicts poor prognosis in epithelial ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is the most common histologic type of epithelial ovarian cancer (EOC). Due to its poor survival outcomes, it is essential to identify novel biomarkers and therapeutic targets. The hippo pathway is crucial in various cancers, including gynaecological cancers. Herein, we examined the expression of the key genes of the hippo pathway and their relationship with clinicopathological significance, immune cells infiltration and the prognosis of HGSOC. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data were curated to analyse the mRNA expression as well as the clinicopathological association and correlation with immune cell infiltration in HGSOC. The protein levels of significant genes in the HGSOC tissue were analysed using Tissue Microarray (TMA)-based immunohistochemistry. Finally, DEGs pathway analysis was performed to find the signalling pathways associated with VGLL3. VGLL3 mRNA expression was significantly correlated with both advanced tumor stage and poor overall survival (OS) (p=0.046 and p=0.003, respectively). The result of IHC analysis also supported the association of VGLL3 protein with poor OS. Further, VGLL3 expression was significantly associated with tumor infiltrating macrophages. VGLL3 expression and macrophages infiltration were both found to be independent prognostic factors (p=0.003 and p=0.024, respectively) for HGSOC. VGLL3 was associated with four known and three novel cancer-related signalling pathways, thus implying that VGLL3 is involved in the deregulation of many genes and pathways. Our study revealed that VGLL3 may play a distinct role in clinical outcomes and immune cell infiltration in patients with HGSOC and that it could potentially be a prognostic marker of EOC.

Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer

Objective: To investigate the mechanism of signal transducer and activator of transcription 3 (STAT3) and cancer associated fibroblasts (CAF) jointly generate chemo-resistance in epithelial-ovarian cancer and their effect on prognosis. Methods: A total of 119 patients with high-grade ovarian serous cancer who received surgery in Cancer Hospital of Chinese Academy of Medical Sciences from September 2009 to October 2017 were collected. The clinico-pathological data and follow-up data were complete. Multivariate Cox regression model was used to analyze the prognostic factors. Ovarian cancer tissue chips of patients in our hospital were prepared. EnVision two-step method immunohistochemistry was used to detect the protein expression levels of STAT3, the specific markers of CAF activation, fibroblast activating protein (FAP), and type Ⅰ collagen (COL1A1) secreted by CAF. The relationship between the expression of STAT3, FAP, COL1A1 protein and drug resistance and prognosis of ovarian cancer patients was analyzed, and the correlation between the expression of three proteins was analyzed. These results were verified through the gene expression and prognostic information of human ovarian cancer tissues collected in the GSE26712 dataset of gene expression omnibus (GEO) database. Results: (1) Multivariate Cox regression model analysis showed that chemotherapy resistance was an independent risk factor for overall survival (OS) of ovarian cancer (P<0.001). (2) The expression levels of STAT3, FAP, and COL1A1 proteins in chemotherapy resistant patients were significantly higher than those in chemotherapy sensitive patients (all P<0.05). Patients with high expression of STAT3, FAP, and COL1A1 had significantly shorter OS than those with low expression (all P<0.05). According to the human ovarian cancer GSE26712 dataset of GEO database, patients with high expression of STAT3, FAP, and COL1A1 also showed shorter OS than patients with low expression (all P<0.05), the verification results were consistent with the detection results of ovarian cancer patients in our hospital. (3) Correlation analysis showed that the protein level of STAT3 was positively correlated with FAP and COL1A1 in our hospital's ovarian cancer tissue chips (r=0.47, P<0.001; r=0.30, P=0.006), the analysis of GEO database GSE26712 dataset showed that the expression of STAT3 gene and FAP, COL1A1 gene were also significantly positively correlated (r=0.31, P<0.001; r=0.52, P<0.001). Conclusion: STAT3 and CAF could promote chemotherapy resistance of ovarian cancer and lead to poor prognosis.

Identification of metabolic biomarkers for diagnosis of epithelial ovarian cancer using internal extraction electrospray ionization mass spectrometry (iEESI-MS).

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. The poor prognosis of EOC is mainly due to its asymptomatic early stage, lack of effective screening methods, and a late diagnosis in the advanced stages of the disease. This study investigated metabolomic abnormalities in epithelial ovarian cancers. Our study developed a novel strategy to rapidly identify the metabolic biomarkers in the plasma of the EOC patients using Internal Extraction Electrospray Ionization Mass Spectrometry (IEESI-MS) and Liquid Chromatography-mass Spectrometry (HPLC-MS), which could distinguish the differential metabolites in between plasma samples collected from 98 patients with epithelial ovarian cancer, including 78 cases with original (P), and 20 cases with self-configuration (ZP), as well as 60 healthy subjects, including 30 cases in the original sample (H), 30 cases in self-configuration (ZH), and 6 cases in a blind sample (B). Our study detected 880 metabolites based on criteria variable importance in projection (VIP) > 1, among which 26 metabolites were selected for further identification. They are mainly metabolism-related lipids, amino acids, nucleic acids, and others. The metabolic pathways associated with the differential metabolites were explored by the KEGG analysis, a comprehensive database that integrates genome, chemistry, and system function information. The abnormal metabolites of EOC patients identified by IEESI-MS and HPLC-MS included Lysophosphatidylcholine (16:0) [Lyso PC (16:0)], L-Phenylalanine, L-Leucine, Phenylpyruvic acid, L-Tryptophan, and L-Histidine. Identifying the abnormal metabolites of EOC patients through metabolomics analyses could provide a new strategy to identify valuable potential biomarkers for the screening and early diagnosis of EOC.

Stratification of ovarian cancer borderline from high-grade serous carcinoma patients by quantitative serum NMR spectroscopy of metabolites, lipoproteins, and inflammatory markers.

Background: Traditional diagnosis is based on histology or clinical-stage classification which provides no information on tumor metabolism and inflammation, which, however, are both hallmarks of cancer and are directly associated with prognosis and severity. This project was an exploratory approach to profile metabolites, lipoproteins, and inflammation parameters (glycoprotein A and glycoprotein B) of borderline ovarian tumor (BOT) and high-grade serous ovarian cancer (HGSOC) for identifying additional useful serum markers and stratifying ovarian cancer patients in the future. Methods: This project included 201 serum samples of which 50 were received from BOT and 151 from high-grade serous ovarian cancer (HGSOC), respectively. All the serum samples were validated and phenotyped by 1H-NMR-based metabolomics with in vitro diagnostics research (IVDr) standard operating procedures generating quantitative data on 38 metabolites, 112 lipoprotein parameters, and 5 inflammation markers. Uni- and multivariate statistics were applied to identify NMR-based alterations. Moreover, biomarker analysis was carried out with all NMR parameters and CA-125. Results: Ketone bodies, glutamate, 2-hydroxybutyrate, glucose, glycerol, and phenylalanine levels were significantly higher in HGSOC, while the same tumors showed significantly lower levels of alanine and histidine. Furthermore, alanine and histidine and formic acid decreased and increased, respectively, over the clinical stages. Inflammatory markers glycoproteins A and B (GlycA and GlycB) increased significantly over the clinical stages and were higher in HGSOC, alongside significant changes in lipoproteins. Lipoprotein subfractions of VLDLs, IDLs, and LDLs increased significantly in HGSOC and over the clinical stages, while total plasma apolipoprotein A1 and A2 and a subfraction of HDLs decreased significantly over the clinical stages. Additionally, LDL triglycerides significantly increased in advanced ovarian cancer. In biomarker analysis, glycoprotein inflammation biomarkers behaved in the same way as the established clinical biomarker CA-125. Moreover, CA-125/GlycA, CA-125/GlycB, and CA-125/Glycs are potential biomarkers for diagnosis, prognosis, and treatment response of epithelial ovarian cancer (EOC). Last, the quantitative inflammatory parameters clearly displayed unique patterns of metabolites, lipoproteins, and CA-125 in BOT and HGSOC with clinical stages I-IV. Conclusion: 1H-NMR-based metabolomics with commercial IVDr assays could detect and identify altered metabolites and lipoproteins relevant to EOC development and progression and show that inflammation (based on glycoproteins) increased along with malignancy. As inflammation is a hallmark of cancer, glycoproteins, thereof, are promising future serum biomarkers for the diagnosis, prognosis, and treatment response of EOC. This was supported by the definition and stratification of three different inflammatory serum classes which characterize specific alternations in metabolites, lipoproteins, and CA-125, implicating that future diagnosis could be refined not only by diagnosed histology and/or clinical stages but also by glycoprotein classes.

The polymorphism rs4705342 in the promoter of miR-143/145 is related to the risk of epithelial ovarian cancer and patient prognosis.

To evaluate the effects of two genetic variants in the promoter of the miR-143/145 cluster on the risk of epithelial ovarian cancer (EOC) and the prognosis of EOC patients. Genotypes were determined by the polymerase chain reaction and ligase detection reaction method in 563 EOC patients and 576 healthy women. The expression of miR-143 and miR-145 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in fifty-two EOC tissues. The rs4705342 CC genotype frequencies in EOC patients were higher than those in the controls (P = 0.014). Furthermore, the CC genotype of rs4705342 was associated with an advanced FIGO stage of EOC patients (P = 0.046). Patients with the rs4705342 CC genotype had shorter progression-free survival (PFS) and overall survival (OS) times than those carrying the TT genotype in multivariable analysis adjusting for clinical variables (HR = 1.30, 95% CI = 1.04-1.62, P = 0.020; HR = 1.33, 95% CI = 1.05-1.70, P = 0.020). In addition, the miR-145 levels were lower in EOC tissues with the rs4705342 CC genotype than in those with the TT genotype (P = 0.005). The CC genotype of rs4705342 was related to an increased risk of EOC and poor prognosis of EOC patients, and rs4705342 may serve as a molecular marker for predicting the development of EOC and the clinical outcome of EOC patients.

Abstract 4401: The precision chemotherapy to improve the epithelial ovarian cancer prognosis

Abstract Purpose: Recurrence is common in ovarian cancer patients, even in those patients who show complete response after first-line chemotherapy, 80% of the patients experience a recurrence. So gynecologic oncologists often have to consider several factors when choosing next chemotherapy regimen. Therefore, this study aimed to find serial chemotherapy regimen choice to anticipate patients’ better prognosis. Materials and Methods: We reviewed 656 patients diagnosed ovary cancer in one tertiary institutional hospital between 2006 and 2020. Patents’ clinic-pathologic characteristics, primary treatment, chemotherapy regimens, survival outcomes were collected. We divided patients into several groups according to their chemotherapy regimen by mechanism of action and compared them. 1st line chemotherapy(CTx) type 1: carboplatin-paclitaxel, carboplatin-docetaxol, cisplatin-paclitaxel, cisplatin-docetaxol2nd line CTx type 1: carboplatin-paclitaxel, carboplatin-docetaxol, cisplatin-paclitaxel, cisplatin-docetaxol2nd line CTx type 4: carboplatin-gemcitabine2nd maintenance CTx type 2: PARP inhibitor(PARPi)2nd line CTx Type 5: Platinum + topoisomerase inhibitor 2nd line CTx Type 6(cisplatin-vinorelbine)2nd line CTx Type 8(topoisomerase inhibitor only) 2nd line CTx Type12 (single taxol) The survival rate of ovary cancer patients decreased from stage 1 to stage 4.Among 1st line CTx type 1 and 2nd line CTx type(1 or 4) patients, those who used PARPi in 2nd line maintenance CTx(n=14) had a higher death rate than those who did not receive maintenance CTx or received that other than PARPi(hazard ratio 1.44). In the 1st line CTx 1~4 group, we divided patients according to 2nd line CTx type. We compare 2nd line CTx type 5 group(n=30) with type 6+8+12 group(n=26). The death rate was of type 5 group was higher than type 6+8+12 group. And Overall survival of 2nd line CTx type 5 group was 22 months, that of 2nd line CTx type 6+8+12 group was 26 months. Conclusion: When changing the chemotherapy regimen in the recurrence of ovarian cancer, the survival rate or overall survival may vary depending on the order in which the regimen is used. If we collect patients data more broadly, the predictive power will be better. Citation Format: Seongeun Pak, Youn Jin Choi. The precision chemotherapy to improve the epithelial ovarian cancer prognosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4401.