Epithelial Ovarian Carcinoma Patients Research Articles

Differentiation of ovarian serous carcinoma from ovarian clear cell carcinoma using a 10-gene signature selected by comprehensive gene expression analysis.

Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.

Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a "real-life setting".

The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.

Identifying Serum Small Extracellular Vesicle MicroRNA as a Noninvasive Diagnostic and Prognostic Biomarker for Ovarian Cancer.

There remains a lack of effective and noninvasive methods for the diagnosis and prognosis prediction of epithelial ovarian carcinoma (EOC). Here, we investigated the possibility of serum-derived small extracellular vesicle (sEV) microRNAs (miRNAs) as potential biomarkers for distinguishing between benign and malignant adnexal masses and predicting the prognosis of EOC patients. A serum sEV miRNA model for identifying the EOC (sEVmiR-EOC) was successfully established in the training cohort. Furthermore, the sEVmiR-EOC model was confirmed in the testing cohort and validation cohort, demonstrating robust diagnostic accuracy. The sEVmiR-EOC model showed better performance than carbohydrate antigen 125 (CA125) in discriminating patients with stage I EOC from benign patients. Using EOC samples and follow-up data, we identified miR-141-3p and miR-200c-3p as potential prognostic predictors. Finally, we confirmed the change of the sEVmiR-EOC RiskScore between the preoperative and postoperative samples and found that the sEVmiR-EOC model could predict the prognosis of EOC patients.

Prognostic factors and clinic-pathologic characteristics of ovarian tumor with different histologic subtypes-a SEER database population study of 41,376 cases.

Ovarian cancer is considered the leading cause of cancer-related deaths among all gynecological malignancies and a significant reason for mortality in women. This cohort study aimed to explore the survival trends of malignant ovarian tumors (MOT), cancer antigen 125 (CA125) level, and clinicopathological prognostic factors of MOT by histological subtype. Using the Surveillance, Epidemiology, and End Results (SEER) database, a total of 41,411 MOT cases diagnosed between January 2005 and December 2014 were extracted. According to the histological classification of MOT, four categories were included: epithelial ovarian carcinoma (EOC), malignant ovarian germ cell tumors (MOGCTs), malignant ovarian sex cord-stromal tumors (MOSCSTs) and ovarian neuroendocrine tumors (ONTs). We analyzed disease-specific survival (DS) and overall survival (OS) among the four categories, and their histological subtypes. Kaplan-Meier method was used to estimate survival curves, and log-rank test was used to evaluate differences between curves. Univariate and multivariate Cox proportional hazards models were applied to evaluate the prognostic impact of MOT. Significant predictors related to improved OS were younger age, low grade, early FIGO stage and localized SEER stage, while positive/elevated CA125 level was a risk factor. For MOGCT and MOSCST, 3-, 5- and 10-year DS rate estimates were all >80%, followed by ONT around 70%. Malignant epithelial cancer showed low DS rate at 3-year (70.7%), 5-year (58.7%), and 10-year (47.3%). EOC patients had the worst outcome, whereas MOGCT cases had the most favorable survival. Positive/elevated CA125 level led to poor prognosis. Furthermore, younger age, low grade, early FIGO stage and localized SEER stage were significant predictors for improved OS.

Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma.

To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in epithelial ovarian carcinoma (EOC) treated with primary surgery followed by platinum-based chemotherapy. The records of primary EOC treated between Jan 1st 2002 and Dec 31st 2016 were reviewed according to the including and excluding criteria. CIN was defined as absolute neutrophil count (ANC) after chemotherapy <2.0 × 109/L. Patients with CIN were further divided into mild and severe CIN (ANC <1.0 × 109/L), early-onset and late-onset (>3 cycles) CIN. Clinical characteristic was compared by chi-square test. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier analysis, univariate and multivariate Cox regression models. Among 735 EOC patients enrolled, no significant differences of the prognosis were found between patients with and without CIN, early and late CIN, mild and severe CIN. However, Kaplan-Meier curve (65 vs 42months for CIN vs non-CIN, P = .007) and Cox regression analysis (HR 1.499, 95% CI 1.142-1.966; P = .004) both revealed that CIN was significantly related with better OS in advanced EOC patients, but not for PFS. So, subgroup analysis was further conducted and date suggested that CIN was an independent predictor of better survival in advanced EOC with suboptimal surgery (PFS: 18 vs 14months, P = .013, HR 1.526, 95% CI 1.072-2.171, P = .019; OS: 37 vs 27 months, P = .013, HR 1.455, 95% CI 1.004-2.108; P = .048). CIN might be used as an independent prognostic indicator of advanced EOC, especially for those patients with suboptimal surgery.

Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy.

Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.

Prognostic Outcome of Mesenchymal Transition Biomarkers in Correlation with EGFR Expression in Epithelial Ovarian Carcinoma Patients

CD44 is an epithelial-mesenchymal transition (EMT) surface receptor that regulates the interactivity between the cells and the extracellular matrix, thereby promoting cell migration. The epidermal growth factor receptor (EGFR) family is a trans-membrane kinase-related protein. It regulates cell adhesion proteins, which may promote cell proliferation and invasiveness. Mesenchymal epithelial transition (MET) is another EMT receptor that stimulates cell proliferation, invasion, survival, and angiogenesis. This study aimed to evaluate the prognostic impact of CD44, EGFR expressions, and MET gene amplification in epithelial ovarian cancer (EOC). This is a retrospective cohort study, including 85 cases of EOC. CD44 and EGFR expressions were evaluated in both epithelial and stromal cells by immunohistochemistry. Tumor cells also underwent a cytogenetic analysis using fluorescent in situ hybridization (FISH) to detect MET gene amplification. High CD44 expression in tumors was significantly associated with serous subtypes (P=0.001), peritoneal deposits (P=0.002), and advanced stage (P=0.002). EGFR high tumor expression demonstrated a significant association with lymph node metastasis (P=0.038) and the advanced stage of EOC (P=0.016). Increased copy number of the MET gene was significantly associated with partial therapy response (P=0.030). CD44 and EGFR tumor high expression was associated with poor overall survival (OS). In addition, MET gene gain in tumors was associated with a shorter OS (P=0.000). EMT biomarkers (CD44 and MET) and EGFR expression in EOC are independent prognostic factors for OS. MET gene increase copy number was detected in cases of serous neoplasm and associated with poor survival and minimal therapy response.

Survival Outcomes in the Patients of Ovarian Epithelial Carcinomas Treated with Fertility-Sparing Surgery: A Study from a Developing Country

Objective: To assess the outcomes of fertility-sparing surgery in patients with ovarian epithelial carcinoma treated at our centre.&#x0D; Study Design: Retrospective longitudinal study.&#x0D; Place and Duration of Study: Shaukat Khanum Memorial Cancer Hospital &amp; Research Center, Lahore Pakistan, from Jul 2001 to Aug 2015.&#x0D; Methodology: We studied 31 patients with ovarian epithelial carcinoma who underwent fertility-sparing surgery at Shaukat Khanum Memorial Hospital. The detail regarding patients and tumour characteristics, along with outcomes of the intervention, was obtained from secondary data kept in the electronic hospital information system.&#x0D; Results: A total of 132 patients with ovarian epithelial carcinoma were identified; 31 patients underwent fertility-sparing surgery (Stage-IA, n=19; Stage-IC, n=12). By histopathology, 14(45.0%) had mucinous cystadenocarcinoma, 7(22.6%) serous adenocarcinoma, 6(19.4%) endometroid, and 4(12.9%) with clear cell pathology. The mean duration of follow-up was 52.6±2.3 months (18-118 months) after fertility-sparing surgery. Five-year recurrence-free survival was 81.0%. (Three-year=89.0%), using the Kaplan-Meier graph. Three patients had successful pregnancies, with one having a twin pregnancy.&#x0D; Conclusion: Fertility-sparing surgery should be considered for children of early-stage epithelial ovarian carcinoma patients as it preserves fertility and endocrine function while avoiding recurrence.

Whole-exome sequencing of epithelial ovarian carcinomas differing in resistance to platinum therapy.

Epithelial ovarian carcinoma (EOC) is highly fatal because of the risk of resistance to therapy and recurrence. We performed whole-exome sequencing of blood and tumor tissue pairs of 50 patients with surgically resected EOC. Compared with sensitive patients, platinum-resistant patients had a significantly higher somatic mutational rate in &lt;i&gt;TP53&lt;/i&gt; and lower in several genes from the Hippo pathway. We confirmed the pivotal role of somatic mutations in homologous recombination repair genes in platinum sensitivity and favorable prognosis of EOC patients. Implementing the germline homologous recombination repair profile significantly improved the prediction. In addition, distinct mutational signatures, for example, SBS6, and overall mutational load, somatic mutations in &lt;i&gt;PABPC1&lt;/i&gt;, &lt;i&gt;PABPC3&lt;/i&gt;, and &lt;i&gt;TFAM&lt;/i&gt; co-segregated with the resistance status, high-grade serous carcinoma subtype, or overall survival of patients. We generated germline and somatic genetic landscapes of prognostically different subgroups of EOC patients for further follow-up studies focused on utilizing the observed associations in precision oncology.

Efficacy, prognostic value of circulating tumor DNA (ctDNA) in ovarian cancer patients (122)

<b>Objectives:</b> Detection of ovarian cancer progression is crucial in improving patient prognosis. However, existing tests based on biomarker and radiological imaging are insufficient for the early detection of recurrent ovarian cancer. Blood sample-based ctDNA samples are easily obtained and can be used for disease monitoring in ovarian cancer patients undergoing primary surgery. <b>Methods:</b> Patients diagnosed with epithelial ovarian carcinoma and control patients undergoing surgery for benign ovarian mass with CA-125 above 35 were enrolled. For ctDNA analysis, 10 mL of Whole blood samples were collected before surgery and 3, 6, 9, 12 months after surgery. Library preparation and target capture were done using a commercial kit and custom target gene panel targeting nine genes (<i>ARID1A, BRCA1, BRCA2, CCNE1, KRAS, MYC, PIK3CA, PTEN,</i> and <i>TP53</i>). Next-generation sequencing (NGS) was done with the NextSeq 550Dx System (Illumina, USA). Data analysis was performed using the custom analysis pipeline (Dxome, Korea). Variants are classified into four tiers based on their clinical significance in cancer diagnosis, prognosis, and therapeutics following the standards and guidelines established by the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. We curated only tier I/II variants as a meaningful variation. <b>Results:</b> We analyzed 352 whole blood samples from 172 patients, including 93 patients with carcinoma (high or low-grade serous, mucinous, clear cell, or endometrioid) and 79 patients with the benign or borderline ovarian disease. Among 93 patients with carcinoma, 69.9% (65/93) were identified with tier I/II (pathogenic) somatic mutations (<i>TP53, BRCA1, BRCA2, ARID1A, MYC, PIK3CA, PTEN, KRAS</i>) from preoperatively collected samples at baseline. No pathogenic mutations were identified in benign/borderline tumor patients (0/79). For the genes covered by ctDNA and tissue-NGS assays, a total number of 76 tier I/II somatic mutations were detected in 42 patients' tissue samples, of which 90.8% (69/76) were also detected temporally matched whole blood samples. Of the 42 tissue samples with mutations, 92.9% (39/42) had at least one concordant genomic mutation in ctDNA analysis. Among ten patients with cancer progression, 80.0% (8/10) patients were identified with the same list of mutations as the baseline. In these eight patients, ctDNA enabled early detection of future progression by an average of 41 days (maximum of 143 days) than the conventional methods. Based on three months of follow-up ctDNA, persistently elevated group patients had a worse prognosis than other groups (zero conversion, non-detectable) (figure 1).Fig. 1 <b>Conclusions:</b> Our preliminary analysis suggests that ctDNA-based surveillance may serve an important role in detecting disease progression in ovarian cancer, providing genetic characteristics of cancer. Further applicability of ctDNA in clinical decision-making should be explored.

MUC16: The Novel Target for Tumor Therapy

黏蛋白16（mucin16, MUC16），又称癌抗原125（carbohydrate antigen 125, CA125），是1981年美国科学家Bast等从卵巢上皮癌抗原中检测出且能被单克隆抗体OC125识别的一种糖蛋白抗原。CA125在正常卵巢组织中不存在，但在卵巢上皮癌患者的血清中常见升高。CA125是卵巢上皮癌诊断和监测复发最常用的血清学生物标志物。MUC16在多种肿瘤中高表达，可以与半乳糖凝集素-1/3（galectin-1/3）、间皮素、唾液酸结合的免疫球蛋白样凝集素-9（sialic acid-binding immunoglobulin-type lectins-9, Siglec-9）等配体结合，通过多种肿瘤相关信号通路，对肿瘤发生发展、迁移侵袭及肿瘤免疫具有重要作用。靶向MUC16的治疗方式已经取得一定成效，相关临床前研究以及临床试验正在进行当中，MUC16可能是一个有潜力的肿瘤治疗新靶点。本文重点阐述MUC16在肿瘤发生发展中的作用，关注其在肿瘤治疗中的研究现状，为后续靶向MUC16的肿瘤治疗研究提供参考。

Somatic genomic landscape of East Asian epithelial ovarian carcinoma and its clinical implications from prospective clinical sequencing: A Korean Gynecologic Oncology Group study (KGOG 3047).

Through the wide adaptation of next-generation sequencing (NGS) technology within clinical practice, molecular profiling of the tumor has been the principal component of personalized treatment. In our study, we have generated a large collection of cancer genomes on East Asian epithelial ovarian carcinoma (EOC) patients and demonstrate the feasibility and utility of NGS platforms to explore the dynamic interrelations of major cancer driver alterations and their impacts on clinical prognosis and management. A total of 652 EOC patients have undergone clinical NGS panels to determine the prevalence of germline and somatic mutations. Notably, TP53 was the most frequently altered event (73%), followed by both BRCA1 and BRCA2 (22% each) and MYC (19%) through pan-EOC analysis. When analyzed based on individual histopathological levels, TP53 mutation was highly dominant in high-grade serous and mucinous histology, whereas mutations in PIK3CA and ARID1A were mostly observed in clear cell carcinoma, and KRAS, BRAF, and CDKN2A mutations were enriched in endometrioid, low-grade serous, and mucinous tumors, respectively. The network-based probabilistic model showed significant co-occurrences of TP53 with BRCA1 and ALK with BRCA2, NOTCH1, and ROS1, whereas mutual exclusivity of TP53 with KRAS and PIK3CA was evident. Furthermore, we utilized machine-learning algorithms to identify molecular correlates that conferred increased sensitivity to platinum and olaparib treatments including somatic mutations in BRCA1, ATM, and MYC. Conversely, patients with ALK mutation were considerably resistant to both treatment modalities. Collectively, our results demonstrate the clinical feasibility of prospective genetic sequencing to facilitate personalized treatment opportunities for patients with EOC.

Abstract 775: Evaluation of Erb-B2 expression from archival tumor tissue in early stage epithelial ovarian carcinoma patient prognosis

Abstract In this retrospective study, Erb-B2 expression was assessed in 106 patients using Paraffin-Embedded Tissue (PET) to determine the prognostic value in Epithelial Ovarian Carcinoma (EOC) patients diagnosed at Saskatoon Cancer Center between the years 1983-1995. Relationship between Erb-B2 positivity and patient tumor characteristics was assessed for Overall Survival (OS) and Relapse-Free Survival (RFS) by Kaplan-Meier method. Based on the intensity of stain with a polyclonal antibody (A485, 1/400 dilution), cases with markedly intense cytoplasmic and membranous immunoreactivity were classified as Erb-B2 over-expressors. Erb-B2 was overexpressed in 13 (12%) cases. The mean age of the patients was 56 years (range 18-84 years). The patient population consisted of 64 Stage I and II, Early Stage (ES) and 36 cases with Stage III and IV Advanced Stage (AS). Data on histologic grade was available in 81 cases. 58 patients received platinum-containing regimen, 13 melphalan, and in 9 cases combination chemotherapy. Erb-B2 expression did not influence OS and RFS in these patients. Similarly, there was no significant relation to OS and RFS between Erb-B2 and age, grade, and patients with No Evidence of Disease (NED). Of the 64 cases with ES disease, 16 cases had Grade 2 tumor with Erb-B2 over-expression in 4 cases. Grade 2 tumors with Erb-B2 overexpression indicated significant relationship to OS and RFS, p=0.01, (median = 30 months, CI: 26 - 68) and p=0.05, (median = 15 months, CI: 13 - 68). Furthermore, in 21 cases with ES, Endometrioid histology and Erb-B2 expressors 6/21 (28%) experienced significantly shorter OS compared to non-expressors p=0.005, (median = 48 months, CI: 22 - 74) (mean = 134 months, CI: 124 - 144). In conclusion, Erb-B2 overexpression could be detected in only limited EOC cases in PET and appears to have no prognostic influence. Additionally, endometrioid carcinoma and grade 2, ES certainly reflect the importance of sub-group analysis. In ovarian carcinoma distribution of stage, histology, and grading of tumor cells are conventional markers for prognosis. Finally, Erb-B2 status detected by immunohistochemistry, in a subgroup of patients with high-degree of HER2 positivity/focal amplification may likely have better clinical outcome with anti-HER2 agents. Citation Format: Kavitha Advikolanu Rao, Anthony Magliocco, Andrew Maksymiuk. Evaluation of Erb-B2 expression from archival tumor tissue in early stage epithelial ovarian carcinoma patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 775.

The Association between Human Epididymis Secretory Protein 4 and Metabolic Syndrome.

Individuals with metabolic syndrome (MetS) are known to have an increased risk of carcinogenesis. Human epididymis protein 4 (HE4) is a tumor marker and prognostic factor for epithelial ovarian carcinoma (EOC) patients. However, no studies have evaluated the association between MetS and HE4 levels. This study aimed to evaluate the relationship between HE4 levels and MetS in the National Health and Nutrition Examination Survey (NHANES 2001–2002). This cross-sectional analysis assessed all five components of MetS and HE4 levels in 2104 females (age ≥20 years) from the NHANES dataset. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria. The analysis indicated MetS in 593 individuals, and the β coefficient of their HE4 levels was 0.097 (95% CIs, 0.028–0.166, p = 0.006). Specifically, the β coefficients of the HE4 levels of participants with 1, 2, 3, and ≥4 features of MetS were 0.072 (95% confidence interval (CI): −0.015–0.159), 0.125 (95% CI: 0.030–0.220), 0.161 (95% CI: 0.053–0.270), and 0.242 (95% CI: 0.117–0.368), respectively, and all p values were <0.001. The p-value for the trend was <0.001. There was a significant association between the presence of MetS and HE4 levels. There were positive relationships between HE4 levels and an increased number of MetS components (with 1, 2, 3, and ≥4 features of MetS, all p values <0.001). Among the MetS components, low high-density lipoprotein levels and high triglyceride levels were independently associated with HE4 levels.

[Establishment and application of a nomogram model for prognostic risk prediction in patients with epithelial ovarian cancer].

Objective: To explore the prognostic factors of epithelial ovarian carcinoma (EOC), construct a nomogram model, and evaluate the prognosis of EOC patients. Methods: A retrospective analysis was performed on clinicopathological data of 208 cases of EOC patients who received initial treatment in the First Affiliated Hospital of Army Medical University from August 11, 2016 to July 11, 2018, including age, preoperative ascites, preoperative neoadjuvant chemotherapy, surgical method, pathological type, pathological differentiation degree, surgical pathology stage, preoperative and post-chemotherapy serum cancer antigen 125 (CA125) level, human epididymal protein 4 (HE4) level, platelet count and platelet/lymphocyte number ratio (PLR). The univariate and multivariate Cox risk ratio models were used to analyze the related factors affecting progression free survival (PFS) in EOC patients, and the prediction nomogram of PFS in EOC patients was established to evaluate its efficacy in predicting PFS. Results: Univariate analysis showed that preoperative neoadjuvant chemotherapy, pathological type, pathological differentiation degree, surgical pathology stage, serum CA125 and HE4 level before operation and after chemotherapy, platelet count and PLR before operation and after chemotherapy were significantly correlated with PFS in EOC patients (all P<0.05). Multivariate analysis showed that surgical pathology stage, preoperative PLR, serum CA125 and HE4 level after chemotherapy were independent prognostic factors affecting PFS of EOC patients (all P<0.01). The index coefficient of the prediction model for the prognosis of EOC patients established by this method was 0.749 (95% CI: 0.699-0.798), which had good prediction ability, and could help clinicians to more accurately evaluate the prognosis of EOC patients. Conclusion: The nomogram model constructed based on surgical pathology stage, preoperative PLR, serum CA125 and HE4 level after chemotherapy could effectively predict the PFS of EOC patients after initial treatment, could help clinicians to screen high-risk patients, provide individualized treatment, and improve the prognosis of EOC patients.

Tumor BRCA Testing in Epithelial Ovarian Cancers: Past and Future-Five-Years' Single-Institution Experience of 762 Consecutive Patients.

Simple SummaryTumor BRCA testing is crucial in the clinical management of women affected by epithelial ovarian cancer (EOC). In the present study, we aimed to report the results of five years of experience in tumor BRCA testing performed in a single-institution diagnostic setting. We profiled 762 consecutive EOC patients with a failure rate of less than 1% and less than two weeks of turnaround time, which is consistent with the clinical needs. We identified 23.4% of cases with pathogenic/likely pathogenic mutations, including 76% of patients affected by germline and 24% by somatic alterations. Here, we proposed a comprehensive and multidisciplinary clinical workflow that could be successfully followed for the identification of somatic as well as germline alterations, maximizing the benefit of BRCA testing both from a therapeutic and risk assessment perspective.The establishment of PARP inhibitors in the treatment of epithelial ovarian carcinoma (EOC) has prompt BRCA assessment at the time of diagnosis. We described our five years of experience of tumor BRCA testing, as part of a multidisciplinary workflow for the management of EOC patients. We used a BRCA next-generation sequencing (NGS) test for profiling formalin-fixed, paraffin-embedded (FFPE) EOCs of 762 consecutive patients, with a success rate of 99.7% and a median turnaround time of 12 days. We found 178 (23.4%) cases with pathogenic/likely pathogenic (P/LP) mutations, 74 (9.7%) cases with variants of uncertain significance and 508 (66.8%) wild type tumors. Among 174 patients without P/LP mutations and investigated with multiple-ligation probe-amplification analysis on peripheral blood, two (1.1%) were positive for large rearrangements. Patients with P/LP alterations and/or with positive family history were referred to genetic counselling. Comparing tumor and blood NGS test results of 256 patients, we obtained a tumor test negative predictive value of 100% and we defined 76% of P/LP alterations as germline and 24% as somatic variants. The proposed workflow may successfully identify EOC patients with BRCA1/2 alteration, guiding both therapeutic and risk assessment clinical decisions.

FOXA1 can be modulated by HDAC3 in the progression of epithelial ovarian carcinoma

FOXA1 is associated with malignant tumors, but the function of FOXA1 in EOC is unclear. HDAC3 can influence the proliferation, migration and invasion ability of EOC. In this study, we wanted to explore the function of FOXA1 in ovarian cancer and the relationship between HDAC3 and FOXA1.The expression of HDAC3 and FOXA1 was detected by immunohistochemical staining of primary lesions from 127 epithelial ovarian carcinoma patients. A proliferation assay, a Transwell assay, an apoptosis assay and animal experiments were used to assess the proliferation, invasion and apoptosis abilities of ovarian cancer cells before and after transfection with FOXA1. The relevance of the in vitro findings was confirmed in xenografts. The H-scores for FOXA1 and HDAC3 staining in FIGO stage III-IV were noticeably higher and predicted adverse clinical outcomes in patients with ovarian cancer. The expression level of HDAC3 was significantly correlated with the expression level of FOXA1. Invasion, proliferation and apoptosis capacity and tumor formation were decreased in the FOXA1-knockdown cells. Experiments in xenografts confirmed that HDAC3 mediated tumor formation. In conclusion, FOXA1 can be modulated by HDAC3 through the Wnt/β-catenin signaling pathway, and FOXA1 plays essential roles in the proliferation, apoptosis and invasion of EOC cell lines and xenograft experiments.

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

Exploration of Potential Diagnostic Value of Protein Content in Serum Small Extracellular Vesicles for Early-Stage Epithelial Ovarian Carcinoma.

Epithelial ovarian carcinoma (EOC) is one of the most common gynecologic malignancies with a high mortality rate. Serum biomarkers and imaging approaches are insufficient in identifying EOC patients at an early stage. This study is to set up a combination of proteins from serum small extracellular vesicles (sEVs) for the diagnosis of early-stage EOC and to determine its performance. A biomarker for early-stage ovarian cancer (BESOC) cohort was used as a Chinese multi-center population-based biomarker study and registered as a Chinese Clinical Trial ChiCTR2000040136. The sEV protein levels of CA125, HE4, and C5a were measured in 299 subjects. Logistic regression was exploited to calculate the odds ratio and to create the sEV protein model for the predicted probability and subsequently receiver-operating characteristic (ROC) analysis. The combined sEV marker panel of CA125, HE4, and C5a as a sEV model obtained an area under curve (AUC) of 0.912, which was greater than the serum model (0.809), by ROC analysis to identify EOC patients from the whole cohort. With the cutoff of 0.370, the sensitivity and specificity of the sEV model were 0.80 and 0.89, which were much better performance than the serum markers (sensitivity: 0.55~0.66; specificity: 0.59~0.68) and the risk of ovarian malignancy algorithm (ROMA) index approved by the U.S. Food and Drug Administration (sensitivity: 0.65; specificity: 0.61), to identify EOC patients from patients with benign ovarian diseases or other controls. The sEV levels of CA125 significantly differed among early-stage and late-stage EOC (p < 0.001). Moreover, the AUC of ROC to identify early-stage EOC patients was 0.888. Further investigation revealed that the sEV levels of these 3 proteins significantly decreased after cytoreductive surgery (CA125, p = 0.008; HE4, p = 0.025; C5a, p = 0.044). In summary, our study showed that CA125, HE4, and C5a levels in serum sEVs can identify EOC patients at the early stage, elucidating the possibility of using a sEV model for the diagnosis of early-stage EOC.

Somatic mutations of DNA damage repair (DDR) genes in patients with epithelial ovarian cancer

Objectives: Gene mutations are proved to be associated in epithelial ovarian cancer. The majority of researches focus on BRCA1/2 in ovarian serous carcinoma. The incidence of ovarian clear cell carcinoma and endometrioid carcinoma are estimated to be 15% respectively in East Asia, especially in Japan and Taiwan, which is far more prevalent than in the Western countries. However, the somatic gene mutations of DNA damage repair genes in ovarian clear cell carcinoma and endometrioid carcinoma is unclear. Methods: We investigated the somatic mutations of epithelial ovarian cancer patients using a panel containing DNA damage repair genes by next generation sequencing method. Totally 172 epithelial ovarian carcinoma patients, including 69 serous carcinoma, 39 endometrioid carcinoma and 64 clear cell carcinoma, were enrolled. Results: Totally 78 patients with DDR somatic gene mutations were noted, including 48 (69.6%) in serous carcinoma, 13 (33.3%) in endometrioid carcinoma and 17 (26.6%) in clear cell carcinoma. In 69 serous carcinoma patients, gene mutations were 39 TP53 (56.5%), 4 BRCA2 (5.8%), 4 RAD51C (5.8%), 3 MUTYH (4.3%), 3 ERCC8 (4.3%), 1 BRCA1 (1.4%), 1 BRIP1 (1.4%), 1 FANCG (1.4%), 1 RAD51D (1.4%), 1 MLH3 (1.4%), 1 MSH6 (1.4%), 1 OGG1 (1.4%), 1 XRCC6 (1.4%) and 1 ATM (1.4%). In 39 endometrioid carcinoma, gene mutations were 6 TP53 (15.4%), 5 ATM (12.8%), 3 MSH2 (7.7%), 2 MUTYH (5.1%), 2 MLH3 (5.1%), 2 RAD50 (5.1%), 1 BRCA2 (2.6%), 1 MSH6 (2.6%), 1 FANCC (2.6%), 1 FANCM (2.6%), 1 MRE11 (2.6%), 1 MLH1 (2.6%) and 1 MSH3 (2.6%). In 64 clear cell carcinoma, gene mutations were 6 MUTYH (9.4%), 3 TP53 (4.7%), 2 BRCA2 (3.1%), 2 ERCC8 (3.1%), 1 BRCA1 (1.6%), 1 FANCI (1.6%), 1 RAD50 (1.6%), 1 MLH1 (1.6%), 1 MLH3 (1.6%), 1 MSH6 (1.6%), 1 XRCC4 (1.6%), 1 POLD1 (1.6%), 1 CHEK2 (1.6%) and 1 BARD1 (1.6%). In homologous recombination repair genes, the percentage of somatic mutations was 15.9%, 7.7% and 6.3% for serous, endometrioid and clear cell carcinoma (p=0.154, chi-square test). In mismatch repair genes, the percentage of somatic mutations was 2.9%, 15.4% and 4.7% for serous, endometrioid and clear cell carcinoma respectively (p=0.003, chi-square test). In double strand break repair genes, the percentage of somatic mutations was 17.4%, 7.7% and 6.3% for serous, endometrioid and clear cell carcinoma (p=0.092, chi-square test). In single strand break repair genes, the percentage of somatic mutations was 13.0%, 20.5% and 15.6% for serous, endometrioid and clear cell carcinoma (p=0.591, chi-square test). In cell cycle regulation genes, the percentage of somatic mutations was 58.0%, 23.1% and 6.3% for serous, endometrioid and clear cell carcinoma (p Conclusions: The pattern of somatic gene mutations of DNA damage repair genes differs in the serous, endometrioid and clear cell carcinoma patients. Our findings could provide the basis of precision medicine strategy for ovarian cancer treatment.