Advanced Serous Ovarian Carcinoma Research Articles

Role of Fyn expression in predicting the sensitivity to platinum‑based chemotherapy in patients with ovarian serous carcinoma.

Ovarian serous carcinoma is a gynecological malignancy associated with a high mortality rate, which is commonly diagnosed in the first instance at a late stage and has a propensity to develop resistance to platinum-based chemotherapy. Identifying reliable biomarkers for platinum sensitivity is critical for improving patient outcomes. The present retrospective study included 64 patients with high-grade serous ovarian carcinoma (Federation of Gynecology and Obstetrics stages III or IV). Patients were classified as platinum-sensitive (no relapse within 6 months of the last platinum administration) or platinum-resistant (relapse within 6 months). Immunohistochemical analysis was performed to evaluate Fyn expression in tumor tissues, and Fyn knockdown experiments were performed using the OVSAHO ovarian cancer cell line to assess carboplatin sensitivity. Fyn expression was significantly higher in platinum-resistant patients compared with in platinum-sensitive patients (P<0.01). A weighted Fyn expression score was developed and a cutoff score of 6 was determined to predict platinum sensitivity with a specificity of 65.5% and a sensitivity of 62.9%. Patients with low Fyn expression (score ≤6) exhibited higher platinum sensitivity and longer overall survival (P<0.05). Multivariate analysis identified Fyn expression and postoperative residual tumor size as independent predictors of platinum sensitivity (P=0.033 and P=0.023, respectively). In vitro, Fyn knockdown significantly increased carboplatin sensitivity in ovarian cancer cells (P<0.05). Fyn, a member of the Src family of kinases, serves a crucial role in various cellular functions and has been implicated in chemotherapy resistance. The results demonstrated a notable association between Fyn expression and platinum sensitivity in ovarian serous carcinoma. The findings suggested that Fyn may serve as a predictive biomarker for response to platinum-based chemotherapy, offering the potential for more personalized treatment strategies. To the best of our knowledge, the present study is the first to establish an association between Fyn expression and platinum sensitivity in advanced ovarian serous carcinoma. Prospective studies with larger, multi-center cohorts and comprehensive biomarker analyses are recommended to validate and extend these results, ultimately improving therapeutic strategies and patient prognosis.

Immunohistochemical Profiling of PD-1, PD-L1, CD8, MSI, and p53 and Prognostic Implications in Advanced Serous Ovarian Carcinoma: A Retrospective Study.

Advanced high-grade serous ovarian carcinoma is a serious malignant neoplasm with a late diagnosis and high mortality rate. Even when treated with standard therapy, such as surgery followed by carboplatin and paclitaxel chemotherapy, the prognosis remains unfavorable. Immunotherapy is a treatment alternative that requires further study. Therefore, we aimed to evaluate the expression of PD-1, PD-L1, CD8, MSI (MLH1, MSH2, MSH6, and PMS2), and p53 in the paraffin samples of high-grade serous ovarian carcinoma. A retrospective study of 28 southern Brazilian patients with advanced serous ovarian carcinoma (EC III or IV) was conducted between 2009 and 2020. The expression of these proteins was evaluated using immunohistochemistry, and the results were correlated with the patients' clinicopathological data. At diagnosis, the mean age was 61 years, and the most common clinical stage (60%) was EC III. Among the cases, 84.6% exhibited p53 overexpression, 14.8% had MSI, 92.0% were sensitive to platinum, and more than 50.0% relapsed after treatment. Patients with MSI had a lower CD8/PD-1 ratio and more relapses (p = 0.03). In conclusion, analysis of immunotherapeutic markers in paraffin-embedded advanced serous ovarian carcinoma samples is feasible and may assist in prognosis.

Mutational landscape of low-grade serous carcinoma of the ovary.

5578 Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that are potential therapeutic targets. We present an analysis of comprehensive genomic profiling (CGP) of a large series of low grade serous ovarian carcinoma patients assayed in a nationwide cancer network. Methods: 40 Pts with advanced low grade serous ovarian carcinoma (LGSOC) underwent hybrid-capture based CGP for up to 324 cancer-related genes on archival tumor tissue or 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 thru 06-2021. Clinically relevant genomic alterations (CRGA) were defined as associated with targeted therapies or mechanism-driven clinical trials. The treatment histories for these patients were obtained with IRB-approved retrospective review. Results: Median age was 44 years (range, 25-65), 68% were White and 23% were Black. Genomic alterations (GA) were identified in 80% (32/40) of LGSOC, of which 22 (55%) had a clinically relevant genomic alteration (CRGA). There were no apparent racial differences between mutation frequencies. The table below details the frequency of the most common of these clinically relevant mutations. Additionally, 1 patient had an ESR1 activating mutation commonly seen in acquired hormone therapy resistance in breast cancer; and single cases of the following mutations were also noted: TSC1, PTCH1, PTEN, FGFR1, and AKT2. Conclusions: In a large series of Low Grade Serous Ovarian Cancer patients assayed with CGP, 55% of pts had mutations potentially targeted by precision medicine therapy. The most common target is KRAS, seen in 33% of patients, these are potentially treatable with FAK and MEK inhibitors. Another 10% of patients had either a BRCA or ATM mutations making PARP inhibitor therapy an additional targeted treatment option. While mutations in the RAS pathway are most common in LGSOC they are not the only actionable target. Furthermore, this approach might also help identify baseline or acquired resistance to the hormone therapies often used to treat this cancer. The results of this study demonstrate the significant heterogeneity of genomic alterations in this rare cancer and highlight the importance of genomic profiling in this cancer which has a marked propensity for recurrence. [Table: see text]

Clinical significance of metabolism-related genes and FAK activity in ovarian high-grade serous carcinoma

BackgroundAdministration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC).MethodsThe RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed (https://portal.gdc.cancer.gov/). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant.ResultsIn the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307).ConclusionIn the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis.

Survival benefits of retroperitoneal lymphadenectomy for optimally-resected advanced ovarian high-grade serous carcinoma: a multi-institutional retrospective study.

ObjectiveThe survival benefits of retroperitoneal lymphadenectomy (RLNA) for epithelial ovarian cancer (EOC) remain controversial because clinical behaviors differ among subtypes. The purpose of the present study was to clarify whether RLNA increases the survival rate of advanced high-grade serous carcinoma (HGSC).MethodsThis was a retrospective cohort analysis of 3,227 patients with EOC treated between 1986 and 2017 at 14 institutions. Among them, 335 patients with stage IIB-IV HGSC who underwent optimal cytoreduction (residual tumor of <1 cm) were included. Patients were divided into the RLNA group (n=170) and non-RLNA group (n=165). All pathological slides were assessed based on a central pathological review. Oncologic outcomes were compared between the two groups in the original and weighted cohorts adjusted with the inverse probability of treatment weighting.ResultsThe median observation period was 49.8 (0.5–241.5) months. Overall, 219 (65%) out of 335 patients had recurrence or progression, while 146 (44%) died of the disease. In the original cohort, RLNA was a significant prognostic factor for longer progression-free survival (PFS) (hazard ratio [HR]=0.741; 95% confidence interval [CI]=0.558–0.985) and overall survival (OS) (HR=0.652; 95% CI=0.459–0.927). In the weighted cohort in which all variables were well balanced as standardized differences decreased, RLNA was also a significant prognostic factor for more favorable oncologic outcomes (PFS, adjusted HR=0.742; 95% CI=0.613–0.899) and OS, adjusted HR=0.620; 95% CI=0.488–0.787).ConclusionThe present study demonstrated that RLNA for stage III-IV HGSC with no residual tumor after primary debulking surgery contributed to better oncologic outcomes.

Bioinformatic Analysis for Influential Core Gene Identification and Prognostic Significance in Advanced Serous Ovarian Carcinoma.

Background and objectives: Ovarian cancer is one of the leading causes of death among women worldwide. Most newly diagnosed ovarian cancer patients are diagnosed in advanced stages of the disease. Despite various treatments, most patients with advanced stage ovarian cancer, including serous ovarian cancer (the most common subtype of ovarian cancer), experience recurrence, which is associated with extremely poor prognoses. In the present study, we aimed to identify core genes involved in ovarian cancer and their associated molecular mechanisms, as well as to investigate related clinicopathological implications in ovarian cancer. Materials and methods: Three gene expression cohorts (GSE14407, GSE36668, and GSE38666) were obtained from the Gene Expression Omnibus databases to explore potential therapeutic biomarkers for ovarian cancer. Nine up-regulated and six down-regulated genes were screened. Three publicly available gene expression datasets (GSE14407, GSE36668, and GSE38666) were analyzed. Results: A total of 14 differently expressed genes (DEGs) were identified, among which nine genes were upregulated (BIRC5, CDCA3, CENPF, KIF4A, NCAPG, RRM2, UBE2C, VEGFA, and NR2F6) and were found to be significantly enriched in cell cycle regulation by gene ontology analysis. Further protein–protein interaction network analysis revealed seven hub genes among these DEGs. Moreover, Kaplan–Meier survival analysis showed that a higher expression of CDCA3 and UBE2C was associated with poor overall patient survival regardless of tumor stage and a higher tumor histologic grade. Conclusion: Altogether, our study suggests that CDCA3 and UBE2C may be valuable biomarkers for predicting the outcome of patients with advanced serous ovarian cancer.

Neutrophil-to-lymphocyte ratio is associated with sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

The role of the neutrophil-to-lymphocyte ratio (NLR) in predicting sensitivity to chemotherapy and prognosis has attracted great interest in several types of cancer. In the present study, the correlation between pre-chemotherapy NLR and sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma was examined by retrospectively reviewing the medical records of 50 patients with stage III-IV serous ovarian carcinoma from 2005 to 2012. Patients were divided into high-NLR (32 patients) and low-NLR (18 patients) groups according to a cutoff value of 2.47. This cutoff was calculated using a receiver operating characteristic (ROC) curve that demonstrated 84% specificity and 60% sensitivity. Patient characteristics, sensitivity to platinum-based chemotherapy and prognosis were subsequently compared. The results revealed no significant difference in patient characteristics between the two groups. In the low-NLR group, 14 of 18 patients (77.8%) were sensitive to platinum-based chemotherapy, whereas 11 of 32 were sensitive in the high-NLR group (34.4%) (P=0.007). Overall and disease-free survival (DFS) were significantly longer in the low-NLR than in the high-NLR group (P=0.013 and P=0.043, respectively). The current results suggested that pre-chemotherapeutical NLR may serve as a biomarker of sensitivity to platinum-based chemotherapy and prognosis in patients with advanced serous ovarian carcinoma.

Up-regulation of HDAC6 Results in Poor Prognosis and Chemoresistance in Patients With Advanced Ovarian High-grade Serous Carcinoma.

Ovarian high-grade serous carcinoma (HGSC) gradually acquires chemoresistance after recurrence. Our previous study on ovarian clear-cell carcinoma found histone deacetylase 6 (HDAC6) overexpression led to chemoresistance. This study aimed to evaluate HDAC6 as a predictor of chemoresistance and a therapeutic target for ovarian HGSC. The clinical significance of HDAC6 as a predictor of prognosis and chemoresistance in HGSC was immunohistochemically evaluated. In addition, expression of programmed cell death ligand-1 (PD-L1), and hypoxia-inducible factor-1α (HIF1α) were analyzed using clinical samples from 88 patients with ovarian HGSC, and their clinicopathological characteristics were reviewed. Twenty-three patients had high HDAC6 expression, 10 positive PD-L1 expression, and 33 high HIF-1α expression. HDAC6 up-regulation was correlated with not undergoing interval debulking surgery (p<0.001), incomplete surgical resection (p=0.002), and frequent occurrence of stable disease/progressive disease according to the Response Evaluation Criteria in Solid Tumors (p=0.005) criteria. On Kaplan-Meier analysis, high HDAC6 expression was significantly associated with reduced progression-free (p=0.001) and overall (p=0.008) survival. On multivariate analysis, high HDAC6 expression (hazard ratio=1.65, 95% confidence interval 1.03-2.66; p=0.039) and surgery status were independent prognostic factors of progression-free survival. PD-L1 and HIF1α expression positively correlated with that of HDAC6. HDAC6 may become a potential therapeutic target in patients with ovarian HGSC since its up-regulation is considered to be associated with a poor prognosis in patients with this cancer.

Differences between primary peritoneal serous carcinoma and advanced serous ovarian carcinoma: a study based on the SEER database

ObjectiveThis study aimed to compare clinical features and overall survival (OS) between patients with primary peritoneal serous carcinoma (PPSC) and those with advanced serous ovarian carcinoma (ASOC) and to identify prognostic factors.MethodsPatients diagnosed with PPSC and ASOC from 2010 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were enrolled. Pearson’s chi-square test was used to compare clinical features. The primary endpoint was OS. The Kaplan–Meier method and log–rank test were used to perform the survival analysis. Propensity score matching was also conducted. Univariate, multivariate and subgroup analyses were performed using the Cox proportional hazards model.ResultsA total of 708 PPSC patients and 7610 ASOC patients were enrolled. The clinical features of PPSC patients were noticeably different from those of ASOC patients. The survival analysis showed that PPSC patients had poorer outcomes than ASOC patients. Even after the clinical features were balanced, PPSC patients still had poorer survival. Univariate and multivariate analyses indicated that older age, higher tumor grade and advanced American Joint Committee on Cancer stage were adverse prognostic factors in both groups, while surgery and chemotherapy were protective factors. A subgroup analysis demonstrated that most factors favored ASOC patients. The total distant metastasis rates of PPSC and ASOC were similar. Liver or lung metastasis was common, but bone and brain metastases were rare. A higher proportion of liver metastasis was observed in the ASOC group.ConclusionThe clinical features and survival outcomes between PPSC patients and ASOC patients are clearly different, and PPSC is more aggressive than ASOC.

A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma

BackgroundMost ovarian cancer patients are diagnosed at a late stage with 85% of them relapsing after surgery and standard chemotherapy; for this reason, new treatments are urgently needed. Ovarian cancer has become a candidate for immunotherapy by reason of their expression of shared tumor-associated antigens (TAAs) and private mutated neoantigens (NeoAgs) and the recognition of the tumor by the immune system. Additionally, the presence of intraepithelial tumor infiltrating lymphocytes (TILs) is associated with improved progression-free and overall survival of patients with ovarian cancer. The aim of active immunotherapy, including vaccination, is to generate a new anti-tumor response and amplify an existing immune response. Recently developed NeoAgs-based cancer vaccines have the advantage of being more tumor specific, reducing the potential for immunological tolerance, and inducing robust immunogenicity.MethodsWe propose a randomized phase I/II study in patients with advanced ovarian cancer to compare the immunogenicity and to assess safety and feasibility of two personalized DC vaccines. After standard of care surgery and chemotherapy, patients will receive either a novel vaccine consisting of autologous DCs pulsed with up to ten peptides (PEP-DC), selected using an agnostic, yet personalized, epitope discovery algorithm, or a sequential combination of a DC vaccine loaded with autologous oxidized tumor lysate (OC-DC) prior to an equivalent PEP-DC vaccine. All vaccines will be administered in combination with low-dose cyclophosphamide. This study is the first attempt to compare the two approaches and to use NeoAgs-based vaccines in ovarian cancer in the adjuvant setting.DiscussionThe proposed treatment takes advantage of the beneficial effects of pre-treatment with OC-DC prior to PEP-DC vaccination, prompting immune response induction against a wide range of patient-specific antigens, and amplification of pre-existing NeoAgs-specific T cell clones.Trial registration This trial is already approved by Swissmedic (Ref.: 2019TpP1004) and will be registered at http://www.clinicaltrials.gov before enrollment opens.

Pathological Chemotherapy Response Score in Patients Affected by High Grade Serous Ovarian Carcinoma: The Prognostic Role of Omental and Ovarian Residual Disease.

Background: The chemotherapy response score (CRS) has emerged as a simple and reproducible histopathological grading system for assessing chemotherapy response in patients affected by ovarian high-grade serous carcinoma.Objective: To evaluate the prognostic impact of histological tumor response in ovarian and omental surgical specimens from patients with advanced stage ovarian high-grade serous carcinoma.Study Design: A cohort of 161 women were identified from the database of Department of Gynecology, “Fondazione Policlinico Universitario Agostino Gemelli IRCCS” of Rome, Italy between January 2014 and December 2017 with a follow-up of 65 months. All the omentum, the ovarian tissue and peritoneal samples, defined as “other sites,” were reviewed by gynecological pathologists to assign a CRS of 1–3 to the omentum and ovarian sites and a score of 0–1 to the peritoneal tissue. The Cox proportional hazards regression and the log-rank test were used to assess the survival pattern and the prognostic value of the CRS adjusting for age and stage. The Kaplan-Meier method was applied to estimate the progression free and overall survival.Results: The evaluation of adnexal disease showed significant differences in PFS, both in univariate and in multivariate analyses. On PFS univariate analysis, ovCRS1 vs. ovCRS3: HR, 2.27; 95% CI, 1.37–3.77; p = 0.001; ovCRS2 vs. ovCRS3: HR, 1.83; 95% CI, 1.03–3.23; p = 0.04, and on PFS multivariate model ovCRS1 vs. ovCRS3; HR, 2.53; 95% CI, 1.5–4.24; p = 0.001 and ovCRS2 vs. ovCRS3; HR, 1.90; 95% CI, 1.08–3.37; p = 0.03. Regarding the omental residual disease, as expected, CRS showed a significant prognostic value for OS and PFS; in detail the median PFS of patients with CRS1, 2 and 3 was 15, 15, and 22 months, respectively, the median OS was 41 and >50 months, respectively. Moreover, the univariate analysis for OS suggested that in our cohort the “other sites” score of 0 was significantly associated with an improvement in overall survival compared to score 1.Conclusions: We demonstrated for the first time the prognostic significance of adnexal CRS confirming also the prognostic role of omental CRS.

Study on the expression and meaning of FBXW7 and ENO1 in high and low grade serous ovarian adenocarcinoma tissue

Objective To investigate the expression and significance of FBXW7 and ENO1 in ovarian serous adenocarcinoma of different grades. Methods Immunohistochemistry was used to study the expression of FBXW7 and ENO1 in 60 cases of ovarian serous adenocarcinoma.The relationship between FBXW7 and ENO1 proteins and the prognosis of ovarian serous adenocarcinoma was analyzed. Results The positive rate of FBXW7 expression was 22.5% (9/40) in 40 cases of ovarian high grade adenocarcinoma and 10 cases in 15 cases of normal oviduct.The positive rate of FBXW7 expression was 66.7% (10/15), and the difference was statistically significant (P=0.003). The expression of FBXW7 in 20 cases of low grade adenocarcinoma was 5 cases, and the positive rate was 25.0%(5/20). In 15 cases of normal ovarian tissue, 9 cases were positive, and the positive rate was 60.0%(9/15). The difference was statistically significant (P=0.04). The expression of ENO1 protein was 27 in 40 cases of high grade adenocarcinoma, and the positive rate of expression was 67.5%(27/40).5 cases were positive in 15 normal fallopian tubes, and the positive rate was 33.3%(5/15). The difference was statistically significant (P=0.024). The expression of ENO1 protein was 15 in 20 cases of low grade adenocarcinoma, and the positive rate of expression was 75.0%(15/20). In 15 cases of normal ovarian tissue, 4 cases were positive, and the positive rate was 26.7%(4/15). The difference was statistically significant (P=0.006). There was no correlation between the low expression of FBXW7 and the high expression of ENO1 in high grade ovarian adenocarcinoma (P=0.199), but there was a significant correlation between the low expression of FBXW7 and the high expression of ENO1 in low grade ovarian adenocarcinoma (P<0.05). In low grade serous adenocarcinoma, the 5-year survival rates were 44.4% and 32.1% respectively, with no significant difference (P=0.052). In ovarian high-grade serous adenocarcinoma, the 5-year survival rates of high-expression group and low-expression group were 20.0% and 7.7%, respectively, with no significant difference (P=0.097). In low grade ovarian serous adenocarcinoma, the 5-year survival rate was 7.4% in high expression group and 50.0% in low expression group (P=0.023). The 5-year survival rates of ENO1 in high-grade serous adenocarcinoma were 0% and 40.0% in high-expression group and low-expression group respectively (P=0.001). Conclusion The low expression of FBXW7 in ovarian adenocarcinoma suggests that FBXW7 may be a tumor suppressor gene in ovarian serous adenocarcinoma, and ENO1 may be an oncogene in ovarian adenocarcinoma.The high expression of FBXW7 in serous adenocarcinoma indicates that ENO1 may be an oncogene, and the survival rate of FBXW7 in serous adenocarcinoma is higher than that in low expression group.The survival rate of the high-expression group was lower than that of the low-expression group.Therefore, they may become a new diagnostic index and therapeutic target for ovarian serous adenocarcinoma. Key words: FBXW7; ENO1; Advanced ovarian serous carcinoma; Ovaroian low-level serous carcinoma; Immunohistochemistry method

Expressions and clinical significances of paired box gene 2 and cyclin D1 in advanced ovarian serous carcinoma

Objective: To investigate the expressions and clinical significances of paired box gene 2 (Pax2) and cyclin D1 protein in advanced ovarian serous carcinoma. Methods: From January 2003 to December 2013, the pathologic tissues of 202 patients with advanced ovarian serous cancer (Ⅲ-Ⅳ) who underwent initial cytoreductive surgery were collected. The expressions of Pax2 and cyclin D1 protein were detected by immunohistochemistry in tissue microarray. The relationships of their expressions with the clinicopathological features and prognosis of the patients were analyzed. Results: The positive rate of Pax2 protein expression of the 202 patients with ovarian serous adenocarcinoma was 24.8% (50/202) and that of cyclin D1 was 25.2% (51/202). The expressions of Pax2 and cyclin D1 were not significantly related with age, clinical stage and pathological grade of ovarian serous adenocarcinoma patients (P>0.05). The median overall survival (OS) time of Pax2-negative patients was 53 months and the progression-free survival (PFS) time was 29 months. The median OS time of Pax2-positive patients was 66 months and PFS time was 33 months, the OS of Pax2-negative patients was significant different from that of Pax2-positive patients (χ(2)=4.06, P=0.04). The median PFS time of Pax2-negative patients was not significant different from that of Pax2-positive patients (χ(2)=2.43, P=0.11). The median OS time of cyclin D1-negative patients was 62 months and PFS time was 30 months. The median OS time of cyclin D1-positive patients was 48 months and PFS time was 22 months. The median OS time of cyclin D1-negative patients was significantly different from that of cyclin D1-positive patients (χ(2)=4.71, P=0.03), while the median PFS time of cyclin D1-negative patients was marginally different from that of cyclin D1-positive patients (χ(2)=0.59, P=0.41). Multivariate analysis showed that the expression of Pax2 was an independent factor of the prognosis for patients with ovarian serous adenocarcinoma (RR=0.597, 95% CI 0.371-0.962, P<0.034). Conclusion: The expressions of Pax2 and cyclin D1 are associated with the prognosis of patients with advanced ovarian serous adenocarcinoma while Pax2 is an independent prognostic factor.

Primary and recurrent ovarian high-grade serous carcinomas display similar microRNA expression patterns relative to those of normal ovarian tissue.

Most patients with epithelial ovarian cancer eventually die due to recurrence. However, little is known about the microRNA (miRNA) expression pattern and its involvement in recurrent ovarian cancer. We analyzed miRNA expression profiles related to the recurrence of advanced ovarian high-grade serous carcinoma (HGSC) using miRNA microarrays. Between May 2006 and December 2012, 37 ovarian HGSC patients underwent secondary cyto-debulking surgery at recurrence. Among them, only 8 pairs of primary and recurrent tumor samples were deemed to be adequate for analysis. The expression profiles of primary ovarian HGSC compared with normal ovarian tissue were significantly consistent with those of recurrent ovarian HGSC compared with normal ovarian tissue (correlation coefficient = 0.81, P = 0.0078). Among 31 miRNAs that increased by more than 4-fold in primary tumors compared with normal ovarian tissue, 27 were also significantly increased in recurrent tumor samples. Likewise, among 35 miRNAs that decreased by more than 4-fold in primary tumors compared with normal ovarian tissue, 34 were also significantly decreased in recurrent tumor samples. We identified 60 miRNAs that were significantly increased in recurrent serous ovarian carcinoma compared with primary tumor tissue, including miR-630, miR-370, and miR-575. Additionally, 52 miRNAs were significantly decreased in recurrent samples, including miR-509-3p, miR-514a-3p, and miR-506-3p. Our results demonstrate that primary and recurrent ovarian HGSC displayed similar miRNA expression patterns. Nevertheless, altered miRNA expression could be implicated in the recurrence of ovarian HGSC, and further study is needed to validate these data in independent cases using a homogeneous methodology.

Predicting Ovarian Cancer Patients' Clinical Response to Platinum-Based Chemotherapy by Their Tumor Proteomic Signatures.

Ovarian cancer is the deadliest gynecologic malignancy in the United States with most patients diagnosed in the advanced stage of the disease. Platinum-based antineoplastic therapeutics is indispensable to treating advanced ovarian serous carcinoma. However, patients have heterogeneous responses to platinum drugs, and it is difficult to predict these interindividual differences before administering medication. In this study, we investigated the tumor proteomic profiles and clinical characteristics of 130 ovarian serous carcinoma patients analyzed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), predicted the platinum drug response using supervised machine learning methods, and evaluated our prediction models through leave-one-out cross-validation. Our data-driven feature selection approach indicated that tumor proteomics profiles contain information for predicting binarized platinum response (P < 0.0001). We further built a least absolute shrinkage and selection operator (LASSO)-Cox proportional hazards model that stratified patients into early relapse and late relapse groups (P = 0.00013). The top proteomic features indicative of platinum response were involved in ATP synthesis pathways and Ran GTPase binding. Overall, we demonstrated that proteomic profiles of ovarian serous carcinoma patients predicted platinum drug responses as well as provided insights into the biological processes influencing the efficacy of platinum-based therapeutics. Our analytical approach is also extensible to predicting response to other antineoplastic agents or treatment modalities for both ovarian and other cancers.

Carcinoma Seroso Papilar Peritoneal Primario: serie de casos Hospital Clínico Universidad de Chile 2010-2015

The primary peritoneal cancer is a low prevalence disease, within which primary papillary serous carcinoma of the peritoneum is the most frequent with an incidence of 6.78 cases per million inhabitants. Predominates in females and its main differential diagnosis is advanced ovarian papillary serous carcinoma, for which immunohistochemis­try and clinical and pathological classifications are the way to differentiate base on the World Health Organization classification for tumor lesions. Objective: Describe the immunohistochemical results of a series of cases studied in Universidad de Chile Clini­cal Hospital and to compare them with the literature. Material and Methods: Descriptive retrospective study based on analysis of biopsies from 12 cases between January 2010 and March 2015 classifying them according to age, sex and biopsy register. Routine histological te­chnique was performed in addition to the immunohistochemical staining for WT1, cytokeratin and other reagents according to the differential diagnoses. Results: The age distribution was 47 to 75 years, mean 60 years, 100% of cases female. Immunohistochemical reagents were predominant WT1 (53.8%) and cytokeratin-7 (38.5%). Conclusion: This carcinoma is a rare entity in routine clinical practice, with similarities to ovarian serous carci­noma. There is consensus on the diagnosis of this condition, which must be oriented according to the criteria of the Gynecologic Oncology Group. Clinical suspicion can lead the pathologist to perform immunohistochemical study and thus have an accurate diagnosis to determine the therapeutic approach of the surgeon.

Survival of Patients With Mucinous Ovarian Carcinoma and Ovarian Metastases: A Population-Based Cancer Registry Study.

Patients with mucinous ovarian carcinoma (MOC) generally have a favorable prognosis, although in advanced stage, prognosis is significantly worse compared to patients with serous ovarian carcinomas (SOCs). This might be due to the difficulties in distinguishing MOC from metastatic tumors. In the current study, we investigate prognosis of MOC compared to other types of ovarian cancer and to synchronous metastases to the ovary (sMO). Age, laterality, International Federation of Gynecology and Obstetrics stage, tumor grade, treatment, and survival were extracted from the Eindhoven Cancer registry for all patients diagnosed with ovarian carcinomas or sMO between 1990 and 2012. Five-year survival analysis and Cox proportional hazards analysis were conducted. A total of 3556 patients with primary ovarian carcinoma (of which 474 mucinous) and 289 with sMO were identified. In advanced stage, 5-year survival of patients with MOC was comparable to survival of patients with sMO (11% vs 11%, P = 0.32) and decreased compared to patients with SOC (26%, P < 0.01). For MOC, there was no clinically significant effect on 5-year survival of either debulking (12% vs 8%, P < 0.01) or chemotherapy (12% vs 10%, P = 0.02). Patients with advanced stage MOC have a worse prognosis than advanced stage SOC. Survival is almost identical to that of patients with sMO. Effects of chemotherapy and debulking are limited in patients with MOC, which may be explained by suboptimal treatment due to the admixture of metastases in advanced stage MOC. Methods to differentiate between primary MOC and metastatic disease are needed to provide optimal treatment and insight in prognosis.

Abstract 3715: Survival of patients with mucinous ovarian carcinoma and ovarian metastases: A population-based cancer registry study

Abstract Objectives: Patients with mucinous ovarian carcinoma (MOC) generally have a favorable prognosis, although in advanced stage, prognosis is significantly worse compared to patients with serous ovarian carcinomas (SOC). This might be due to the difficulties in the distinction of MOC from metastatic tumors. In the current study we investigate prognosis of MOC compared to other types of ovarian cancer and to synchronous metastases to the ovary (sMO). Materials and methods: Age, laterality, FIGO stage, tumor grade, treatment and survival were extracted from the Eindhoven Cancer registry for all patients diagnosed with ovarian carcinomas or sMO between 1990 and 2012. 5-year survival analysis and Cox proportional hazard analysis were conducted. Results: 3,556 patients with primary ovarian carcinoma (of which 474 mucinous) and 289 with sMO were identified. In advanced stage, 5-year survival of patients with MOC was comparable to survival of patients with sMO (11% vs. 11%, p = 0.32) and decreased compared to patients with SOC (26%, p&amp;lt;0.01). For MOC there was no clinically significant effect on 5-year survival of either debulking (12% vs. 8%, p&amp;lt;0.01) or chemotherapy (12% vs. 10%, p = 0.02) as compared to patients with SOC (28 vs. 13% after chemotherapy, p&amp;lt;0.01 and 29% vs. 5% after debulking, p&amp;lt;0.01). Multivariate regression analysis for age, tumor grade and subtype including sMO was carried out, showing a significantly better overall survival for SOC compared to MOC (HR 0.51, p&amp;lt;0.01), whereas there was no difference for sMO compared with MOC (HR 1.16, p = 0.19). Conclusion: Patients with advanced stage MOC have a worse prognosis than advanced stage SOC. Survival is almost identical to that of patients with sMO, which might indicate that (a large part of) advanced stage MOC are in fact metastases. This may partly explain the limited effects of chemotherapy and debulking in patients with MOC. Methods to differentiate between primary MOC and metastatic disease are needed to provide optimal treatment and insight in prognosis. Citation Format: Michiel Simons, Nicole Ezendam, Johan Bulten, Iris Nagtegaal, Leon Massuger. Survival of patients with mucinous ovarian carcinoma and ovarian metastases: A population-based cancer registry study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3715. doi:10.1158/1538-7445.AM2015-3715

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma

BackgroundWe compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels. MethodsA multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined. FindingsPatients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8pg/mL, advanced SOC 9.0pg/mL, early-stage OCCC 4.2pg/mL and early-stage SOC 5.0pg/mL, P=0.006). Advanced OCCC (hazard ratio [HR] 3.38, P<0.0001), thrombocytosis (HR 1.42, P=0.032) and elevated IL-6 (HR 8.90, P=0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5-year progression-free and overall survival rates than those with advanced SOC (P<0.01), and thrombocytosis was an independent predictor of decreased survival outcomes (P<0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P=0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P=0.07). InterpretationAdvanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC.

Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers

BackgroundPlatinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC.MethodsA total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival < 6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients.ResultsMedian ascites levels of IL-6, IL-10 and osteoprotegerin (OPG) were significantly higher in women with advanced serous EOC than in controls (P ≤ 0.012). There were no significant difference in the median ascites levels of leptin, soluble urokinase plasminogen activator receptor (suPAR) and CCL18 among serous EOC women and controls. In Receiver Operator curve (ROC) analysis, IL-6, IL-10 and OPG had a high area under the curve value of 0.905, 0.832 and 0.825 respectively for distinguishing EOC from benign controls. ROC analysis of individual cytokines revealed low discriminating potential to stratify patients according to their sensitivity to first-line treatment. The combination of biomarkers with the highest discriminating potential was with CA125 and leptin (AUC = 0.936, 95 % CI: 0.894–0.978).ConclusionIL-6 was found to be strongly associated with advanced serous EOC and could be used in combination with serum CA125 to discriminate benign and EOC. Furthermore, the combination of serum CA125 and ascites leptin was a strong predictor of clinical resistance to first-line therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1511-7) contains supplementary material, which is available to authorized users.