SPME-LC/MS-based serum metabolomic phenotyping for distinguishing ovarian cancer histologic subtypes: a pilot study.

Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological cancer. The outcomes of EOC are complicated, as it is often diagnosed late and comprises several heterogenous subtypes. As such, upfront treatment can be highly challenging. Although many significant advances in EOC management have been made over the past several decades, further work must be done to develop early detection tools capable of distinguishing between the various EOC subtypes. In this paper, we present a sophisticated analytical pipeline based on solid-phase microextraction (SPME) and three orthogonal LC/MS acquisition modes that facilitates the comprehensive mapping of a wide range of analytes in serum samples from patients with EOC. PLS-DA multivariate analysis of the metabolomic data was able to provide clear discrimination between all four main EOC subtypes: serous, endometrioid, clear cell, and mucinous carcinomas. The prognostic performance of discriminative metabolites and lipids was confirmed via multivariate receiver operating characteristic (ROC) analysis (AUC value > 88% with 20 features). Further pathway analysis using the top 57 dysregulated metabolic features showed distinct differences in amino acid, lipid, and steroids metabolism among the four EOC subtypes. Thus, metabolomic profiling can serve as a powerful tool for complementing histology in classifying EOC subtypes.

Risk of epithelial ovarian cancer Type I and II after hysterectomy, salpingectomy and tubal ligation-A nationwide case-control study.

The proposed different origins and pathways to of the dualistic model of epithelial ovarian cancer (EOC) may affect and alter the potential risk reduction related to hysterectomy, salpingectomy and tubal ligation. The aim of our study was to analyze associations between hysterectomy, salpingectomy or tubal ligation and risk reduction of EOC Type I and II. In this nationwide register-based case-control study, women diagnosed with EOC, Fallopian tube or primary peritoneal cancer between 2008 and 2014 were included. Cases were classified into Type I and II according to histology and predefined criteria. The exposure variables: hysterectomy, salpingectomy and tubal ligation were identified from national registries. Conditional logistic regression analyses were performed to evaluate associations between Type I and II EOC and the exposure variables. Among 4669 registered cases, 4040 were eligible and assessed for subtyping resulting in 1033 Type I and 3007 Type II. Ten controls were randomly assigned to each case from the register of population. In regression analyses, women with previous salpingectomy had a significantly lower risk of EOC Type II (odds ratio [OR] 0.62; 95% confidence interval [95%CI] 0.45-0.85) but not Type I (OR 1.16; 95%CI 0.75-1.78). Hysterectomy was associated with a reduced risk of both EOC Type I (OR 0.71; 95%CI 0.52-0.99) and Type II (OR 0.81; 95%CI 0.68-0.96). Similar estimates were obtained for tubal ligation, although without statistical significance. The association between salpingectomy and reduced risk of EOC Type II supports the proposed theory of high-grade serous cancer originating from the tubal fimbriae.

Wilms' tumor 1 antigen immunoreactivity in epithelial ovarian cancer - diagnostic and prognostic value.

OBJECTIVES: Ovarian cancer is a heterogeneous disease, with a number of different histological subtypes with various responses to treatment. Wilms' tumor 1 (WT1) immunoreactivity is used to distinguish between OC's various subtypes. However, little is known about the protein's role as a prognostic factor. Thus, the main aim of our study was to evaluate the relationship between WT1 expression and patient overall survival (OS) and lymph node metastases. MATERIALS AND METHODS: Study group consisted of 164 women aged 22-84, diagnosed with epithelial ovarian cancer (EOC). WT1 expression in histological slides was assessed by immunohistochemistry. RESULTS: Serous tumors were the most common subtype among EOC (n = 126; 76.8%), followed by endometrioid (n = 20; 12.2%), clear-cell (n = 14; 8.5%) and mucinous cancer (n = 4; 2.4%). Of all serous EOC, WT1-positive tumors accounted for 75.6% of cases and this number was significantly higher than in other histological subtypes (p < 0.0001). Patients with lymph node metastases were more likely to have WT1-positive than WT1-negative tumors (p = 0.006). There was no significant correlation between WT1 immunoreactivity and OS across the whole study group of EOC patients (p = 0.6); however, in the group of non-serous (mucinous, endometrioid and clear-cell) EOC subjects, WT1 immunoreactivity was associated with shorter OS (p = 0.046). CONCLUSIONS: WT1 immunoreactivity may be helpful in differentiating primary epithelial serous carcinomas from non-serous ovarian cancers; however, its prognostic role in EOC is rather uncertain.

Prognostic Values of Transforming Growth Factor-Beta Subtypes in Ovarian Cancer.

PURPOSE: To explore the potential role of the transforming growth factor-beta (TGF-ß) subtypes in the prognosis of ovarian cancer patients. Materials and Methods. The prognostic roles of individual TGF-ß subtypes in women with ovarian cancer were retrieved from the Kaplan-Meier plotter (KM plotter) database. In addition, the Oncomine database and immunohistochemistry were used to observe the mRNA and protein expression of TGF-ß subtypes between human ovarian carcinoma and normal ovarian samples, respectively. RESULTS: TGF-ß1 and TGF-ß4 were totally uncorrelated with survival outcomes in women with ovarian cancer. Increased TGF-ß2 and TGF-ß3 mRNA expression was markedly related to unfavorable prognosis, especially in women with serous, poorly differentiated, and late-stage ovarian carcinoma. High expression levels of TGF-ß2 were related to worse progression-free survival (PFS) while TGF-ß3 was linked to unfavorable overall survival (OS) and PFS in women with TP53-mutated ovarian cancer. TGF-ß2 was associated with poor OS and PFS from treatment with chemotherapy with platins, Taxol, or a platin+Taxol. However, overexpression of TGF-ß3 was associated with poor OS from the use of platins and poor PFS of Taxol or a platin+Taxol in women with ovarian carcinoma. Furthermore, the expression of TGF-ß2 mRNA and protein was higher but only TGF-ß3 mRNA expression was higher in cancerous tissues than in normal ovarian samples. CONCLUSION: Higher expression of TGF-ß2 functioned as a significant predictor of poor prognosis in women with ovarian cancer, especially those with TP53 mutations or who were undergoing chemotherapy with platins, Taxol, or a platin+Taxol.

Subtype specific biomarkers associated with chemoresistance in epithelial ovarian cancer.

In spite of the advent of many high throughput technologies, tumor tissue biomarkers are still the gold standard for diagnosis and prognosis of different malignancies including epithelial ovarian cancer (EOC). EOC is a heterogeneous disease comprised of five major subtypes which show distinct clinicopathological features and therapy response. Acquirement of chemoresistance toward therapy is a major challenge for successful treatment outcome in EOC patients. Several markers have been tested by immunohistochemical method to evaluate their prognostic merit to predict clinical outcome. However, a vast majority of such markers have been assessed for high-grade serous and clear cell ovarian cancer, among all subtypes of EOC. The current review elaborates upon those biomarkers that can potentially predict chemoresistance with subtype specificity.

The molecular origin and taxonomy of mucinous ovarian carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

Molecular profiling and molecular classification of endometrioid ovarian carcinomas.

OBJECTIVE: Endometrioid ovarian carcinomas (EOCs) comprise 5-10% of all ovarian cancers and commonly co-occur with synchronous endometrioid endometrial cancer (EEC). We sought to examine the molecular characteristics of pure EOCs in patients without concomitant EEC. METHODS: EOCs and matched normal samples were subjected to massively parallel sequencing targeting 341-468 cancer-related genes (n = 8) or whole-genome sequencing (n = 28). Mutational frequencies of EOCs were compared to those of high-grade serous ovarian cancers (HGSOCs; n = 224) and EECs (n = 186) from The Cancer Genome Atlas, and synchronous EOCs (n = 23). RESULTS: EOCs were heterogeneous, frequently harboring KRAS, PIK3CA, PTEN, CTNNB1, ARID1A and TP53 mutations. EOCs were distinct from HGSOCs at the mutational level, less frequently harboring TP53 but more frequently displaying KRAS, PIK3CA, PIK3R1, PTEN and CTNNB1 mutations. Compared to synchronous EOCs and pure EECs, pure EOCs less frequently harbored PTEN, PIK3R1 and ARID1A mutations. Akin to EECs, EOCs could be stratified into the four molecular subtypes: 3% POLE (ultramutated), 19% MSI (hypermutated), 17% copy-number high (serous-like) and 61% copy-number low (endometrioid). In addition to microsatellite instability, a subset of EOCs harbored potentially targetable mutations, including AKT1 and ERBB2 hotspot mutations. EOCs of MSI (hypermutated) subtype uniformly displayed a good outcome. CONCLUSIONS: EOCs are heterogeneous at the genomic level and harbor targetable genetic alterations. Despite the similarities in the repertoire of somatic mutations between pure EOCs, synchronous EOCs and EECs, the frequencies of mutations affecting known driver genes differ. Further studies are required to define the impact of the molecular subtypes on the outcome and treatment of EOC patients.

Development and Validation of a Predictive Score for Preoperative Diagnosis of Early Stage Epithelial Ovarian Cancer

Objective: To develop and validate a simplified multi-parameter risk-based scoring system for preoperative diagnosis of early stage epithelial ovarian cancer. Methods: All women presented with adnexal mass and were scheduled for operation at Phrapokklao hospital during September 2013 ­ December 2017 were included and categorized according to their histopathologic reports into early stage ovarian cancer groups and benign ovarian tumor groups. Multivariable logistic regression was used to explore for potential predictors. The selected logistic coefficients were transformed into risk-based scoring system. Internal validation was done with bootstrapping procedure. Results: A total of 270 participants were included in analysis and predictive model development, 54 in early stage ovarian cancer group and 216 in benign ovarian tumor group. Menopausal status, two abnormal ultrasound findings (presence of solid component or ascites), tumor size and serum CA-125 level were used for derivation of the scoring system. The score-based model showed area under ROC of 0.88 (95%CI 0.82-0.93). The developed scoring system ranged from 0 to 51 was classified into 3 subcategories for clinical practicability. The positive predictive values for the presence of early stage ovarian cancer were 2.07 (95%CI 0.43-6.05) for low risk patient, 29.13(95%CI 19.65-41.58) for moderate risk patient, and 95.45(95%CI 77.16-99.88) for high risk patient. Conclusion: This simplified risk-based scoring system for preoperative diagnosis of early stage ovarian cancer could aid general physicians or general gynecologists in evaluation of patients presenting with ovarian tumors and help gynecologic oncologists in management planning and prioritization of patients for operation.

Treatment of Rare Epithelial Ovarian Tumors.

Traditionally, the management of epithelial ovarian cancer has been approached using a one-size-fits-all mentality. This strategy does not acknowledge the differences in epidemiology and clinical behavior of many of the histologic and molecular subgroups of ovarian cancer, specifically the rare histologies. While cytoreductive surgery followed by adjuvant platinum and taxane-based chemotherapy is the mainstay of primary treatment of epithelial ovarian cancer as a group, further investigation of novel therapeutics is critical for improving outcomes of these rare histologies. This article focuses on the management of non-high grade serous histologies of ovarian cancer.

Changes in the Management and Prognosis of Ovarian Cancer Due to the New FIGO and WHO Classifications: A Case Series Observational Descriptive Study. Seven Years of Follow-up.

OBJECTIVE: Ovarian cancer is the deadliest of gynecologic cancers. In recent years, International Federation of Gynecology and Obstetrics (FIGO) and the World Health Organization (WHO) classifications were revised. We compared the major changes between the classifications and examined the effects on the therapy and prognosis of the ovarian, fallopian tubes, and peritoneum cancer in our series according to both classifications. METHODS/MATERIALS: We performed an observational descriptive study of 210 patients who were diagnosed with a malignant ovarian tumor from 2010 to 2016. The accepted FIGO and WHO classifications at each point in time were registered. We reclassified both data, obtaining both classifications for each patient. The changes in the therapeutic management and prognosis were examined. RESULTS: In both FIGO classifications of our case series, most patients with ovarian cancer were in FIGO stage III. We found that 4.2% of the previous stage IIIC patients have changed to stage IIIA2 or stage IIIB, with better prognosis and survival rate. In the new WHO classification, the main change, in our case series, was the increase in the high-grade serous carcinoma percentage. According to the current recommendations, we observed 7.56% more patients in early ovarian cancer stages treated with platinum and taxane. In both early and advanced ovarian cancer group, high-grade serous carcinoma tumors were predominant. CONCLUSIONS: The newly created WHO and FIGO classifications have improved the ability to predict the prognosis and consequently to change the therapeutic managements of patients with ovarian cancer.