Types Of Epithelial Ovarian Cancer Research Articles

BRCA1/2 Mutation Types Do Not Affect Prognosis in Ovarian Cancer Patients.

Background: High grade serous ovarian carcinoma (HGSOC) is the most lethal type of epithelial ovarian cancer, with a prevalence of germline BRCA1/2 mutations as high as 20%. Our objective is to determine whether the location of mutations in the different domains of the BRCA1/2 genes affects the clinical outcome of HGSOC patients. Methods: A total of 51 women with BRCA1 or BRCA2 mutated ovarian cancer were identified. Progression-free survival (PFS) and overall survival (OS) were analyzed. Results: In our study cohort, 35 patients were carriers of germline mutations in BRCA1 and 16 in BRCA2. The median PFS time following completion of the primary therapy was 23.8 months (95% CI 20.1–27.5) and the median OS was 92.9 months (95% CI 69.8–116.1) in all BRCA carriers. After multivariate analysis, no significant association among the location or type of BRCA1/2 mutation with PFS or OS was identified. Notably, significant differences in PFS between carriers of identical mutations in the same BRCA gene were detected. Conclusions: Among HGSOC patients, BRCA1/2 carriers with mutations in different locations of the genes show no significant difference in survival outcomes, in terms of PFS and OS, suggesting the potential effect of other genetic abnormalities and co-contributing risk factors.

Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data

ObjectiveTo identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. MethodsAll consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism. ResultsA total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62−0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71−0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. ConclusionA (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.

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.

Abstract 2137: Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer

Abstract The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in invasive processes, but the molecular factors that drive aggressive behavior remain nebulous. In this study, we analyzed two types of EOC at opposite ends of the invasiveness spectrum, high-grade serous ovarian cancers (HGSOCs) and serous borderline tumors (SBTs). We identified differentially expressed genes to guide follow on studies of regulatory networks. Initially, in a discovery sample set, we generated transcriptome sequences to identify 11 differentially expressed genes in SBTs and HGSOCs, and a nonoverlapping set of 17 differentially expressed genes stage II and stage III HGSOCs. We validated the classification performance of these gene expression signatures on a validation set of SBT and HGSOC with classification rates of 94 and 98% using the 11-gene and 17-gene sets, respectively. Transcription factor binding sites enriched in the differentially expressed gene promoter regions were examined by Chip-seq analysis in ovarian cancer and other cell lines. We identified a suite of transcription factors implicated in the differential regulation associated with invasiveness, including ERα, RARA, PITX1, FOXA1/FOXF1, and BHLHE41/E40. These data implicate estrogen responsive gene regulatory networks in ovarian cancers and suggest that dynamic regulatory interactions determine malignant EOC outcomes. Citation Format: Yichao Li, Sushil Kumar Jaiswal, Rupleen Kaur, Dana Alsaadi, Xiaoyu Liang, Frank Drews, Julie A. DeLoia, Thomas Krivak, Hanna M. Petrykowska, Valer Gotea, Lonnie Welch, Elnitski Laura. Differential gene expression identifies a transcriptional regulatory network involving ESR1and PITX1 in invasive epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2137.

In silico screening identifies a novel small molecule inhibitor that counteracts PARP inhibitor resistance in ovarian cancer

Poly ADP-ribose polymerase (PARP) inhibitors are promising targeted therapy for epithelial ovarian cancer (EOC) with BRCA mutations or defective homologous recombination (HR) repair. However, reversion of BRCA mutation and restoration of HR repair in EOC lead to PARP inhibitor resistance and reduced clinical efficacy of PARP inhibitors. We have previously shown that triapine, a small molecule inhibitor of ribonucleotide reductase (RNR), impaired HR repair and sensitized HR repair-proficient EOC to PARP inhibitors. In this study, we performed in silico screening of small molecule libraries to identify novel compounds that bind to the triapine-binding pocket on the R2 subunit of RNR and inhibit RNR in EOC cells. Following experimental validation of selected top-ranking in silico hits for inhibition of dNTP and DNA synthesis, we identified, DB4, a putative RNR pocket-binding inhibitor markedly abrogated HR repair and sensitized BRCA-wild-type EOC cells to the PARP inhibitor olaparib. Furthermore, we demonstrated that the combination of DB4 and olaparib deterred the progression of BRCA-wild type EOC xenografts and significantly prolonged the survival time of tumor-bearing mice. Herein we report the discovery of a putative small molecule inhibitor of RNR and HR repair for combination with PARP inhibitors to treat PARP inhibitor-resistant and HR repair-proficient EOC.

Cellular models of development of ovarian high-grade serous carcinoma: A review of cell of origin and mechanisms of carcinogenesis.

High‐grade serous carcinoma (HGSC) is the most common and malignant histological type of epithelial ovarian cancer, the origin of which remains controversial. Currently, the secretory epithelial cells of the fallopian tube are regarded as the main origin and the ovarian surface epithelial cells as a minor origin. In tubal epithelium, these cells acquire TP53 mutations and expand to a morphologically normal ‘p53 signature’ lesion, transform to serous tubal intraepithelial carcinoma and metastasize to the ovaries and peritoneum where they develop into HGSC. This shifting paradigm of the main cell of origin has revolutionarily changed the focus of HGSC research. Various cell lines have been derived from the two cellular origins by acquiring immortalization via overexpression of hTERT plus disruption of TP53 and the CDK4/RB pathway. Malignant transformation was achieved by adding canonical driver mutations (such as gain of CCNE1) revealed by The Cancer Genome Atlas or by noncanonical gain of YAP and miR181a. Alternatively, because of the extreme chromosomal instability, spontaneous transformation can be achieved by long passage of murine immortalized cells, whereas in humans, it requires ovulatory follicular fluid, containing regenerating growth factors to facilitate spontaneous transformation. These artificially and spontaneously transformed cell systems in both humans and mice have been widely used to discover carcinogens, oncogenic pathways and malignant behaviours in the development of HGSC. Here, we review the origin, aetiology and carcinogenic mechanism of HGSC and comprehensively summarize the cell models used to study this fatal cancer having multiple cells of origin and overt genomic instability.

Spotlight on oncologic outcomes and prognostic factors of pure endometrioid ovarian carcinoma

AimTo determine the prognostic factors related to recurrence and survival, and to evaluate the need for adjuvant chemotherapy in patients with endometrioid type epithelial ovarian cancer (EEOC). MethodsThis study included 63 EEOC patients who were surgically staged. ResultsThe FIGO 2014 stage was stage I in 41 (65 %) patients, stage II in 8 (12.5 %) patients, stage III in 14 (22.5 %) patients. 5-year failure-free survival (FFS) was 78 % in the entire cohort. 15 (23.8 %) patients had disease failure. In univariate analysis, advanced stage (II&III), high grade tumor, presence of ascites, bilateral tumor, presence of omental metastasis, positive peritoneal cytology were prognostic factors for poor FFS. Only the stage was determined to be an independent prognostic factor for disease-failure. According to multivariate analysis, stage II&III was related to a statistically significant hazard ratio for a disease failure of 3.49 (95 % confidence interval: 1.029−11.841; p = 0.045). The effectiveness of adjuvant chemotherapy was assessed for 41 patients with stage I. Eleven (26.8 %) patients with stage I did not receive adjuvant chemotherapy. Whereas 5-year FFS was 88 % in patients receiving adjuvant chemotherapy, that was 91 % in patients without adjuvant chemotherapy (p = 0.923). ConclusionThe independent prognostic factor for recurrence in EEOC was stage only. Adjuvant chemotherapy was not related to improvement in FFS in the early stage EEOC that were completely staged.

Utility of Preoperative Inflammatory Markers to Distinguish Epithelial Ovarian Cancer from Benign Ovarian Masses.

Background: Inflammatory markers have been reported to be predictors for the presence of epithelial ovarian cancer (EOC), however, the cut-off value of each marker remains unclear and predictive capability of the markers in different histology types of EOC is still unknown.Methods: A total of 207 patients with benign ovarian masses and 887 EOC patients who underwent surgical resection, and were pathologically diagnosed were included. We compared the difference of preoperative inflammatory markers between benign ovarian masses and EOC patients. Stratified analysis by histology subtype was further conducted. Logistic regression analyses and receiver operating characteristic (ROC) curves was used to evaluate the predictive capability of the markers.Results: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were significantly associated with all stages and subtypes of EOC (P<0.001). The optimal cut-off points based on ROC curve analyses for NLR, PLR, and LMR were found to be 2.139 (AUC=0.749, P<0.001), 182.698 (AUC=0.730, P<0.001), and 3.619 (AUC = 0.709, P<0.001), respectively. In low CA125 level patients, high level of NLR and PLR increase the risk of endometrioid EOC, while low level of LMR were significantly associated with an increased risk of serous EOC.Conclusions: In addition to CA125, NLR, PLR, and LMR could be used as predictors of EOC and preoperative inflammatory markers may be used as a potential biomarker for predicting different histotypes of EOC.

The Treatment of Clear Cell Ovarian Cancer with the Poly(ADP- Ribose) Polymerase (PARP1) Inhibitors (AG14361,Veliparib,Olaparib) as Chemosensitizers.

Introduction: Most of those who get ovarian cancer will die from this cancer. Of the major types of ovarian cancer clear cell carcinoma is the most aggressive and chemoresistant type of epithelial ovarian cancer. Here the sensitivity of clear cell ovarian carcinoma to poly adenosine diphosphate [ADP-ribose] polymerase (PARP) inhibitors is tested. Methodology: Ovarian cancer cell lines were treated with the PARP inhibitors AG14361, Veliparib, or Olaparib alone or in combination with cisplatin, carboplatinum, doxorubicin, 5-fluorouracil (5-FU), gemcitabine and paclitaxel for 72 hours. The IC50 concentrations were calculated. Each experiment was replicated 10 times. Results: As single agents the PARP inhibition of ovarian cancer among serous, endometroid and clear cell ovarian cancer cell lines was similar. Clear cell ovarian cancer seemed particularly susceptible to chemo-sensitization by PARP inhibitors with paclitaxel, 5-FU, carboplatin, doxorubicin and/or cisplatin. Antagonism was seen with gemcitabine. Conclusion: PARP inhibitors are exceptional chemosensitizers of clear cell ovarian cancer to treatment with most standard chemotherapy agents.

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer.

Simple SummarySeveral genes have been confirmed as risk genes for epithelial ovarian cancer (EOC). There are five main types of EOC, with different molecular changes and clinical characteristics, suggesting they should be considered different diseases. This review summarises the contribution of rare inherited mutations to EOC susceptibility, focussing on the frequency in each EOC type. Susceptibility genes can have a major clinical impact, reducing ovarian cancer incidence by screening of family members to detect women at higher risk than the general population. They can also lead to the development of new targeted treatments.A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed.

Current and future strategies for treatment of ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is one of the five histological types of epithelial ovarian cancer (EOC). OCCC comprises 23% of all EOC cases in Japan, whereas the rate of OCCC in North America and Europe is much lower. OCCC is generally categorized as a rare gynecologic malignancy, and there is limited evidence for specific treatment. The clinical basis for treatment of OCCC is mostly based on retrospective studies, many of which were performed in Japan. Until recently, most randomized clinical trials for EOC have included OCCC; therefore, current treatment for OCCC is basically the same as that for other histologic types of EOC. However, the clinical characteristics of OCCC differ from those of high-grade serous carcinoma, particularly for chemosensitivity, and there is a need to develop new treatment for OCCC. The molecular background of OCCC has unique features: tumors are usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, whereas p53 mutations are common in high-grade serous or endometrioid carcinomas. These features may help in development of new treatment for OCCC. In this review, we described the current evidence for treatment of OCCC, including surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, and we discuss ongoing clinical trials and preclinical studies of new treatment approaches for OCCC.

MR imaging of epithelial ovarian cancer: a combined model to predict histologic subtypes.

To compare the performance of clinical features, conventional MR image features, ADC value, T2WI, DWI, DCE-MRI radiomics, and a combined multiple features model in predicting the type of epithelial ovarian cancer (EOC). In this retrospective analysis, 61 EOC patients were confirmed by histology. Significant features (p < 0.05) by multivariate logistic regression were retained to establish a clinical model, conventional MRI morphological model, ADC model, and traditional model. The radiomics model included FS-T2WI, DWI, and DCE-MRI, and also, a multisequence model was established. A total of 1070 radiomics features of each sequence were extracted; then, univariate analysis and LASSO were used to select important features. Traditional models were combined with a combined radiomics model to establish a mixed model. The predictive performance was validated by receiver operating characteristic curve (ROC) analysis, calibration curve, and decision curve analysis (DCA). A stratified analysis was conducted to compare the differences between the combined radiomics model and the traditional model in identifying early- and late-stage EOC. Traditional models showed the highest performance (AUC = 0.96). The performance of the mixed model (AUC = 0.97) was not significantly different from that of the traditional model. The calibration curve showed that the traditional model had the highest reliability. Stratified analysis showed the potential of the combined radiomics model in the early distinction of the two tumor types. The traditional model is an effective tool to distinguish EOC type I/II. Combined radiomics models have the potential to better distinguish EOC types in early FIGO stage disease. • The combined radiomics model resulted in a better predictive model than that from a single sequence model. • The traditional model showed higher classification accuracy than the combined radiomics model. • Combined radiomics models have the potential to better distinguish EOC types in early FIGO stage disease.

Upregulation of cyclase-associated actin cytoskeleton regulatory protein 2 in epithelial ovarian cancer correlates with aggressive histologic types and worse outcomes.

Cyclase-associated actin cytoskeleton regulatory protein 2 (CAP2) regulates actin dynamics to control cell cycles and cell migration. CAP2 overexpression contributes to cancer progression in several tumor types; however, the role of CAP2 expression in ovarian cancer remains unclear. This study aimed to clarify the significance of CAP2 expression in epithelial ovarian tumor. We evaluated CAP2 expression in ovarian cancer cell lines using quantitative real-time polymerase chain reaction, western blotting and immunocytochemistry and examined the effect of CAP2 silencing in migration and proliferation assays. CAP2 immunohistochemistry was conducted using tissue specimens from 432 ovarian carcinoma patients; a further 55 borderline and benign 65 lesions were analyzed. CAP2 expression levels were defined as low, intermediate or high, for correlation analysis with clinicopathological factors. CAP2 expression was significantly higher in cell lines from Type II ovarian cancer than in those in Type I, and knockdown of CAP2 showed decreased migration and proliferation. Higher levels of CAP2 expression in human tissues were associated with Type II histology, residual lesion, lymph node metastasis, ascites cytology and higher clinical stage. High CAP2 expression levels were observed in 26 (23.4%) of 111 Type II ovarian cancers and in 16 (5.0%) of 321 Type I cancers but not in any borderline or benign lesions. Multivariate analyses showed that CAP2 expression in ovarian cancer is an independent prognostic factor for recurrence-free survival (P=0.019). CAP2 expression is upregulated in aggressive histologic types of epithelial ovarian cancer and serves as a novel prognostic biomarker for patient survival.

Evaluation of miR-22 and miR-21 as diagnostic biomarkers in patients with epithelial ovarian cancer.

Among the 11 most common cancers, ovarian cancer is the fifth leading cause of death after lung, breast, colorectal and pancreatic cancer. Although diagnosis of ovarian cancer in early stages is followed by various successful treatments, no accurate and reliable method is available at present. Currently microRNAs are being explored as signature biomarkers for early detection of various types of cancer. However little information is available on expression and correlation of microRNA in ovarian cancer. In this study, we have chosen two microRNA on the basis of their altered frequency in epithelial ovarian cancer cases. The main objective of this study is to evaluate the expression of microRNA-22 and microRNA-21 along with various clinicopathological parameters. Expression level of microRNA-22 and microRNA-21 in different stages and subtypes of epithelial ovarian carcinoma has been analyzed to find out its role as a potential diagnostic biomarker. Present study has been conducted in the serum of 80 epithelial ovarian cancer patients and 80 age matched healthy women. Quantitative real time PCR was used to compare the expression of miR-22 and miR-21 between the cases and control groups. Statistical analysis showed 7.85-fold increase in miR-21 expression and 2.1-fold reduction in miR-22 expression of ovarian cancer patients. Increased serum level of miR-21 in ovarian cancer patients and decreased level of miR-22 has been correlated with advanced international federation of gynecology and obstetrics (FIGO) stage and histological sub types of epithelial ovarian cancer. Serous ovarian carcinoma was the most common cancer in the present study. Calculated fold change value for miR-21 was 3.98 and - 2.86 for miR-22 in serous ovarian cancer. Fold change value in the miR-21 expression in advanced stage was 6.29 and 4.25 in early stage. Whereas lower calculated fold change was observed for miR-22 in advanced stage than in early stage (- 2.16). Present study revealed up-regulated expression of miR-21 and down regulated expression of miR-22 in the serum of epithelial ovarian cancer patients. Both of these could be validated as good diagnostic biomarkers for early detection of ovarian cancer.

Rethinking of treatment strategies and clinical management in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC), with unique clinical and molecular characteristics compared with other histological types of epithelial ovarian cancer (EOC), behaves like a distinct entity and has a poorer prognosis than other EOC types, especially in advanced stages. In addition, OCCC comprises approximately 27% of all EOC cases in Japan, compared with 12% in Western countries. Historically, patients with OCCC have been eligible for chemotherapeutic and surgical trials of EOC. It has been difficult to evaluate the specific impact of these trials on the prognosis of women with OCCC because of its rarity and unique molecular characteristics. Recent studies of OCCC revealed significant molecular variations related to carcinogenesis and molecular targets that could directly facilitate patient stratification and subsequent precision medicine. Thus, treatment strategies specific for OCCC based on its clinical and molecular characteristics are urgently needed. In this review, we highlight the management and treatment of OCCC from clinical aspects.

Prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer

Aims:This study was aimed at investigating the prognostic impact of pretreatment thrombocytosis in epithelial ovarian cancer (EOC) patients in Lagos, Nigeria.Methods:This was a retrospective cohort study involving the review of the clinical record of 72 patients with histologically confirmed EOC who were managed at the Lagos University Teaching Hospital, Lagos, Nigeria over a 7-year period from January 2010 to December 2016. Information on the sociodemographic data and platelet counts at diagnosis of EOC were retrieved from the patients’ medical records. Descriptive statistics were then computed for all baseline patients’ characteristics. Survival analyses were carried out using the Kaplan-Meier estimates. Multivariate analysis of these data was performed with the Cox proportional hazards model.Results:This study revealed that the prevalence of pretreatment thrombocytosis was 41.7% among the women with EOC. Fifty-three (73.6%) of the women had the advanced-stage disease (FIGO stage III-IV) while 52 (72.2%) had high-grade disease (II-III). The majority (66.7%) of the women had a serous histological type of EOC while 76.4% had documented recurrence. Pretreatment thrombocytosis was significantly associated with the women’s parity (P = 0.009), serum carbohydrate antigen 125 levels (P = 0.018), median progression-free survival (PFS) (P < 0.001), 3-year median overall survival (OS) (P < 0.001), type of primary treatment (P = 0.002), extent of cytoreduction (P < 0.001), presence of ascites (P = 0.002), International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.008), and histological type (P = 0.011). Pretreatment thrombocytosis was negatively associated with PFS (hazard ratio [HR] = 0.25; 95% CI 0.83, 0.75; P = 0.014) and 3-year OS (HR = 0.03; 95% CI 0.03, 0.27; P = 0.002).Conclusions:The study suggests that pretreatment thrombocytosis may be a useful predictor of survivals in EOC patients.

Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.

Abstract GMM-053: ROLE OF LATS AND DYRK1A KINASES IN THE PATHOGENESIS AND TREATMENT OF HGSOC

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with 75% of women presenting with metastatic disease at the time of diagnosis. High Grade Serous Ovarian Carcinoma (HGSOC) is the most common and aggressive type of epithelial ovarian cancer, with 5-year survival rate of 30% for most patients. Developing of accurate experimental models of HGSOC is necessary to elucidate the disease pathogenesis and to evaluate new treatments. Our study is aimed at determining the roles of the Large Tumor Suppressor 1 and 2 kinases (LATS1/2), and their downstream effector Dual-specificity tyrosine(Y)-Regulated Protein Kinase 1A (DYRK1A), in HGSOC pathogenesis and treatment sensitivity. The Cancer Genome Atlas study revealed copy number losses of the LATS1, LATS2 and DYRK1A genes in 65%, 59% and 38% of HGSOC cases, respectively. Previous studies found that LATS1/2 and DYRK1A mediate a crosstalk between the Hippo tumor suppressor pathway and the G0/G1 cell cycle checkpoint. However, the role of these kinases in HGSOC pathogenesis is not known. We found that loss of both LATS1 and LATS2, or DYRK1A results in increased proliferation of SKOV3 ovarian cancer cells in 2D or 3D cultures, mediated in part by disruption of the DREAM complex that represses cell cycle-regulated genes. Interestingly, we observed upregulation of cyclin D1 and increased phosphorylation of retinoblastoma (RB) family proteins in SKOV3 cells depleted of LATS1/2 or DYRK1A kinases, indicative of aberrant activation of CDK4/6. Similar changes were observed upon depletion of LATS1/2 or DYRK1A using non-transformed human fallopian epithelial cells, suggesting that genetic losses of these kinases could contribute to the HGSOC pathogenesis. Furthermore, we tested whether an aberrant activation of CDK4/6 in SKOV3 cells with low levels of LATS1/2 or DYRK1A could increase their sensitivity to pharmacological CDK4/6 inhibitors such as palbociclib. Using metabolic cell proliferation assays, we found that loss of LATS1/2 or DYRK1A resulted in a significant decrease of palbociclib IC50 in SKOV3 cells. Interestingly, palbociclib treatment increased the DREAM assembly in these cells, resulting in downregulation of DREAM-regulated cell cycle factors such as cyclin A or B-Myb. Our results show that loss of LATS1/2 or DYRK1A could contribute to HGSOC pathogenesis by CDK4/6-mediated disruption of RB family function. Further studies are underway to validate our findings in vivo using orthotopic ovarian tumor xenografts in mice and a bioluminescence imaging approach. In addition, these models will be used for validation of novel therapeutic approaches for HGSOC, such as palbociclib, as well as for the mechanistic studies of the EOC pathogenesis. Citation Format: Fatmata Sesay, Siddharth Saini, Larisa Litovchick. ROLE OF LATS AND DYRK1A KINASES IN THE PATHOGENESIS AND TREATMENT OF HGSOC [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-053.

Abstract GMM-046: CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS

Abstract BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and the fifth leading cause of cancer deaths among women in the United States. An even poorer prognostic type of EOC is BRCA wild-type CCNE1 (cyclin E) amplified/gain tumors. This subtype of EOC is characterized by unchecked replication, high levels of genomic instability, and replicative stress. CCNE1 amplified EOC is mutually exclusive to BRCA mutated EOC in part because CCNE1 amplified cells require functional BRCA for survival. Bromodomain and extraterminal 4 (BRD4) amplified ovarian cancer is a recently discovered subtype of BRCA wild-type EOC, and is also associated with poor outcomes. OBJECTIVE: To determine if mRNA and immunohistochemical (IHC) profiles of CCNE1 and BRD4 are associated with platinum sensitivity in serous ovarian cancers. METHODS: Copy number analysis data was extracted from The Cancer Genome Atlas (TCGA) for high-grade serous ovarian tumors with BRD4 and CCNE1 (cyclin E) amplification. (www.cbioportal.org). Immunostaining for cyclin E and BRD4 was performed in 130 serous ovarian tumors on a tissue microarray (TMA) IHC in 130 clinically annotated formalin-fixed paraffin-embedded serous tumors from Vanderbilt University Medical Center (VUMC). Staining intensity (1: weak; 2: moderate; 3: strong) and percent of positive nuclei (0-100) were multiplied to yield an H score for NR4A1 expression. Pearson correlation coefficients were determined for mRNA expression of cyclin E and BRD4 in 307 TCGA tumors (RSEM V2 data extracted from the Broad Firehose database) and protein expression of cyclin E and BRD4 in 130 serous ovarian tumors. CCNE1 and BRD4 expression in relation to platinum sensitivity were evaluated using the Mann-Whitney t test. RESULTS: The Cancer Genome Atlas (TCGA) demonstrated about 20% of high-grade serous EOC harbor amplifications in CCNE1 and BRD4. BRD4 amplification overlaps with CCNE1 amplification in 26/57 (46%) of high-grade serous EOC of the TCGA. Immunostaining for cyclin E and BRD4 in 130 serous ovarian tumors on a tissue microarray yielded intermediate-to-high staining of CCNE1 in 52.1% of tumors and intermediate-to-high staining of BRD4 in 71.6% of tumors. Protein expression by IHC between CCNE1 and BRD4 was positively correlated, r= 0.25, (p =0.005). High expression of CCNE1 was associated with platinum resistance (p = 0.023). High BRD4 expression was not associated with platinum resistance (p=0.95). CONCLUSION: TCGA mRNA and TMA IHC expression analysis suggest that a subset of serous ovarian tumors have high levels of CCNE1 and BRD4 expression. High CCNE1 expression is associated with poor prognosis and platinum resistance. High BRD4 expression is not associated with platinum resistance in this cohort. Future studies are warranted to evaluate the subset of tumors with elevated expression of both CCNE1 and BRD4 in relation to platinum resistance and clinical outcomes. Citation Format: Shariska Petersen, Andrew J. Wilson, Dineo Khabele. CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-046.

Ovarian Cancer Genetics and Implications for Imaging and Therapy.

Ovarian cancer is the second most common gynecologic malignancy in the United States. Ovarian cancer has a dismal prognosis when diagnosed at an advanced stage. Therapy for these cancers is determined not only by stage but also by their heterogeneous pathologic features, genetic mutations, and biology. In this review, we will discuss types of epithelial ovarian cancer, and their associated genetic mutations and the implications for imaging and treatment.