Grade Serous Ovarian Carcinoma Research Articles

Prognostic Role of CRS in High Grade Serous Ovarian Tumour Patients Receiving Neoadjuvant Chemotherapy in a Tertiary Care Hospital of Central India

Introduction: Ovarian tumours are rarely diagnosed early, patients presents only when the abdominal mass is appreciable in size. The current mode of treatment involves neoadjuvant chemotherapy with interval debulking surgery, followed by completion of the chemotherapy. The pathological examination of the interval debulking specimen allows an evaluation of the extent of the response to the chemotherapy and sensitivity of the tumour to the same. The Chemotherapy Response Score (CRS) developed by Bohm S et al., is being used to predict the prognosis of these patients. The advent of molecular genetics has allowed us to categorise tumours as per the mutations they possess, the prominent in High Grade Serous Carcinoma (HGSC) being TP53, BRCA1/2 and Homologous Recombination Deficiency (HRD). This knowledge is used to cater to the specific therapeutic needs of the patients. Aim: To apply the CRS to cases of high grade serous carcinomas of the ovary, presenting to the centre and association of the score with their survival. Materials and Methods: A total of 30 patients of high grade serous carcinoma of ovary who received neoadjuvant chemotherapy and had interval debulking surgery were included in the study. The histopathological examination of the resected specimen was done with special emphasis on the omental deposits and the degree of necrosis, fibrosis, inflammation, macrophages and residual tumour. Chi square statistics with p-value association of was done, to establish significance. Results: The histological parameters of necrosis, chronic inflammation and residual tumour in the omental deposits were found to be the most significant in association of to the CRS scores. Also, the CRS grading was associated with the survival of the patients. Conclusion: The CRS was found to associate well with the survival of the patients. This study recommends that CRS score be done in all post NACT high grade serous ovarian tumours, which will guide further treatment.

A Rare Case of Synchronous Ovarian Adenocarcinoma and Squamous Cell Carcinoma of Cervix

Synchronous tumours of gynaecological malignancies occur rarely and most of these cases are represented by synchronous ovarian and endometrial cancer. Synchronous malignancies of cervix and ovary are rare with poor prognosis. Only few cases of synchronous cancer of cervix and ovary are found in the literature as case reports. Here, we report a case of a 63 year old patient who was diagnosed with synchronous squamous cell carcinoma of cervix and high grade serous carcinoma of ovary in which her clinical presentation, investigation and intraoperative findings were atypical. Patient presented with postmenopausal bleeding and mass per abdomen. Pipelle sampling revealed squamous cell carcinoma of cervix. Examination under anaesthesia noted endocervical growth measuring 3×4 cm with endoluminal extension into the whole endometrial cavity. Computerized tomography (CT) imaging showed left ovarian mass measuring 10.0×11.7 cm. Uterine corpus involvement in this case mislead us to the initial diagnosis of ovarian metastasis in cervical cancer. The distinct histopathological features of the ovary, cervix and endometrial lesion post operatively helped in establishing the diagnosis of two separate primaries which was synchronous cervical and ovarian cancer rather than metastatic spread of one primary malignancy.

Primary High Grade Serous Carcinoma of the Fallopian Tube: A Case Report

A 49-year-old, perimenopausal nulliparous woman with lower abdominal pain and abnormal uterine bleeding. Clinical and radiological findings suggested a right adnexal tumor. CA-125 level was moderately elevated. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was done. Peroperative findings revealed a soft to friable growth arising from right fallopian tube with no involvement of ovaries. Histopathologic examination confirmed it to be a high grade serous carcinoma, FIGO stage IA. The histomorphology resembled high grade serous carcinoma of ovary, however ovaries on both sides appeared unremarkable. Surgery was uneventful and the patient was discharged after seven days of hospital stay. She did not receive postoperative chemotherapy or radiotherapy and is under follow-up. The case is reported for its occurrence in an uncommon anatomic site and preoperative dilemma with relevant review of literature.

Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

BackgroundWe previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors.MethodsChanges in cell phenotype and function following knockdown of wild-type p53 (p53-KD) were assessed using OCCCa cells expressing endogenous HNF-1β and ARID1A. The prognostic significance of molecules that were deregulated following p53-KD was also examined using 129 OCCCa/OHGSeCa cases.Resultsp53-KD cells had increased expression of Snail, phospho-Akt (pAkt), and pGSK3β, and decreased E-cadherin expression, leading to epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The cells also exhibited acceleration of cell motility and inhibition of cell proliferation and apoptosis. Next generation sequencing revealed that fibronectin (FN) expression was significantly increased in the p53 KD-cells, in line with our observation that wild-type p53 (but not mutant p53) repressed FN1 promoter activity. In addition, treatment of OCCCa cells with FN significantly increased cell migration capacity and decreased cell proliferation rate, independent of induction of EMT features. In clinical samples, FN/p53 scores were significantly higher in OCCCa/OHGSeCa with the HNF-1β+/p53+/ARID1A+ immunophenotype when compared to others. Moreover, high FN/high p53 expression was associated with the worst overall survival and progression-free survival in OCCCa/OHGSeCa patients.ConclusionThese findings suggest that upregulation of FN following loss of p53 function may impact the biological behavior of OCCCa/OHGSeCa, particularly in tumors with an HNF-1β+/p53+/ARID1A+ immunophenotype, through alterations in cell mobility and cell proliferation. The accompanying induction of EMT/CSC properties and inhibition of apoptosis due to p53 abnormalities also contribute to the establishment and maintenance of tumor phenotypic characteristics.4HYHfp8oPTLQGnKo7co1TGVideo

Ascites as a subject of studies in ovarian cancer

Ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. High- grade serous ovarian carcinoma is the most common histological subtype of ovarian cancer. The majority of ovarian cancer patients present with malignant ascites at diagnosis. Peritoneal dissemination is one of the most unfavorable factors for tumor progression and recurrence. A more precise visualization of peritoneal carcinomatosis can be achieved by transabdominal ultrasound. However, the prognostic factors associated with malignant ascites in ovarian cancer are currently not well understood. Among the clinical parameters, the volume of ascites has the greatest information in terms of prognosis of disseminated ovarian cancer. Ovarian cancer with small-volume ascites has a more favorable therapeutic prognosis. Ascites is an easily accessible and valuable source of cellular and extracellular components contained in it that are involved in ovarian carcinogenesis. Ascites represents an accessible and valuable source of material to identify signals that influence tumor growth. At present, among the soluble high- and low molecular components of ascites, an active search for additional prognostic and predictor factors is being conducted, providing insights into the molecular mechanisms for clinical phenotypes of ovarian cancer.

Comparison of benign peritoneal fluid- and ovarian cancer ascites-derived extracellular vesicle RNA biomarkers

BackgroundExtracellular vesicles (EVs) are considered as a new class of resources for potential biomarkers. We analyzed expression of specific mRNA and miRNA in EVs derived from ovarian cancer ascites and the ideal controls, peritoneal fluids from benign patients for potential early detection and prognostic biomarkers.MethodsFluids were collected from subjects with benign cysts or endometrioma (n = 10), or low/high grade serous ovarian carcinoma (n = 8). EV particles were captured using primarily ExoComplete filterplate or ultracentrifugation and analyzed by nanoparticle tracking analysis, ELISA, and scanning electron microscopy. EV RNAs extracted from two ascites and three peritoneal fluids were submitted for next-generation sequencing. The expression of 34 mRNA and 18 miRNAs in the EVs isolated from patient fluids and cell line media was determined using qPCR.ResultsEVs isolated from patient samples had concentrations greater than 1010 EV particles/mL and 30% were EpCAM-positive based on ELISA. EV particle sizes averaged 113 ± 11.5 nm. The qPCR studies identified five mRNA (CA11, MEDAG, LAMA4, SPINT2, NANOG) and six miRNA (let-7b, miR23b, miR29a, miR30d, miR205, miR720) that were significantly differentially expressed between cancer ascites and peritoneal fluids. In addition, CA11 mRNA was decreased to 0.5-fold and SPINT2 and NANOG mRNA were significantly increased up to 100-fold in conditioned media of cancer cells compared to immortalized ovarian surface and fallopian tube epithelial cell lines, the hypothesized cells of origin for ovarian cancer development.ConclusionsThis study indicates that EV mRNA profiles can reflect the disease stage and may provide a potentially novel source for discovery of biomarkers in ovarian cancer.

Abstract A07: Homologous recombination mutations and overall survival in high-grade serous, endometrioid, and clear cell ovarian carcinomas.

Abstract Background: Defects in homologous recombination (HR) DNA repair are common in high grade serous ovarian, peritoneal and fallopian tube carcinoma (HGSOC). Other than mutations in BRCA1 and BRCA2 (BRCA1/2), the molecular causes of HR deficiency have not been well delineated. The frequency of HR deficiency in non-serous ovarian carcinoma is not known. We previously identified that germline and somatic HR mutations in 13 genes in OC was associated with improved survival. We sought to replicate these data in an independent tumor set, while sequencing a larger number of DNA repair genes. Methods: We used BROCA-HR to sequence 65 DNA repair genes in germline (blood) and tumor DNA from 363 women with ovarian (262), peritoneal (91), or fallopian tube (10) carcinoma from an institutional tissue bank. Cox proportional hazards models, adjusted for stage and residual tumor after cytoreduction, were used to assess associations between mutations in DNA repair genes in HR or related pathways and overall survival from diagnosis. Results: In total, 96/363 (25%) patients had 59 germline and 45 somatic deleterious mutations in HR genes, including 34 germline and 22 somatic BRCA1/2 mutations. Damaging mutations found in other HR genes included 25 germline and 23 somatic in the following genes: 5 ATM, 6 ATR, 1 BAP1, 2 BARD1, 6 BLM, 2 BRIP1, 2 BRE, 1 BRCC3, 2 CHEK2, 1 ERCC1, 1 FANCG, 1 FANCI, 2 FANCL, 8 FANCM, 1 NBN, 2 PALB2, 1 RAD51D, 1 RBBP8, 1 SLX4, 1 UIMC1 and 1 XRCC2. Of 322 HGSOC, HR mutations occurred in 86 patients (26.7%) including 54 (16.8%) germline and 32 somatic (9.9%). HR mutation rates were similar across the different non-serous histologies. Of 13 clear cell OC, 2 (15.3%) had germline mutations in non-BRCA1/2 HR genes and 3 (23.1%) had PTEN/PIK3CA mutations. Of 27 endometrioid OC, 3 (11.1%) had HR mutations (1 germline BRCA1, and 2 non-BRCA1/2 somatic HR mutations). PTEN/PIK3CA mutations were identified in 9 (2.8%) HGSOC, 3 (23.1%) clear cell and 2 (7.5%) endometrioid. HR mutations demonstrated a trend towards improved long-term overall survival (hazard ratio = 0.78, 96% CI 0.57-1.05) after accounting for stage and debulking status. Conclusions: These data not only indicate that damaging HR mutations, both germline and somatic, are found in endometrioid and clear cell as well as HGSOC, but also confirm our previous results showing an association between HR mutations and improved overall survival in OC. We are now sequencing 163 additional non-serous OC to augment the current analysis and these data will be available at presentation. Citation Format: Maria I. Harrell, Matthew J. Maurer, Ethan P. Heinzen, Ming K. Lee, Kimberly R. Kalli, Kathy J. Agnew, Ann L. Oberg, Tom Walsh, Barbara M. Norquist, Lynn C. Hartmann, Scott H. Kaufmann, Elizabeth M. Swisher. Homologous recombination mutations and overall survival in high-grade serous, endometrioid, and clear cell ovarian carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A07.

Abstract 4442: TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizing agents in monoclonal cells and comparison of clinical outcomes from The Cancer Genome Atlas data

Abstract TP53 is mutated in 96% of high grade serous epithelial ovarian carcinomas (HGS EOC) sequenced by The Cancer Genome Atlas (TCGA). Missense mutations at hot spot codons R273, R248, and R175 are the most common oncogenic TP53 mutations among ovarian cancers. To evaluate if TP53 hot spot mutations confer selective resistance to microtubule stabilizing agents (MSAs), the effects of MSAs on hot spot TP53 mutant ovarian carcinoma cell lines were determined. HGS EOCs that expressed one of the three most common TP53 hot spot missense mutations were also identified and studied using TCGA datasets. The human TP53 wild-type ovarian carcinoma cell line A2780 was stably transfected with an empty vector pCMV-neo or a missense TP53 mutation at hot spot codon 175 (m175), 248 (m248), or 273 (m273). Doubling times and inhibitory concentrations of each cell line treated with the MSAs paclitaxel, epoB, and ixabepilone were determined. Effects of epoB on TP53 expression, phosphorylation, and acetylation, as well as TP53-regulated expression of p21 and mdm2, were examined by Western blot analysis. Expression of TP53 target genes p21, GADD45, BAX, PIDD, NF-kB2, PAI-1, and MDR1 was also measured by RT-PCR. Available TCGA genomic and clinical datasets of HGS EOCs were used to identify patients whose tumors expressed one of the three most common TP53 hot spot mutations. Progression free and overall survival outcomes, TP53 expression levels, and available disease and treatment parameters of patients with the hot spot mutations were compared. PARP cleavage, cell growth and cytotoxicity studies demonstrate that the TP53 mutant cell line m248 is resistant to epoB and is not acetylated during epoB treatment. p21 and PAI-1 were induced by epoB in A2780 cells. Expression of p21, GADD45 and PAI-1 in mutant cell lines was generally down regulated. The cell line m273 is 2-3-fold resistant to paclitaxel, possibly due to high expression of MDR1. Patients identified from available TCGA ovarian cancer datasets whose tumors expressed a TP53 missense mutation at codon R273 (n = 15), R248 (n = 11), or R175 (n = 15) demonstrated 10.8, 12.3 and 17.8 months (p = 0.54) median progression free survival and 84.1, 36.1, and 60.6 months (p = 0.23) median overall survival outcomes, respectively. Differences in TP53 expression level, debulking status, disease stage and grade, and age at presentation between cases grouped according to hot spot mutation were not significant. Monoclonal human ovarian cancer cells with different TP53 hot spot mutations were selectively resistant to MSAs paclitaxel and epoB. Patients with HGS EOC and a TP53 hot spot mutation had comparable charactertistics and outcomes. Mutational studies in monoclonal cell lines may offer limited insight regarding clinical disease in HGS EOC considering the established high genetic instability and heterogeneity of HGS EOC. Citation Format: Brandon-Luke L. Seagle, Gerda Hofstteter, Chia-Ping Yang, Kevin Eng, Oluwatosin Odunsi-Akanji, Kunle Odunsi, Shohreh Shahabi. TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizing agents in monoclonal cells and comparison of clinical outcomes from The Cancer Genome Atlas data. [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 4442. doi:10.1158/1538-7445.AM2015-4442

TP53 mutations in circulating tumor DNA for response monitoring in patients with high grade serous carcinoma of ovary

TP53 mutations in circulating tumor DNA for response monitoring in patients with high grade serous carcinoma of ovary