Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)^positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, m 2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

BackgroundNovel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors.MethodsExpression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought. The effect of glycolysis pathway inhibitors on the growth of a panel of ovarian cancer cell lines was assessed by use of the SRB proliferation assay. Combination studies were undertaken combining these inhibitors with cytotoxic agents.ResultsMean expression levels of GLUT1 and HKII were higher in high grade serous ovarian cancer (HGSOC), the most frequently occurring subtype, than in non-HGSOC. GLUT1 expression was also significantly higher in advanced stage (III/IV) ovarian cancer than early stage (I/II) disease. Growth dependency of ovarian cancer cells on glucose was demonstrated in a panel of ovarian cancer cell lines. Inhibitors of the glycolytic pathway (STF31, IOM-1190, 3PO and oxamic acid) attenuated cell proliferation in platinum-sensitive and platinum-resistant HGSOC cell line models in a concentration dependent manner. In combination with either cisplatin or paclitaxel, 3PO (a novel PFKFB3 inhibitor) enhanced the cytotoxic effect in both platinum sensitive and platinum resistant ovarian cancer cells. Furthermore, synergy was identified between STF31 (a novel GLUT1 inhibitor) or oxamic acid (an LDH inhibitor) when combined with metformin, an inhibitor of oxidative phosphorylation, resulting in marked inhibition of ovarian cancer cell growth.ConclusionsThe findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4521-4) contains supplementary material, which is available to authorized users.

BACKGROUNDA review of clinicopathologic features and outcome in women with carcinosarcoma of the ovary (also known as malignant mixed mesodermal tumor [MMMT]) compared with a group of women with serous adenocarcinoma (SAC) of the ovary was conducted.METHODSBetween 1984 and 2002, 1568 patients with epithelial ovarian carcinoma and 70 patients with ovarian carcinosarcoma underwent treatment at the Edinburgh Cancer Centre. Analysis was performed on 65 patients with MMMT, and 746 patients with SAC were selected as a group for comparison. Baseline variables were recorded prospectively and response to chemotherapy and progression‐free and cause‐specific survival between the groups were compared.RESULTSPatients with carcinosarcoma had a mean age of 66.6 years, which is significantly older than those with SAC (62.0 years) (P < 0.001). The objective response rate to platinum‐based chemotherapy was found to be significantly lower in patients with carcinosarcoma (25% vs. 60%; P = 0.02). Cause‐specific survival in the carcinosarcoma group was poor and significantly shorter than that observed in the SAC group (median survival of 8.2 months vs. 20.7 months; P < 0.0001). Progression‐free survival in patients with carcinosarcoma also was found to be significantly shorter compared with patients with SAC (median progression‐free survival of 6.4 months vs. 12.1 months; P < 0.001). Achieving optimal debulking at the time of initial surgery was found to be a highly significant factor in patients with carcinosarcoma with regard to determining outcome (median survival of 14.8 months for patients with optimally debulked International Federation of Gynecology and Obstetrics Stage III disease vs. 3.1 months for patients with suboptimally/nondebulked Stage III disease; P < 0.001).CONCLUSIONSOvarian carcinosarcoma is a distinct entity with a poor prognosis. Patients with carcinosarcoma differ from those with SAC with regard to having an older mean age of onset, an inferior response to platinum‐based chemotherapy, and worse progression‐free and cause‐specific survival. The extent of benefit from chemotherapy is unclear. Cancer 2004. © 2004 American Cancer Society.

Although sporadic EOC commonly remains confined to the peritoneum, BRCA1/2-deficient ovarian cancer frequently metastasizes to viscera. These data extend the ovarian BRCAness phenotype, imply BRCA1/2-deficient ovarian cancer is biologically distinct, and suggest that patients with visceral metastases should be considered for BRCA1/2 sequencing.

BACKGROUND. Clinicopathological features and outcome of women with endometrioid and serous ovarian adenocarcinoma were compared. METHODS. Between 1984 and 2004, baseline and follow‐up data were prospectively recorded on 1545 patients with ovarian cancer. Of these, 270 had pure endometrioid tumors; 659 had pure serous adenocarcinoma of the ovary. Response to platinum‐based chemotherapy (PBC) overall survival, stage‐for‐stage median progression‐free survival (PFS), and cause‐specific median survival were compared. Independent predictors of survival were examined by using multivariate analyses. RESULTS. Median age of diagnosis for patients with endometrioid tumors was younger than those with serous adenocarcinoma of the ovary (60 years vs 62 years; P = .013). They presented more often with early disease (stage I and II; 50% vs 17%; P < .001), had less ascites, and had better performance status both overall and for stage II and III disease. More endometrioid tumors were optimally debulked overall (71% vs 45%; P < .001), but there was no difference according to stage. Objective and CA125 PBC response rates were not significantly different, but median PFS was better for patients with endometrioid tumors (24 months vs 13 months; P < .0001) as was overall median survival (48 months vs 22 months; P < .0001). This relation remained for stage II and III disease and for moderately and poorly differentiated tumors. Patients with concurrent endometrioid ovarian and endometrial malignancies had a survival advantage compared with those with ovarian malignancies alone. Independent predictors of survival after PBC were histological type, debulking status, and disease stage. CONCLUSIONS. Despite similar PBC response rates, endometrioid histology is associated with better survival compared with serous adenocarcinoma of the ovary, even with stage III or poorly differentiated tumors. Cancer 2008. © 2008 American Cancer Society.

Objective Investigate the clinical landscape of ovarian carcinoma (OC) over time. Design Register-based prospectively collected data.

Background Ovarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention. Methods We curated the largest pathologically confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival and comparison against high-grade serous ovarian carcinoma (HGSOC). Results Eighty-two OCS patients were identified; overall survival was poor (median 12.7 months). In all, 79% demonstrated epithelial components of high-grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with endometrioid carcinomatous components. Earlier stage, complete resection and platinum-containing adjuvant chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older (P < 0.0001), more likely to be FIGO stage I (P = 0.025), demonstrated lower chemotherapy response rate (P = 0.001) and had significantly poorer survival (P < 0.0001). Conclusion OCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Histological subclassification does not identify patient subgroups with distinct survival. Aggressive adjuvant chemotherapy should be considered for all cases, including those with early-stage disease.