High-grade Epithelial Ovarian Cancer Research Articles

A Study of Mirvetuximab Soravtansine in Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

A Study of Mirvetuximab Soravtansine in Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

Upfront Maintenance Poly(Adenosine Diphosphate Ribose) Polymerase Inhibitors in Ovarian Cancer: A Ray of Hope or Just a Mirage!

AbstractPoly(adenosine diphosphate ribose) polymerase inhibitors (PARPis), when used in patients harboring tumor with homologous recombination deficiency, with or without BRCA mutation, have shown favorable outcomes in relapsed, advanced metastatic breast and ovarian cancers. Olaparib, niraparib, and rucaparib have been approved as maintenance therapy in platinum-sensitive, relapsed, high-grade epithelial ovarian cancer (EOC) responsive to platinum doublet. Olaparib and rucaparib as monotherapy are also indicated in patients who have progressed on three or more lines of chemotherapy, irrespective of platinum sensitivity, in germline or somatic BRCA 1/2-mutated, PARPi-naive patients. Recently, four large multicentric, international Phase III randomized clinical trials have reported outcomes of PARPi in first-line advanced EOC as maintenance therapy either alone or in combination with bevacizumab. Previously bevacizumab, pazopanib, nindetanib, or maintenance chemotherapy in first-line setting has resulted in modest improvements in progression free survival, albeit with significant toxicities and poor cost-effectiveness. We offer in this review to dissect the data pertaining to randomized clinical trials of PARPi use as maintenance therapy in upfront EOCs and ruminate about its role in the contemporary management of ovarian cancers.

PIK3R1W624R Is an Actionable Mutation in High Grade Serous Ovarian Carcinoma.

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.

A Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

A Study of Mirvetuximab Soravtansine vs. Investigator's Choice of Chemotherapy in Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers With High Folate Receptor-Alpha Expression

Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression.

BackgroundRecent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function.MethodsOvarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression.FindingsHerein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers.InterpretationOur results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer.FundThis work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Foundation (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW).

Genome-wide bioinformatics analysis reveals CTCFL is upregulated in high-grade epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy that threatens the health of females. Previous studies have demonstrated that the survival outcomes of patients with different EOC grades varied. Therefore, the EOC grade is considered to serve as a distinctive prognostic factor. To date, the evaluation of ovarian cancer grade relies on pathological examination and a quantitative index for diagnosis is lacking. Furthermore, the dysregulation of genes has been demonstrated to exert pivotal functions in the carcinogenesis of EOCs. Therefore, the identification of effective biomarkers associated with EOC grade is of importance for the development of therapeutic regimens, and also contributes to the prediction of EOC prognosis. Microarrays have been increasingly applied for the identification of potential molecular biomarkers for numerous diseases including EOC. In the present study, four public microarray datasets (GSE26193, GSE63885, GSE30161 and GSE9891) were analyzed. A total of 6,103 upregulated probes corresponding to 5,766 genes, and 4,004 downregulated probes corresponding to 3,707 genes were identified in the GSE26193, GSE63885 and GSE30161 datasets. ALK and LTK ligand 2 was the most downregulated gene associated with the tumor grade, while CCCTC-binding factor like (CTCFL), EGF like domain multiple 6, radical S-adenosyl methionine domain containing 2 and SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 were the most upregulated genes associated with EOC grade. The GSE9891 dataset was added for further analysis. Only one probe (1552368_at) encoding for CTCFL was identified to be consistently upregulated in the four examined datasets. Immunohistochemical analysis was used to detect the expression of CTCFL between low- and high-grade EOC tissues and revealed that the EOC grade was closely associated with CTCFL level. This was corroborated via the reverse transcription-quantitative polymerase chain reaction. Taken together, the results of the present study suggested that CTCFL is upregulated in high-grade epithelial ovarian cancer.

Long non-coding RNA LINC01627 is a prognostic risk factor for epithelial ovarian cancer.

Ovarian malignancies are commonly diagnosed cancers of the female reproductive system. Recent studies have revealed that long non-coding RNAs (lncRNAs) can regulate a variety of oncological processes. In the present study, ovarian cancer expression datasets were searched in the GEO database using the GPL570 platform. Differential lncRNA expression between normal ovarian tissues and ovarian tumors were analyzed using the R package ‘limma’, and patient prognosis was accessed using the package ‘survival’. Four databases, GSE14001, GSE18520, GSE38666 and GSE40595, were used for the analysis. A total of 64 lncRNAs were highly expressed and 4 were downregulated within these four databases. Prognostic analysis of the 68 lncRNAs in the four databases was performed, and revealed that the expression of long intergenic non-protein coding RNA 1627 (LINC01627) was negatively associated with patient prognosis in GSE19829 and GSE62193; there was no association between LINC01627 expression and patient's prognosis in GSE18520 or GSE63885. To investigate the proposed association between LINC01627 and patient prognosis, meta-analysis revealed that the total hazard ratio was 1.38 and the 95% confidence interval was between 1.04 and 1.83. Subgroup analysis revealed that LINC01627 may predict patient prognosis in high-grade, advanced and serous epithelial ovarian cancer, which was a risk factor for prognosis. Further assessment was performed in clinical samples and ovarian cancer cells, where the knockdown of LINC01627 inhibited the proliferative and migratory capacities of HO8910 and HEY cells. Collectively, the present results suggested that lncRNA LINC01627 may serve an oncogenic role in the development of epithelial ovarian tumors.

Abstract CT157: An open-label Phase II study of combination of TSR-042, bevacizumab, and niraparib in patients with platinum-resistant ovarian cancer (OC): Cohort A of the OPAL trial

Abstract Background: Most patients with advanced OC relapse after initial standard platinum-based chemotherapy, and eventually the disease becomes platinum-resistant. Niraparib (ZEJULA®) was the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the United States and Europe for maintenance treatment in patients with recurrent OC regardless of BRCA mutation status. Preclinical evidence suggests that niraparib activates the stimulator of interferon genes pathway to increase immune cell infiltration and synergizes with anti-PD-1 therapy. Additionally, hypoxia induces contextual synthetic lethality by impairing homologous recombination, and therefore induction of hypoxia by inhibition of angiogenesis could lead to synergy with PARPi. In the TOPACIO/KEYNOTE-162 trial, niraparib in combination with pembrolizumab has shown efficacy in recurrent, platinum-resistant OC. Niraparib in combination with the anti-angiogenic agent bevacizumab is under study for the treatment of recurrent platinum-sensitive OC (AVANOVA trial) and advanced OC following response on frontline platinum-based chemotherapy (OVARIO trial). TSR-042 is an anti-PD-1 humanized monoclonal antibody that has shown clinical activity as monotherapy in early phase trials. Cohort A of the OPAL trial will evaluate the novel triple combination of the PARPi niraparib, angiogenesis inhibitor bevacizumab, and PD-1 inhibitor TSR-042 in patients with platinum-resistant OC who are naïve to PARPi therapy. Methods: Eligible patients will have high-grade recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer of the ovary and progressed ≤6 months from completion of ≥4 cycles of platinum-based chemotherapy. Additional key eligibility criteria include 1-2 prior lines of anticancer therapy for OC, no prior therapy with an anti-PD-1 or anti-PD-L1 antibody, and no prior therapy for OC with a PARPi. Patients will receive a combination regimen of 500 mg TSR-042 on day 1 of each 3-week cycle for 4 cycles, then 1000 mg on day 1 of every other cycle beginning on cycle 5 until progression or toxicity, 15 mg/kg bevacizumab on day 1 of each 3-week cycle for up to 15 months, and niraparib 300 mg or 200 mg (for patients <77 kg or platelet count <150,000/µL at screening) daily until disease progression or toxicity. The primary endpoint is to evaluate treatment efficacy by confirmed objective response rate per investigator-assessed RECIST v1.1 criteria. Secondary objectives are evaluation of progression-free survival, overall survival, duration of response, and disease control rate. Exploratory objectives are to identify potential biomarkers of tumor response, including BRCA status and homologous recombination repair gene status and to evaluate the evolution of the molecular profile of the tumor and tumor microenvironment in response to treatment. Clinical trial identification: NCT03574779 Citation Format: Joyce Liu, Camille Gunderson, Andrea Wahner Hendrickson, Elena Ratner, Elisabeth Diver, John Moroney, Rebecca C. Arend, Melinda Louie-Gao, Sarah Wang, Katarina Luptakova, Gottfried E. Konecny. An open-label Phase II study of combination of TSR-042, bevacizumab, and niraparib in patients with platinum-resistant ovarian cancer (OC): Cohort A of the OPAL trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT157.

Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer

BackgroundIn many malignancies including ovarian cancer, different angiogenic factors have been related to poor prognosis. However, data on their relations to each other or importance as a prognostic factor in ovarian cancer is missing. Therefore, we investigated the expressions of VEGF-A, VEGF-C, and VEGF-D, and the receptors VEGFR1, VEGFR2, and VEGFR3 in patients with malignant epithelial ovarian neoplasms. We further compared expression levels between primary tumors and related distant omental metastases.MethodsThis study included 86 patients with malignant ovarian epithelial tumors and 16 related distant metastases. Angiogenic factor expression was evaluated using immunohistochemistry (n = 102) and qRT-PCR (n = 29).ResultsCompared to primary high grade serous ovarian tumors, the related omental metastases showed higher expressions of VEGF-A (p = 0.022), VEGF-D (p = 0.010), and VEGFR1 (p = 0.046). In univariate survival analysis, low epithelial expression of VEGF-A in primary tumors was associated with poor prognosis (p = 0.024), and short progression-free survival was associated with high VEGF-C (p = 0.034) and low VEGFR3 (p = 0.002). The relative expressions of VEGF-D, VEGFR1, VEGFR2, and VEGFR3 mRNA determined by qRT-PCR analyses were significantly correlated with the immunohistochemically detected levels of these proteins in primary high grade serous ovarian cancer and metastases (p = 0.004, p = 0.009, p = 0.015, and p = 0.018, respectively).ConclusionsThe expressions of VEGF receptors and their ligands significantly differed between malignant ovarian tumors and paired distant metastases. VEGF-A, VEGF-D, and VEGFR1 protein expressions seem to be higher in distant metastases than in the primary high grade serous ovarian cancer lesions.

KCNMA1-AS1 attenuates apoptosis of epithelial ovarian cancer cells and serves as a risk factor for poor prognosis of epithelial ovarian cancer.

To explore the role of KCNMA1-AS1 in epithelial ovarian cancer (EOC) and its underlying mechanism. We first screened out the differentially expressed lncRNAs (KCNMA1-AS1) in the GEO (gene expression omnibus) database. The relationship between KCNMA1-AS1 expression and prognosis of EOC with different pathological types was analyzed by meta-analysis. Subsequently, KCNMA1-AS1 expressions in EOC tissues and normal ovarian tissues were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlation between KCNMA1-AS1 level with progression-free survival (PFS) and overall survival (OS) of EOC was analyzed. Furthermore, proliferation and migration of EOC cells transfected with the corresponding plasmids were analyzed by Cell Counting Kit-8 (CCK-8) and transwell assay, respectively. Apoptosis-related genes in EOC cells were detected by Western blot. KCNMA1-AS1 was a risk factor for prognosis in high-grade, advanced and serous EOC. Upregulated KCNMA1-AS1 was found in EOC tissues than that of normal tissues, showing the diagnostic potential of KCNMA1-AS1 in EOC. Statistical analysis indicated that KCNMA1-AS1 was not correlated with the DFS, OS, age, histological type, lymph node metastasis and recurrence, but related to FIGO stage of EOC patients. For in vitro experiments, the proliferation and migration of were enhanced, and apoptosis of HO8910 cells overexpressing KCNMA1-AS1 was inhibited. Furthermore, elevated expressions of Caspase-3 and Caspase-9, as well as reduced expression of Bcl-xL, were observed after KCNMA1-AS1 knockdown in EOC cells. KCNMA1-AS1 is overexpressed in EOC and negatively correlated with its prognosis. KCNMA1-AS1 participates in the occurrence and development of EOC by promoting proliferation, migration and inhibiting apoptosis of ovarian cancer cells via apoptosis pathway.

Germline genetic testing in ovarian cancer patients: Identifying barriers to care and opportunities for improvement.

e13142 Background: Despite recommendations that all patients with non-mucinous high grade epithelial ovarian cancer (EOC) undergo germline genetic testing, only 10-15% of patients nationwide are tested. The aim of this study was to determine the rate of genetic testing at a single academic institution, identify patient characteristics associated with undergoing testing and improve delivery of care by identifying barriers to testing. Methods: An IRB-approved single institution ovarian cancer database was used to identify patients with non-mucinous high grade EOC treated between 1996 and 2017. The rate of genetic testing was calculated and the referral and testing process was mapped. Patient demographics, clinical characteristics and family history was obtained from the medical record. Univariate and multivariate logistic regression was performed. Results: From 1996 to 2017, 588 patients were treated for non-mucinous EOC. Of those, 200 patients (34%) were referred for genetic counseling and 175 (30%) were tested. Younger patients were more likely to undergo testing. Fewer African Americans had genetic testing than Caucasians (18% vs 33%, p = 0.003) and patients with public insurance were less likely to undergo testing compared to those with private insurance (23% vs 34%, p = 0.005). Patients with recurrent disease were less likely to undergo testing but rates did not vary by cancer stage or histology. A family history of cancer was the most significant predictor (43% vs 11%, OR = 5.85, p < 0.001). For patients diagnosed in the past 5 years, the testing rate improved to 57.9%. When the referral and testing process was mapped, a complex internal referral system was revealed. Barriers to testing included provider awareness, additional patient visits, patient preference and insurance coverage. Conclusions: Rates of germline genetic testing for patients with ovarian cancer have increased over time as guidelines for genetic testing have evolved, however, over two thirds of patients were not tested and African Americans were less likely to be tested. These findings support increasing provider education and patient counseling, testing directly in the gyn/oncology office and consideration for instituting a Traceback program.

DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.

Somatic BRCA Mutation in High Grade Epithelial Ovarian Cancer Patients

Aim: To identify the frequency of somatic BRCA mutation in epithelial ovarian cancer (EOC), particularly those with high grade subtypes. Methods: Patients diagnosed with EOC included fallopian tube cancer or peritoneal cancer who had surgery during January 2015 to December 2016 were included. High grade subtypes included high grade serous carcinoma, poorly differentiated endometrioid carcinoma, and clear cell carcinoma. BRCA1 and BRCA2 mutations were tested using DNA extracted from formalin-fixed paraffin embedded block or a fresh tumor specimen then analyzed by next generation sequencing system. Patients who had no germline BRCA mutation in their peripheral blood DNA investigated by bi-directional Sanger sequencing were diagnosed as having somatic BRCA mutation.Results: 36 patients were enrolled; majority of the patients (33patients; 97.2%) had EOC, 1 patient (2.8%) had fallopian tube cancer and 2 patients (5.6%) had peritoneal cancer. 28 patients (77.8%) had high grade serous carcinoma, 6 (16.7%) had poorly differentiated endometrioid carcinoma, and 2 (5.6%) had clear cell carcinoma. BRCA1 mutation was detected in tumor tissues of 2 patients (5.6%). These two patients had high grade serous carcinoma and significant family history of breast and/or ovarian cancers. However, BRCA1 mutations were detected in the peripheral blood in both of them.Conclusion: Only 5.6% of BRCA1 mutation was detected in ovarian tumor tissues, all mutations were found in high grade serous subtype. However, BRCA mutations were detected in the peripheral blood in both of them. Germline BRCA mutation was diagnosed, thus there were no somatic mutations in this study.

Cost\u2013utility analysis of germline BRCA1/2 testing in women with high-grade epithelial ovarian cancer in Spain

PurposeGermline mutations in BRCA1 and/or BRCA2 genes (gBRCA1/2m) are associated with an increased risk of breast cancer (BC) and ovarian cancer (OC). The aim of this study was to estimate the efficiency of providing germline BRCA1/2 testing to high-grade epithelial ovarian cancer (HGEOC) patients without family history of OC or BC and the subsequent testing and management of their relatives with gBRCA1/2m in Spain.Methods/patientsIncident HGEOC patients without family history of OC or BC who were gBRCA1/2m carriers and their relatives were simulated in a 50-year time horizon. The study compared two scenarios: BRCA1/2 testing vs no testing, using the perspective of the Spanish National Health Service. Cancer risk among gBRCA1/2m carriers was estimated based on their age and whether they had undergone risk-reducing surgeries. Direct healthcare costs and utilities of patients who developed EOC and BC were also included. A probabilistic sensitivity analysis (PSA) with 5 thousand simulations was developed considering ± 25% of the base-case value.ResultsThe BRCA1/2-testing scenario amounted to €13,437,897.43 while the no-testing scenario amounted to €12,053,291.17. It was estimated that the screening test improved the quality of life among the patients’ relatives by 43.8 quality-adjusted life years (QALYs). The incremental cost–utility ratio (ICUR) was €31,621.33/QALY in the base case. The PSA showed that 89.12% of the simulations were below the €50,000/QALY threshold.ConclusionProviding this screening test to HGEOC patients and their relatives is cost-effective and it allows one to identify a target population with high risk of cancer to provide effective prevention strategies.

Olaparib Tablet: A Review in Ovarian Cancer Maintenance Therapy.

Olaparib (Lynparza®), a first-in-class poly (ADP-ribose) polymerase (PARP) inhibitor, has recently been approved in a new tablet formulation as maintenance treatment for recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Relative to an earlier capsule formulation, the tablet formulation of olaparib has improved bioavailability, thereby reducing pill burden and offering a more convenient dosage regimen. In the phase III SOLO2 study, maintenance treatment with olaparib tablets significantly prolonged median PFS (primary endpoint) relative to placebo in patients with platinum-sensitive, recurrent, ovarian cancer bearing gBRCA mutations. Results from an earlier phase II study (Study 19) assessing the capsule formulation supported these findings, with a significant PFS benefit (primary endpoint) observed with olaparib relative to placebo as maintenance therapy in patients with platinum-sensitive, recurrent, ovarian cancer, with or without BRCA mutations. Olaparib tablet had a manageable tolerability profile, with most adverse events of mild or moderate severity. Given its efficacy and manageable tolerability profile, olaparib tablets provide a useful maintenance treatment option for recurrent, platinum-sensitive ovarian cancer, regardless of BRCA mutation status, with the tablet formulation providing a more convenient dosing option.

Response to pembrolizumab in a heavily treated patient with metastatic ovarian carcinosarcoma

BackgroundOvarian carcinosarcoma is a rare malignancy associated with a high rate of cancer-related mortality even at early stages. Guidelines for systemic treatment have been difficult to establish because the disease is commonly excluded from prospective clinical trials. Ovarian carcinosarcoma is usually managed as high-grade epithelial ovarian cancer despite major histologic differences. Owing to the rarity and poor prognosis of ovarian carcinosarcoma, salvage treatments and their efficacy have been poorly described.Case presentationA patient heavily treated for ovarian carcinosarcoma showed an objective response to an immune checkpoint inhibitor, pembrolizumab. Pembrolizumab in this patient appeared to provide tumor control in multifocal metastatic sites.ConclusionsPembrolizumab should be evaluated in prospective trials for the treatment of ovarian carcinosarcoma and further work is needed to identify patients most likely to respond to this type of intervention.

Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth

BackgroundThe disruption of E-cadherin-mediated adhesion is considered an important driver of tumor progression. Nevertheless, numerous studies have demonstrated that E-cadherin promotes growth- or invasion-related signaling, contrary to the prevailing notion. During tumor progression, epithelial ovarian cancer (EOC) maintains E-cadherin expression and can positively affect EOC cell growth by contributing to PI3K/AKT activation. In polarized epithelia PLEKHA7, a regulator of the zonula adherens integrity, impinges E-cadherin functionality, but its role in EOCs has been never studied.MethodsEx-vivo EOC cells and cell lines were used to study E-cadherin contribution to growth and EGFR activation. The expression of the proteins involved was assessed by real time RT-PCR, immunohistochemistry and western blotting. Cells growth and drug susceptibility was monitored in different 3-dimensional (3D) systems. Recombinant lentivirus-mediated gene expression, western blotting, immunoprecipitation and confocal microscopy were applied to investigate the biological impact of PLEKHA7 on E-cadherin behaviour. The clinical impact of PLEKHA7 was determined in publicly available datasets.ResultsWe show that E-cadherin expression contributes to growth of EOC cells and forms a complex with EGFR thus positively affecting ligand-dependent EGFR/CDK5 signaling. Accordingly, 3D cultures of E-cadherin-expressing EOC cells are sensitive to the CDK5 inhibitor roscovitine combined with cisplatin. We determined that PLEKHA7 overexpression reduces the formation of E-cadherin-EGFR complex, EGFR activation and cell tumorigenicity. Clinically, PLEKHA7 mRNA is statistically decreased in high grade EOCs respect to low malignant potential and low grade EOCs and correlates with better EOC patient outcome.ConclusionsThese data represent a significant step towards untangling the role of E-cadherin in EOCs by assessing its positive effects on EGFR/CDK5 signaling and its contribution to cell growth. Hence, the inhibition of this signaling using a CDK5 inhibitor exerts a synergistic effect with cisplatin prompting on the design of new therapeutic strategies to inhibit growth of EOC cells. We assessed for the first time in EOC cells that PLEKHA7 induces changes in the asset of E-cadherin-containing cell-cell contacts thus inhibiting E-cadherin/EGFR crosstalk and leading to a less aggressive tumor phenotype. Accordingly, PLEKHA7 levels are lower in high grade EOC patient tumors and EOC patients with better outcomes display higher PLEKHA7 levels.

2336 Novel PGF2a synthesis pathway in epithelial ovarian cancer

OBJECTIVES/SPECIFIC AIMS: To understand the role of PGF2a and to characterize a novel cyclooxyrgenase (COX)-independent prostaglandin synthesis pathway in epithelial ovarian cancer. METHODS/STUDY POPULATION: We used high grade epithelial ovarian cancer cell line (OVCAR3) as a model to study our pathway. Our main mode of PGF2a detection is through mass spectrometry. RESULTS/ANTICIPATED RESULTS: Our current results suggest the OVCAR3 cells may synthesize PGF2a independently of COX enzymes. We anticipate this novel pathway may be dependent on the TGFb pathway. DISCUSSION/SIGNIFICANCE OF IMPACT: Understanding the role and synthesis pathway of PGF2a may allow us to uncover a novel therapeutic pathway for high grade ovarian cancer.

Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance

ObjectiveThe aim of this study was to compare response rates and survival in women with “platinum resistant” epithelial ovarian cancer (EOC) who received further platinum-based or non‑platinum chemotherapy for treatment at first relapse. MethodsPatients with high-grade EOC (including fallopian tube and peritoneal cancer) of all histologies recruited to the Australian Ovarian Cancer Study (AOCS) and treated with platinum-based primary chemotherapy were included. Response to second-line chemotherapy, overall survival (OS) and survival after treatment for first progression (OS2) were determined in all histologies and separately in women with high-grade serous tumors. ResultsOf the 341 patients classified as platinum-resistant by the 6-month threshold, 243 (71%) were treated with chemotherapy at relapse. CA-125 response rates to platinum-based chemotherapy were significantly higher compared to non‑platinum chemotherapy (51% vs 21%, P < 0.001). Among patients with a platinum-free interval (PFI) of 3–6 months, OS2 in patients treated with platinum was significantly longer compared to individuals receiving non‑platinum-based treatment (median 17.67 months, 95% CI: 14.79–20.75 vs. 10.62 months, 95% CI: 8.02–12.72, P = 0.022). The patterns were similar when restricted to patients with high-grade serous histology. In patients with PFI <3 months, there was no significant difference in response or survival according to type of second-line treatment. ConclusionsOur findings further question the use of a 6-month PFI as an arbitrary threshold for subsequent treatment decision-making. Some patients considered “platinum resistant” still derive clinical benefit from platinum-based chemotherapy. Biomarkers of platinum sensitivity are needed in clinical practice to identify potential responders who should be offered re-treatment with platinum.

Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer.

Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) proteins (PARP-1, PARP-2 and PARP-3) that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD) genes are particularly sensitive to PARP inhibitors because of “synthetic lethality”, whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA-mutant and BRCA–wild-type epithelial ovarian cancers (EOCs). Dose-escalation Phase I studies have established the recommended Phase II dose to be 600 mg twice a day for oral rucaparib. Phase II and III studies have defined its role as treatment for BRCA-mutant recurrent high-grade EOC and as maintenance treatment for platinum-sensitive relapsed EOC following response to platinum-based chemotherapy. Genomic loss of heterozygosity has also been investigated as a potential signature of HRD and as a potential predictive biomarker of response. Treatment-induced adverse events (AEs) have been observed in almost all patients treated with rucaparib, but mainly lower grade; with the most common being nausea, vomiting, asthenia/fatigue, anemia and transient transaminitis. The majority of AEs occurred early in treatment, were transient and have been easily managed with supportive treatment, dose interruption or discontinuation. This review will analyze the results of clinical trials investigating efficacy and safety of rucaparib in patients with ovarian cancer.