Outcome In Ovarian Cancer Patients Research Articles

Tumor necrosis factor receptor modulator spermatogenesis-associated protein 2 is a novel predictor of outcome in ovarian cancer.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor‐α (TNF‐α) as a key mediator. Recently, spermatogenesis‐associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF‐induced inflammation and apoptosis. The available data on TNF‐α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real‐time polymerase chain reaction in tissues of 171 patients with low‐grade serous (LGSOC), high‐grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non‐malignant control tissues. We stimulated OC cells (OVCAR3) with pro‐inflammatory (TNF‐α, interleukin [IL]‐1β) and mitogenic stimuli (IL‐6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro‐inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, r s = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression‐free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF‐α and IL‐1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies.

The mTOR downstream regulator (p-4EBP1) is a novel independent prognostic marker in ovarian cancer

Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine the classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. This study aims to investigate the prognostic role of p-mTOR and its major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. p-mTOR, p-4EBP1 and p-P70S6K protein expression was assessed on 195 consecutive ovarian epithelial cancers and correlated to clinicopathological features and survival. We found that high cytoplasmic expression of p-4EBP1 and p-P70S6K was associated with a serous type carcinoma (p = .005) and an advanced FIGO stage (p = .012), respectively. Univariate outcome analysis showed an inverse association between a high expression of p-4EBP1 expression and overall ovarian cancer survival (OS; p = .005) and progression-free survival (PFS; p = .005). p-P70S6K showed an inverse association with PFS (p = .001). Multivariate analyses indicated that p-4EBP1 was an independent predictor of both OS and PFS (p = .016 and p = .041, respectively). Therefore, we concluded that p-4EBP1 high protein expression is an independent predictor of outcome in ovarian cancer patients. Therefore, it could be used as a potential biomarker for prognostic stratification and treatment decisions.Impact statementWhat is already known on this subject? The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer.What do the results of this study add? In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer.What are the implications of these findings for clinical practice and/or further research? p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management.

Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin.

Ovarian cancer stem cells (OCSCs) are sources of tumor chemoresistance and recurrence. A hypoxic microenvironment contributes to the chemoresistance of cancer stem cells (CSCs), but the underlying mechanism is not fully understood yet. Here, we show that increased HIF‐2α expression is associated with enhanced stemness of OCSCs and poor outcomes in ovarian cancer patients. OVCAR‐3 and CAOV‐3 sphere‐forming (OVCAR‐3 S and CAOV‐3 S) cells with OCSC‐like properties showed strong resistance to adriamycin (ADR). Hypoxia (1% O2) induced high expression of both HIF‐1α and especially HIF‐2α, and increased the resistance of OVCAR‐3 S and CAOV‐3 S cells to ADR. Notably, treatment with ADR further increased the expression of HIF‐2α, but not that of HIF‐1α. Knockdown of HIF‐2α expression substantially attenuated the resistance of OVCAR‐3 S and CAOV‐3 S cells to ADR, and the HIF‐2α overexpression had the opposite effect. Furthermore, in mouse models xenografted with OCSCs, HIF‐2α depletion significantly inhibited tumor growth and sensitized OCSCs to ADR in vivo. Mechanistically, HIF‐2α directly promotes transcription/expression of BCRP, a gene encoding a transporter protein responsible for pumping drugs (e.g., ADR) out of cells, which in turn increases drug resistance due to increased drug transportation. Collectively, our studies reveal a novel drug‐resistant mechanism in ovarian cancer by which hypoxia (and ADR treatment)‐induced HIF‐2α overexpression endows OCSCs with resistance to ADR by promoting BCRP expression and ADR transportation. Therefore, targeting the HIF‐2α/BCRP axis holds therapeutic potential for treating drug‐resistant ovarian cancer.

Downregulated Salt-inducible Kinase 3 Expression Promotes Chemoresistance in Serous Ovarian Cancer via the ATP-binding Cassette Protein ABCG2.

Background: Epithelial ovarian cancer (EOC) has a high tumor-associated mortality rate among gynecological cancers. Although CA125 is a well-studied biomarker for ovarian cancer, it is also elevated under numerous conditions, resulting in decreased specificity. Recently, we identified a novel tumor-associated antigen, salt-inducible kinase 3 (SIK3), during tumorigenesis in ovarian cancer. However, the association between SIK3 expression and patient outcomes in ovarian cancer remains unclear.Materials and Methods: We collected EOC samples from 204 patients and examined tumor SIK3 expression by immunohistochemistry (IHC) and CA125 expression in tumors and serum. The expression levels of SIK3 and CA125 were correlated with patient survival. SIK3 expression was silenced with SIK3-specific shRNAs to investigate the possible mechanisms related to chemoresistance in serous-type ovarian cancer cell lines OVCAR4 and SKOV3.Results: In advanced-stage serous ovarian cancer, patients with low SIK3 expression have poorer overall survival (OS) and progression-free survival (PFS) than patients with high SIK3 expression. Ovarian cancer cells with SIK3 knockdown display increased chemoresistance to Taxol plus cisplatin treatment, which is associated with the upregulation of the ABCG2 transporter. In addition, in serous ovarian cancer, SIK3 expression is inversely correlated to ABCG2 expression, and patients with low SIK3 and high ABCG2 expression have worse prognosis than patients with high SIK3 and low ABCG2 expression.Conclusion: Our results demonstrated that serous EOC patients with low SIK3 expression have poor prognosis, which is associated with chemoresistance mediated by ABCG2 upregulation. SIK3 and ABCG2 expression levels may be potential prognostic markers to predict the outcome in serous EOC patients.

Clinical significance of c-Met and phospho-c-Met (Tyr1234/1235) in ovarian cancer

Objectivec-Met is expressed in human ovarian cancer tissues, and its phosphorylation activates signaling cascades that might affect the behavior of cancer cells. In this study, we evaluated the association of c-Met and phosphorylated c-Met (phospho-c-Met) expressions with the clinical outcomes of ovarian cancer patients. Materials and methodsArchived tissue from surgical specimens of 269 ovarian cancer patients who underwent a debulking operation in MacKay Memorial Hospital between 2004 and 2012 were collected. Tissue microarrays were stained with anti-Met and anti-phospho-Met (Tyr1234/1235) monoclonal antibodies. Immunostaining intensity was scored on a scale of 0–3+. High expression was defined as more than 50% of moderate and intense staining. Patients’ clinical data were reviewed until April 2017 for analysis. ResultsThe proportion of high c-Met expression was significantly higher in patients with cancer in early stages (Federation of Gynecology and Obstetrics stages I and II) and low histologic grades (grades 1 and 2) (79.70%, p = 0.0008 and 80.15%, p ≤ 0.0001, respectively). However, no association was found between phospho-c-Met and FIGO stage or the histologic grade. Ovarian clear cell carcinoma and mucinous carcinoma had much higher c-Met expression (95.16% and 87.10%, p ≤ 0.0001 and p = 0.0292, respectively). Although the overall survival did not differ significantly, low expressions of c-Met and phospho-c-Met were obviously associated with poor progression-free survival respectively (p = 0.0034, HR: 0.5264, 95% CI: 0.3326–0.8330 and p = 0.0136, HR: 0.5626, 95% CI: 0.3709–0.8535). ConclusionLow c-Met expression was associated with poor clinical outcomes.

Prognostic values of S100 family members in ovarian cancer patients

ObjectiveExhibiting high consistence in sequence and structure, S100 family members are interchangeable in function and they show a wide spectrum of biological processes, including proliferation, apoptosis, migration, inflammation and differentiation and the like. While the prognostic value of each individual S100 in ovarian cancer is still elusive. In current study, we investigated the prognostic value of S100 family members in the ovarian cancer.MethodsWe used the Kaplan Meier plotter (KM plotter) database, in which updated gene expression data and survival information are from 1657 ovarian cancer patients, to assess the relevance of individual S100 family mRNA expression to overall survival in various ovarian cancer subtypes and different clinicopathological features.ResultsIt was found that high expression of S100A2 (HR = 1.18, 95%CI: 1.04–1.34, P = 0.012), S100A7A (HR = 1.3, 95%CI: 1.04–1.63, P = 0.02),S100A10 (HR = 1.2, 95%CI: 1.05–1.38, P = 0.0087),and S100A16 (HR = 1.23, 95%CI: 1–1.51, P = 0.052) were significantly correlated with worse OS in all ovarian cancer patients, while the expression of S100A1 (HR = 0.87, 95%CI: 0.77–0.99, P = 0.039), S100A3 (HR = 0.83, 95%CI: 0.71–0.96, P = 0.0011), S100A5 (HR = 0.84, 95%CI: 0.73–0.97, P = 0.017), S100A6 (HR = 0.84, 95%CI: 0.72–0.98, P = 0.024), S100A13 (HR = 0.85, 95%CI:0.75–0.97, P = 0.014) and S100G (HR = 0.86, 95%CI: 0.74–0.99, P = 0.041) were associated with better prognosis. Furthermore, we assessed the prognostic value of S100 expression in different subtypes and the clinicopathological features, including pathological grades, clinical stages and TP53 mutation status, of ovarian cancer patients.ConclusionComprehensive understanding of the S100 family members may have guiding significance for the diagnosis and outcome of ovarian cancer patients.

Clinical relevance of cytoskeleton associated proteins for ovarian cancer.

Ovarian cancer has a high mortality rate and up to now no reliable molecular prognostic biomarkers have been established. During malignant progression, the cytoskeleton is strongly altered. Hence we analyzed if expression of certain cytoskeleton-associated proteins is correlated with clinical outcome of ovarian cancer patients. First, in silico analysis was performed using the cancer genome atlas (TCGA), the human expression atlas and Pubmed. Selected candidates were validated on 270 ovarian cancer patients by qRT-PCR and/or by western blotting. In silico analysis revealed that mRNAs of 214 cytoskeleton-associated proteins are detectable in ovarian cancer tissue. Among these, we selected 17 proteins that participate in cancer disease progression and cytoskeleton modulation: KIF14, KIF20A, KIF18A, ASPM, CEP55, DLGAP5, MAP9, EB1, KATNA1, DIAPH1, ANLN, SCIN, CCDC88A, FSCN1, GSN, VASP and CDC42. The first ten candidates interact with microtubules (MTs) and the others bind to actin filaments. Validation on clinical samples of ovarian cancer patients revealed that the expression levels of DIAPH1, EB1, KATNA1, KIF14 and KIF18A significantly correlated with clinical and histological parameters of ovarian cancer. High DIAPH1, EB1, KATNA1 and KIF14 protein levels were associated with increased overall survival (OAS) of ovarian cancer patients, while high DIAPH1 and EB1 protein levels were also associated with low differentiation of respective tumors (G2/3). Moreover, DIAPH1 was the only protein, whose expression significantly correlated with increased recurrence-free interval (RFI). Mainly the expression levels of the MT-associated proteins analyzed in this study, correlated with prolonged survival of ovarian cancer patients. From > 200 genes initially considered, 17 cytoskeletal proteins are involved in cancer progression according to the literature. Among these, four proteins significantly correlated with improved survival of ovarian cancer patients.

Abstract 1325: DIRAS3 (ARHI) is required for amino acid-mediated autophagy and nutrient deprivation in dormant ovarian cancers

Abstract The persistence of dormant, drug-resistant cancer cells after cytoreductive surgery and combination chemotherapy is a major challenge that contributes to poor outcomes for ovarian cancer patients. Despite normalization of CA125 and negative imaging following primary treatment, “second look” surgery can detect small, quiescent, poorly vascularized nodules of persistent ovarian cancer in ~50% of patients. After positive second look operations, persistent ovarian cancer may take months or years to become clinically evident, consistent with tumor dormancy. Autophagy is one mechanism by which persistent, potentially dormant cancer cells could survive in a nutrient poor environment. Autophagy or “self-eating” is a catabolic process by which organelles and misfolded proteins are degraded and recycled to provide energy that could protect dormant cancer cells from acute starvation in the face of an inadequate blood supply. Autophagy can be induced by multiple mechanisms. Our group has found that, in contrast to primary ovarian cancers, the cancer cells in &amp;gt;80% of positive second look biopsies exhibit autophagy and express DIRAS3 (ARHI). DIRAS3 is an imprinted tumor suppressor gene that is downregulated in &amp;gt;60% of primary ovarian cancers by multiple mechanisms including loss of heterozygosity, CpG promoter methylation, transcriptional repression (E2F1/4) and miRNA regulation (miR-221/222). Re-expression of DIRAS3 prevents ovarian cancer growth, inhibits motility, induces autophagy and establishes tumor dormancy in xenografts. When DIRAS3 is upregulated in human ovarian carcinoma cell lines from a doxycycline-inducible promoter in nu/nu murine xenografts cancer cells remain dormant until DIRAS3 is downregulated permitting cell cycling, vascularization and progressive growth. Autophagy is required for survival of dormant xenografts in that treatment with chloroquine, a functional inhibitor of autophagy, markedly delays outgrowth of ovarian cancer xenografts when DIRAS3 is downregulated. Mechanisms by which DIRAS3 is upregulated and autophagy induced in positive second look specimens remains poorly understood. We have found that amino acid deprivation upregulates DIRAS3 and induces autophagy. Knockdown of DIRAS3 markedly decreases induction of autophagy following nutrient deprivation. We have identified that amino acid deprivation results in decreased E2F1/E2F4 expression and transcriptional upregulation of DIRAS3, but changes in promoter methylation or miRNA regulation are not observed. Knockdown of E2F1 or E2F4, both genetically and pharmacologically increase DIRAS3 expression and autophagy. Taken together these results suggest that nutrient deprivation results in transcriptional upregulation of DIRAS3-mediated autophagy and thus likely presents a mechanism by which DIRAS3 is upregulated in dormant, second look ovarian cancer tumor specimens. Citation Format: Margie Nicole Sutton, Gilbert Y. Huang, Jinhua Zhou, Zhen Lu, Robert C. Bast. DIRAS3 (ARHI) is required for amino acid-mediated autophagy and nutrient deprivation in dormant ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1325.

Comparing the impact of dose reductions and delays on ovarian cancer patient outcomes with three-weekly versus dose dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort.

5568Background: To determine if chemotherapy dose reductions and delays in the adjuvant setting impact ovarian cancer pt outcomes. Secondary objective is comparing deliverability of three weekly an...

Evaluation of the peritoneal surface disease severity score (PSDSS) in ovarian cancer patients undergoing cytoreductive surgery and HIPEC: Two pathogenetic types based study.

Clinical experience suggests that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) play an important role in the management of ovarian cancer. In order to improve patient selection, the peritoneal surface disease severity score (PSDSS) was previously introduced for use in colorectal cancer patients. However, almost no data exist regarding the utility of the PSDSS index in ovarian cancer patients. A retrospective study of the effectiveness of CRS and HIPEC was carried out in 59 patients with ovarian cancer. The PSDSS was based on three criteria: symptoms, extent of peritoneal dissemination, and primary tumor structure as assessed by histology and biomarker expression. The overall survival time for patients with ovarian cancer in PSDSS Stage I was 48 ± 25.3 months. For PSDSS Stage II, the survival time was 26.5 ± 4.7 months. For PSDSS Stage III, it was 15.5 ± 4 months, and for PSDSS Stage IV, it was 6 ± 4.3 months. A multivariate analysis showed that the PSDSS stage was the only independent survival predictor. These data demonstrate that a PSDSS based on two pathogenetic types may be useful for predicting survival outcomes in ovarian cancer patients treated with CRS/HIPEC.

Dose-dense weekly chemotherapy in advanced ovarian cancer: An updated meta-analysis of randomized controlled trials.

The use of dose-dense weekly chemotherapy in the management of advanced ovarian cancer (OC) remains controversial. The aim of this meta-analysis was to evaluate the efficacy of dose-dense regimen to improve clinical outcomes in OC patients with the inclusion of new trials. For this updated meta-analysis, PubMed Medline and Scopus databases and meeting proceedings were searched for eligible studies with the limitation of randomized controlled trials, comparing dose-dense chemotherapy versus standard treatment. Trials were grouped in two types of dose-dense chemotherapy: weekly dose-dense (both paclitaxel and carboplatin weekly administration) and semi-weekly dose-dense (weekly paclitaxel and three weekly carboplatin administration). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (http://www.cochrane.org). Primary end-point was progression-free survival (PFS). Four randomized controlled trials comprising 3698 patients were identified as eligible. Dose-dense chemotherapy had not a significant benefit on PFS (HR 0.92, 95% CI 0.81-1.04, p = 0.20). When the analysis was restricted to both weekly and semi-weekly dose-dense data, a no significant interaction between dose-dense and standard regimen was confirmed (HR 1.01, 95% CI 0.93-1.10 and HR 0.82, 95% CI 0.63-1.08, respectively). In the absence of PFS superiority of dose-dense schedule, three weekly schedule should remain the standard of care for advanced OC.

Transcriptome-based signature predicts the effect of taxol in serous ovarian cancer

Taxol is a widely used chemotherapy drug used clinically for ovarian cancer, although the response to Taxol among individuals varies due to the heterogeneity among ovarian cancer patients. In this work, we analyzed differences in the prognostic effect of gene expression and Taxol usage in the Cancer Genome Atlas (TCGA) dataset and identified specific genes associated with the Taxol effect. Using the Cox regression model, a risk model (Taxol score) was developed to assess the outcome of ovarian cancer patients who underwent chemotherapy with Taxol. According to the results, survival was significantly associated with the Taxol score. Moreover, the patients in the high and low Taxol score group had different responses to Taxol. This result was further validated in another two independent datasets. The correlation between clinicopathological indicators was also analyzed, and we determined that the Taxol score is not associated with age, pathological stage, or Taxol treatment, while there was significant correlation with tumor size and grade. Gene Set Enrichment Analysis (GSEA) showed that various signaling pathways including ECM receptor, drug metabolism and ascorbate metabolism pathways were significantly enriched in the high Taxol score group. Collectively, these results indicate that the model is robust for predicting the effectiveness of Taxol by reflecting the various cell statuses of serous ovarian carcinoma.

Predicting Chemotherapy Treatment Outcomes in Ovarian Cancer Patients Using Gene Expression Analysis

Ovarian cancer is the abnormal development of cells found in the ovaries. It is the fifth most fatal cancer amongst woman and has an overall five-year survival rate of 45% (American Cancer Society, 2016). For women with newly-diagnosed, advanced stage ovarian cancer, the current standard of care is surgery – to remove as much of the cancer as possible – followed by chemotherapy – to kill the remaining tumour cells (Cancer.Net Editorial Board, 2016). However, chemotherapy can have devastating side-effects such as infection, nausea, reduced cognitive&#x0D; function, and death (Sun, et al., 2005). Using patients’ genomic profiles to predict how well they will respond to the standard of care will be valuable for patients when deciding whether to pursue standard or alternative forms of treatment. This study uses ovarian cancer patient data compiled by The Cancer Genome Atlas (TCGA). Clinical data – such as patient age, gender, ethnicity, disease severity and treatment undergone – is used to define which patients responded well to chemotherapy. Patient gene expression data – which gives insight into which genes are up- or down-regulated – will be used to identify markers of chemotherapy response. This will be done using differential gene expression analysis – to identify individual genes that contribute to chemotherapy-response – and network analysis – to understand how the expression of these genes functions as a system. To make the results of the study clinically relevant, chemotherapy-response markers will be correlated to single nucleotide polymorphisms – a form of genetic variation that is much quicker to test for in a patient than gene expression.

Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs.

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631-44. ©2017 AACR.

Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients.Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort.Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2 After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20-0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; P = 0.001).Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326-33. ©2017 AACR.

The Impact of Obesity on Performing Lymphadenectomy and Its Outcome in Ovarian Cancer Patients

Background: This study discusses the effect of obesity on the number of lymph nodes harvested during systematic LND and the LND-related complications in ovarian cancer patients. Methods: This retrospective study enrolled women with ovarian cancer who were consecutively subjected to open surgical resection that included systematic LND (pelvic and para-aortic) in the Oncology Center in Mansoura University (OCMU) during the period between January 2012 and June 2017. Patients were categorized according to the recommendations of World Health Organization by their BMI as non-obese (BMI 30.0 kg/m2) and obese (BMI ≥ 30.0 kg/m2). Results: Seventy-seven women with ovarian cancer were enrolled in the study according to our inclusion and exclusion criteria. 43 females (55.8%) were grouped as obese and 34 (44.2%) as non-obese. Lymph nodes retrieved in total and in different stations separately (pelvic and para-aortic) were all similar among patients in both groups. LND-related intraoperative complications were observed in 8 patients (18.6%) in the obese group and 3 patients in the non-obese group (8.8%) (P = 0.347). Hospital stay was the same in the two groups with a median of 4 days (IQR 3 - 5). Postoperative complications occurred in 13 patients (30.2%) in the obese group and only in one patient (3%) in the non-obese group (P = 0.004). Conclusion: Obese ovarian cancer patients may safely undergo comprehensive staging involving extensive lymph node dissection in open surgeries without significant increase in the rates of intraoperative complications. Whereas, postoperative complications (wound infection and thromboembolic events) tend to occur at higher rates with obese patients. Trial registration: This study was retrospectively registered and approved at faculty of Medicine Mansoura University, Egypt with IRB approval number R.18.02.46.

Impact of the time interval from completion of neoadjuvant chemotherapy to initiation of postoperative adjuvant chemotherapy on the survival of patients with advanced ovarian cancer

ObjectiveTo investigate the relationship of the time interval from the completion of neoadjuvant chemotherapy (NAC) to the initiation of postoperative adjuvant chemotherapy (POAC) with the survival outcomes in patients with ovarian cancer. MethodsWe retrospectively investigated 220 patients with pathologically confirmed epithelial ovarian cancer who received NAC at Yonsei Cancer Hospital between 2006 and 2016. The time interval was defined as the period from the completion of NAC, spanning interval debulking surgery (IDS), to the initiation of POAC. ResultsThe median time interval was 42 (range 16–178) days; 103 patients (53.1%) received POAC within 42days after NAC while 91 patients (46.9%) received it after 42days. There were no significant differences in patient characteristics between these 2 groups. Kaplan-Meier analysis showed that patients with longer time intervals (>42days) had poorer progression-free survival and overall survival (P=0.039 and 0.005, respectively). In the multivariate analysis, patients with longer time intervals had significantly poorer progression-free (hazard ratio, 1.41; 95% confidence interval, 0.98–2.03; not significant) and overall survivals (hazard ratio, 2.03; 95% confidence interval, 1.16–3.54). When the patients were categorized according to time interval quartiles (≤37, 38–42, 43–50, and >50days), longer time intervals were associated with higher risks of recurrence and death (P for trend: 0.006 and <0.001, respectively). ConclusionThe time interval from the completion of NAC to the initiation of POAC appears to influence survival. Efforts to reduce the time interval might improve the outcomes in ovarian cancer patients undergoing NAC.

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells.

Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.

The expression of miRNAs is associated with tumour genome instability and predicts the outcome of ovarian cancer patients treated with platinum agents

miRNAs, a class of short but stable noncoding RNA molecules, have been revealed to play important roles in the DNA damage response (DDR). However, their functions in cancer genome instability and the consequent clinical effect as the response to chemotherapy have not been fully elucidated. In this study, we utilized multidimensional TCGA data and the known miRNAs involved in DDR to identify a miRNA-regulatory network that responds to DNA damage. Additionally, based on the expression of ten miRNAs in this network, we developed a 10-miRNA-score that predicts defects in the homologous recombination (HR) pathway and genome instability in ovarian cancer. Importantly, consistent with the association between HR defects and improved response to chemotherapeutic agents, the 10-miRNA-score predicts the outcome of ovarian cancer patients treated with platinum agents, with a surprisingly better performance than the indexes of DNA damage. Therefore, our study demonstrates the implication of miRNA expression on cancer genome instability and provides an alternative method to identify DDR defects in patients who show the best effect with platinum drug treatment.

Immunotherapy in ovarian cancer

Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure.