Venous Thromboembolism In Ovarian Cancer Research Articles

Why are thromboembolic events so common in ovarian cancer? An investigation of tumor-mediated molecular markers (236)

<b>Objectives:</b> It is well known that cancer patients with concurrent venous thromboembolism (VTE) have poorer oncologic outcomes. Even though 25-40% of ovarian cancer patients develop a VTE, the role of tumor-specific molecular factors in VTE development is not known. Therefore, we aimed to perform a comprehensive multi-platform omics analysis to identify factors in ovarian cancer that could be related to the development of VTE or the associated impact on patient outcomes. <b>Methods:</b> Patients diagnosed with high-grade serous ovarian carcinoma (HGSOC) between 2013 and 2019 with frozen tissue and matched germline blood samples available were screened for a concurrent diagnosis of VTE. We performed a multiplatform omics analysis, including bulk RNA sequencing (RNA-seq), proteomics, and DNA whole-exome sequencing (WES), followed by integrated analysis on a total of 32 patient samples (<i>n</i>=16, VTE; <i>n</i>=16, non-VTE as controls). Bioinformatics analyses were then carried out to identify potential molecular abnormalities that could contribute to the pathology of VTE in ovarian cancer. <b>Results:</b> The timing of VTE varied across the 16 cases of VTE, ranging from the onset at the time of diagnosis of ovarian cancer (<i>n</i>=9; 56%), during neoadjuvant chemotherapy (NACT; <i>n</i>=2, 12.5%), and within 28 days of surgery or during adjuvant chemotherapy <i>(n</i>=5; 31.3%). The average overall survival (OS) of patients with VTE was 2.05 years (SD: 1.35); however, OS for the control group could not be calculated since more than 80% (<i>n</i>=13, 81.3%) are still alive with the disease after a mean of 3.5 years (SD: 1.07). RNA-seq analysis revealed 130 differentially expressed genes in VTE versus control. Most notably, the <i>F3</i> gene, which encodes tissue factors, was upregulated in nearly all VTE samples compared to controls. A Cox regression using age, grade, and gene expression indicated an association with worse overall survival for <i>GAPDHP65</i> and <i>NRSN2-AS1</i> with hazard ratios of >1.5 (p=0.018 and p<0.001, respectively). On proteomics analysis, we quantified over 7,300 proteins in VTE versus control, of which 255 were significantly altered (p<0.01). Principal component analysis showed that these altered proteins explained 47.5% of the variance between groups. They did not demonstrate a relationship with the onset of VTE timing, suggesting tumor-mediated changes independent of ovarian cancer treatment status. Among the significantly altered putative drug targets, we identified platelet-derived growth factor subunit B (PDGFB) elevated nearly tenfold in the VTE versus the control group. We also observed a profound trend of increased collagen 1A1 and 3A1 in the VTE group. The proteins elevated in the VTE group were biased towards an expression within the extracellular space. Integrated analyses with RNA-seq data indicate a strong correlation of protein and transcript abundance in 64 candidate proteins (Spearman Rho=0.677, p<0.0001). WES analysis revealed predominantly missense mutations in the form of single-nucleotidepolymorphisms (SNPs). Several distinct genes were mutated within the VTE cohort compared to the control group; however, these did not reach statistical significance, likely due to the small sample size. <b>Conclusions:</b> We provide the first multiplatform comprehensive multi-omics analysis of HGSOC based on VTE development. These findings suggest substantial molecular differences in tumors from patients who develop VTE compared to those that do not. These findings could have implications for risk stratification and preventative and treatment strategies for VTE.

Molecular Correlates of Venous Thromboembolism (VTE) in Ovarian Cancer.

Simple SummaryOvarian cancer is the most lethal form of gynecologic cancer. The prognosis is worse for patients with ovarian cancer who also develop a blood clot in their legs or lungs, known as a venous thromboembolism (VTE). Between 10-30% of women with ovarian cancer will develop a VTE but the mechanism behind this high incidence is not well understood. The aim of this study was to assess for the presence of tumor-specific molecular markers of VTE in order to better understand the relationship between ovarian cancer and VTE. We performed a comprehensive analysis assessing the proteomic and genomic profiles of 32 patients with ovarian cancer and identified that there are molecular differences in patients with a VTE compared to those without.Background: The incidence of venous thromboembolism (VTE) in patients with ovarian cancer is higher than most solid tumors, ranging between 10–30%, and a diagnosis of VTE in this patient population is associated with worse oncologic outcomes. The tumor-specific molecular factors that may lead to the development of VTE are not well understood. Objectives: The aim of this study was to identify molecular features present in ovarian tumors of patients with VTE compared to those without. Methods: We performed a multiplatform omics analysis incorporating RNA and DNA sequencing, quantitative proteomics, as well as immune cell profiling of high-grade serous ovarian carcinoma (HGSC) samples from a cohort of 32 patients with or without VTE. Results: Pathway analyses revealed upregulation of both inflammatory and coagulation pathways in the VTE group. While DNA whole-exome sequencing failed to identify significant coding alterations between the groups, the results of an integrated proteomic and RNA sequencing analysis indicated that there is a relationship between VTE and the expression of platelet-derived growth factor subunit B (PDGFB) and extracellular proteins in tumor cells, namely collagens, that are correlated with the formation of thrombosis. Conclusions: In this comprehensive analysis of HGSC tumor tissues from patients with and without VTE, we identified markers unique to the VTE group that could contribute to development of thrombosis. Our findings provide additional insights into the molecular alterations underlying the development of VTE in ovarian cancer patients and invite further investigation into potential predictive biomarkers of VTE in ovarian cancer.

Association of the Khorana Score with development of venous thromboembolism in ovarian cancer.

5555 Background: The Khorana score is a previously validated method to identify patients at high risk of VTE during chemotherapy who would potentially benefit from thromboprophylaxis. The objectives of our study were to evaluate risk factors and timing associated with VTE in a large cohort of ovarian cancer patients and to assess the predictive ability of the Khorana score in this population. Methods: After IRB approval, a retrospective analysis was performed of all patients with ovarian cancer in the Albert Einstein Tumor Registry who received treatment between 2000 and 2020. Demographic, clinical, surgical and histologic data and information regarding timing of VTE were abstracted from the medical record. Khorana scores were retrospectively calculated for all patients who received chemotherapy based on their pre-chemotherapy laboratory indices. Bivariate analysis and multivariable logistic regression were used to examine the association between Khorana score and VTE. Results: A total of 472 patients were included over a median follow-up time of 33.7 (13.3, 61.1) months of whom 142 (31%) underwent diagnostic imaging to rule out VTE. A total of 62 patients (15%) were diagnosed with VTE with a median time from presentation to VTE of 8.7 (2.7, 30.3) months. Individual covariates which were significantly associated with VTE included stage III-IV disease, epithelial histology, open surgery, radical tumor debulking, and presence of residual disease after surgery. Of the 254 patients who received chemotherapy for their disease, 36 (14%) developed VTE within 3 weeks of receiving chemotherapy. Patients with Khorana scores of 2 (OR 1.73 95% CI 0.88-3.42) or 3 (OR 0.89 95% CI 0.33-2.44) were not significantly more likely to develop VTE during chemotherapy compared to patients with a score of 1. However, patients with a score of 4 were 6.74 times more likely to develop a VTE during chemotherapy (95% CI 1.39 - 32.73). Overall, a Khorana score of 2 or higher conferred no significant increased risk of developing VTE during chemotherapy than a score of 1 (OR 1.61 95% CI 0.85- 3.02). In a multivariable model, the Khorana score was not significantly associated with risk of VTE and a Khorana score of 2 or higher could explain only 0.86% of the variability in predicting VTE. The only variables significantly associated with VTE after adjustment were stage III-IV disease and hyperlipidemia. Conclusions: Patients with ovarian cancer are at high risk of developing VTE many months after diagnosis and initiation of chemotherapy. Current ASCO and SGO guidelines recommend thromboprophylaxis for those initiating chemotherapy with a Khorana score of 2 or higher, however our study found that these patients are not at increased risk compared to those with a score of 1. Future models should be developed and validated in large population-based cohorts to determine if there is a more accurate strategy to identify women with ovarian cancer who are at risk for VTE.

Venous thromboembolisms and rheology in ovarian cancer patients after postoperative adjuvant paclitaxel and carboplatin therapy.

In ovarian cancer patients, chemotherapy can be an independent risk factor for the development of thromboembolic complications, such as venous thromboembolism (VTE). The factors and their values that lead to the development of VTE are remaining unknown in patients undergoing chemotherapy with paclitaxel and carboplatin. This study investigated serial rheological parameters (D-dimer, red blood cell count, hematocrit, and plasma viscosity) for VTE that developed following chemotherapy for ovarian cancer. Forty-eight ovarian cancer patients undergoing chemotherapy were enrolled in this study. A significant difference in the mean values of plasma viscosity and hematocrit was observed between the VTE group (n = 5) and the non-VTE group (n = 43) (P < 0.10). Univariate and multiple regression analyses by stepwise selection identified plasma viscosity as the independent variable associated with VTE development. The VTE incidence was the same as in previous reports. The results support the contention that plasma viscosity could be an index for development of VTE in ovarian cancer after chemotherapy.

Incidence et impact de la maladie thrombo-embolique sur la prise en charge du cancer de l’ovaire

ObjectiveOvarian cancer is a risk factor for venous thromboembolism (VTE), which worsens overall survival. The main objective of our study was to calculate the incidence of VTE in our population. We analyzed VTE impact on diagnosis and management of ovarian cancer. MethodsWe conducted a retrospective, monocentric study in ovarian, fallopian tube and primary peritoneal cancer patients, divided into 2 groups (« Presence of VTE » and « Absence of VTE »). A univariate and multivariate analysis of factors associated with VTE was performed, and we compared delays of management in both groups. ResultsAmong 157 patients included in the study, 22.9% presented a VTE, and 52.8% were asymptomatic. The VTE was diagnosed prior to any treatment in 61.1% of patients and revealed the ovarian cancer in 27.8% of cases. In multivariate analysis, tumor size (OR=1.1, 95% CI: 1–2.21, P=0.012), malnutrition (OR=3.79, 95% CI: 1.16–12,4, P=0.028) and Ddimer level above 1.5μg/mL (OR=13.8, 95% CI 1.2–152.8, P=0.02) were significantly associated with VTE. No significant difference was found between the two groups in diagnostic or therapeutic strategy, as well as in delays of management. ConclusionWe report a high incidence of VTE in ovarian cancer, including a lot of asymptomatic events. An early diagnosis with clinical examination and Ddimer level could improve its management and its prognosis.

A new risk model to predict venous thromboembolism in ovarian cancer

A new risk model to predict venous thromboembolism in ovarian cancer

High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors.

Thromboembolic events occur frequently in ovarian cancer patients. Tissue factor (TF) is often overexpressed in tumours, including ovarian clear-cell carcinoma (CCC), a subtype with a generally poor prognosis. TF-coagulation factor VII (fVII) complexes on the cell surface activate downstream coagulation mechanisms. Moreover, cancer cells secrete extracellular vesicles (EVs), which act as vehicles for TF. We therefore examined the characteristics of EVs produced by ovarian cancer cells of various histological subtypes. CCC cells secreted high levels of TF within EVs, while the high-TF expressing breast cancer cell line MDA-MB-231 shed fewer TF-positive EVs. We also found that CCC tumours with hypoxic tissue areas synthesised TF and fVII in vivo, rendering the blood of xenograft mice bearing these tumours hypercoagulable compared with mice bearing MDA-MB-231 tumours. Incorporation of TF into EVs and secretion of EVs from CCC cells exposed to hypoxia were both dependent on the actin-binding protein, filamin-A (filA). Furthermore, production of these EVs was dependent on different protease-activated receptors (PARs) on the cell surface. These results show that CCC cells could produce large numbers of TF-positive EVs dependent upon filA and PARs. This phenomenon may be the mechanism underlying the increased incidence of venous thromboembolism in ovarian cancer patients.

Beyond prophylaxis: extended risk of venous thromboembolism in ovarian cancer

Bourne, Beth E. BS; Langstraat, Carrie MD; McGree, Michaela E. BS; Amy, Weaver MS; Sarangi, Shikha MBBS; Mokri, Bahareh MD; Heit, John A. MD; Mariani, Andrea MD; Cliby, William A. MD, FACS; Bakkum, Jamie MD Author Information

Tumour expresion of tissue factor and tissue factor pathway inhibitor in ovarian cancer- relationship with venous thrombosis risk

Ovarian cancer is known to display a particular association with venous thromboembolism (VTE) with reports up to 42% of patients developing thromboembolic complications. Tissue Factor (TF) and its inhibitor Tissue Factor Pathway Inhibitor (TFPI) have been implicated in VTE risk in cancer. The aim of this study was to measure tumour derived TF and TFPI and to investigate their potential role in VTE in ovarian cancer patients. TF and TFPI mRNA expression was measured using TaqMan real time PCR in 99 ovarian tumour samples. Nineteen cases complicated by VTE were matched to 19 cases without VTE. TF and TFPI protein levels were measured using ELISA and immunohistochemistry was used to localize TF expression. The role of TF expression on overall survival was also determined. TF mRNA and protein expression was increased in tumours from patients with clear cell carcinoma (p<0.001). TF protein expression was also increased in endometroid carcinoma (P<0.01) compared with benign tumours. TFPI mRNA expression was increased in clear cell carcinoma (P<0.01). TF mRNA and antigen level was increased in malignant tumours of patients who developed VTE compared with matched malignant õtumours of patients who remained thrombosis free (P<0.01). There was no difference in TFPI expression between the two groups. TF expression in ovarian cancer is significantly higher in patients who develop VTE. TF expression was increased in clear cell ovarian cancer and endometroid cancer and this may explain the higher risk of VTE in these subgroups. TF derived from these tumours may be the trigger for VTE in ovarian cancer.

Venous thromboembolism in ovarian cancer: incidence, risk factors and impact on survival

ObjectivesOvarian cancer has a higher incidence of venous thromboembolism (VTE) than other cancers. Clear cell cancers carry the highest risk at 11–27%. The aim of this study was to identify the predisposing factors for VTE in a population of ovarian cancer patients and to determine the influence of VTE on overall survival. Study designVTE events were identified from hospital and general practice/community care records for all patients with ovarian cancer who were diagnosed and treated in a tertiary cancer center between 2006 and 2010. ResultsThe overall incidence of VTE was 9.7% (33) in 344 patients. Sixteen (48%) had pulmonary embolism. Six (18%) presented with VTE. Five (15%) had VTE diagnosed during pre-treatment routine CT scanning. Eleven (33%) developed VTE following surgery and eleven (33%) developed VTE during chemotherapy. Risk factors associated with the occurrence of VTE were BMI≥30 (p<0.01), clear cell carcinoma (p<0.05), advanced stage (p<0.01), high grade (p<0.01) and CA125>500IU/ml (p<0.001). The occurrence of VTE was associated with decreased overall survival time (p<0.001). ConclusionThe incidence of VTE is high in ovarian cancer especially in the clear cell subtype. VTE adversely affects survival in ovarian cancer. Obesity, high grade and stage of cancer, clear cell subtype and high CA 125 level should be incorporated into protocols of VTE prophylaxis in women with ovarian cancer.

Elevated preoperative plasma D-dimer levels and the incidence of venous thromboembolism in Japanese females with gynecological cancer.

The purpose of the present study was to determine the incidence of increased levels of D-dimer and associated factors in preoperative patients with gynecological cancer. Furthermore, we determined the incidence and risk factors associated with preoperative venous thromboembolism (VTE). Overall, 456 patients with invasive gynecological cancer scheduled to undergo surgery were recruited. Preoperative plasma D-dimer levels were measured and patients whose plasma D-dimer concentration exceeded the pre-set cut-off value underwent computed tomography scanning. The incidence of elevated D-dimer and VTE was identified as significantly higher in patients with ovarian cancer. Multivariate analysis revealed that advanced age, low hemoglobin levels and elevated C-reactive protein (CRP) levels were independent factors for preoperative elevations in plasma D-dimer levels. Advanced age was an independent risk factor for preoperative VTE. Massive ascites and the presence of co-morbidities were independent risk factors for preoperative VTE in ovarian cancer. Advanced age and stage were independent risk factors for preoperative VTE in endometrial cancer. Advanced age was an independent risk factor for preoperative VTE in cervical cancer. Plasma D-dimer levels and the incidence of preoperative VTE were higher in patients with ovarian cancer compared with those with other gynecological cancers. Advanced age, low hemoglobin levels and elevated CRP levels were significant factors associated with elevated plasma D-dimer levels and age was an independent risk factor for preoperative VTE in gynecological cancer.

Venous thromboembolism in ovarian cancer

Objective. To determine the incidence, time-course, and risk factors associated with the development of thromboembolism (VTE) in a population-based study of women with ovarian cancer. Methods. Using the California Cancer Registry, cases diagnosed with ovarian cancer for a 6-year period were identified. These cases were linked with the California Patient Discharge Data Set to determine the incidence of VTE. Proportional hazards modeling was performed to analyze the strength of specified risk factors to predict development of VTE or death within 2 years. Results. Among 13,031 cases with ovarian cancer, 5.2% were diagnosed with a VTE event within 24 months after diagnosis. The cumulative incidence varied from 1.4% among women with local stage disease to 6.7% among women with advanced disease. The person-time incidence rate of VTE decreased over time, with the highest rate noted during the first 3 months. In a multivariate model, significant risk factors for VTE included advancing age, increasing number of chronic comorbid conditions, more advanced cancer stage, invasive histology, and absence of any major surgery. For all stages of cancer, development of VTE within 2 years was a significant risk factor for decreased survival, and the magnitude of the risk was greatest among the cases diagnosed with localized disease (HR 4.7, 95% CI: 2.3–9.5). Conclusions. VTE occurred in a significant proportion of ovarian cancer patients and adversely impacted survival, particularly among cases with local or regional stage cancer.

Diagnostic and prognostic importance of venous thromboembolism in ovarian cancer

Background: Cancer and its chemotherapy are well known risk factors for venous thromboembolism. The later can be the first sign of an occult malignancy, especially if it is recurrent one. Venous thromboembolism is also a common cause of morbidity and mortality among cancer patients. In time of the first presentation of venous thromboembolism in the context of underlying cancer the advanced stage of cancer is usually present and this is associated with poor prognosis. Ovarian cancer which is diagnosed within four months after an episode of venous thromboembolism is usually in advanced stages with more aggressive biological properties. Conclusions: Low-molecular-weight-heparins are the cornerstone of treatment and prophylaxis of venous thromboembolism associated with cancer for the first 3 to 6 months after acute venous thromboembolic event. In accordance with current consensus they are replaced with oral anticoagulants after 6 months of treatment. According to recent trials lowmolecular- weight-heparins cause less side effects and there are less recurrent venous throm boembolisms than with peroral anticoagulant therapy. Accordingly their impact on improved survival of cancer patients is under intensive research. Unfortunately, there is currently no screening test for ovarian cancer which would lead to improved survival.