Metastatic Epithelial Ovarian Cancer Research Articles

Correlation between plasma PSGL-1 and FIGO stage, tumor metastasis, and survival in epithelial ovarian cancer.

Plasma circulating P-selectin glycoprotein ligand-1 (PSGL-1) levels and its clinical correlation in patients with epithelial ovarian cancer (EOC) are unknown. The study determined plasma PSGL-1 levels in EOC patients and investigated its relationship with clinicopathological factors and prognosis. Plasma PSGL-1 levels were measured using ELISA in 69 patients with EOC, 34 patients with benign ovarian cystadenoma, and 36 healthy controls. Subsequently, the relationship between PSGL-1 levels and clinicopathological characteristics of patients, as well as the prognosis of EOC patients, was examined. Additionally, the specificity and sensitivity of plasma PSGL-1 were assessed through ROC curve analysis. Plasma PSGL-1 was upregulated in EOC patients compared with healthy subjects and/or patients with benign ovarian cystadenoma (p < 0.01). Elevated levels of PSGL-1 in the plasma were positively associated with advanced FIGO stage (p < 0.001), tumor size (p = 0.001), tumor metastasis (p = 0.036), and tumor recurrence (p = 0.013), while was negatively correlated with residual tumor size (p < 0.001). Kaplan-Meier survival analysis showed that high plasma PSGL-1 levels were associated with progression-free survival (p = 0.0345). In univariate and multivariate Cox regression analyses, PSGL-1 (HR = 1.456, p = 0.009) was an independent prognostic marker. Plasma PSGL-1 levels distinguished EOC patients and healthy individuals (AUC = 0.905), patients at late and early FIGO stages (AUC = 0.886), and metastatic and non-metastatic EOC (AUC = 0.722). The expression of plasma PSGL-1 is significantly increased in patients with EOC, serving as a reliable biomarker to differentiate between healthy individuals and those with EOC. Furthermore, PSGL-1 in patients is correlated with prognostic indicators, such as advanced FIGO stage, tumor lymph node metastasis, and progression-free survival.

Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy.

Introduction: High-grade serous ovarian cancer (HGSOC) is the most prevalent and deadliest subtype of epithelial ovarian cancer (EOC), killing over 140,000 people annually. Morbidity and mortality are compounded by a lack of screening methods, and recurrence is common. Plasminogen-activator-inhibitor 1 (PAI-1, the protein product of SERPIN E1) is involved in hemostasis, extracellular matrix (ECM) remodeling, and tumor cell migration and invasion. Overexpression is associated with poor prognosis in EOC. Platelets significantly increase PAI-1 in cancer cells in vitro, and may contribute to the hematogenous metastasis of circulating tumor cells (CTCs). CTCs are viable tumor cells that intravasate and travel through the circulation-often aided by platelets - with the potential to form secondary metastases. Here, we provide evidence that PAI-1 is central to the platelet-cancer cell interactome, and plays a role in the metastatic cascade. Methods: SK-OV-3 cells where PAI-1 had been silenced, treated with healthy donor platelets, and treated with platelet-conditioned medium were used as an in vitro model of metastatic EOC. Gene expression analysis was performed using RNA-Seq data from untreated cells and cells treated with PAI-1 siRNA or negative control, each with and without platelets. Four cohorts of banked patient plasma samples (n = 239) were assayed for PAI-1 by ELISA. Treatment-naïve (TN) whole blood (WB) samples were evaluated for CTCs in conjunction with PAI-1 evaluation in matched plasma. Results and discussion: Significant phenotypic changes occurring when PAI-1 was silenced and when platelets were added to cells were reflected by RNA-seq data, with PAI-1 observed to be central to molecular mechanisms of EOC metastasis. Increased proliferation was observed in cells treated with platelets. Plasma PAI-1 significantly correlated with advanced disease in a TN cohort, and was significantly reduced in a neoadjuvant chemotherapy (NACT) cohort. PAI-1 demonstrated a trend towards significance in overall survival (OS) in the late-stage TN cohort, and correlation between PAI-1 and neutrophils in this cohort was significant. 72.7% (16/22) of TN patients with plasma PAI-1 levels higher than OS cutoff were CTC-positive. These data support a central role for PAI-1 in EOC metastasis, and highlight PAI-1's potential as a biomarker, prognostic indicator, or gauge of treatment response in HGSOC.

Response to subsequent platinum-based chemotherapy post PARP inhibitor in recurrent epithelial ovarian cancer.

5578 Background: Maintenance therapy with PARP inhibitors (PARPi) can increase progression free survival (PFS) for recurrent or metastatic platinum-sensitive epithelial ovarian cancer (EOC). Little is known about disease trajectory following treatment with these agents, though some evidence suggests a decreased response to subsequent platinum-based chemotherapy. This retrospective cohort study assessed real-world response rates to platinum-based chemotherapy for recurrent high grade EOC following treatment with a PARPi. Methods: All patients prescribed a PARPi as maintenance therapy for recurrent or metastatic EOC at the Ottawa Regional Cancer Center (ORCC) from September 2017 to May 2022 were included. PFS following penultimate therapy (line of therapy preceding PARPi initiation) as well as the PFS following subsequent platinum-based chemotherapy in patients with disease progression more than 6 months after penultimate therapy were calculated. Incidence of platinum resistance in patients with disease progression following PARPi therapy was determined. Results: 91 patients were included in the analysis including 54 patients on niraparib and 36 patients on olaparib. Follow-up after initiation of PARPi ranged from 4.6 months to 62.0 months with a median of 16.3 months. 54 (59.3%) of patients experienced disease progression after initiation of PARPi therapy, including 10 (11.0%) who progressed within 6 months of their penultimate therapy. Of the 44 patients who experienced disease progression more than 6 months following penultimate therapy, 32 (72.7%) were rechallenged with platinum-based chemotherapy. Of these, 16 (50.0%) experienced further disease progression with 14 (43.8%) progressing within 6 months of their platinum rechallenge. Median PFS following platinum rechallenge was 4.4 months (from 0.8 months to 34.9 months), significantly lower than previous reports. Conclusions: Patients who experienced disease progression following PARPi therapy showed a poor response to subsequent platinum-based chemotherapy, even when progression occurred more than 6 months after completion of their penultimate platinum-based chemotherapy. This supports the theory that PARPi resistance may be a surrogate for platinum resistance and raises concern for possible contribution of PARPi in the induction of platinum resistance in recurrent EOC.

GSTM1, GSTP1, p53 as some probable predictors of prognosis in primary and metastatic epithelial ovarian cancer

Objectives: Ovarian carcinomas are responsible for the death of more women than all other gynecologic malignancies in the Western world. Ovarian carcinomas are detected in an advanced stage of the disease in approximately 80% of the patients. Glutathione S-transferases (GSTs) are an important family involved in the detoxification of several xenobiotics. Thus, this mechanism protects tissues from the harmful effects of oxidative stress and chemical-induced damages. The expression of them may contribute to the characteristics of ovarian carcinoma as they can metabolise both exogenous and endogenous compounds, which are implicated in the development of ovarian cancer. Therefore, our aim was to determine the expressions of GST Mu 1 (GSTM1), GST Pi 1 (GSTP1), and also p53, which is a tumor suppressor gene, in benign and malign ovarian tumors and metastasis tissues. Methods: A total of the 99 patients with ovarian tumor enrolled in the study. Thirty-one of the tissues was benign tumor, 17 was malign tumor and 51 was metastasis. The immunohistochemical GSTM1, GSTP1, and p53 staining characteristics of these tissues were investigated. Results: The highest GSTM1, GSTP1, and p53 expression was noted in the malignant group followed by the metastasis group. GSTP1 expression was significantly higher in malignant tissues than benign ones (p = 0.015). No statistically significant difference was observed in the level of GSTM1 expression between groups (p = 0.524). p53 expression was significantly higher in the metastasis and malignant tissues than the benign ones (p &amp;lt; 0.001). Conclusions: The higher expressions of GSTP1 and p53 in malignant and metastasis tissues than benign ones indicate that these expressions could be important biomarkers in ovarian cancer development and progression. Further studies with more cases are required to confirm the results of our present study.

Comparison of Human Epididymis Protein 4, Cancer Antigen 125, and Ultrasound Prediction Model in Differentiating Benign from Malignant Adnexal Masses.

This study aimed to compare the diagnostic performance of carcinogenic antigen (CA) 125, (HE)-4 (Human epididymis protein 4), and ultrasound (International Ovarian Tumor Analysis [IOTA]) Simple Rules individually and to derive a composite score in the differentiating ovarian cancer from benign ovarian mass. Consecutive patients (n = 100) with pelvic mass admitted during February 2018-August 2019 were included prospectively. Patients with either known case of epithelial ovarian cancer (EOC) or metastatic EOC were excluded. The primary outcome was to assess the sensitivity and specificity of CA-125, HE-4, and IOTA Simple Rules in predicting benign from malignant mass independently, while secondary outcome was derivation of a new model incorporating these variables using multivariate logistic regression analysis to predict benign from malignant lesions. Receiver operator curve (ROC) was drawn to redefine the best-performing cutoff values and difference between area under the ROC (AUROC) were compared by DeLong's method. Out of 100 cases of adnexal mass selected, the sensitivity and specificity of CA-125 were 73.8% and 77.6%, HE-4 were 90.5% and 87.9%, and IOTA Simple Rules were 92.9% and 81.0%. CA-125, HE-4, and IOTA Simple Rules were independently associated with the likelihood of malignancy/borderline (P < 0.001). The area under the curve for the "composite score" (AUC = 0.93) was the highest and was significantly better than that of CA-125 (AUC = 0.786) (P = 0.004 using DeLong's test) and comparable with HE-4 (AUROC = 0.90; P = 0.128 using DeLong's Test). The sensitivity and specificity of HE-4 and IOTA Simple Rules for predicting malignant ovarian tumor was better than those of CA-125. The diagnostic performance of "composite score" was comparable to those of either HE-4 or IOTA Simple Rules and significantly better than CA-125.

Adaptations of key metabolic pathways in primary and metastatic epithelial ovarian cancer (253)

Objectives: Patients with ovarian cancer (OC) often present with advanced-stage disease at diagnosis; however, the molecular mechanisms which drive the aggressive nature of OC metastases have not been well characterized. Metastasizing cancer cells undergo metabolic reprogramming to utilize available lipids in the metastatic niche of the omentum. This study aimed to understand the compensatory metabolic mechanisms that enable this OC metastasis. Our work focused on understanding the contributions of the pentose phosphate pathway (PPP)—a key mechanism responsible for redox homeostasis—in enabling this evolution. Methods: Using gene expression data of matched human primary and omental tumor samples (n=30), we performed targeted analysis of metabolic gene expression changes, which revealed upregulation of the PPP in omental metastases. We then performed in vitro and in vivo experiments using pre-clinical ovarian cancer models (SKOV3, IGROV, HEYA8). Given the canonical role of the PPP in maintaining redox homeostasis, we assessed oxidative stress in organoid cultures from omental metastases harvested at mouse necropsy and in cultures grown in omental conditioned media. Inhibition of the rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PD), was performed via shRNA knockdowns and treated with a pharmacological inhibitor. HeyA8 tumor-bearing mice were treated with the G6PD inhibitor, and the metastatic burden was evaluated using IVIS during treatment and in peritoneal organs following the sacrifice. Statistical significance was established using unpaired two-tailed Student’s t-tests. Results: Differential analysis of metabolic gene expression and pathway analysis revealed upregulation of the PPP in omental metastases compared to primary ovarian tumors (p<0.05, EnrichR Score = 800). Primary tumors and omental metastases were harvested from SKOV3, HeyA8, and IGROV1 tumor-bearing mice at necropsy and used to establish organoids. DCFH-DA, a fluorogenic probe for ROS, measured higher levels of oxidative stress in metastatic organoids than primary tumors (normalized F525= 11.3623, p<0.0005). SKOV3 organoids expressing HyPer, a ratiometric biosensor of intracellular H2O2, exhibited higher oxidative stress when grown in omental conditioned media versus basal organoid media (normalized F420/F500=1.27, p<0.05). Pharmacological and shRNA inhibition of G6PD sensitized cells to oxidative stress, reducing cell viability in vitro (p<0.05). Treatment with a G6PD inhibitor in vivo significantly decreased tumor growth and metastases compared to vehicle treatment (p<0.005). Objectives: Patients with ovarian cancer (OC) often present with advanced-stage disease at diagnosis; however, the molecular mechanisms which drive the aggressive nature of OC metastases have not been well characterized. Metastasizing cancer cells undergo metabolic reprogramming to utilize available lipids in the metastatic niche of the omentum. This study aimed to understand the compensatory metabolic mechanisms that enable this OC metastasis. Our work focused on understanding the contributions of the pentose phosphate pathway (PPP)—a key mechanism responsible for redox homeostasis—in enabling this evolution. Methods: Using gene expression data of matched human primary and omental tumor samples (n=30), we performed targeted analysis of metabolic gene expression changes, which revealed upregulation of the PPP in omental metastases. We then performed in vitro and in vivo experiments using pre-clinical ovarian cancer models (SKOV3, IGROV, HEYA8). Given the canonical role of the PPP in maintaining redox homeostasis, we assessed oxidative stress in organoid cultures from omental metastases harvested at mouse necropsy and in cultures grown in omental conditioned media. Inhibition of the rate-limiting enzyme of the PPP, glucose-6-phosphate dehydrogenase (G6PD), was performed via shRNA knockdowns and treated with a pharmacological inhibitor. HeyA8 tumor-bearing mice were treated with the G6PD inhibitor, and the metastatic burden was evaluated using IVIS during treatment and in peritoneal organs following the sacrifice. Statistical significance was established using unpaired two-tailed Student’s t-tests. Results: Differential analysis of metabolic gene expression and pathway analysis revealed upregulation of the PPP in omental metastases compared to primary ovarian tumors (p<0.05, EnrichR Score = 800). Primary tumors and omental metastases were harvested from SKOV3, HeyA8, and IGROV1 tumor-bearing mice at necropsy and used to establish organoids. DCFH-DA, a fluorogenic probe for ROS, measured higher levels of oxidative stress in metastatic organoids than primary tumors (normalized F525= 11.3623, p<0.0005). SKOV3 organoids expressing HyPer, a ratiometric biosensor of intracellular H2O2, exhibited higher oxidative stress when grown in omental conditioned media versus basal organoid media (normalized F420/F500=1.27, p<0.05). Pharmacological and shRNA inhibition of G6PD sensitized cells to oxidative stress, reducing cell viability in vitro (p<0.05). Treatment with a G6PD inhibitor in vivo significantly decreased tumor growth and metastases compared to vehicle treatment (p<0.005).

Outcomes in older patients with metastatic epithelial ovarian cancer: Are we providing equitable care? (600)

Outcomes in older patients with metastatic epithelial ovarian cancer: Are we providing equitable care? (600)

Long Term Survival of GOG 252 ‘Randomized Trial of Intravenous Versus Intraperitoneal Chemotherapy plus Bevacizumab in Advanced Ovarian Carcinoma: An NRG Oncology/GOG Study’ (021)

<b>Objectives:</b> The primary objective of this analysis of GOG 252 is to assess the overall survival of the subgroup of participants with metastatic epithelial ovarian cancer, with no more than microscopic residual disease, following their primary cytoreductive surgery followed by three chemotherapy regimens and bevacizumab. The results of the response to chemotherapy based on the CA-125 nadir are also included. <b>Methods:</b> Patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 weekly, with IV carboplatin AUC 6 on day 1 (IV carbo arm), versus IV paclitaxel 80 mg/m2 weekly, with IP carboplatin AUC 6 on day 1 (IP carbo arm) versus IV paclitaxel 135 mg/m2 IV on day 1 every three weeks, IP cisplatin 75 mg/m2 on day 2, and IP paclitaxel 60 mg/m2 on day 8 (IP Cisplatin arm). All participants received bevacizumab 15 mg/kg IV on day 1 every three weeks for cycles 2-22. CA-125 was drawn before each cycle of chemotherapy, and q3 months for the first two years and q6 months for the next three years and then annually. CT was performed postoperatively and before enrollment, and then every six months for five years and then annually. <b>Results:</b> A total of 1560 patients were enrolled of whom 900 (57.7%) had no more than microscopic residual disease as assessed by the surgeon. For this analysis, an excellent response to front line chemotherapy was to see a nadir of CA-125 < 10 before cycle 4. The median duration of follow up was 9.2 years. There were 573 with recurrent disease (63.7%) and 413 deaths (45.9%). There was no statistically significant difference in PFS between treatment groups (p=0.735, log-rank Chi square=0.617 with 2 DF). The hazard of progression or death is relatively high for the first 3-4 years and then declines. The estimates of proportion of patients alive and recurrence-free at 10 years were 0.32, 0.33, and 0.32, respectively. The probability of living at least 10 years was 0.473, 0.467 and 0.470. The CA-125 nadir after cycle 1 and before cycle 4 of less than 10 was 53.5% 51.5%, and 34.4% in the three arms, respectively. The median PFS was 28.5 months for those with CA-125 nadir > 10 IU and 44.2 months for those less than or equal to 10 IU. The median survival for CA-125 nadir greater than 10 was 89 months. <b>Conclusions:</b> The overall survival of these patients was remarkable and was 108.6, 114.2, and 107.9 months, respectively. The proportional hazard model stratified by stage indicates the hazard of death is 38.5% higher among those with nadir values of CA-125 > 10. The quality of life was best in the intravenous arm.Fig. 1

Abstract 1564: Endothelial Notch activation is essential for the education of tumor associated macrophages

Abstract Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers worldwide. Notch1 receptors (N1ICD) are frequently activated in Endothelial cells (ECs) of human tumors to facilitate metastasis. Using VE-Cadherin-CreERT2 transgenic mice to induce gene recombination exclusively in ECs, we explored the role of Notch signaling in ECs in vivo. RbpjiΔEC (VE-Cad-CrERT2xRbpjflox) mice inhibit the canonical Notch signaling upon tamoxifen administration. We modeled metastatic epithelial ovarian cancer (EOC) by injecting the mouse ovarian cancer cell line ID8 intraperitoneally. After four weeks of tumor growth, we observed a significant decreased tumor burden and reduced infiltration of monocyte-derived macrophages into the TME upon EC-specific Rbpj deletion. In vitro, we also confirmed a decreased infiltration of human monocytes through an EC barrier upon Rbpj deletion in human ECs. We isolated tumor-associated macrophages (TAMs) from RbpjΔEC tumor bearing mice and their littermate controls and performed microarray analysis. TCs educate TAMs through CD44-mediated cholesterol depletion. Several bioinformatic analyses showed that TAM from RbpjiΔEC mice were not able to induce the expected signature of TAMs in metastatic EOC because cholesterol depletion cannot take place. This indicates that the TC-induced macrophage education requires the presence of Rbpj in ECs. In vitro experiments showed that CD44 expression was downregulated in monocytes co-cultured with ECs lacking RBPJ. Analysis of the angiocrine factors regulated by Notch signaling revealed CXCL2 as a novel Rbpj-mediated Notch target gene: activation of Notch1 in ECs in vitro induced the production of the chemotactic cytokine CXCL2, whereas Rbpj-deletion (CRISPR-Cas9 technology) in N1ICD transduced ECs abolished CXCL2 expression. In addition, CXCL2 stimulation increased CD44 expression. In keeping with this, the analysis of publicly available ovarian cancer patient’s datasets we found that CXCL2 expression correlates with CD44 expression, suggesting that CXCL2 induces CD44 also in patients. CD44 is a co-receptor of a complex involving CXCR2 and CD74, which without CD44 it is not possible to signal. CD74 expression has been associated with worse prognosis in metastatic ovarian cancer and associated with an immunosuppressive phenotype in macrophages. Bioinformatic analyses of publicly available data showed that Rbpj in ECs is necessary for the immunosuppressive role of CD74. Finally, T cells sorted from RbpjiΔEC tumor bearing mice showed stronger cytotoxic activity (LDH-cytotoxicity assay) than those sorted from their littermate controls. In summary, ovarian cancer cells employ the tumor endothelium to secrete CXCL2 in order to facilitate an immunosuppressive microenvironment. Citation Format: Ronja Mülfarth, Elisenda Alsina-Sanchis, Iris Moll, Sarah Böhn, Adrian Stögbauer, Francesca De Angelis Rigotti, Lena Wiedmann, Jacqueline Taylor, Andreas Fischer, Juan Rodriguez Vita. Endothelial Notch activation is essential for the education of tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1564.

Clinical Dose Preparation of [177Lu]Lu-DOTA-Pertuzumab Using Medium Specific Activity [177Lu]LuCl3 for Radioimmunotherapy of Breast and Epithelial Ovarian Cancers, with HER2 Receptor Overexpression.

Background: The overexpression of human epidermal growth factor receptor 2 (HER2) is commonly associated with metastatic breast cancer and epithelial ovarian cancer. The U.S. Food and Drug Administration (FDA) has approved Trastuzumab as an anti-HER2 agent for the metastatic breast and epithelial ovarian cancer. However, Trastuzumab has severe limitations in the treatment of metastatic breast cancer associated with ligand-dependent dimerization of HER2 receptor at the extracellular domain-II (ECD-II) region. The therapeutic approach in combination of pertuzumab and trastuzumab is found to be effective in preventing HER2 dimerization at the ECD-II region. The radioimmunotherapeutic approach, utilizing both these anti-HER2 agents (trastuzumab/pertuzumab), radiolabeled with [177Lu]Lu3+, has proved to be clinically efficacious with promising potential. Toward this, the formulation for clinical doses of [177Lu]Lu-DOTA-pertuzumab has been optimized using medium specific activity (0.81 GBq/μg) [177Lu]LuCl3. Materials and Methods: Preconcentrated pertuzumab was conjugated with p-NCS-benzyl-DOTA. Purified DOTA-benzyl-pertuzumab conjugate was radiolabeled with carrier-added [177Lu]LuCl3. Quality control parameters were evaluated for the [177Lu]Lu-DOTA-pertuzumab. In vivo biodistribution was carried out at different time points postadministration. Specific cell binding, immunoreactivity, and internalization were investigated by using SKOV3 and SKBR3 cells. Results: In this study, the authors reported a consistent and reproducible protocol for clinical dose formulations of [177Lu]Lu-DOTA-pertuzumab, with a radiochemical yield of 86.67% ± 1.03% and radiochemical purity (RCP) of 99.36% ± 0.36% (n = 10). Preclinical cell binding studies of [177Lu]Lu-DOTA-pertuzumab revealed specific binding with SKOV3 and SKBR3 cells up to 24.4% ± 1.4% and 23.2% ± 0.8%, respectively. The uptakes in SKOV3- and SKBR3-xenografted tumor in severe combined immunodeficiency mice were observed to be 25.9% ± 0.8% and 25.2% ± 1.2% ID/g at 48 and 120 h postinjection, respectively. Conclusions: A protocol was optimized for the preparation of ready-to-use clinical dose of [177Lu]Lu-DOTA-pertuzumab, in hospital radiopharmacy settings. The retention of RCP of the radiopharmaceutical, on storage in saline and serum, at -20°C, up to 120 h postradiolabeling, confirmed its in vitro stability.

EVALUATING THE TREATMENT OUTCOMES OF TOPOTECAN MONOTHERAPY IN PATIENTS&amp;NBSP;WITH RECURRENT, METASTATIC PLATINUM-RESISTANT EPITHELIAL OVARIAN CANCER

Abstract: Background: Topotecan monotherapy is an effective treatment in recurrent, metastatic platinum-resistant epithelial ovarian cancer, but this regimen has not been well studied in Vietnam. This study aimed to tackle this problem. Methods: Study of 32 ovarian cancer patients in recurrent or metastatic setting, progressed after platinum-based chemotherapy were treated with Topotecan at Hanoi Oncology Hospital, National Cancer Hospital and Hanoi Medical University Hospital between January 2016 and July 2019. Results: Mean age was 58.6 ± 7 (43 – 72). Most patients had been treated with more than one regimen. 51.3% of all patients gained clinical benefit. Median progresssion free survival was 6.1 months. Median overall survival was 11.8 months. Most toxicities was in grade 1 or 2 with the most common complaint was fatigue. Conclusion: Topotecan is a considerable option in platinum-resistant ovarian cancer with certain clinical benefits. Key words: recurrent, metastatic setting ovarian cancer, platinum resistance, topotecan

Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer.

Simple SummaryIn most patients with ovarian cancer, their disease eventually becomes resistant to chemotherapy. The timing and type of treatment given are therefore highly important. Currently, treatment choice is mainly based on the subtype of cancer (from a histological point of view), prior response to chemotherapy, and the time it takes for the disease to recur. In this study, we combined complete genome data of the tumor with clinical data to better understand treatment responses. In total, 132 tumor samples were included, all from patients with disease that had spread beyond the primary location. By clustering the samples based on genetic characteristics, we have identified subgroups with distinct response rates and survival outcomes. We suggest that in the future, this data can be used to make more informed treatment choices for individuals with ovarian cancer.The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment.

IGF1R-α6 integrin-S100A4 network governs the organ-specific metastasis of chemoresistant epithelial ovarian cancer cells

Recurrent metastatic epithelial ovarian cancer (EOC) is challenging and associated with treatment limitations, as the mechanisms governing the metastatic behavior of chemoresistant EOC cells remain elusive. Using orthotopic xenograft mouse models of sensitive and acquired platinum-taxol-resistant A2780 EOC cells, we studied the mechanistic role of insulin like growth factor 1 receptor (IGF1R) signaling in the regulation of organ-specific metastasis of EOC cells undergoing acquirement of chemoresistance. Biochemical assays and organ-specific fibroblast-EOC cell co-culture were used to study the differential metastatic characteristics of sensitive vs. chemoresistant EOC cells, and the key molecule/s underlying the organ-specific homing of chemoresistant EOC cells were identified through subtractive LC/MS profiling of the co-culture secretome. The role of the identified molecule was validated through genetic/pharmacologic perturbation experiments. Acquired chemoresistance augmented organ-specific metastasis of EOC cells and enhanced lung homing, particularly for the late-stage chemoresistant cells, which was abrogated after IGF1R silencing. Escalation of chemoresistance (intrinsic and acquired) conferred EOC cells with higher adhesion toward primary lung fibroblasts, largely governed by the α6 integrin-IGF1R dual signaling axes. Subtractive analysis of the co-culture secretome revealed that interaction with lung fibroblasts induced the secretion of S100A4 from highly resistant EOC cells, which reciprocally activated lung fibroblasts. Genetic and pharmacologic inhibition of S100A4 significantly lowered distant metastases and completely abrogated lung-tropic nature of late-stage chemoresistant EOC cells. These results indicate that chemoresistance exacerbates organ-specific metastasis of EOC cells via the IGF1R-α6 integrin-S100A4 molecular network, of which S100A4 may serve as a potential target for the treatment of recurrent metastatic EOC.

The blood transcriptome prior to ovarian cancer diagnosis: A case-control study in the NOWAC postgenome cohort.

Epithelial ovarian cancer (EOC) has a 5-year relative survival of 50%, partly because markers of early-stage disease are not available in current clinical diagnostics. The aim of the present study was to investigate whether EOC is associated with transcriptional profiles in blood collected up to 7 years before diagnosis. For this, we used RNA-stabilized whole blood, which contains circulating immune cells, from a sample of EOC cases from the population-based Norwegian Women and Cancer (NOWAC) postgenome cohort. We explored case-control differences in gene expression in all EOC (66 case-control pairs), as well as associations between gene expression and metastatic EOC (56 pairs), serous EOC (45 pairs, 44 of which were metastatic), and interval from blood sample collection to diagnosis (≤3 or >3 years; 34 and 31 pairs, respectively). Lastly, we assessed differential expression of genes associated with EOC in published functional genomics studies that used blood samples collected from newly diagnosed women. After adjustment for multiple testing, this nested case-control study revealed no significant case-control differences in gene expression in all EOC (false discovery rate q>0.96). With the exception of a few probes, the log2 fold change values obtained in gene-wise linear models were below ±0.2. P-values were lowest in analyses of metastatic EOC (80% of which were serous EOC). No common transcriptional profile was indicated by interval to diagnosis; when comparing the 100 genes with the lowest p-values in gene-wise tests in samples collected ≤3 and >3 years before EOC diagnosis, no overlap in these genes was observed. Among 86 genes linked to ovarian cancer in previous publications, our data contained expression values for 42, and of these, tests of LIME1, GPR162, STAB1, and SKAP1, resulted in unadjusted p<0.05. Although limited by sample size, our findings indicated less variation in blood gene expression between women with similar tumor characteristics.

Combination of nigericin with cisplatin enhances the inhibitory effect of cisplatin on epithelial ovarian cancer metastasis by inhibiting slug expression via the Wnt/β‑catenin signalling pathway

Epithelial ovarian cancer (EOC) is the most lethal cancer among female genital tumours. Standard therapies, including postoperative chemotherapy, exhibit high proportions of recurrence and resistance. Novel therapeutic strategies are combined with chemotherapy. Emerging studies have demonstrated that nigericin, an H+, K+ and Pb2+ ionophore, exhibits promising anticancer activity in various types of malignancy, such as colorectal and epithelial ovarian cancer. Our previous study suggested that nigericin could regulate EOC cell proliferation, migration and invasion, and may be a novel chemotherapy candidate for EOC. However, to the best of our knowledge, the effects of combined therapy with cisplatin, and the associated underlying mechanisms, are not yet fully understood. The present study aimed to clarify the effects of combined chemical therapy with nigericin and cisplatin on EOC cells and to reveal its mechanism. Wound healing, Transwell, cell viability and colony formation assays were used to measure the migration, invasion and proliferation of EOC cells. Western blotting was used to detect protein expression. A slug overexpression lentivirus was used to create a slug overexpression model in SK-OV-3 cells. Small interfering RNA was used to knock down slug expression. Nigericin combined with cisplatin enhanced the inhibitory effects of cisplatin on the migration and colony formation of EOC cells. Nigericin also enhanced the inhibitory effects of cisplatin on the expression levels of MMP7, as well as the inhibitory effects of cisplatin on the expression levels of β-catenin and GSK-3β, indicating that nigericin and cisplatin regulated in the Wnt/β-catenin signalling pathway. When slug was knocked down, the effect of nigericin was weakened. Overexpression of slug could repress the inhibitory effect of nigericin on the Wnt/β-catenin signalling pathway. Furthermore, nigericin inhibited slug expression by enhancing its modification through small ubiquitin-like modifiers (SUMOs; referred to as SUMOylation). Overall, the present results demonstrated that nigericin combined with cisplatin might serve as a novel therapeutic strategy in patients with metastatic EOC because the combined therapy had higher effectiveness than single drug use. The underlying mechanism of combined therapy maybe the enhanced inhibitory effect of slug through its nigericin-induced SUMOylation.

Efficacy and safety of nanosomal docetaxel lipid suspension based chemotherapy in metastatic ovarian carcinoma: A retrospective study.

The aim of the current study was to assess the efficacy and safety of nanosomal docetaxel lipid suspension (NDLS) based chemotherapy in patients with metastatic epithelial ovarian carcinoma. In the present multicenter study, the medical records of patients who received NDLS (60-75 mg/m2; 3-weekly cycles) based chemotherapy for metastatic epithelial ovarian cancer in routine clinical care were retrospectively evaluated. Patients were followed-up from September 2014 until September 2018. The efficacy endpoints were the overall response rate (ORR) and disease control rate measured in accordance with the Response Evaluation Criteria in Solid Tumours 1.1. Overall survival (OS) and safety were also evaluated. Of the 13 patients evaluated, 46.2% (6/13) received NDLS-based first-line chemotherapy and 53.8% (7/13) patients received second-line chemotherapy [platinum-sensitive, 57.1% (4/7); platinum-resistant, 42.9% (3/7)]. The ORRs were 60.0% (3/5) and 57.1% (4/7) for patients receiving first- and second-line chemotherapy, respectively. The estimated median OS for patients receiving NDLS-based first-line chemotherapy was 17.4 months (follow-up duration, 4.3-49.4 months). The estimated median OS was 26.1 months (follow-up duration, 5.1-37.5 months) in patients with platinum-sensitive disease, whereas the OS was 14.8 months (follow-up duration, 3.5-14.8 months) in patients with platinum-resistant disease. No grade III/IV adverse events (AEs) were observed; ≥1 AE in grade I-II was reported in 84.6% (11/13) of patients. Overall, NDLS-based chemotherapy was efficacious and well-tolerated in the management of metastatic epithelial ovarian carcinoma.

Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation

Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was performed to compare the expression of PD-L1 in primary epithelial ovarian cancer (EOC) and their corresponding peritoneal metastases, as well as to evaluate its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastasis were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p < 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the discordance of PD-L1 expression between primary EOC and corresponding peritoneal metastases suggests that its assessment as a potential biomarker for predicting response to anti-PD-L1 therapy may require analysis of metastatic lesions.

Palliative Radiation Therapy for Metastatic, Persistent, or Recurrent Epithelial Ovarian Cancer: Efficacy in the Era of Modern Technology and Targeted Agents

PurposeMetastatic, persistent, or recurrent epithelial ovarian cancer (MPR-EOC) remains a significant threat to patient mortality despite advances in novel targeted agents. Radiation therapy (RT) is often used as a palliative option. We report outcomes of a large series of MPR-EOC patients treated with modern palliative RT (PRT) in an era of novel systemic therapies. Methods and MaterialsA retrospective review was conducted of women treated with PRT for MPR-EOC between 2007 and 2019 at an academic institution. Clinical response rates were recorded at <1 month, 1 to 3 months, and >3 months. Radiographic responses were categorized by RECIST 1.1 criteria. Overall response rate (ORR) was the sum of complete and partial response. Linear regression analyses of baseline characteristics were conducted for statistical testing. ResultsEighty-six patients with PMR-OC received 120 courses of palliative RT. Median follow-up was 8.6 months. Median age was 61 (range, 22-82). Thirty-six percent of women received central nervous system (CNS)-directed RT. In addition, 43% received targeted therapies before RT. Clinical ORR within 1 month and at last follow-up for non-CNS lesions was 79% and 61% (69% and 88% for CNS lesions, respectively). High-grade serous lesions were more likely to have clinical response (P = .04). Biologically effective doses (BED) >39 Gy were associated with improved clinical response in CNS lesions (P = .049). Bony sites were associated with worse clinical (P = .004) response in non-CNS lesions compared with soft tissue or nodal sites. Acute or late grade 3+ toxicities with bevacizumab were low (8.7%/4.3%). ConclusionsPRT offers excellent rates of response for symptomatic patients with MPR-EOC within 1 month of treatment, with durable responses beyond 3 months. High-grade serous lesions were associated with improved response in all patients. Higher BED and soft tissue or nodal sites were associated with improved response in CNS and non-CNS patients, respectively. Acute or late toxicities with bevacizumab and PRT were low. Prospective investigation is warranted to determine the optimal PRT regimen.

A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer.

Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.

Novel Molecular Targets for Tumor-Specific Imaging of Epithelial Ovarian Cancer Metastases.

In epithelial ovarian cancer (EOC), the strongest prognostic factor is the completeness of surgery. Intraoperative molecular imaging that targets cell-surface proteins on tumor cells may guide surgeons to detect metastases otherwise not visible to the naked eye. Previously, we identified 29% more metastatic lesions during cytoreductive surgery using OTL-38, a fluorescent tracer targeting folate receptor-α (FRα). Unfortunately, eleven out of thirteen fluorescent lymph nodes were tumor negative. The current study evaluates the suitability of five biomarkers (EGFR, VEGF-A, L1CAM, integrin αvβ6 and EpCAM) as alternative targets for molecular imaging of EOC metastases and included FRα as a reference. Immunohistochemistry was performed on paraffin-embedded tissue sections of primary ovarian tumors, omental, peritoneal and lymph node metastases from 84 EOC patients. Tumor-negative tissue specimens from these patients were included as controls. EGFR, VEGF-A and L1CAM were highly expressed in tumor-negative tissue, whereas αvβ6 showed heterogeneous expression in metastases. The expression of EpCAM was most comparable to FRα in metastatic lesions and completely absent in the lymph nodes that were false-positively illuminated with OTL-38 in our previous study. Hence, EpCAM seems to be a promising novel target for intraoperative imaging and may contribute to a more reliable detection of true metastatic EOC lesions.