Platinum-resistant Epithelial Ovarian Carcinoma Research Articles

Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy.

Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.

Surgery in platinum-resistant recurrent epithelial ovarian carcinoma.

BACKGROUNDOvarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy, accounting for 90% of all primary ovarian tumors. The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear.AIMTo evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC.METHODSThis was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018. Patient baseline data were obtained from clinical records. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by B-mode ultrasound, computed tomography, or magnetic resonance imaging. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), chemotherapy-free interval (CFI), and complications. Follow-up ended on April 15, 2019.RESULTSA total of 38 patients were included. R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) patients required organ resection. Nine (23.7%) patients had operative complications, 36 (94.7%) received chemotherapy, and five (13.2%) had targeted therapy. Median PFS and OS were 10 (95%CI: 8.27-11.73) months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months. R0 resection and postoperative chemotherapy significantly prolonged PFS and OS (all P < 0.05), and R0 resection also significantly prolonged CFI (P < 0.05). Grade ≥ 3 complications were observed, including rectovaginal fistula (n = 1), intestinal and urinary fistulas (n = 1), and renal failure-associated death (n = 1). Except for the patient who died after surgery, all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment.CONCLUSIONSecondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.

Biomarkers of outcome with weekly paclitaxel in platinum-resistant high-grade serous or endometrioid ovarian carcinoma

Objective: The purpose of this study was to evaluate biomarkers of outcome with weekly paclitaxel monotherapy in platinum-resistant epithelial ovarian carcinoma using shallow whole genome sequencing (sWGS).

Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC)

Objective: Despite a high response rate to first-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. The objective of the present study was to evaluate the frequency of long-term survivors and to identify the prognostic factors associated with long-term survival in a French cohort of 566 patients.Methods: Patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for EOC in 13 French centers between 1991 and 2010 were included. Long-term survivors were defined as patients who survived more than 5 years after HIPEC and CRS, irrespective of relapse.Results: Seventy-eight long-term survivors were analyzed. The median follow-up was 74 months. Median age at the time of first HIPEC was 55.4 years (range [22.6–77.6]. Seven patients had advanced EOC and 71 patients had recurrent EOC (37 patients had platinum-resistant EOC and 32 had platinum-sensitive disease). More than half of the long-term survivors had high-grade serous ovarian cancer (HGSOC). In univariate analysis, age ≥50 years (p = .004), peritoneal cancer index (PCI) ≤ 8 (p = .049) and CA-125 < 100 (p = .02) were associated with long-term survival. There was a trend towards an association between higher CC-score and long-term survival (p = .057).Conclusion: Age ≥50 years, PCI ≤8 and CA125 < 100 were associated with long-term survival in univariate analysis. There was a trend towards the significance of CC-score. Platinum-status was not associated with long-term survival.

MiR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma.

Drug resistance remains the major clinical barrier to successful treatment in epithelial ovarian carcinoma (EOC) patients, and the evidence of microRNA involvement in drug resistance has been recently emerging. Endothelin-1 (ET-1)/ETA receptor (ETAR) axis is aberrantly activated in chemoresistant EOC cells and elicits pleiotropic effects promoting epithelial-to-mesenchymal transition (EMT) and the acquisition of chemoresistance. However, the relationship between ETAR and miRNA is still unknown. Hence, in this study we evaluated whether dysregulation of miRNA might enhance ETAR expression in sensitive and resistant EOC cells. Based on bioinformatic tools, we selected putative miRNA able to recognize the 3′UTR of ETAR. An inverse correlation was observed between the expression levels of miR-30a and ETAR in both EOC cell lines and tumor samples. miR-30a was found to specifically bind to the 3′UTR of ETAR mRNA, indicating that ETAR is a direct target of miR-30a. Overexpression of miR-30a decreased Akt and mitogen activated protein kinase signaling pathway activation, cell proliferation, invasion, plasticity, EMT marker levels, and vascular endothelial growth factor release. Interestingly, ectopic expression of miR-30a re-sensitized platinum-resistant EOC cells to cisplatinum-induced apoptosis. Consistently, resistant EOC xenografts overexpressing miR-30a resulted in significantly less tumor growth than controls. Together our study provides a new perspective on the regulatory mechanism of ETAR gene. Interestingly, our findings highlight that blockade of ETAR regulatory axis is the mechanism underlying the tumor suppressor function of miR-30a in chemoresistant EOC cells.

The efficacy and safety of Oxaliplatin-Vinorelbine as a second-line chemotherapy combination in patients with platinum-resistant pretreated epithelial ovarian cancer: A retrospective study

Purpose: The main purpose of this study was to analyze the effects and tolerability of Oxaliplatin-Vinorelbine combination on Platinum-resistant epithelial ovarian carcinoma (EOC) patients. Methods: A single centered retrospective study comprising of 34 patients was conducted, and all 34 patients were treated with Vinorelbine 30 mg/m 2 on day 1 and 8 along with Oxaliplatin 100 mg/m 2 on day 1 of 3 weeks treatment cycle following progressive platinum-resistant EOC. Results: The combination showed an overall response rate (ORR) of 18% (95% CI, 4.4 - 31.6) where 2 (6%) patients had complete response and 4 (12%) patients had partial response. Stable disease was observed in 9 (26%) patients and progressive disease in 19 (56%) patients. Median diseases free survival, median relapse free survival and median time to progression was 17.05 months, 4.4 months, and 1.25 months, respectively. Hematological toxicities were mild; only 1 (2.9%) patient had G3 anemia and major non-hematological toxicities include nausea-vomiting, diarrhea, constipation, hepatotoxicity, fatigueness and alopecia, which are mainly limited to G1-G2 and reversible. Conclusion: The effect of this combination is moderate as a second line treatment of platinum resistant EOC; however, in comparison with other regimens of Vinorelbine and Oxaliplatin, the activity is substandard but the toxicity profile is well tolerable. Further multicenter evaluation is needed for the better understanding of the therapeutic efficacy of the combination.

912P - Salvage Chemotherapy in Recurrent Ovarian Cancer: a Combination of Gemcitabine and Treosulfan is Equally Active in Platinum-Resistant and Platinum-Sensitive Disease

ABSTRACT Aim: The prognosis of heavily pretreated patients (pts) with epithelial ovarian carcinoma (EOC) and related malignancies having failed multiple chemotherapy (CTx) regimens is poor, irrespectively of the individual platinum-resistance status. In preceding studies, the combination of treosulfan and prolonged low-dose gemcitabine (GeT) has shown promising activity in platinum-resistant EOC. This non-interventional study has been set up in order to obtain more detailed informations regarding the clinical value of GeT given under routine conditions. Methods: 59 pts with recurrent EOC (n = 54), fallopian tube cancer (FTC; n = 2), peritoneal papillary-serous carcinoma (PPSC; n = 2), and type II endometrial carcinoma (EC-II; n = 1) who did not qualify for recruitment into a controlled clinical trial were included in this study. Pts had failed a median of 3 (range 1-11) prior Ctx, 37 were platinum-resistant (group R) and 22 were sensitive (group S). GeT was administered for 1-11 q2w cycles with treosulfan at 1 g/m2 PO on days 1-4 and gemcitabine at 450 mg/m2 IV (3 h infusion) on day 1. Adverse effects were scored according to CTCAE 4.0, responses were classified according to the integrated GCIG criteria. PFS and OS were calculated from the start of GeT until progression or death from any reason or loss to follow up. Results: GeT was generally well tolerated. Hematological side-effects were frequent but manageable with G3-4 neutropenia seen in 6, G3-4 anemia in 8, G3 fever in 3 and G3 infection in 1 pt. Non-hematological side effects exceeded G2 in only 4 pts. In 1 pt, GeT was prematurely stopped due to toxicity (allergic exanthema). A total of 8 CR and 19 PR accounted for an ORR of 45.8%. Adding 16 pts with SD, the clinical benefit rate (CBR) was 72.9%. PFS was 17.3 weeks (wks) and OS was 67.6 wks. No significant differences between groups R and S were found in regard to ORR (40.5% vs 54.5%), CBR (70.3% vs 77.3%), PFS (17.0 vs 18.4 wks), and OS (63.0 vs 72.6 wks). Moreover, prior Ctx with one of the single agents did not lower the likelihood to benefit from GeT. Conclusions: GeT given under routine conditions is well-tolerated and efficacious in heavily pretreated pts with recurrent EOC, FTC, PPSC, and EC-II by exhibiting chemomodulatory properties. Its particularly promising activity in platinum-resistant disease should be further explored in large-scaled prospective clinical trials. Disclosure: All authors have declared no conflicts of interest.

Salvage therapy of intensively pretreated patients with epithelial ovarian cancer and other Müllerian tract carcinomas with treosulfan and gemcitabine

Objectives: The prognosis of intensively pretreated patients (pts) with epithelial ovarian carcinoma (EOC) and related malignancies having failed multiple chemotherapy (CTx) regimens is poor, irrespectively of the individual platinum-resistance status. In preceding studies, the combination of treosulfan and prolonged low-dose gemcitabine (GeT) has shown promising activity in pretreated, mainly platinum-resistant EOC. This retrospective study has been set up in order yield more detailed information about the clinical value of GeT administered under routine conditions.

Protein network mapping of platinum-resistant and poor-survival ovarian cancer.

5560 Background: Epithelial ovarian carcinoma (EOC) is the fifth leading cause of tumor related death in the female population, with only 30% of patients alive at 5 years after diagnosis. Platinum resistance is a major cause of treatment failure. The aim of the study was to perform broad-scale drug target activation mapping of EOC to identify new druggable targets for personalized therapy. Methods: 72 ovarian primary lesions collected from chemo-naïve EOC patients were analyzed. Highly enriched tumor epithelial cells were isolated by laser capture microdissection, lysed and subjected to reverse phase protein microarray analysis for multiplexed protein pathway activation mapping. The activation/phosphorylation level of 156 key signaling proteins was analysed. Based on the disease-free interval to platinum therapy, 61 stage II-IV patients were segregated into platinum-resistant (&lt;6 months), platinum-sensitive (6-12 months), and platinum-supersensitive disease (&gt;12 months). One-way analysis of variance was used to detect significant differences among the three groups in the drug target activation profile. Results: Expression of the drug target PDGF Receptor β and activation of ErbB2/HER2 (Y1248) were significantly higher in patients with resistant disease compared to sensitive groups (respectively, p 0.0033 and p 0.0134), while the expression of Estrogen receptor α was greater in the supersensitive group (p 0.0295). Moreover, overall survival analysis including all stages revealed that the expression level of Cox2 is significantly higher in patients with shorter survival (HR: 2.48, p 0.0179). Conclusions: Functional drug target activation mapping revealed the unique signaling architecture of platinum-resistant EOC. If confirmed in independent study sets, these results suggest that the utilization of drugs targeting PDGF Receptor β and ErbB2/HER2 could be evaluated in platinum resistant EOC and/or in combination with platinum therapy in order to overcome acquired resistance. Finally, this study indicates that Cox2 may play an important role in aggressive EOC, and that the addition of Cox-inhibitors to standard of care could be rationally evaluated as a novel therapeutic regimen for ovarian cancer.

Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer

We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Induction of VEGF secretion in ovarian cancer by PDGF BB

5557 Background: We identified the PDGFR as a potential target in epithelial ovarian carcinoma (EOC). This led us to test whether inhibition of the receptor affects ovarian cancer cell proliferation and survival and regulates other processes critical to tumor growth and metastasis. We postulated that the PDGF-PDGFR axis regulates VEGF secretion in EOC. Methods: VEGF secretion in ovarian tumors, cancer cells, serum and ascites was measured by IHC, Western Blot and ELISA. The HOG Gyn03–62 protocol was a phase II protocol for patients with recurrent platinum resistant EOC. Patients were treated with imatinib and docetaxel. Serum and tumor samples from patients enrolled on this protocol were analyzed for VEGF. Results: VEGF expression was quantified by IHC in ovarian tumors. Of 21 PDGFR expressing ovarian tumors, seven specimens immunostained strongly for VEGF and six tumors demonstrated 2+ VEGF reactive extracellular (secreted) material. PDGF and VEGF secretion was measured in 17 specimens of malignant EOC ascites. The levels of PDGF BB and VEGF were strongly correlated (Pearson coefficient =0.728, p-value=0.001), suggesting that the two pathways interconnect. There was no correlation between PDGF AA and VEGF levels. VEGF levels were measured in 13 paired serum samples from patients enrolled in the clinical protocol HOG: Gyn03–62, before and after treatment. VEGF serum levels were stabilized or decreased in 9 of 13 EOC patients treated with imatinib. In conditioned media from primary cells, VEGF secretion was four fold higher for tumor derived cells than for cells derived from the normal ovarian epithelium. PDGF increased ten-fold VEGF secretion in PDGFR expressing immortalized ovarian cells (C272/hTert/E7 and C889/hTert), while imatinib reduced VEGF production to basal state. The effects of imatinib were mediated via inhibition of Akt and MAPK pathways, by stabilization of HIF1 alpha. In ovarian cancer cells overexpressing consitutively active Akt, imatinib inhibited only partially the secretion of VEGF compared to control cells, suggesting that the PI3K/Akt pathway is significantly implicated in PDGF-stimulated VEGF secretion. Conclusions: These results suggest that by blocking the PDGFR, imatinib inhibits VEGF production. This affects the tumor microenvironment favoring ovarian tumor growth and metastasis. No significant financial relationships to disclose.

The efficacy of tamoxifen in patients with advanced epithelial ovarian cancer

Activity of tamoxifen as a salvage therapy in patients with advanced epithelial ovarian cancer was evaluated by a number of studies. In this study, we evaluated efficacy of tamoxifen in our patients with platinum-resistant epithelial ovarian carcinoma. A retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer. Twenty-nine eligible patients were included to the study. There were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease. All patients were progressed after initiation of tamoxifen. Median progression-free survival was 4 mo (95% CI: 2.98-5.02). Disease progression of 19 (65%) patients were shown within the first 6 mo after initiation of tamoxifen. Progression-free survival was between 6 and 12 mo for 7 (24%) patients and > or =12 mo for 3 (10%) patients. The median survival after initiation of tamoxifen was 15 mo (95% CI: 7.2-22.8). No toxicity attributable to tamoxifen was seen in any of the patients. The only independent prognostic factor that had a significant predictive value for progression- free survival was the response to tamoxifen treatment (p = 0.043, hazard ratio: 0.12, 95% CI: 0.01-0.94). Considering minimal side effects and ability to cause objective responses, there is a place for tamoxifen in treatment of patients with platinum-resistant ovarian cancer. A phase III trial is required to con- firm the value of the drug in patients presenting these clinical settings.

Developmental Chemotherapy and Management of Recurrent Ovarian Cancer

Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapies remains a priority. In particular, several nonplatinum agents have demonstrated activity in phase II trials among patients with recurrent platinum-resistant EOC. These agents include gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have indicated a biologic basis for combinations of these agents with platinum, which has been attributed to inhibition of pathways involved in DNA repair. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxic effects, necessitating significant dose reductions and prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) and other organizations have conducted pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial that will compare four new combinations against carboplatin and paclitaxel. The selection of candidate regimens for this trial illustrates the challenges of drug development in EOC, emphasizing the role of phase II trials in patients with recurrent disease and indicating potential strategies to help evaluate newer biologic and molecular-targeted reagents.

Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation.

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (betatubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.