Advanced-stage Ovarian Carcinoma Research Articles

Role of systematic lymphadenectomy at the time of interval debulking surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection

ObjectiveTo evaluate the role of systematic lymphadenectomy at the time of interval cytoreductive surgery for patients with advanced-stage epithelial ovarian carcinoma who achieved complete gross resection.MethodsThe National Cancer DataBase was...

Methylation of the Selected TP53 Introns in Advanced-Stage Ovarian Carcinomas.

Objective: Advanced-stage ovarian cancer (OC) is among the most fatal female genital tract neoplasms worldwide. Although different genetic mechanisms have been shown to be involved in ovarian carcinogenesis, the role of TP53 introns methylation is still unresolved. We performed methylation analysis of introns 1, 3, and 4 of the TP53 to identify patterns in primary stage III OCs, corresponding metastases, and healthy tissues. Methods: The study involved samples of paraffin-embedded tissues obtained from 80 patients with stage III OCs, who underwent surgery at the Department of Gynecology and Gynecologic Oncology of the Military Institute of Medicine in Warsaw, Poland. Altogether, 40 serous-type G2/3 OCs and 40 endometrioid-type G2/3 OCs were included. From the same patient, metastatic and normal tissues were simultaneously analyzed. As a control group, 80 tissue samples were collected from patients after bariatric operations. Human ovarian cancer A2780 cell line was also investigated. Total genomic DNA was isolated from paraffin-embedded tissue blocks and the methylation analysis was performed by bisulfite DNA conversion, DNA amplification with specific primers, cloning, and DNA sequencing. Results: All of the samples of intron 1 of TP53 were un-methylated in OCs, metastatic tissues, and in healthy tissues from the same patient. Also, no methylation of TP53 intron 1 was detected in cells from the human A2780 ovarian cancer cell line and in all samples from control group. In all samples, introns 3 and 4 of the TP53 were methylated in primary tumors, metastatic tissue, and in healthy tissue from the same patient, in human A2780 ovarian cell line, and in DNA samples from healthy patients. None of the clinicopatholocal features was related to the TP53 introns methylation status. Conclusions: Our data on TP53 introns methylation sheds new light on the mechanism of p53 activity for a better understanding of cancer biology. The study suggests the existence of an additional regulation rule of TP53 activity that involves demethylation-methylation mechanisms. Methylation at introns 3 and 4 may also overall help in protecting TP53 against damage by viral restrictases or viral DNA integration.

Impact of adjuvant chemotherapy on the overall survival of patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery

ObjectiveTo investigate the use and outcomes of adjuvant chemotherapy for patients with advanced-stage low-grade serous ovarian carcinoma following primary cytoreductive surgery.MethodsPatients diagnosed between 2010 and 2015 with International Federation of...

MAGE-A10 Protein Expression in Advanced High Grade Serous Ovarian Cancer Is Associated with Resistance to First-Line Platinum-Based Chemotherapy.

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens (CTAs) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets for cancer immunotherapies. We analyzed the correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at the protein level and the effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. The correlation between the expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria and platinum sensitivity, measured as platinum-free interval (PFI), progression free (PFS), and overall survival (OS) was explored. The MAGE-A10 protein expression predicted unresponsiveness to platinum-based chemotherapy (p = 0.005), poor platinum sensitivity (p < 0.001), poor PFS (p < 0.001), and OS (p < 0.001). Multivariate analysis identified MAGE-A10 protein expression as an independent predictor of poor platinum sensitivity (p = 0.005) and shorter OS (p < 0.001). Instead, no correlation was observed between the NY-ESO-1 protein expression and response to platinum-based chemotherapy (p = 0.832), platinum sensitivity (p = 0.168), PFS (p = 0.126), and OS (p = 0.335). The MAGE-A10 protein expression reliably identified advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted immunotherapy could represent an important alternative therapeutic option in these cancers.

Survival Effect of Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma During the Platinum Era: A Meta-Analysis.

To evaluate the relative effect of percent maximal cytoreductive surgery and other prognostic variables on survival among cohorts of patients with advanced-stage ovarian carcinoma treated with platinum-based chemotherapy. Eighty-one cohorts of patients with stage III or IV ovarian carcinoma (6,885 patients) were identified from articles in MEDLINE (1989 through 1998). Linear regression models, with weighted correlation calculations, were used to assess the effects on log median survival time of the proportion of each cohort undergoing maximal cytoreduction, dose-intensity of the platinum compound administered, proportion of patients with stage IV disease, median age, and year of publication. There was a statistically significant positive correlation between percent maximal cytoreduction and log median survival time, and this correlation remained significant after controlling for all other variables (P < .001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. When actuarial survival was estimated, cohorts with ≤ 25% maximal cytoreduction had a mean weighted median survival time of 22.7 months, whereas cohorts with more than 75% maximal cytoreduction had a mean weighted median survival time of 33.9 months-an increase of 50%. The relationship between platinum dose-intensity and log median survival time was not statistically significant. During the platinum era, maximal cytoreduction was one of the most powerful determinants of cohort survival among patients with stage III or IV ovarian carcinoma. Consistent referral of patients with apparent advanced ovarian cancer to expert centers for primary surgery may be the best means currently available for improving overall survival.

Contribución de PET/CT a la diferenciación de derrame pleural benigno y maligno en pacientes con cáncer de ovario

ObjectiveThe present study investigates the ability of non-invasive contribution of positron emission tomography (PET)/computed tomography (CT) to distinguish between benign pleural effusions (BPE) and malignant pleural effusions (MPE) in patients diagnosed with ovarian carcinoma (OC). Material and methodIncluded in the study were 32 OC patients with a PE diagnosis. The cases with BPE and MPE were compared in terms of the PE maximum standardized uptake value (SUVmax), PE SUVmax/mean standardized uptake (SUVmean) value of the mediastinal blood pool (TBRp), the presence of pleural thickening, the presence of supradiaphragmatic lymph node, unilateral or bilateral PE, pleural effusion diameter, patient age and CA125 value. ResultsThe mean age of the 32 patients was 57±2.8 years. TBRp>1.1, pleural thickening and supradiaphragmatic lymph node were observed significantly more frequently in the MPE than the BPE cases. While no pleural nodules were detected in patients with BPE, they were present in 7 of the patients with MPE. The rates of distinction between the MPE and BPE cases were as follows: the sensitivity of the TBRp value was 95.2% and specificity was 72.7%; the sensitivity of pleural thickness was 80.9% and specificity was 81.8%; the sensitivity of supradiaphragmatic lymph node was 38% and specificity was 90.9%; and the sensitivity of the pleural nodule was 33.3% and specificity was 100%. There were no significant differences between two groups in any other factors. ConclusionPleural thickening and TBRp values ascertained through PET/CT may aid the distinction between MPE-BPE, especially in patients with advanced stage OC with a poor general condition, or those who cannot undergo surgery.

The effect of maintenance hormone therapy on overall survival in advanced-stage low-grade serous ovarian carcinoma: A risk-set matched retrospective study.

5568 Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare malignancy often treated similarly to high-grade serous ovarian carcinoma (HGSOC) despite differences in clinical behavior and carcinogenesis. Observational studies suggest that, among patient with advanced-stage LGSOC, maintenance hormonal therapy (HT) following primary treatment is associated with improved progression free survival. We conducted a multi-institutional observational study to investigate whether HT is associated with an overall survival advantage in this setting. Methods: We included patients with histologically confirmed stage III or IV LGSOC diagnosed between Jan 1, 2004, and Dec 31, 2019, treated in Commission on Cancer accredited cancer programs in the US. Patients who received HT within 6 months of diagnosis were matched to controls who did not initiate HT during this timeframe. The primary outcome was risk of death from any cause, within five-years of initiation of HT or observation. For each treated patient, we employed risk-set propensity score matching to identify a control in a manner that avoided the introduction of immortal-time-bias, and balanced groups with respect to year of diagnosis, upfront treatment strategy, age, stage, race/ethnicity, comorbidity index, insurance status, zip-code median income, and cancer program type. Results: There were 296 patients who initiated HT within 6 months of diagnosis, and 2,805 potential controls. Patients who received HT were more often treated in academic medical centers (55% vs 44%), diagnosed later in the study period (62% vs 23% diagnosed in 2018-2019), and received upfront chemotherapy less frequently (55% vs 83%). After risk set and propensity score matching, we identified 204 patients treated with HT and 204 untreated controls, who were otherwise similar with respect to measured covariates. In the matched cohort, maintenance HT was associated with a reduction in the risk of death (hazard ratio 0.61; 95% CI 0.37-0.99), corresponding to a 60-month survival of 71% compared with 61%, and an improvement in 5-year life expectancy of 3.6 months (95% CI 0.004-7.2). Conclusions: Maintenance hormone therapy following primary management of LGSOC is associated with an overall survival benefit compared with observation.

The contribution of PET/CT to the differentiation of benign and malignant pleural effusion in patients with ovarian carcinoma

ObjectiveThe present study investigates the ability of non-invasive contribution of positron emission tomography (PET)/computed tomography (CT) to distinguish between benign pleural effusions (BPE) and malignant pleural effusions (MPE) in patients diagnosed with ovarian carcinoma (OC). Material and methodsIncluded in the study were 32 OC patients with a PE diagnosis. The cases with BPE and MPE were compared in terms of the PE maximum standardized uptake value (SUVmax), PE SUVmax/mean standardized uptake (SUVmean) value of the mediastinal blood pool (TBRp), the presence of pleural thickening, the presence of supradiaphragmatic lymph node, unilateral or bilateral PE, pleural effusion diameter, patient age and CA125 value. ResultsThe mean age of the 32 patients was 57±2.8 years. TBRp>1.1, pleural thickening and supradiaphragmatic lymph node were observed significantly more frequently in the MPE than the BPE cases. While no pleural nodules were detected in patients with BPE, they were present in 7 of the patients with MPE. The rates of distinction between the MPE and BPE cases were as follows: the sensitivity of the TBRp value was 95.2% and specificity was 72.7%; the sensitivity of pleural thickness was 80.9% and specificity was 81.8%; the sensitivity of supradiaphragmatic lymph node was 38% and specificity was 90.9%; and the sensitivity of the pleural nodule was 33.3% and specificity was 100%. There were no significant differences between two groups in any other factors. ConclusionsPleural thickening and TBRp values ascertained through PET/CT may aid the distinction between MPE-BPE, especially in patients with advanced stage OC with a poor general condition, or those who cannot undergo surgery.

The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis.

The identification of therapeutic approaches to improve response to platinum-based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a large family of ubiquitin proteases implicated in a variety of cellular functions and may contribute to tumor aggressive features through regulation of processes such as proliferation and cell death. Among the subfamily of ubiquitin-specific peptidases, USP8 appears to be involved in modulation of cancer cell survival by still poorly understood mechanisms. Thus, we used ovarian carcinoma cells of different histotypes, including cisplatin-resistant variants with increased survival features to evaluate the efficacy of molecular targeting of USP8 as a strategy to overcome drug resistance/modulate cisplatin response. We performed biochemical analysis of USP8 activity in pairs of cisplatin-sensitive and -resistant cells and found increased USP8 activity in resistant cells. Silencing of USP8 resulted in decreased activation of receptor tyrosine kinases and increased sensitivity to cisplatin in IGROV-1/Pt1 resistant cells as shown by colony forming assay. Increased cisplatin sensitivity was associated with enhanced cisplatin-induced caspase 3/7 activation and apoptosis, a phenotype also observed in cisplatin sensitive cells. Increased apoptosis was linked to FLIPL decrease and cisplatin induction of caspase 3 in IGROV-1/Pt1 cells, cisplatin-induced claspin and survivin down-regulation in IGROV-1 cells, thereby showing a decrease of anti-apoptotic proteins. Immunohistochemical staining on 65 clinical specimens from advanced stage ovarian carcinoma indicated that 40% of tumors were USP8 positive suggesting that USP8 is an independent prognostic factor for adverse outcome when considering progression free survival as a clinical end-point. Taken together, our results support that USP8 may be of diagnostic value and may provide a therapeutic target to improve the efficacy of platinum-based therapy in ovarian carcinoma.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands

ObjectiveStandard surgical treatment of advanced-stage ovarian carcinoma with electrosurgery cannot always result in complete cytoreductive surgery (CRS), especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of a neutral argon plasma device can help increase the complete cytoreduction rate.Patients and Methods327 patients with FIGO stage IIIB–IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were randomized to either surgery with neutral argon plasma (PlasmaJet) (intervention) or without PlasmaJet (control group). The primary outcome was the percentage of complete CRS. The secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30-day morbidity, and quality of life (QoL).ResultsComplete CRS was achieved in 119 patients (75.8%) in the intervention group and 115 patients (67.6%) in the control group (risk difference (RD) 8.2%, 95% confidence interval (CI) –0.021 to 0.181; P = 0.131). In a per-protocol analysis excluding patients with unresectable disease, complete CRS was obtained in 85.6% in the intervention group and 71.5% in the control group (RD 14.1%, 95% CI 0.042 to 0.235; P = 0.005). Patient-reported QoL at 6 months after surgery differed between groups in favor of PlasmaJet surgery (95% CI 0.455–8.350; P = 0.029). Other secondary outcomes did not differ significantly.ConclusionsAdjuvant use of PlasmaJet during CRS for advanced-stage ovarian cancer resulted in a significantly higher proportion of complete CRS in patients with resectable disease and higher QoL at 6 months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.)Trial RegistrationApproved by the Medical Ethics Review Board of the Erasmus University Medical Center Rotterdam, the Netherlands, NL62035.078.17 on 20-11-2017. Recruitment started on 30-1-2018.

Omental Macrophagic "Crown-like Structures" Are Associated with Poor Prognosis in Advanced-Stage Serous Ovarian Cancer.

The tumor microenvironment is a well-recognized framework in which immune cells present in the tumor microenvironment promote or inhibit cancer formation and development. A crown-like structure (CLS) has been reported as a dying or dead adipocyte surrounded by a ‘crown’ of macrophages within adipose tissue, which is a histologic hallmark of the inflammatory process in this tissue. CLSs have also been found to be related to formation, progression and prognosis of some types of cancer. However, the presence of CLSs in the omentum of advanced-stage high-grade serous ovarian carcinoma (HGSOC) has not been thoroughly investigated. By using CD68, a pan-macrophage marker, and CD163, an M2-like polarization macrophage marker, immunohistochemistry (IHC) was performed to identify tumor-associated macrophages (TAMs) and CLSs. This retrospective study analyzed 116 patients with advanced-stage HGSOC who received complete treatment and had available clinical data from July 2008 through December 2016 at National Cheng Kung University Hospital (NCKUH) (Tainan, Taiwan). Based on multivariate Cox regression analysis, patients with omental CD68+ CLSs had poor OS (median survival: 24 vs. 38 months, p = 0.001, hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.41–3.61); patients with omental CD163+ CLSs also had poor OS (median survival: 22 vs. 36 months, HR: 2.14, 95%CI: 1.33–3.44, p = 0.002). Additionally, patients with omental CD68+ or CD163+ CLSs showed poor PFS (median survival: 11 vs. 15 months, HR: 2.28, 95%CI: 1.43–3.64, p = 0.001; median survival: 11 vs. 15 months, HR: 2.17, 95%CI: 1.35–3.47, respectively, p = 0.001). Conversely, the density of CD68+ or CD163+ TAMs in ovarian tumors was not associated with patient prognosis in advanced-stage HGSOC in our cohort. In conclusion, we, for the first time, demonstrate that the presence of omental CLSs is associated with poor prognosis in advanced-stage HGSOC.

USP19 and RPL23 as Candidate Prognostic Markers for Advanced-Stage High-Grade Serous Ovarian Carcinoma.

Simple SummaryAlthough ovarian cancer is one of the leading causes of deaths among female patients with cancer, some patients live longer than others. In order to predict the outcome of patients with ovarian cancer, we investigated the expression levels of all human genes in 51 patients with ovarian cancer and constructed a prediction model based on artificial intelligence. The model identified two genes—USP19 and RPL23—as the most important genes for this prediction. Cancer recurrence occurred more frequently in the patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels. The same pattern was observed in 208 independent patients with ovarian cancer listed in The Cancer Genome Atlas. Therefore, we suggest USP19 and RPL23 as candidate biomarkers for predicting the survival of patients with ovarian cancer.Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas; this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy.

Towards a functional model of drug sensitivity in advanced-stage ovarian cancer: clinical correlation of drug sensitivity assays in organoid tissue cultures

Objectives: Though many ovarian cancer patients respond to primary treatment, a significant portion will not respond and are considered ‘platinum resistant/refractory.’ Such patients experience a significantly worse prognosis relative to those who are ‘platinum sensitive.’ Pre-treatment prediction of platinum sensitivity has eluded scientists, which forces clinicians to undergo a ‘trial and error’ method of treatment by which resistant patients are forced to try and fail a futile line of therapy. Patient-derived organoid (PDO) cultures represent a potentially powerful functional model which preserves tumor heterogeneity (Hill et al, 2018). Here, we describe the successful culture of 4 PDOs from patients with advanced stage ovarian carcinoma and their correlation with clinical treatment outcome. Methods: Fresh tissue was obtained from the patients’ debulking surgery. It was digested, and a cell pellet was created. The pellet was washed several times, re-suspended in Matrigel, plated, and grown at 37oC over several days. PDOs were treated with standard doses of carboplatin (1 µM) and paclitaxel (10 nM). The percent of viable cells at 72 hours was measured using the CellTiter-Glo 3D platform (Promega, Madison, WI). The patients’ clinical charts were then reviewed 6 months after the completion of primary chemotherapy to determine clinical platinum sensitivity as defined by clinical parameters. Results: PDOs were successfully obtained from each of the four patients with advanced stage ovarian carcinoma. Three patients had primary disease, and 1 patient was being treated for a recurrence. The patient with recurrent disease received chemotherapy immediately prior to her debulking surgery, and the rest underwent primary debulking surgery with chemotherapy to follow. Three patients had high grade serous histology, and 1 patient had low grade serous histology. Three patients ultimately had platinum resistant disease, and their PDOs all demonstrated >50% cell viability in response to carboplatin and paclitaxel with 2 resistant PDOs demonstrating a remarkable 90% and 95% cell viability. The PDO from the patient with platinum sensitive disease by clinical criteria demonstrated 49% cell viability in response to treatment (Table 1). Download : Download high-res image (123KB) Download : Download full-size image Conclusions: We describe the successful creation of PDOs from fresh tissue obtained from debulking surgery in advanced stage ovarian cancer patients. If we use ≥50% cell viability as our initial, preliminary sensitivity threshold, results from the PDO drug sensitivity assay correlate with clinical platinum sensitivity in this pilot feasibility. We propose to confirm the predictability of drug sensitivity thresholds in future, larger studies using PDOs. Currently, there is no standardized drug sensitivity assay or response parameters defined as predictable for PDOs. Such work will be integral in the formation of a functional model of drug sensitivity, which can be used in the clinic to predict platinum sensitivity without requiring a patient to try and fail futile treatments.

Dual germline and somatic testing in women with high-grade epithelial ovarian, tubal, and peritoneal cancer: a prospective systemic quality improvement initiative

<h3>Objectives:</h3> Germline and somatic genetic testing can have significant implications for women with ovarian, fallopian tube or peritoneal carcinoma, including therapeutic decisions, prognostic counseling and cascade testing. However, there are obstacles to universal implementation of testing when it is dependent on clinician initiative. Therefore, we implemented a prospective quality improvement (QI) initiative that aimed to assure universal germline and somatic testing in women with newly diagnosed advanced stage, high grade disease. <h3>Methods:</h3> A systematic program was established to ensure that all patients with newly diagnosed, advanced stage ovarian, tubal or peritoneal carcinoma who were scheduled for formal genetics consultation underwent dual Myriad MyRisk multigene germline testing and Myriad MyChoice somatic testing for <i>BRCA1/2</i> mutations and genomic instability. The primary objective was to compare the frequency of germline and somatic testing between the pre-initiative (1/1/2015 - 3/31/2018) and post-initiative (4/1/2018- 7/1/2020) periods. Secondary objectives included comparison of time intervals between diagnosis and testing, incidence of ‘insufficient samples' for somatic testing, and clinical utilization of results. Descriptive statistics were used. Paired Student's T test was used to compare continuous variables; chi-square test was used to compare discrete variables. <h3>Results:</h3> There were 209 women in this study: 122 in the pre-intervention cohort and 87 in the post-intervention cohort. Among women in the pre-intervention group, 90 (74%) and 48 (39%) underwent germline and somatic testing, respectively, compared to 77 (89%) and 66 (76%) in the post-intervention cohort. Implementation of a systemic referral system with dual testing doubled the rate of somatic testing (p<0.01). Among all women who underwent germline testing, 10.1% had a g<i>BRCA1</i> mutation and 2.4% a g<i>BRCA2</i> mutation. Of all who underwent somatic testing, 6.2% had a s<i>BRCA1</i> mutation and 4.3% a s<i>BRCA2</i> mutation. All germline <i>BRCA1</i> and <i>BRCA2</i> mutations were also identified on somatic testing. There were 20 cases (9.5%) with negative germline multigene panels also lacking somatic <i>BRCA1/2</i> mutations that were found to have genomic instability. Among the 114 patients who received somatic testing, 29 (25.4%) had biomarkers (<i>BRCA1/2</i> mutation or genomic instability) predictive of major benefit from poly-ADP ribose polymerase inhibitors (PARPi) despite lacking germline mutations. Median time from diagnosis to germline testing decreased to 3.7 months in the post-intervention compared to 6.2 months in the pre-intervention cohort. <h3>Conclusions:</h3> Systematic referral for both germline and somatic genetic testing significantly increased the frequency of somatic testing, and results were obtained sooner in patients with advanced ovarian, fallopian tube and peritoneal cancers. In patients who underwent dual testing and lacked germline mutations, 25% had either a somatic <i>BRCA1</i> or <i>BRCA2</i> mutation or genomic instability that could help direct therapy. Since both germline and somatic mutations and genomic instability status increasingly play a role in directing therapy, earlier and consistent testing is of the upmost importance.

Platinum refractory advanced stage ovarian clear cell carcinoma: time to reconsider primary therapy?

Objectives: Clear Cell Ovarian Carcinoma (CCOC) is known for its chemoresistance, high rates of relapse, and poor overall survival. Despite this, upfront treatment has remained relatively unchanged for decades. The objective of this study was to compare demographic and pathologic characteristics of patients with rapidly progressive versus chemo-sensitive advanced stage (III or IV) CCOC in order to better identify a cohort of patients who may benefit from innovative upfront treatment strategies. Methods: After IRB approval, patients diagnosed with CCOC between 2008 and 2020 at our University were identified and reviewed. Demographic information including age, parity, and menopausal status at time of diagnosis was collected in addition to tumor data such as percent clear cell and the presence or absence of coexisting endometriosis. Those diagnosed with stage I or II disease and those who have not yet completed adjuvant therapy were excluded. Progression-free survival (time from chemotherapy completion to progression or death) was estimated with a Kaplan-Meier curve. Patients were divided into one of two cohorts: chemo-sensitive (lack of progression or death at one year from chemotherapy completion) or rapidly progressive (evidence of progression or death within one year) and cohorts were compared using Wilcoxon rank-sum tests and Fisher's exact tests. Results: Thirty-four patients met inclusion criteria. All subjects underwent surgical staging or debulking and adjuvant platinum/taxane chemotherapy. Median progression-free survival was 6.1 months (95% confidence interval: 3.3-24.3 months). Thirteen patients (43.3%) were identified as chemo-sensitive, and seventeen (56.7%) as rapid progressors. Four patients did not have enough follow-up to be classified. All rapid progressors recurred or progressed within seven months of primary chemotherapy completion. The cohort of patients with rapidly progressive disease were younger (median age 53 vs 64, p=0.048) and more likely to be premenopausal (41% vs 7.7%, p=0.11). Rates of endometriosis, pure clear cell histology and residual disease after surgery were also higher in this group (53% vs 31%, p=0.34, 65% vs 46%, p=0.5 and 65% vs 46%, p=0.5 respectively), although these differences did not reach statistical significance. Download : Download high-res image (53KB) Download : Download full-size image Conclusions: Over half of patients with advanced clear cell ovarian carcinoma demonstrated rapid progression following or during platinum based chemotherapy. Further characterization of this cohort is indicated and molecular studies are underway to better identify patients that will experience no benefit from the current standard of care. Targeting this cohort of women with innovative, upfront clinical trials is warranted.

Impact of systematic lymphadenectomy at the time of interval debulking surgery on the survival of patients with advanced-stage epithelial ovarian carcinoma following neoadjuvant chemotherapy

<h3>Objectives:</h3> In light of evidence from the LION trial, we aimed to evaluate the impact of systematic lymphadenectomy (LN) at the time of interval debulking surgery (IDS) for patients with advanced stage epithelial ovarian carcinoma. <h3>Methods:</h3> Patients with stage III-IV epithelial ovarian carcinoma without a history of another tumor who underwent neoadjuvant chemotherapy and underwent interval debulking with complete gross resection (CGR) were identified in the National Cancer Database (2010-2015). Based on pathology report patients who did not undergo any lymphadenectomy and those who underwent systematic lymphadenectomy (defined as at least 20 lymph nodes removed) were selected for further analysis. Median overall survival was compared with the log-rank test and a Cox multivariate model was constructed to control for confounders. <h3>Results:</h3> A total of 1060 patients who met the inclusion criteria were identified. Median patient age was 64 years while the majority had serous tumors (95.8%) and did not have co-morbidities (79.2%). Systematic LND was performed for 125 (11.8%) patients with a median of 29 LNs (range 20-72) removed. Rate of positive LNs was 62.4%, while median number of positive LN was 5 (range 1-28). Patients who underwent systematic LND had higher rate of unplanned readmission (8.9% vs 1.6%, p<0.001), and median hospital stay (6 vs 4 days, p<0.001). Median OS for patients who did not undergo LND was 40.38 months compared to 44.19 for those who underwent systematic LND, p=0.40. After controlling for patient age, insurance status, race, presence of comorbidities, tumor histology, and disease stage, performance of systematic LND was not associated with better survival (HR: 0.98, 95% CI: 0.80, 1.19). Lastly, median overall survival of patients with positive LNs (n=78) was 40.05 months. <h3>Conclusions:</h3> Systematic lymphadenectomy is rarely performed at the time of interval debulking surgery and was not associated with a survival benefit.

Impact of delay in adjuvant chemotherapy administration for patients with advanced-stage epithelial ovarian carcinoma undergoing primary debulking surgery with bowel resection

<h3>Objectives:</h3> Patients with epithelial ovarian carcinoma (EOC) undergoing primary debulking surgery (PDS) with small or large bowel resection have a higher risk of postoperative complications that could delay administration of adjuvant chemotherapy. The aim of the present study was to evaluate the impact of chemotherapy delay in the survival of patients with EOC undergoing bowel resection using a hospital-based database. <h3>Methods:</h3> The National Cancer Database (NCDB) was accessed and patients diagnosed between 2004-2015 with stage III-IV EOC without a history of another tumor who underwent PDS that included small or large bowel resection with known surgery-chemotherapy interval and at least one month of follow-up were identified. Overall survival (OS) was compared between patients who received multi-agent chemotherapy 2-6 week (group 1), 7-9 weeks (group 2) and 10-12 weeks (group 3) from surgery with the log-rank test. A Cox multivariate model was constructed to control for confounders. Impact of chemotherapy delay was also evaluated among patients who achieved complete gross resection (CGR) and those who had macroscopic disease. <h3>Results:</h3> A total of 9274 patients who met the inclusion criteria were identified; 69.8% received adjuvant chemotherapy 2-6 weeks from surgery while 24.5% and 5.7% received chemotherapy 7-9 weeks and 10-12 weeks respectively. Patients in group 2 (30.2%) and 3 (36.6%) were more likely to experience a prolonged hospital stay (>10 days) following PDS compared to those in group 1 (19.4%), p<0.001. Rates of unplanned re-admission within 30-days from surgery in group 1,2 and 3 were 7.7%, 9.2% and 11.3% respectively, p=0.002. Median OS for patients in group 1 was 44.78 months compared to 42.25 and 39.89 for those in groups 2 and 3 respectively, p=0.103. After controlling for patient age, race, presence of comorbidities insurance, tumor histology and stage, compared to patients in group 1 those in group 2 (HR: 1.04, 95% CI: 0.98, 1.10) and group 3 (HR 1.05, 95% CI: 0.94, 1.17) did not have worse survival. Status of residual disease was available for 3659 patients; 46% achieved CGR. For patients with CGR, median OS for those in group 1 and 2 was 55.46 and 52.70 months compared to 42.18 for those in group 3, p=0.015. After controlling for aforementioned variables those in group 3 had worse survival (HR: 1.37, 95% CI: 1.04, 1.82) compared to patients in group 1 while there was no difference in survival between group 2 and 1 (HR: 1.06, 95% CI: 0.90, 1.27). For patients with macroscopic residual disease, timing of chemotherapy administration was not associated with survival; median OS for patients in group 1, 2 and 3 was 41.3, 42.74 and 41.13 months respectively, p=0.82. <h3>Conclusions:</h3> For patients with advanced stage EOC undergoing PDS with bowel resection extreme delay in adjuvant chemotherapy administration over 10 weeks from surgery may be associated with a negative impact on the survival of those who achieve CGR.

Impact of facility-volume on achieving a textbook oncologic outcome following primary debulking surgery for advanced-stage epithelial ovarian carcinoma

<h3>Objectives:</h3> Composite outcomes have emerged as a more accurate marker of optimal oncologic care. We evaluated the impact of facility-volume on achieving a ‘textbook oncologic outcome' (TOO) among patients diagnosed with advanced stage epithelial ovarian carcinoma (EOC) undergoing primary debulking surgery (PDS) followed by adjuvant chemotherapy. <h3>Methods:</h3> Patients diagnosed between 2004-2015 with stage IIIC-IV EOC who underwent PDS at the reporting facility followed by adjuvant chemotherapy were identified in the National Cancer Database. Annual facility PDS volume was calculated and high-volume facilities were defined those performing at least 12 PDS per year. TOO was defined as achievement of complete gross resection (CGR), no 90-day mortality, no prolonged hospitalization (>10 days), no unplanned readmission within 30-days from discharge, and initiation of adjuvant chemotherapy within 42 days from surgery and evaluated among patients with available data for all variables. Median overall survival (OS) was compared with the log-rank test and a Cox multivariate model was constructed to control for confounders. <h3>Results:</h3> A total of 19875 patients were used to calculate annual PDS facility-volume. Final analysis cohort included 6984 patients with available data for all variables of interest; 14.8% were managed at a high-volume center. A TOO was achieved for 1764 (25.3%) patients. Rate of CGR was 42.8%, while rate of prolonged hospitalization was 15.2%. Unplanned re-admission (8%) and death within 90-days (1.4%) were rare, while 28.6% of patients experienced a delay in chemotherapy administration. Patients managed at high-volume centers were more likely to achieve a TOO (28.1% vs 24.8%, p=0.022). After controlling for age, race, insurance, and comorbidities, PDS at a high-volume center was associated with a higher likelihood of achieving a TOO (OR: 1.17, 95% CI: 1.01, 1.36). Median OS of patients who did and did not achieve a TOO was 58.45 and 42.51 months respectively, p<0.001. After controlling for histology, stage, comorbidities, patient age, race, and type of insurance, TOO was associated with better survival (HR: 0.64, 95% CI: 0.59, 0.70). <h3>Conclusions:</h3> PDS at a high-volume center was associated with superior oncologic outcomes for patients with advanced-stage EOC. Centralization of care of these patients to centers of excellence should be considered.

Outcomes of comprehensive lymphadenectomy for patients with advanced stage ovarian carcinoma and rare histologic sub-types

ObjectiveTo investigate the prognostic significance of comprehensive lymphadenectomy at the time of primary debulking surgery for patients with rare histologic sub-types of epithelial ovarian carcinoma and clinically advanced stage disease...