Post-surgical ctDNA-based molecular residual disease detection in patients with stage I uterine malignancies.

INTRODUCTION: Among uterine malignancies, endometrial cancer (EC) is the most common cancer of the female reproductive tract. Traditionally, risk stratification in EC is determined by standard clinicopathological risk factors. Although circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker in various malignancies, its clinical validity in EC remains to be established. METHODS: In this analysis of real-world data, 267 plasma samples from 101 patients with stage I EC were analyzed using a tumor-informed ctDNA assay (Signatera™ bespoke mPCR-NGS). Patients were followed post-surgically and monitored with ctDNA testing for a median of 6.8 months (range: 0.37-19.1). RESULTS: Patients who tested ctDNA-positive at both their first time point and longitudinally experienced inferior recurrence-free survival (RFS) (HR = 6.2; p = 0.0006 and HR = 15.5; p < 0.0001, respectively), and showed a recurrence rate of 58% and 52%, vs. 6% and 0%, respectively for the ctDNA-negative patients. Most ctDNA-positive patients had high-risk histologies or sarcoma, versus low-risk and high-intermediate risk (H-IR) EC. Furthermore, patients with high-risk histologies who were ctDNA-positive showed shorter RFS compared to those who tested negative (HR = 9.5; p = 0.007), and those who tested positive in the low/H-IR cohort (HR = 0.25; p = 0.04). Post-surgically, detectable ctDNA was highly prognostic of clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as histologic risk group, mismatch repair (MMR), and p53 status. CONCLUSION: Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification.

Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial.

OBJECTIVE: HER2 mutations are associated with poor prognosis and are detected in 3-6% of cervical cancers. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, had activity in several HER2-mutant cancer types in the phase 2 SUMMIT basket study. We present updated and final results from the cervical cancer cohort of SUMMIT. METHODS: Eligible patients had HER2-mutant, metastatic or recurrent cervical cancer progressing after platinum-based treatment for advanced/recurrent disease. Patients received neratinib 240 mg/day; loperamide was mandatory during cycle 1. Confirmed objective response rate (ORR) was the primary endpoint. Duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and safety were secondary endpoints. RESULTS: Twenty-two patients were enrolled; 18 (81.8%) had endocervical adenocarcinoma; median two prior systemic chemotherapy regimens (range 1-4). The most common HER2 variant was S310F/Y mutation (n = 13; 59.1%). Four patients had confirmed partial responses (ORR 18.2%; 95% CI 5.2-40.3); 6 had stable disease ≥16 weeks (CBR 45.5%; 95% CI 24.4-67.8). Median DoR was 7.6 months (95% CI 5.6-12.3). Median PFS was 5.1 months (95% CI 1.7-7.2). All-grade diarrhea (90.9%), nausea (54.5%), and constipation (54.5%) were the most common adverse events. Five patients (22.7%) reported grade 3 diarrhea. There were no grade 4 adverse events, no diarrhea-related treatment discontinuations, and two grade 5 adverse events, unrelated to neratinib: dyspnea (n = 1) and embolism (n = 1). CONCLUSIONS: Neratinib resulted in durable responses and disease control in patients with HER2-mutant metastatic/recurrent cervical cancer in SUMMIT. These findings support next-generation sequencing and tailored therapy for select patients with advanced cervical cancer. All responses occurred in patients with endocervical adenocarcinoma. Further assessment of neratinib in this setting is warranted. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up.

PURPOSE: To investigate whether circulating tumor DNA (ctDNA) assessment in patients with muscle-invasive bladder cancer predicts treatment response and provides early detection of metastatic disease. EXPERIMENTAL DESIGN: We present full follow-up results (median follow-up: 68 months) from a previously described cohort of 68 neoadjuvant chemotherapy (NAC)-treated patients who underwent longitudinal ctDNA testing (712 plasma samples). In addition, we performed ctDNA evaluation of 153 plasma samples collected before and after radical cystectomy (RC) in a separate cohort of 102 NAC-naïve patients (median follow-up: 72 months). Total RNA sequencing of tumors was performed to investigate biological characteristics of ctDNA shedding tumors. RESULTS: Assessment of ctDNA after RC identified metastatic relapse with a sensitivity of 94% and specificity of 98% using the expanded follow-up data for the NAC-treated patients. ctDNA dynamics during NAC was independently associated with patient outcomes when adjusted for pathologic downstaging (HR = 4.7; P = 0.029). For the NAC-naïve patients, ctDNA was a prognostic predictor before (HR = 3.4; P = 0.0005) and after RC (HR = 17.8; P = 0.0002). No statistically significant difference in recurrence-free survival for patients without detectable ctDNA at diagnosis was observed between the cohorts. Baseline ctDNA positivity was associated with the Basal/Squamous (Ba/Sq) subtype and enrichment of epithelial-to-mesenchymal transition and cell cycle-associated gene sets. CONCLUSIONS: ctDNA is prognostic in NAC-treated and NAC-naïve patients with more than 5 years follow-up and outperforms pathologic downstaging in predicting treatment efficacy. Patients without detectable ctDNA at diagnosis may benefit significantly less from NAC, but additional studies are needed.

Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032).

OBJECTIVE: This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCAwt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. METHODS: This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). RESULTS: The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5-19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively), and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy - Ovarian Symptom Index scores, worsened over time compared with baseline scores. CONCLUSIONS: The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

Clinical outcomes in patients with COVID-19 and gynecologic cancer: A society of gynecologic oncology COVID-19 and gynecologic cancer registry study.

OBJECTIVES: Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS: The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS: Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS: Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.

Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance. METHODS: Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes. RESULTS: Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056). CONCLUSIONS: The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

Olaparib treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: Phase II LIGHT study primary analysis.

OBJECTIVE: Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non­platinum chemotherapy in patients with BRCA1/BRCA2-mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. METHODS: In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. CONCLUSIONS: Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies.

Molecular profiles of endometrial cancer tumors among Black patients.

OBJECTIVES: Disparate outcomes exist between Black and White patients with endometrial cancer (EC). One contributing factor is the disproportionately low representation of Black patients in clinical trials and in tumor molecular profiling studies. Our objective was to investigate molecular profiles of ECs in a cohort with a high proportion of tumors from Black patients. METHODS: A total of 248 EC samples and self-reported race data were collected from 6 institutions. Comprehensive tumor profiling and analyses were performed by Caris Life Sciences. RESULTS: Tumors from 105 (42%) Black and 143 (58%) White patients were included. Serous histology (58% vs 36%) and carcinosarcoma (25% vs 16%), was more common among Black patients, and endometrioid was less common (17% vs 48%) (p < 0.01). Differences in gene mutations between cohorts corresponded to observed histologic differences between races. Specifically, TP53 mutations were predominant in serous tumors. In endometrioid tumors, mutations in ARID1A were the most common, and high rates of MSI-H, MMRd, and TMB-H were observed. In carcinosarcoma tumors, hormone receptor expression was high in tumors of Black patients (PR 23.4%, ER 30.8%). When stratified by histology, there were no significant differences between tumors from Black and White women. CONCLUSIONS: This cohort had a high proportion of tumors from Black women. Distinct molecular profiles were driven primarily by more aggressive histologic subtypes among Black women. Continued effort is needed to include Black women and other populations under-represented in EC molecular profiling studies as targeted therapies and personalized medicine become mainstream.

Health Care Resource Utilization and Costs Associated with Disease Progression in Ovarian Cancer.

INTRODUCTION: Ovarian cancer (OC) is one of the leading causes of cancer mortality among women in the United States. With the approval of first-line maintenance therapies, patients with OC experienced prolonged first-line progression-free survival. While the literature addresses some costs associated with OC, further research is needed on the costs of progression that are potentially deferred or prevented by early maintenance. The objective of this study was to capture the health care resource utilization and costs of patients with advanced OC who never received poly(ADP ribose) polymerase (PARP) inhibitor maintenance. METHODS: We conducted a descriptive retrospective analysis of treatment patterns and the consequences of progression through several lines of therapy (LOTs) in patients with OC, using claims from commercial and Medicare Advantage health plan members in the United States from the Optum Research Database between January 1, 2010, and April 30, 2019. Patients were required to have an index OC diagnosis (≥ 2 non-diagnostic claims). We examined up to 4 LOTs and the time between treatments. RESULTS: A total of 5498 women met the eligibility criteria. As the number of LOTs increased, the median duration of each line decreased from 137 days in LOT1 to 94 days in LOT4, and the time between lines also decreased from 245 to 0 days. Ambulatory care visits were a major driver of health care resource utilization, with a median of about 6 monthly visits during active treatment. The mean total monthly health care costs for patients with at least 2 LOTs were US$8588 (SD: $8533) before LOT2 and increased to $15,358 (SD: $21,460) during or after LOT2. CONCLUSIONS: Prolonging progression-free survival after first-line treatment in patients with OC may provide the opportunity to delay or prevent later treatment, the financial toxicity felt by patients, and the economic burden to the health care system associated with progression.

Ovarian cancer is a complex disease in which > 70% of patients are diagnosed with advanced disease, and one of the leading causes of cancer mortality among women in the United States. A variety of maintenance therapy options, including bevacizumab, PARP inhibitors, and PARP plus bevacizumab combination therapies, have demonstrated improvements in progression-free survival. By delaying disease progression after completion of first-line therapy, a simultaneous decrease in post-progression health care costs may be seen. The objective of this study was to capture the health care resource utilization and costs of patients with advanced ovarian cancer who did not receive a PARP inhibitor at any time in their treatmentIn patients never receiving a PARP inhibitor, this study documented substantial health care resource usage and costs associated with progression beyond the first line of treatment (surgery and/or chemotherapy) in ovarian cancer. These were largely driven by the number of ambulatory care visits. When these visits are combined with emergency department visits and inpatient stays, high costs are incurred by both patients and third-party payersProlonging progression-free survival after first-line treatment in patients with ovarian cancer may delay or prevent the need for later treatment, the financial burden felt by patients, and the economic burden to the health care system associated with subsequent disease progressions.

Same-day discharge after robotic surgery for endometrial cancer.

To assess the safety of same-day discharge (SDD) following robotic-assisted endometrial cancer staging and identify risk factors for postoperative admission in a diverse population. A review of patients who underwent robotic-assisted endometrial cancer staging from April 1, 2017 to April 1, 2019 was performed. Patients were evaluated for SDD if they met the following criteria: tolerating oral intake, voiding spontaneously, ambulating, negative orthostatic vitals, postoperative hemoglobin ≤ 2 g/dL from baseline, pain controlled on oral medications, and desire to be discharged. Risk factors for admission were identified. One hundred eighty-seven patients were identified. SDD criteria were met in 158, of which 132 (83.5%) were discharged same day. Median length of stay was 4.5 h. Reasons for admission despite meeting criteria were late surgery time (n = 15), abnormal vitals (n = 9), and personal concerns (n = 2), with risk factors being age ≥ 68 years (OR 2.72; 95% CI, 1.13-6.59), start time 1400 or later (OR = 11.25; 95% CI, 4.35-29.10), ASA ≥ 4 (OR 23.82; 95% CI, 2.54-223.15), history of CVA/MI (OR 5.61; 95% CI, 1.07-29.52), and operative time ≥ 120 min (OR = 3.83; 95% CI 1.36-10.77). Of the SDD cohort, 2 patients (1.3%) presented to the emergency room within 30 days (postoperative day 5 and 23). SDD following robotic-assisted endometrial cancer staging is safe and feasible. Age ≥ 68 years, surgery start time after 1400, ASA ≥ 4, history of CVA/MI, and operative time ≥ 120 min appear predictive of inpatient admission despite meeting SDD criteria.

Integrin-Linked Kinase Is a Novel Therapeutic Target in Ovarian Cancer.

OBJECTIVE: The objective of this study is to identify and validate novel therapeutic target(s) in ovarian cancer. BACKGROUND: Development of targeted therapeutics in ovarian cancer has been limited by molecular heterogeneity. Although gene expression datasets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to cancerous cells. METHODS: We used microarray to compare the gene expression of treatment-naïve ovarian cancer tissue samples to pair-matched normal adjacent ovarian tissue from 24 patients. Ingenuity Pathway Analysis (IPA) was used to identify target pathways for further analysis. Integrin-linked kinase (ILK) expression in SKOV3 and OV90 cells was determined using Western blot. ILK was knocked down using CRISPR/Cas9 constructs. Subcutaneous xenograft study to determine the effect of ILK knockdown on tumor growth was performed in NOD SCID gamma mice. RESULTS: Significant upregulation of the ILK pathway was identified in 22 of the 24 cancer specimens, identifying it as a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. Knockdown of ILK in SKOV3 cells resulted in decreased cell proliferation and tumor growth, and inhibition of downstream kinase, AKT (protein kinase B). These results were further validated using an ILK-1 chemical inhibitor, compound 22. CONCLUSION: Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer, which warrants further investigation.

Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.

OBJECTIVE: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors. METHODS: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. RESULTS: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations. CONCLUSIONS: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population. TRIAL REGISTRATION NUMBER: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).

NCCN Guidelines Insights: Ovarian Cancer, Version 1.2019.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Time to chemotherapy in ovarian cancer: Compliance with ovarian cancer quality indicators at a National Cancer Institute-designated Comprehensive Cancer Center.

OBJECTIVE: To assess compliance with, and outcomes related to, the Society of Gynecologic Oncology quality measure in ovarian cancer to administer chemotherapy within 42 days of cytoreductive surgery in patients with epithelial ovarian/fallopian tube/peritoneal cancer. METHODS: Institutional ovarian cancer database was evaluated for compliance with the quality measure to administer chemotherapy within 42 days of cytoreductive surgery. The influence of chemotherapy timing on the risk of death was evaluated, and factors related to the timing of chemotherapy after surgery was assessed. RESULTS: Of 668 patients with epithelial ovarian/fallopian tube/peritoneal cancer who underwent surgical treatment for their disease (primary or interval), 635 met criteria for administration of adjuvant chemotherapy (with stages IA/IB, grade 2 or 3 disease; stage IC or more advanced stage disease). Compliance to administer chemotherapy within 42 days was 59.1%. The adjusted risk of death was not strongly associated with time to chemotherapy within 42 days (aHR: 0.80; 0.61, 1.05) and this did not differ by primary or interval debulking surgery. CONCLUSIONS: In this prospectively maintained database, 59.1% of patients received chemotherapy within 42 days of surgery. The time to chemotherapy interval of within 42 days was not strongly associated with improved survival, particularly when age, stage of disease, insurance enrollment and surgical characteristics were taken into account. Further, the relationship between time to chemotherapy interval of within 42 days and survival did not vary by patients who received primary versus interval debulking surgery or had no residual disease.

Celecoxib versus ketorolac following robotic hysterectomy for the management of postoperative pain: An open-label randomized control trial.

OBJECTIVE: Compare postoperative pain scores following hysterectomy in patients receiving perioperative celecoxib versus postoperative ketorolac as part of a multimodal pain regimen. METHODS: Patients undergoing hysterectomy were randomized to receive scheduled intravenous ketorolac in the immediate postoperative period or oral celecoxib prior to surgery and continued for a total seven days. All patients received a common multimodal pain protocol consisting of scheduled acetaminophen, gabapentin, and opioids as needed. Inpatient pain scores and postoperative opioid use were analyzed. A questionnaire regarding outpatient opioid use and return to normal activities of daily living (ADLs) was returned two weeks postoperatively. RESULTS: 192 patients were assessed for eligibility and 170 patients were randomized. Enrollment of patients undergoing open hysterectomy was closed prematurely for poor accruement (n = 32). 138 patients undergoing robotic hysterectomy were included were analyzed. There were no differences for inpatient pain scores (2.7 ±â€¯1.9 v. 2.4 ±â€¯1.6, p = 0.21). Average length of stay was similar between the two arms (11.6 ±â€¯8.1 h v. 11.9 ±â€¯7.6 h, p = 0.41). Patients in the celecoxib arm used less prescription opioids (6.0 ±â€¯3.6 v. 8.1 ±â€¯4.0, p = 0.001) and stopped using oral opioids earlier (3.8 ±â€¯2.6 days v. 5.7 ±â€¯2.8 days, p < 0.001). No differences were seen in inpatient opioid or anti-emetic usage, perioperative complications, or days to return to ADLs. CONCLUSIONS: There was no difference in inpatient pain scores between patients who received celecoxib or ketorolac as part of multimodal pain control following robotic hysterectomy. Patients who received scheduled celecoxib for seven days after surgery used less prescription narcotics.

Recurrent low grade serous ovarian cancer in a 20 year old woman: A case from the Ohio State University College of Medicine.

A 20 year old with recurrent low-grade serous carcinoma (LGSC) is discussed. The differential diagnosis, pathology, epidemiology, treatment options are discussed. Focus on the molecular pathways of LGSC and the implications of the diagnosis on fertility are highlighted.

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target.

Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.

Perioperative Outcomes for Laparotomy Compared to Robotic Surgical Staging of Endometrial Cancer in the Elderly: A Retrospective Cohort.

OBJECTIVE: This study aimed to compare outcomes of endometrial cancer (EMCA) staging in elderly patients performed either robotically or via laparotomy. METHODS: A retrospective, multi-institutional chart review was conducted of all robotic and laparotomy staging surgeries for EMCA between 2003 and 2009. Charts were reviewed for intraoperative and postoperative complications and morbidities. RESULTS: Seven hundred forty-six women were identified who had undergone EMCA staging either robotically or via laparotomy; 89 and 93 patients 70 years or older underwent staging for EMCA via robotic and laparotomy, respectively. Both groups had similar age and body mass index. Among elderly patients being staged robotically, a higher incidence of pelvic lymphadenectomy, and decreased blood loss, incidence of blood transfusion, and overall complications were seen compared to laparotomy. Postoperatively, elderly patients staged robotically had a shorter median hospital stay (1 vs 4 days, P < 0.001), with no increase in readmission or return to the operating theater. No vessel, bowel, or genitourinary injuries occurred. Vaginal cuff dehiscence after robotic surgery was not significantly different, but wound and fascial complications were significantly increased in patients undergoing laparotomy. Thromboembolism rates were similar between both groups. CONCLUSIONS: Elderly patients can safely undergo robotic EMCA staging with improved outcomes compared to laparotomy. The benefits of robotic staging include higher incidence of completion of lymphadenectomy, decreased hospital stay (without an increase in readmissions or reoperations), decreased transfusions, and decreased wound and fascial complications.

Anticancer potential of diarylidenyl piperidone derivatives, HO-4200 and H-4318, in cisplatin resistant primary ovarian cancer.

We have previously developed a novel class of bi-functional compounds based on a diarylidenyl-piperidone (DAP) backbone conjugated to an N-hydroxypyrroline (-NOH; a nitroxide precursor) group capable of selectively inhibiting STAT3 activation, translocation, and DNA binding activity. HO-4200 and H-4318 are 2 such derivatives capable of inducing apoptosis in ovarian cancer cells through this mechanism and demonstrated efficacy in platinum resistant primary ovarian cancer cell populations and tumor tissues. The improved absorption and cellular uptake of HO-4200 by cancer cells was determined using optical and electron paramagnetic resonance spectrometry. Treatment of ovarian cancer cells with HO-4200 and H-4318 resulted in cleavage of caspase proteins 3, 7, and 9, as well as PARP and inhibition of the pro-survival protein, Bcl-xL, resulting in significantly decreased cell survival and increased apoptosis. HO-4200 and H-4318 significantly inhibit fatty acid synthase (FAS) and pSTAT3 and decreased the expression of STAT3 target proteins: Survivin, c-myc, Bcl-xl, Bcl-2, cyclin D1/D2, and VEGF were suppressed as analyzed using quantitative real time PCR. In addition, HO-4200 and H-4318 significantly inhibited migration/invasion, in primary ovarian cancer cell populations isolated from primary and recurrent ovarian cancer patients. Treatment of freshly collected human ovarian tumor sections with HO-4200 demonstrated significant suppression of pSTAT3 Tyr 705, angiogenesis (VEFG), and markers of proliferation (Ki-67) in ex vivo models. We have shown, for the first time, that the DAP compounds, HO-4200 and H-4318, inhibit cell migration/invasion and induce apoptosis by targeting FAS/STAT3 in human ovarian cancer cells, including primary ovarian cancer cell populations and tumor tissues. Therefore, our results highlight the clinical anti-cancer potential of HO-4200 and H-4318.