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Objective. The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-alpha monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemo-therapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. Gynecologic Oncology (2023) Methods. Eligibility included CA-125

PURPOSE The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer. METHODS This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light. RESULTS From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P < .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P < .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported. CONCLUSION This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.

To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients.All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS).Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4).Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.

Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.

PURPOSE This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer. PATIENTS AND METHODS This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response. RESULTS The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable). CONCLUSION Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.

To determine the effect of distance to closest negative margin on survival after pelvic exenteration (PE).In this retrospective analysis of PE at Moffitt Cancer Center from 2000 to 2019, baseline characteristics, clinical details, and outcomes were ascertained. Distance to closest negative margin was measured. Close and distant negative margins were defined as3 mm and ≥3 mm from malignancy to nearest surgical margin, respectively. Overall survival (OS) and progression-free survival (PFS) were determined, and Kaplan-Meier curves were compared. Cox proportional hazards regression was used to examine the association of margin status with OS and PFS.Of 124 PEs with malignancy, 80 (64.5%) had negative margins. Median survival was 62 (95% confidence interval [CI] 27-70) months for negative and 21 (95% CI 15-29) months for positive margins. Of 76 with negative margins and documented margin length, 26 had close and 50 had distant margins. Median survival was 32 (95% CI 14-62) months for close and 111 (95% CI 42-166) months for distant margins. Distant margins were associated with improved OS (p = 0.0054) and PFS (p = 0.0099) compared to close margins. After adjusting for other prognostic factors, patients with distant margins had significantly decreased risk of all-cause mortality (HR 0.39, 95% CI 0.19-0.78; p = 0.008) and progression (HR 0.48, 95% CI 0.23-0.99; p = 0.04) compared to positive margins. No significant differences in OS or PFS were observed between close and positive margins. This survival benefit remained among those with cervical cancer. Median survival in this cohort was 34.1 (95% CI 2.0-69.8) months for close and 165.7 (95% CI 24.5-165.7) for distant margins.Distant margins following PE are associated with improved OS and PFS compared to close margins.

Perspective on this Article from Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu

Supplementary Data from Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors

Supplementary Figure from Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors

Supplementary material and tables

PDF file, 73K, Extended Toxicity Information.

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Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity. Clin Cancer Res; 18(19); 5489–98. ©2012 AACR.

PDF file, 92K, Volcano Plot.

Purpose:Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer.Patients and Methods:Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib.Results:A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%).Conclusions:Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

PDF file - 103KB, SUPPLEMENTARY EXPERIMENTAL PROCEDURES AND SUPPLEMENTAL REFERENCES.

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Supplementary Figure 3

PDF file - 450KB, Genes/probe sets in patient samples.

PDF file - 65KB, BAD pathway signature genes: probe sets representing 47 unique genes comprising a BAD-pathway signature.

PDF file - 76KB, Diagram of dosing schedules.

Purpose: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival.Experimental Design: Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC50). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets.Results: Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively).Conclusion: The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target. Clin Cancer Res; 17(19); 6356–66. ©2011 AACR.

Supplementary Figure 1

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Objective To describe the incidence, complications, and trends associated with ureteral surgeries on a gynecologic oncology service in the context of a fellowship training program over a 24-year period. Methods We conducted a retrospective cohort analysis of ureteral surgeries by gynecologic oncologists at either Moffitt Cancer Center or Tampa General Hospital from 1997 to 2020. Patient characteristics, predisposing factors, location and type of injury, repair method, postoperative management and complications were abstracted from the medical record. The recent cohort (2005–2020) was compared to our prior series (1997–2004). Results Eighty-eight cases were included. The average number of ureteral surgeries per year decreased from 5.75 (1997–2004) to 2.63 (2005–2020). Of 46 iatrogenic injuries, 45 were recognized and repaired intraoperatively. Ureteral transection was the most common type (85% [39 of 46]) and the distal 5 cm was the most common location of injury (63% [29 of 46]). Ureteroneocystostomy was the most common method of repair (83% [73 of 88]). Postoperative management, including stenting and imaging, has not changed significantly. Length of urinary catheter usage decreased in the recent cohort without associated complications. Five patients had major postoperative complications and 4 involved the urinary tract. Of those with follow-up, 96% (66 of 69) of ureteroneocystostomies and 75% (9 of 12) of ureteroureterostomies had radiologically normal urinary tracts. Conclusions Ureteral surgery is necessary in the case of injury or involvement with invasive disease. There has been a decrease in number of procedures. Ureteroneocystostomy has remained the most common method of reconstruction for both injury and resection with acceptable postoperative complication rates.

Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non–small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.

PARP inhibitors (PARPis) are revolutionizing the treatment of ovarian cancer. Yet for many patients these improvements come at the cost of physical and financial toxicity and responses are typically temporary due to emerging drug resistance. A growing body of pre-clinical and clinical work suggests that when cure is unlikely, it is possible to delay progression and reduce drug use through patient-specific drug scheduling. So-called 'adaptive therapy' dynamically adjusts treatment to preserve drug-sensitive cells which interfere with resistant cells through competition. In a prior study, we developed a mathematical model to describe the treatment response of ovarian cancer cells to the PARPi olaparib in vitro, and we proposed a candidate adaptive PARPi algorithm. Here, we extend our model to capture the dynamics in patients and use it to study the feasibility and potential benefit of adaptive PARPi administration in practice. Our prior model posited that treatment induces cell cycle arrest that moves cells from the proliferating subset of the population to an arrested compartment. The model predicted that while there is scope for treatment reductions, these need to be carefully timed and prolonged treatment breaks should be avoided. Based on these results we proposed an adaptive treatment algorithm in which the olaparib dose is switched between high and low doses, depending on the tumor’s growth rate. To test the translational potential of this strategy, we retrospectively collected data from 53 ovarian cancer patients who received olaparib at the H Lee Moffitt Cancer Center between 2014 and 2021. Using serum CA-125 as a proxy for tumor burden, we first examined whether our mathematical model could capture the patients’ longitudinal dynamics. While the response of some patients was consistent with what we had observed in vitro, in others there was evidence of the emergence of a distinct drug-resistant population, and we extended our mathematical model to account for this. After calibrating and validating the model with the patient data, we tested whether these patients would have benefited from adaptive PARPi treatment. Our simulations suggest that our proposed algorithm is feasible and provides a means for reducing treatment in a patient-specific manner. In addition, in a subset of patients we predict that adaptive therapy could delay progression. Overall, this work corroborates the potential for adaptive PARPi therapy and helps to identify outstanding challenges on the way to clinical translation. Citation Format: Maximilian A. Strobl, Alexandra L. Martin, Christopher Gallagher, Mehdi Damaghi, Mark Robertson-Tessi, Robert Gatenby, Robert M. Wenham, Philip K. Maini, Alexander R. Anderson. Adaptive treatment scheduling of PARP inhibitors in ovarian cancer: Using mathematical modeling to assess clinical feasibility and estimate potential benefits. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5694.

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1–3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors. In patients with high-grade serous ovarian cancer, robust and protective humoral responses are dominated by B-cell-derived polyclonal IgA that binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells.

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3(+) CD8(+)CD103(+)CD69(+) TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1(low)) tissue-resident T cells (TRMstem cells), but not recirculating TCF1(+) T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on similar to 13% of CD8(+) tumor-infiltrating T cells (similar to 3% of CD8(+) clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.

PURPOSE Cervical cancer remains a major health challenge in low- to middle-income countries. We present the experiences of two centers practicing in variable resource environments to determine predictors of improved radiochemotherapy treatment. METHODS AND MATERIALS This comparative review describes cervical cancer presentation and treatment with concurrent chemoradiotherapy with high-dose-rate brachytherapy between 2014 and 2017 at the National Radiotherapy Oncology and Nuclear Medicine Center (NRONMC) in Korle-Bu Teaching Hospital, Accra, Ghana, and Moffitt Cancer Center (MCC), Tampa, FL. RESULTS Median follow-up for this study was 16.9 months. NRONMC patients presented with predominantly stage III disease (42% v 16%; P = .002). MCC patients received para-aortic node irradiation (16%) and interstitial brachytherapy implants (19%). Median treatment duration was longer for NRONMC patients compared with MCC patients (59 v 52 days; P < .0001), and treatment duration ≥ 55 days predicted worse survival on multivariable analysis (MVA; P = .02). Stage ≥ III disease predicted poorer local control on MVA. There was a difference in local control among patients with stage III disease (58% v 91%; P = .03) but not in survival between MCC and NRONMC. No significant difference in local control was observed for stage IB, IIA, and IIB disease. CONCLUSION Although there were significant differences in disease presentation between the two centers, treatment outcomes were similar for patients with early-stage disease. Longer treatment duration and stage ≥ III disease predicted poor outcomes.

Purpose: Preclinical studies show that adavosertib, a WEE1 kinase inhibitor, sensitizes TP53-mutant cells to chemotherapy. We hypothesized that adavosertib, plus chemotherapy, would enhance efficacy versus placebo in TP53-mutated ovarian cancer. Patients and Methods: Following safety run-in, this double-blind phase II trial (NCT01357161) randomized women with TP53-mutated, platinum-sensitive ovarian cancer to oral adavosertib (225 mg twice daily for 2.5 days/21-day cycle) or placebo, plus carboplatin (AUC5) and paclitaxel (175 mg/m2), until disease progression or for six cycles. The primary endpoints were progression-free survival (PFS) by enhanced RECIST v1.1 [ePFS (volumetric)] and safety. Secondary/exploratory objectives included PFS by RECIST v1.1 (single dimension), objective response rate, overall survival, and analysis of tumor gene profile versus sensitivity to adavosertib. Results: A total of 121 patients were randomized to adavosertib (A+C; n = 59) and placebo (P+C; n = 62) plus chemotherapy. Adding adavosertib to chemotherapy improved ePFS [median, 7.9 (95% confidence interval (CI), 6.9–9.9) vs. 7.3 months (5.6–8.2); HR 0.63 (95% CI, 0.38–1.06); two-sided P = 0.080], meeting the predefined significance threshold (P < 0.2). Clinical benefit was observed following A+C for patients with different TP53 mutation subtypes, identifying possible response biomarkers. An increase in adverse events was seen with A+C versus P+C: greatest for diarrhea (adavosertib 75%; placebo 37%), vomiting (63%; 27%), anemia (53%; 32%), and all grade ≥3 adverse events (78%; 65%). Conclusions: Establishing an optimal strategy for managing tolerability and identifying specific patient populations most likely to benefit from treatment may increase clinical benefit. Future studies should consider additional adavosertib doses within the chemotherapy treatment cycle and the potential for maintenance therapy.

Highlights • Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. • The inferior vena cava was the most common site of injury. • Lymph node dissection was the most common time for a vascular injury to occur. • Suture repair or ligation was required to adequately resolve the majority of vascular injuries., Objective Vascular injury during major gynecologic cancer surgery is a rare but potentially fatal complication. The purpose of this study was to review our experience with major vascular injury during gynecologic cancer surgery. Methods This was a retrospective chart review of women undergoing surgery by our gynecologic oncology department from 7/1/99 to 6/30/20 who had a major vascular injury. We identified women who sustained a vascular injury by a combination of CPT code and medical record searches, fellow case logs and a list maintained for an ongoing quality assurance program. Data were expressed as median and range for continuous variables and as frequency and percentage for categorical variables. Fisher’s exact test was used to analyze differences in complication rates between groups. Results Major vascular injury was identified in 52 patients and procedures. The inferior vena cava was the most common site of injury, 32.7% (17/52), followed by the external iliac vein, 23.1% (12/52). Lymph node dissection was the most common time for a vascular injury to occur 51.9% (27/52). The majority of injuries required suture repair, 80.8% (42/52). Estimated blood loss in cases with vascular injury ranged from 100 mL to massive unquantifiable blood loss in the case of an aortic injury. Patients required a median of 2units of packed red blood cells. Postoperative complications included anemia requiring blood transfusion, 19.6% (9/46) and venous thromboembolism, 19.6% (9/46). Conclusions Vascular injury remains a rare but potentially morbid complication of gynecologic oncologic surgery. Prompt recognition and management are imperative in minimizing persistent bleeding and complications.

Germline mutations (e.g., BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from January 1, 2001, to December 31, 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.

Objective To assess whether there were any significant changes in surgical training volume over the past 20 years that might have ramifications toward preparedness for practice. Methods We used deidentified annual summaries of fellow case numbers for the academic years 1999 through 2018. Unpaired t-tests with Welch's correction were performed on all surgical categories for 10-year and 5-year periods. Results The total number of hysterectomies performed each year did not change significantly. The percent of hysterectomies performed by minimally invasive surgery increased significantly starting in 2008. There was a significant decline in the number of radical hysterectomies conducted starting after 2004, which then remained stable. There was also a significant decline in the number of bowel resections/anastomoses performed by fellows on the gynecologic oncology services that occurred and stabilized during the same time frame. There were other significant trends associated with the introduction of minimally invasive techniques. Conclusion The results of this study suggest the need to reevaluate fellowship training and/or the scope of surgical practice in gynecologic oncology.

Purpose OTL38 is a folate-indole-cyanine green-like conjugate to folate receptor alpha (FRa). The objectives of this prospective trial were to assess the safety and efficacy (sensitivity and positive predictive value (PPV)) of OTL38 for intraoperative imaging during epithelial ovarian cancer surgery. Methods Patients with suspected ovarian cancer planned for cytoreductive surgery were eligible to receive OTL38. Near-infrared (NIR) imaging was used to visualize target lesions that were evaluated by two blinded pathologists. A modified intent to treat (mITT) population of lesions from all patients who received OTL38-NIR imaging, underwent surgery, and had at least one FRa + target lesion was used to determine sensitivity and PPV. Two generalized linear models, with and without random effects, were employed to estimate sensitivity and PPV. Results Forty-four patients were evaluated for safety, and 225 lesions from 29 patients (the mITT population) were evaluated for efficacy. When assuming no correlation of interlesional results within a patient, sensitivity was estimated at 85.93% (95% lower boundary CI = 81.19) and PPV at 88.14% (95% lower boundary CI = 83.59). When controlling for actual correlation of detection among multiple lesions within a single patient (a random effect), sensitivity was estimated at 97.97% (95% lower boundary CI = 87.75) and PPV at 94.93% (95% lower boundary CI = 86.13). A total of 48.3% [14/29, (95% CI 0.29–0.67)] of patients had at least one additional lesion detected by OTL38 alone. Eight patients had mild drug-related adverse events including infusion reaction, nausea, vomiting, and abdominal pain. Conclusions OTL38-NIR was safe and efficacious in this phase II study regardless of folate expression levels and merits phase III evaluation.

Objective. To analyze the safety and efficacy of niraparib in patients aged >= 70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. Methods. The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. Results. Patients aged >= 70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged >= 70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients >= 70 years and 17.2 months in patients = 70 years population. The most common grade >= 3 AEs in patients >= 70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%). Conclusions. For patients >= 70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population., TESARO, Inc.

Objective To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence. Methods We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated. Results There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy. Conclusion For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival. Clinical trial registration ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

Highlights • Stage IIIC endometrial cancer (EC) treatment remains controversial. • Radiation therapy improves local control but does not confer survival benefit. • Chemotherapy can improve overall survival. • Advances should result from personalized medicine and therapies guided by predictive biomarkers. • Stage IIIC EC should be treated with chemotherapy; radiation should be individualized., Stage IIIC is the most common stage of locally advanced sub-stage of endometrial cancer, nevertheless, the optimal management for these patients remains controversial. Adjuvant chemotherapy alone more effectively suppressed distant metastases but resulted in a higher rate of pelvic failure, while adjuvant radiation more effectively controlled pelvic recurrences but was associated with more frequent distant metastases. Two recent randomized trials, PORTEC3 and GOG 258, each have attempted to integrate multimodal therapy. However, heterogeneous cohorts analyzed together, including high risk stage I, stage III and stage IV, limit our ability to make conclusions specific to stage IIIC disease. Here, we review clinical evidence pertaining to management and outcomes with stage IIIC uterine carcinoma with brief discussion on evolving approaches. The studies reviewed demonstrate for stage IIIC disease radiation improves local control but does not confer an overall survival benefit and chemotherapy can improve overall survival. The data seem to suggest that aside from the possibility of defining subgroups that may confer an overall survival benefit from combined modality therapy, the future to improving survival lies in the exploration of better therapeutic regimens that will result from tailored biomarker-based therapy.