Prophylactic antibiotics for excision of premalignant vulvar lesions: A pilot randomized controlled trial.

No prospective data have been described to inform guidelines on antibiotic prophylaxis for partial vulvectomies. Thus, we conducted a single-center, pilot, double-blind randomized controlled trial to assess the effectiveness of prophylactic antibiotics to prevent wound complications after partial vulvectomies. Patients were randomly assigned 1:1 to preoperative antibiotics or no preoperative antibiotics. The primary outcome of 30-day postoperative wound complications occurred in 31 (62 %) of all patients, with no differences between groups. The most common wound complications were superficial separation (54.2 % antibiotic prophylaxis vs. 65.3 % no prophylaxis, p = 0.37) and surgical site infection (0 % antibiotic prophylaxis vs 7.7 % no prophylaxis, p = 0.49). However, this study was limited by differences in patient characteristics between the groups. This study provides data to perform power calculations for a trial examining the effect of preoperative antibiotics on surgical site infection.

Characteristics and real-world outcomes of patients with epithelial ovarian cancer who received niraparib plus bevacizumab first-line maintenance therapy in the COMB1NE study.

OBJECTIVE: In the phase 2 OVARIO trial (NCT03326193) investigating niraparib-bevacizumab first-line maintenance, median progression-free survival was 14.2 months (95% confidence interval (CI) 8.6 to 16.8) for patients with homologous recombination (HR)-proficient (HRp) epithelial ovarian cancer, and 12.1 months (95% CI8.0-not evaluated) for patients with undefined HR status. However, real-world data are limited for patients who receive niraparib-bevacizumab first-line maintenance therapy. The COMB1NE study describes real-world clinical outcomes (time to treatment discontinuation; time to next treatment) in patients with epithelial ovarian cancer who received niraparib-bevacizumab first-line maintenance, regardless of first-line bevacizumab use. METHODS: This real-world, retrospective study used a US nationwide electronic health record-derived deidentified database. Eligible patients were 18 years or older at initial epithelial ovarian cancer diagnosis and initiated niraparib-bevacizumab first-line maintenance (January 1, 2017-September 2, 2022) following first-line treatment. The index date was the start of first-line maintenance. Patients were followed until death, last clinical activity, or end of study, whichever occurred first. Time to treatment discontinuation and time to next treatment, a proxy for real-world progression-free survival, were estimated using the Kaplan-Meier method. RESULTS: Among 59 included patients, the median age was 67 years (interquartile range (IQR) 61-76), and 81.4% had stage III/IV epithelial ovarian cancer at diagnosis. Overall, 83.1% of patients had BRCA wild-type with either HRp or HR status unknown disease. Median time to treatment discontinuation of first-line maintenance was 11.8 months (95% CI 8.7 to 13.5). Median time to next treatment was 14.1 months (95% CI 11.3 to 16.6). At 6 months after index, 77.9% of patients had not initiated second-line treatment; at 12 months, 61.3% had not. CONCLUSION: In this real-world study of patients receiving niraparib-bevacizumab first-line maintenance, the majority of whom had HRp/HR status unknown, the median time to next treatment was consistent with observed progression-free survival in patients with similar HR status in the OVARIO study.

Improving diverse patient enrollment in clinical trials, focusing on Hispanic and Asian populations: recommendations from an interdisciplinary expert panel.

Lack of patient diversity in clinical trial enrollment remains an obstacle to achieving equitable healthcare outcomes. Under-representation has resulted in non-generalizable clinical knowledge, inequitable access to treatment, and health disparities among minority and disadvantaged groups. A multidisciplinary panel was convened to consider the challenges of diverse patient accrual and provide actionable solutions to improve representation in clinical trials. The panel was comprised of participants with knowledge in gynecologic oncology and included physician, advanced practice nurse, patient navigator, patient advocate, and pharmaceutical industry representation. Focus was given to recruitment barriers for Asian and Hispanic patients. The panel identified several areas of concern, including explicit and implicit biases for the physician and care teams, language and cultural nuances, inadequate inclusion of family in the decision-making process, and under-representation of women in clinical trials. The panel also identified the important role patient navigators, nurses, and advanced practice providers have in patient recruitment from under-represented populations. The role of study sponsors, and global and regional initiatives, to address historic disparities in clinical trial recruitment were also considered critical. The actionable solutions proposed should enable study sponsors and clinical trial sites to achieve greater diversity in enrollment globally.

Quality of life and survivorship in patients with low-grade ovarian cancer.

OBJECTIVE: High-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. METHODS: Participants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. RESULTS: At baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. CONCLUSIONS: We present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies.

A toolkit for a modern gynecologic oncology tissue bank.

OBJECTIVES: Tissue banking procedures have evolved to keep pace with precision medicine, technology, emerging understanding of racial disparities, and regulatory requirements. However, there is little published guidance regarding strategies to create and maintain a successful biorepository. Our objective is to describe the infrastructure and protocols used by our Gynecologic Oncology Tissue Bank. METHODS: Our Tissue Bank was founded in 1992. In August 2022, internal funding was used to modernize the Tissue Bank. We hired three full-time employees, implemented universal screening of patients treated by gynecologic oncology faculty, updated consenting protocols, and standardized communication with providers. Tumor tissue, blood derivatives, ascites, and pleural fluid were collected from eligible, consenting patients and processed. Patient-derived cell lines and organoids were generated. For quality control purposes, one formalin-fixed, paraffin-embedded (FFPE) sample per tissue site was analyzed by a board-certified pathologist. All samples were labeled and tracked in an OpenSpecimen collection protocol and clinically annotated in a secure database. RESULTS: From August 2022 to October 2023, 227 patients (83% white, 15% Black, 1% Asian) were enrolled and 4249 specimens were collected. Adherent cell lines were generated from 15 patients with ovarian cancer and cell suspensions for organoid generation were collected from 46 patients with ovarian cancer. A recharge center was established to self-sustain the Tissue Bank. Samples have been shared with academic and commercial collaborators. CONCLUSIONS: Our Tissue Bank has enrolled a large number of diverse patients, collected numerous specimen types, and collaborated widely. The procedures described here provide guidance for other institutions establishing similar resources.

Accuracy of surveillance serum squamous cell carcinoma antigen for cervical cancer recurrence after definitive chemoradiation.

OBJECTIVE: Recurrence remains a significant clinical problem for patients with cervical cancer, and early detection may improve outcomes. Serum squamous cell carcinoma antigen (SCCA) is a biomarker of prognosis and response to chemoradiotherapy. We hypothesized that elevated serum SCCA during surveillance is sensitive and specific for recurrence. METHODS: Pre-treatment and follow-up serum SCCA from patients treated with definitive-intent radiotherapy were measured via enzyme-linked immunosorbent assay in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory and analyzed retrospectively. Follow-up SCCA was defined as the value closest to recurrence, or as last available for patients without recurrence. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of follow-up SCCA for recurrence was determined for the whole cohort (Cohort 1), for patients with elevated (Cohort 2), and normal pre-treatment SCCA (Cohort 3). Patterns of failure were also evaluated. RESULTS: Of 227 patients in Cohort 1, 23% experienced recurrence, and 17% died of cervical cancer. Mean follow-up SCCA was 0.9 (±2.5) for patients with no recurrence and 6.0 (±18.7) for patients with recurrence (p=0.02). Sensitivity, specificity, PPV, and NPV of follow-up SCCA for recurrence in Cohort 1 were 38.5%, 97.1%, 80%, and 84.2%, and for patients in Cohort 2 were 54.5%, 95%, 78.3%, and 86.5%, respectively. Four of 86 patients in Cohort 3 had an elevated follow-up SCCA, two of these at the time of recurrence. Elevated pre-treatment SCCA and follow-up SCCA were associated with isolated pelvic recurrence. CONCLUSIONS: Surveillance serum SCCA has high specificity and NPV for recurrence, and may be of limited utility in patients with normal pre-treatment SCCA.

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016.

INTRODUCTION: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.

Molecular profiling of gestational trophoblastic neoplasia: Identifying therapeutic targets.

OBJECTIVE: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets. METHODS: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT). RESULTS: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases. CONCLUSIONS: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.

Rural-urban disparities in psychosocial functioning in epithelial ovarian cancer patients.

OBJECTIVE: Although rural residence has been related to health disparities in cancer patients, little is known about how rural residence impacts mental health and quality of life (QOL) in ovarian cancer patients over time. This prospective longitudinal study investigated mental health and QOL of ovarian cancer patients in the first-year post-diagnosis. METHOD: Women with suspected ovarian cancer completed psychosocial surveys pre-surgery, at 6 months and one-year; clinical data were obtained from medical records. Histologically confirmed high grade epithelial ovarian cancer patients were eligible. Rural/urban residence was categorized from patient counties using the USDA Rural-Urban Continuum Codes. Linear mixed effects models examined differences in psychosocial measures over time, adjusting for covariates. RESULTS: Although disparities were not observed at study entry for any psychosocial variable (all p-values >0.22), urban patients showed greater improvement in total distress over the year following diagnosis than rural patients (p = 0.025) and were significantly less distressed at one year (p = 0.03). Urban patients had a more consistent QOL improvement than their rural counterparts (p = 0.006). There were no differences in the course of depressive symptoms over the year (p = 0.17). Social support of urban patients at 12 months was significantly higher than that of rural patients (p = 0.04). CONCLUSION: Rural patients reported less improvement in psychological functioning in the year following diagnosis than their urban counterparts. Clinicians should be aware of rurality as a potential risk factor for ongoing distress. Future studies should examine causes of these health disparities and potential long-term inequities and develop interventions to address these issues.

The biology of hope: Inflammatory and neuroendocrine profiles in ovarian cancer patients.

INTRODUCTION: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers. METHOD: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression. RESULTS: Greater hope was significantly related to a steeper cortisol slope, ß = -0.193, p = 0.046, and lower night cortisol, ß = -0.227, p = 0.018, plasma IL-6, ß = -0.142, p = 0.033, and ascites IL-6, ß = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol ß = -0.233,p = 0.017 and ascites IL-6, ß = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, ß = 0.211, p = 0.031. CONCLUSIONS: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope.

In situ profiling reveals metabolic alterations in the tumor microenvironment of ovarian cancer after chemotherapy.

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline hydroxylation of hypoxia-inducible factor alpha in the stromal regions. Metabolites more abundant in the epithelial regions of post-NACT PR tumors were involved in the metabolism of nucleotides, and metabolites more abundant in the stromal regions of post-NACT PR tumors were related to aspartate and asparagine metabolism, phenylalanine and tyrosine metabolism, nucleotide biosynthesis, and the urea cycle. A predictive model built on ions with differential abundances allowed the classification of patients' tumor responses as ER or PR with 75% accuracy (10-fold cross-validation ridge regression model). These findings offer new insights related to differential responses to chemotherapy and could lead to novel actionable targets.

Low grade endometrial stromal sarcoma in pregnancy: A case in support of safe abortion access.

Background: Endometrial stromal sarcoma (ESS) is extremely rare in pregnancy. It shares clinical and imaging features with more common pregnancy findings such as leiomyoma and molar gestations, which makes diagnosis challenging. Case: A 36-year-old patient presented at 8 weeks and 1 day gestation for vaginal bleeding. An intrauterine pregnancy with an appropriately sized embryo with heart motion and a 9.5 cm complex uterine mass was found on ultrasound. MRI showed an 11.4 cm cystic mass with nodular septations causing mass effect on the endometrial cavity. After extensive counseling, the patient underwent a gravid abdominal hysterectomy and bilateral salpingectomy. Final pathology showed low grade ESS. Conclusion: This case highlights the importance of evaluating suspicious uterine masses in pregnancy and the necessity for safe abortion access.

Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 "Lynch-like" mismatch repair gene mutation.

OBJECTIVES: To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes. METHODS: 1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves. RESULTS: The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity. CONCLUSIONS: Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer.

BACKGROUND: Treatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec), with its strong immune modulating effect on the tumor microenvironment, may provide re-sensitization to platinum and clinically reverse platinum resistance or refractoriness in platinum-resistant/refractory ovarian cancer. PRIMARY OBJECTIVE: The primary objective is to evaluate the efficacy of intra-peritoneal Olvi-Vec followed by platinum-based chemotherapy and bevacizumab in patients with platinum-resistant/refractory ovarian cancer. STUDY HYPOTHESIS: This phase III study investigates Olvi-Vec oncolytic immunotherapy followed by platinum-based chemotherapy and bevacizumab as an immunochemotherapy evaluating the hypothesis that such sequential combination therapy will prolong progression-free survival (PFS) and bring other clinical benefits compared with treatment with platinum-based chemotherapy and bevacizumab. TRIAL DESIGN: This is a multicenter, prospective, randomized, and active-controlled phase III trial. Patients will be randomized 2:1 into the experimental arm treated with Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or the control arm treated with platinum-doublet chemotherapy and bevacizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients must have recurrent, platinum-resistant/refractory, non-resectable high-grade serous, endometrioid, or clear-cell ovarian, fallopian tube, or primary peritoneal cancer. Patients must have had ≥3 lines of prior chemotherapy. PRIMARY ENDPOINT: The primary endpoint is PFS in the intention-to-treat population. SAMPLE SIZE: Approximately 186 patients (approximately 124 patients randomized to the experimental arm and 62 to the control arm) will be enrolled to capture 127 PFS events. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Expected complete accrual in 2024 with presentation of primary endpoint results in 2025. TRIAL REGISTRATION: NCT05281471.

TP53 mutation and abnormal p53 expression in endometrial cancer: Associations with race and outcomes.

OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.

Well-being and stress vulnerability in ovarian cancer survivors during the COVID-19 pandemic.

OBJECTIVE: This study was designed to examine (1) whether ovarian cancer (OC) survivors would have greater well-being vs. elevated distress compared to community members during a universal health stressor (COVID-19) and (2) how resources and risk factors at diagnosis predicted vulnerability to a subsequent health-related stressor. METHODS: One hundred seventeen OC survivors were recruited from two academic medical centers and compared to a community-based sample on COVID-related distress and disruption. Latent class analysis identified differentially impacted groups of survivors. RESULTS: Survivors reported lower distress than community members. Predictors of higher distress included shorter-term survivorship, greater disruption, and poorer emotional well--being (EWB) at diagnosis. Survivors were divided into high- and low-COVID-19-impact subgroups; high-impact individuals endorsed higher perceived stress and lower EWB at diagnosis. CONCLUSION: Survivors reported lower COVID-related distress than community participants. While depression at diagnosis did not predict later distress, EWB was a strong predictor of response to a novel health-related stressor.

Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins.

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis. IMPLICATIONS: DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250).

PURPOSE: Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS: NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS: Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION: Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

Genetic characterization of primary and metastatic high-grade serous ovarian cancer tumors reveals distinct features associated with survival.

High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and the majority of cases present with metastasis and late-stage disease. Over the last few decades, the overall survival for patients has not significantly improved, and there are limited targeted treatment options. We aimed to better characterize the distinctions between primary and metastatic tumors based on short- or long-term survival. We characterized 39 matched primary and metastatic tumors by whole exome and RNA sequencing. Of these, 23 were short-term (ST) survivors (overall survival (OS) < 3.5 years) and 16 were long-term (LT) survivors (OS > 5 years). We compared somatic mutations, copy number alterations, mutational burden, differential gene expression, immune cell infiltration, and gene fusion predictions between the primary and metastatic tumors and between ST and LT survivor cohorts. There were few differences in RNA expression between paired primary and metastatic tumors, but significant differences between the transcriptomes of LT and ST survivors in both their primary and metastatic tumors. These findings will improve the understanding of the genetic variation in HGSC that exist between patients with different prognoses and better inform treatments by identifying new targets for drug development.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.

OBJECTIVE: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. METHODS: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. RESULTS: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. CONCLUSIONS: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.