David G. Mutch

Multiomic Characterization of Pre- and Post-Neoadjuvant Chemotherapy–Treated Ovarian Cancer Reveals Mediators of Tumorigenesis and Chemotherapy Response

Abstract High-grade serous ovarian cancer (HGSC) accounts for more than 200,000 deaths each year. Despite recent advances in treating HGSC with neoadjuvant chemotherapy, the majority of patients ultimately develop chemotherapy resistance. HGSC is characterized by TP53 mutations and widespread copy-number alterations and occurs frequently in the setting of deleterious germline BRCA1/2 variations, but many cases lack putative driver mutations. In this study, we performed whole-exome, whole-genome, and whole-transcriptome sequencing along with mass spectrometry to characterize the molecular landscape of HGSC in 22 paired samples obtained before and after neoadjuvant chemotherapy. Responsiveness to chemotherapy was determined for each patient. Evidence at the DNA, RNA, and protein level revealed numerous defects in cell–cell and cell–matrix interactions, as well as disruption of cell polarity and cytoskeletal regulation in HGSC, indicating that defects in epithelial integrity were present in the majority of patients with HGSC. Nonresponsive HGSC harbored subclones with putative survival mutations. Additionally, ineffective nonsense-mediated decay resulted in the persistence of transcripts with frameshift mutations that were translated into aberrant proteins detectable in HGSC samples. Together, these findings suggest that HGSC may arise through defects in the maintenance of epithelial integrity that lead to the shedding of malignant cells throughout the peritoneum, and the presence of resistant subclones prior to chemotherapy may decrease the chemosensitivity of patients. Significance: Comprehensive longitudinal characterization of ovarian cancer identifies pathways that promote tumorigenesis and provides insights into regulators of chemotherapy response, which could help develop strategies to improve outcomes for patients.

Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti–PD‐L1, for BRCA wild‐type, platinum‐sensitive, recurrent ovarian cancer

AbstractBackgroundThis phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD‐L1 inhibition, for BRCA wild‐type, platinum‐sensitive, recurrent ovarian cancer (PSROC).MethodsPatients with PSROC who had received one or two prior treatment lines were treated with 28‐day cycles of cobimetinib 60 mg daily (days 1–21) plus niraparib 200 mg daily (days 1–28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild‐type PSROC to receive either doublet or triplet therapy, stratified by genome‐wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum‐free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator‐determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super‐responders (complete response or those with progression‐free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized.ResultsThe ORR in patients who had BRCA wild‐type PSROC was 35% (95% confidence interval, 20%–53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%–44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post‐hoc analyses indicated more favorable ORR and PFS in the homologous recombination‐deficiency‐signature (HRDsig)‐positive subgroup than in the HRDsig‐negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively.ConclusionsChemotherapy‐free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild‐type, HRDsig‐positive or HRDsig‐negative PSROC harboring NF1 or MKNK1 mutations.

The new 2023 endometrial cancer FIGO staging system: balancing innovation with complexity

In August 2023, the International Federation of Gynecology and Obstetrics introduced an updated staging system for endometrial cancer that integrates histopathologic and molecular characteristics (optional) of the tumor alongside with anatomic extent of the disease. This innovative approach aims to improve the prognostication of the system and the identification of treatment-relevant patient populations by more accurately stratifying patients based on tumor biology, representing a significant advancement toward personalized medicine. However, its implementation poses challenges, including the heterogeneous availability of molecular testing worldwide, and the need for further standardization and prospective validation of some of the newly introduced histopathological parameters. To address these innovations and related controversies, a meeting of physicians, including gynecologic oncologists and pathologists, was held. This article summarizes the reflections that emerged from this meeting, focusing on key elements such as the integration of histopathologic features (eg, "high-grade, aggressive histologic types," "substantial lymphovascular space invasion"), molecular classification, and the implications for global reproducibility and applicability. It also addresses the basic approach toward staging: should it offer integrated, patient-relevant information to enable accurate prognostication and inform treatment decisions or should a staging system simply provide a common language to communicate disease extent? The meeting provided an opportunity for a group of physicians to share considerations on this evolving topic. Our article highlights focal points of change in the new staging system and identifies key areas for future research, advocating for collaborative efforts to generate more robust evidence on some variables introduced in the staging system through prospective studies. By addressing these challenges, we aim to improve the applicability and effectiveness of the new International Federation of Gynecology and Obstetrics staging system in real-world scenarios and identify elements that may require further refinement, ultimately advancing precision medicine in endometrial cancer care.

FIGO staging of endometrial cancer: 2023

Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Based on the existing evidence, the substages were defined as follows: The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data.

Long-Term Follow-Up and Overall Survival in NRG258, a Randomized Phase III Trial of Chemoradiation Versus Chemotherapy for Locally Advanced Endometrial Carcinoma

This randomized phase III trial aimed to determine whether treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for four cycles (chemoradiotherapy [C-RT]) increased recurrence-free survival (RFS) and overall survival (OS) when compared with carboplatin and paclitaxel for six cycles (chemotherapy [CT]) in locally advanced endometrial cancer (UC). Previously reported results showed that C-RT did not improve RFS compared with CT. Here we report the final OS analysis. Patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage III-IVA UC or stage I/II serous or clear cell UC and positive cytology were enrolled. The primary objective was RFS. Secondary objectives were OS, toxicity, and quality of life. Cumulative probabilities of OS were estimated using the Kaplan-Meier method. Subgroup analyses of treatment effect for FIGO stage, age, race, gross residual disease, histology, lymph-vascular space invasion, and body mass index were performed. In total, 813 patients were randomly assigned (407 C-RT and 406 CT). The median follow-up was 112 months. Median OS was not achieved in either arm. The stratified hazard ratio for death comparing C-RT versus CT was 1.05 (95% CI, 0.82 to 1.34, log-rank two-sided P value = .72). None of the factors analyzed predicted OS benefit from C-RT. Although C-RT reduced the rate of local recurrence compared with CT, it did not increase OS or RFS in stage III/IVA UC.

TP53 Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

PURPOSE The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with TP53 NGS, predicts the outcome. METHODS From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and TP53 NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a TP53 mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm. RESULTS In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with TP53 missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between TP53 NGS and p53 IHC was 88%. Concordance was 92% when cases with TP53 mutations and POLE mutations or mismatch repair deficiency were removed. CONCLUSION IHC for p53 alone or when integrated with sequencing for TP53 identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.

GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis

Abstract Chemotherapy is often ineffective in advanced-stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared with tumors with a good response to chemotherapy. We showed that chemotherapy-resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared with paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling, which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong preclinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.

Overexpression of enhance of Zeste homolog 2 (EZH2) in endometrial carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

Enhancer of zeste homolog 2 (EZH2) is a histone methyl transferase that mediates epigenetic silencing of tumor suppressor genes. It is commonly over-expressed in several solid tumors and has been shown to be a prognostic biomarker. We investigated patterns of EZH2 expression in endometrial cancer. Evaluation of EZH2 expression was completed on both early and advanced stage endometrioid adenocarcinoma tissues and a subset of matched normal mullerian tissue samples, from participants enrolled in Gynecologic Oncology Group (GOG) protocol 210, using real time reverse transcription polymerase chain reaction (RT-PCR) and western blot (WB) analysis. Non-parametric methods were used to assess differences in mRNA and protein expression respectively with known clinical/pathologic prognostic factors. Survival analysis was performed using techniques including Cox proportional hazards (PH) model to evaluate differences in progression free survival (PFS) and overall survival (OS) based on EZH2 expression. Eighty-seven patient samples were analyzed that included 60 tumors and 27 matched-normal tissue specimens. EZH2 mRNA (p < .0001) and protein expression (p < .0001) in tumor specimens were significantly higher than in matched-normal tissue. In primary tumors, EZH2 protein expression was associated with lympho-vascular space invasion (LVSI, p = .044), and EZH2 mRNA expression was associated with age (p = .037). Differences in EZH2 expression between primary tumors and matched normal tissue were not associated with other known clinical and pathologic factors. However, there did appear to be a trend toward decreased progression-free survival among patients with high EZH2 expression levels. Our results confirm the differential expression of EZH2 in uterine cancers compared to normal tissues. However, there were no statistically significant differences in survival associated with EZH2 expression in patients with endometrial cancer. NCT #: NCT00340808.

Multi-center, international endometrial cancer consortium highlights

The multi-center, international consortium on endometrial cancer held in January 2025 at Mayo Clinic in Rochester, Minnesota brought together leading experts in gynecologic oncology to explore the latest advancements in the understanding, diagnosis, and treatment of endometrial cancer. Discussions centered on key topics, including updates in molecular testing and disease staging, emerging treatment strategies for advanced and recurrent disease, fertility-sparing management, and critical pathology challenges, particularly, the assessment of lympho-vascular space invasion. Each topic was examined in dedicated working group sessions, fostering in-depth exchanges to identify research priorities and develop actionable strategies. This summary highlights the central themes and insights from the meeting, outlining a roadmap for future advancements in the field. By promoting inter-disciplinary collaboration, the meeting laid the foundation for future research, policy recommendations, and clinical innovations aimed at improving patient outcomes.

Uterine leiomyosarcoma

Uterine leiomyosarcoma is a rare and heterogeneous gynecological malignancy that poses a significant clinical challenge due to its aggressive nature and limited treatment options. Its multifactorial etiopathogenesis involves complex cytogenetic and molecular aberrations, including TP53, RB1, and chromothripsis-associated gene alterations. The non-specific clinical presentation, resembling other benign conditions, complicates early and accurate diagnosis, alongside intricate radiological and pathological patterns. Advanced imaging techniques, such as magnetic resonance imaging and computed tomography, are employed to differentiate uterine leiomyosarcoma from benign conditions, but no single test is definitive. For FIGO (International Federation of Gynecology and Obstetrics) stage I uterine leiomyosarcoma, treatment consists of en bloc total hysterectomy ± bilateral salpingo-oophorectomy. Patients with stage II to IV disease amenable to complete resection can undergo surgery followed by adjuvant systemic therapy and/or radiotherapy. Lymphadenectomy is unnecessary in patients lacking bulky nodes. Unresectable or unsuitable cases warrant primary systemic therapy and/or radiotherapy. Managing recurrent disease requires a multimodal approach tailored to factors such as the site and number of metastases, prior radiotherapy, and resectability. Multidisciplinary management and centralization in referral centers are crucial for individualized decision-making. Ongoing research explores the intricate cytogenetic and molecular aberrations of uterine leiomyosarcoma, paving the way for personalized treatment strategies. This review, developed following the European Society of Gynaecological Oncology/Gynecologic Cancer InterGroup/European Reference Network on Rare Adult Solid Cancers guidelines, explores the clinical presentation, diagnostic challenges, and evolving therapeutic strategies for uterine leiomyosarcoma, while also highlighting variations in clinical practice worldwide.

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

Abstract 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.

RAD51 Foci as a Biomarker Predictive of Platinum Chemotherapy Response in Ovarian Cancer

Abstract Purpose: To determine the ability of RAD51 foci to predict platinum chemotherapy response in high-grade serous ovarian cancer (HGSOC) patient-derived samples. Experimental Design: RAD51 and γH2AX nuclear foci were evaluated by immunofluorescence in HGSOC patient-derived cell lines (n = 5), organoids (n = 11), and formalin-fixed, paraffin-embedded tumor samples (discovery n = 31, validation n = 148). Samples were defined as RAD51-High if &amp;gt;10% of geminin-positive cells had ≥5 RAD51 foci. Associations between RAD51 scores, platinum chemotherapy response, and survival were evaluated. Results: RAD51 scores correlated with in vitro response to platinum chemotherapy in established and primary ovarian cancer cell lines (Pearson r = 0.96, P = 0.01). Organoids from platinum-nonresponsive tumors had significantly higher RAD51 scores than those from platinum-responsive tumors (P &amp;lt; 0.001). In a discovery cohort, RAD51-Low tumors were more likely to have a pathologic complete response (RR, 5.28; P &amp;lt; 0.001) and to be platinum-sensitive (RR, ∞; P = 0.05). The RAD51 score was predictive of chemotherapy response score [AUC, 0.90; 95% confidence interval (CI), 0.78–1.0; P &amp;lt; 0.001). A novel automatic quantification system accurately reflected the manual assay (92%). In a validation cohort, RAD51-Low tumors were more likely to be platinum-sensitive (RR, ∞; P &amp;lt; 0.001) than RAD51-High tumors. Moreover, RAD51-Low status predicted platinum sensitivity with 100% positive predictive value and was associated with better progression-free (HR, 0.53; 95% CI, 0.33–0.85; P &amp;lt; 0.001) and overall survival (HR, 0.43; 95% CI, 0.25–0.75; P = 0.003) than RAD51-High status. Conclusions: RAD51 foci are a robust marker of platinum chemotherapy response and survival in ovarian cancer. The utility of RAD51 foci as a predictive biomarker for HGSOC should be tested in clinical trials.

GAS6/AXL Inhibition Enhances Ovarian Cancer Sensitivity to Chemotherapy and PARP Inhibition through Increased DNA Damage and Enhanced Replication Stress

Abstract Over 80% of women with high-grade serous ovarian cancer (HGSOC) develop tumor resistance to chemotherapy and die of their disease. There are currently no FDA-approved agents to improve sensitivity to first-line platinum- and taxane-based chemotherapy or to PARP inhibitors. Here, we tested the hypothesis that expression of growth arrest–specific 6 (GAS6), the ligand of receptor tyrosine kinase AXL, is associated with chemotherapy response and that sequestration of GAS6 with AVB-S6–500 (AVB-500) could improve tumor response to chemotherapy and PARP inhibitors. We found that GAS6 levels in patient tumor and serum samples collected before chemotherapy correlated with ovarian cancer chemoresponse and patient survival. Compared with chemotherapy alone, AVB-500 plus carboplatin and/or paclitaxel led to decreased ovarian cancer-cell survival in vitro and tumor burden in vivo. Cells treated with AVB-500 plus carboplatin had more DNA damage, slower DNA replication fork progression, and fewer RAD51 foci than cells treated with carboplatin alone, indicating AVB-500 impaired homologous recombination (HR). Finally, treatment with the PARP inhibitor olaparib plus AVB-500 led to decreased ovarian cancer-cell survival in vitro and less tumor burden in vivo. Importantly, this effect was seen in HR-proficient and HR-deficient ovarian cancer cells. Collectively, our findings suggest that GAS6 levels could be used to predict response to carboplatin and AVB-500 could be used to treat platinum-resistant, HR-proficient HGSOC. Implications: GAS6/AXL is a novel target to sensitize ovarian cancers to carboplatin and olaparib. Additionally, GAS6 levels can be associated with response to carboplatin treatment.

Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

PURPOSE In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score &lt; 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed. METHODS In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable &lt; 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses. RESULTS KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97). CONCLUSION This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

Effects of the WRITE Symptoms Interventions on Symptoms and Quality of Life Among Patients With Recurrent Ovarian Cancers: An NRG Oncology/GOG Study (GOG-0259)

PURPOSE GOG-259 was a 3-arm randomized controlled trial of two web-based symptom management interventions for patients with recurrent ovarian cancer. Primary aims were to compare the efficacy of the nurse-guided (Nurse-WRITE) and self-directed (SD-WRITE) interventions to Enhanced Usual Care (EUC) in improving symptoms (burden and controllability) and quality of life (QOL). METHODS Patients with recurrent or persistent ovarian, fallopian, or primary peritoneal cancer with 3+ symptoms were eligible for the study. Participants completed baseline (BL) surveys (symptom burden and controllability and QOL) before random assignment. WRITE interventions lasted 8 weeks to develop symptom management plans for three target symptoms. All women received EUC: monthly online symptom assessment with provider reports; online resources; and every 2-week e-mails. Outcomes were evaluated at 8 and 12 weeks after BL. Repeated-measures modeling with linear contrasts evaluated group by time effects on symptom burden, controllability, and QOL, controlling for key covariates. RESULTS Participants (N = 497) reported mean age of 59.3 ± 9.2 years. At BL, 84% were receiving chemotherapy and reported a mean of 14.2 ± 4.9 concurrent symptoms, most commonly fatigue, constipation, and peripheral neuropathy. Symptom burden and QOL improved significantly over time ( P &lt; .001) for all three groups. A group by time interaction ( P &lt; .001) for symptom controllability was noted whereby both WRITE intervention groups had similar improvements from BL to 8 and 12 weeks, whereas EUC did not improve over time. CONCLUSION Both WRITE Intervention groups showed significantly greater improvements in symptom controllability from BL to 8 and BL to 12 weeks compared with EUC. There were no significant differences between Nurse-WRITE and SD-WRITE. SD-WRITE has potential as a scalable intervention for a future implementation study.

Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial

PURPOSE This phase III randomized trial ( NCT00954174 ) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P &lt; .01 for noninferiority, P &gt; .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = &lt; 0.01 for noninferiority, P &lt; .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION PC was not inferior to the active regimen PI and should be standard treatment for UCS.

Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study

PURPOSE The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 ( P = .24). CONCLUSION Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

A Clinical Study of Cobimetinib Administered in Combination With Niraparib, With or Without Atezolizumab to Patients With Advanced Platinum-sensitive Ovarian Cancer

The study will include a safety run-in phase (Stage 1) and a randomization phase (Stage 2). The purpose of Stage 1 is to evaluate the safety of cobimetinib when administered in combination with niraparib (Cohort 1) and cobimetinib with niraparib plus atezolizumab (Cohort 2). Stage 1 will enable patient enrollment in the randomized phase of the study (Stage 2) with both regimens at the recommended dose levels from Stage 1. Stage 2 is a randomized, dose-expansion phase, evaluating clinical outcomes in patients with advanced platinum-sensitive ovarian cancer. All patients will continue to receive study treatment until disease progression (according to "Response Evaluation Criteria in Solid Tumors" (RECIST), Version 1.1, unacceptable toxicity, death, or patient or investigator decision to withdraw, whichever occurs first.

Ruxolitinib Phosphate, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This phase I/II trial studies the side effects and the best dose of ruxolitinib phosphate when given together with paclitaxel and carboplatin and to see how well they work in treating patients with stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate together with paclitaxel and carboplatin may be a better treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer compared to paclitaxel and carboplatin alone.

Symptom Management in Patients With Recurrent or Persistent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

This randomized clinical trial is studying two different symptom management programs to see how well they work compared with usual care in patients with recurrent or persistent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. Developing a symptom management plan may help relieve symptoms related to cancer or cancer treatment and help improve quality of life.

Paclitaxel and Carboplatin or Ifosfamide in Treating Patients With Newly Diagnosed, Persistent or Recurrent Uterine, Ovarian, Fallopian Tube, or Peritoneal Cavity Cancer

This randomized phase III trial studies paclitaxel and carboplatin see how well they work compared with paclitaxel and ifosfamide in treating patients with fallopian tube, or peritoneal cavity cancer that is newly diagnosed, persistent, or has come back (recurrent). Drugs used in chemotherapy, such as paclitaxel, carboplatin, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether paclitaxel is more effective when given with carboplatin or ifosfamide in treating patients with uterine, ovarian, fallopian tube, or peritoneal cavity cancer.

Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

This randomized phase III trial studies carboplatin, paclitaxel, and bevacizumab to see how well they work compared to carboplatin, paclitaxel, and placebo in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal, or fallopian tube cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether carboplatin, paclitaxel, and bevacizumab are more effective than carboplatin, paclitaxel, and placebo in treating ovarian epithelial, primary peritoneal, or fallopian tube cancer.

Molecular Staging of Endometrial Cancer

This study, sponsored by NCI and the Gynecologic Oncology Group (GOG), will collect tissue samples from women with cancer of the endometrium (lining of the uterus). Researchers will use the samples to learn more about endometrial cancer and develop new treatments and methods of prevention. Women with endometrial cancer who are suitable candidates for surgery and who have not had prior retroperitoneal surgery or pelvic or abdominal radiation therapy may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, and endometrial biopsy (surgical removal of a small tissue sample) or dilation and curettage (D \& C). Participants will undergo hysterectomy (surgery to remove the uterus) along with removal of both fallopian tubes and ovaries. This is the standard surgical treatment for endometrial cancer. Lymph nodes in the pelvis near the main blood vessel in the abdomen are also removed to determine if the disease has spread to these nodes. If cancer is found involving other sites, the cancer in those areas may also be removed; examination of the tissues will determine if further therapy beyond surgery is needed. Before surgery, patients will complete a 20-minute questionnaire that includes questions about their background, reproductive history, menstruation and menopause, certain surgeries, birth control pills and hormone replacement therapy, other drugs and medicines, weight and height, smoking, medical history, and family history of cancer. Some of the tissue removed during surgery, plus a urine sample collected from a catheter bag during surgery, and blood drawn before surgery and at follow-up visits 6 weeks and 3 years after surgery, will be sent to the GOG Tissue Bank in Columbus, Ohio. This bank stores, processes, and distributes biological specimens from patients that agree to participate in studies conducted by the GOG. Patients will have follow-up visits 6 weeks after surgery, then every 6 months for the next 2 years, followed annually for the next 7 years, for a total 10-year follow-up. The visits will include an examination and questions about health status and treatments received between visits. Patients whose cancer returns or worsens will undergo another tumor biopsy, if possible, at that time.