ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

BACKGROUND: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear. METHODS: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort. RESULTS: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy. CONCLUSIONS: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

Top advances of the year: Uterine cancer.

Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies. PLAIN LANGUAGE SUMMARY: The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates.

Mismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer.

OBJECTIVE: Molecular profiling is developing to inform treatment in endometrial cancer. Using real world evidence, we sought to evaluate frontline immune checkpoint inhibitor vs chemotherapy effectiveness in advanced endometrial cancer, stratified by Tumor Mutational Burden (TMB) ≥10 mut/MB and microsatellite instability (MSI). METHODS: Patients with advanced endometrial cancer in the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database were included. Data originated from patients treated between January 2011- March 2022 at 280 US clinics. Next-generation sequencing assays were performed via FoundationOne or FoundationOneCDx. Longitudinal clinical data were derived from electronic health records. Immune checkpoint inhibitor treatment included pembrolizumab, dostarlimab, and nivolumab monotherapies. Time to next treatment, time to treatment discontinuation, and overall survival were assessed with the log-rank test and Cox proportional hazard models with adjusted hazard ratios (aHR) for known prognostic factors. We used the Likelihood ratio test to compare biomarker performance. RESULTS: A total of 343 patients received chemotherapy and 28 received immune checkpoint inhibitor monotherapy as frontline treatment. Patients who received monotherapy were more likely to be stage III at diagnosis (immune checkpoint inhibitor: 54.6% vs chemotherapy: 15.0%; p<0.001) and more likely to test MSI-high via next-generation sequencing (immune checkpoint inhibitor: 53.6% vs chemotherapy: 19.2%; p<0.001). In MSI-high cancers, single-agent immune checkpoint inhibitor had a more favorable time to next treatment (aHR: 0.18, p=0.001) and overall survival (aHR 0.29, p=0.045). Additional analyses on 70 unique tumor specimens revealed mismatch repair deficiency (dMMR) via immunohistochemistry and MSI-high via next-generation sequencing concordance (91%), with nominal improvement of MSI over dMMR to predict time to treatment discontinuation (p=0.030), time to next treatment (p=0.032), and overall survival (p=0.22). MSI status was concordant with tumor mutational burden ≥10 in 94.3% of cases. CONCLUSION: Immune checkpoint inhibitors may have improved efficacy over chemotherapy in frontline treatment for advanced endometrial cancer defined by MSI-high using next-generation sequencing as a nominally better predictor of outcomes than dMMR with immunohistochemistry. This provides the biologic rationale of active phase III trials.

Immunotherapy treatment landscape for patients with endometrial cancer: current evidence and future opportunities.

Endometrial cancer is the most common gynecologic cancer in the United States, with a rising incidence and mortality. Traditionally, systemic treatment has included combination platinum- and taxane-based chemotherapy. More recently, the identification of molecular subtypes has transformed the treatment paradigms for patients with endometrial cancer, especially in the immunotherapeutic arena. Given the recent advancements in immune oncology approaches, we review regimens approved by the US Food and Drug Administration as well as the interim results of ongoing phase 3 clinical trials.

KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery.

We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. KEY POINTS: This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.

Practice patterns and survival in FIGO 2009 stage 3B endometrial cancer.

OBJECTIVE: To describe the practice patterns and outcomes of patients with stage 3B endometrial cancer. METHODS: We queried the National Cancer Database for all surgically staged, stage 3 patients between 2012 and 2016. Patients who received any pre-operative therapy were excluded. Demographics, tumor factors, and adjuvant therapy for the stage 3 substages were compared. Logistic regression was used to identify factors associated with adjuvant therapy. Kaplan Meier curves were generated and compared using the log-rank test. Multivariable Cox Proportional Hazards Model was used to adjust for prognostic factors. Findings with p < 0.05 were considered significant. RESULTS: Of 7363 patients with stage 3 disease, 478 (6%) had stage 3B; 1732 (23%) had stage 3A, 3457 (48%) had stage 3C1, and 1696 (23%) had stage 3C2 disease. Post-surgical treatment consisted of: combined chemotherapy (CT) and radiation (RT) (49%), CT alone (28%), RT alone (9%), 14% received no postoperative therapy. Among all stage 3 substages, patients with stage 3B disease were the least likely to receive any CT, and the most likely to receive RT alone. After adjusting for known prognostic factors, patients with stage 3A (Hazard ratio (HR) of death = 0.64) and 3C1 (HR of death = 0.79) disease had significantly worse overall survival compared to stage 3B; survival was not demonstrably different from patients with stage 3C2 disease. Patients with stage 3B disease who received CT + RT had the best overall survival. CONCLUSION: Survival of patients with stage 3B disease is similar to that of patients with para-aortic node metastases and is inferior to all others with stage 3 endometrial cancer. Less frequent CT and a higher rate of post-operative RT alone, describes a distinct practice from that seen in other stage 3 patients.

Assessment of malnutrition by unintentional weight loss and its implications on oncologic outcomes in patient with locally advanced cervical cancer receiving primary chemoradiation.

OBJECTIVES: To determine the prevalence, risk factors for, and clinical implications of unintentional weight loss on oncologic outcomes in locally advanced cervical cancer (LACC) treated with concurrent chemotherapy and contemporary radiation techniques. METHODS: This a single-institution, retrospective cohort study of patients with LACC who received definitive chemoradiation (CRT) from 2010 to 2015. Clinicopathologic factors were abstracted by chart review and characterized using descriptive statistics. Factors associated with severe weight loss (≥10% from baseline) were determined by Chi-square test. Time-to-event analysis was performed using the Kaplan Meier method and regression was performed using the Cox Proportional hazards model. RESULTS: One hundred and eight patients comprised the cohort. The majority of patients were White, obese, and had squamous histology. Almost 80% of patients experienced at least some weight loss, with 14% of patients experiencing severe weight loss. Patients with FIGO 2009 stage 3 or 4 disease had a 3.4-fold increased risk of severe weight loss compared to those with earlier stage disease. Patients who had severe weight loss had a higher risk for death (HR = 2.37, 95% confidence interval [CI] 1.77, 7.37, p = 0.036) and a trend toward high risk for recurrence (HR = 1.43, 95% CI 0.46, 3.32, p = 0.107) compared to patients without severe weight loss. CONCLUSION: Unintentional weight loss is a common symptom of patients with LACC receiving CRT that affects oncologic outcomes, yet it remains under-recognized. Increased awareness of weight loss and malnutrition may encourage interventions to improve this potentially modifiable risk factor for worse prognosis and quality of life.

Trends and geographic variation in women's representation as principal investigators (PI) in phase 3 gynecologic oncology clinical trials.

OBJECTIVE: To investigate the representation of women as principal investigators (PI) in phase 3, gynecologic oncology clinical trials. METHODS: ClinicalTrials.gov was queried for all phase 3 clinical trials with start dates between January 1, 2010 and December 31, 2020 using the search terms: "ovarian cancer", "endometrial cancer", and "cervical cancer". Trial characteristics were abstracted from the website. Gender of the PI was assessed by name, image on institutional website or by querying the trial coordinator. Trials were considered to have women's representation if women were the sole PI or among multiple co-PIs. Chi-square tests and relative risks were used to compare proportions across groups. Linear regression was used to assess trends over time. RESULTS: 200 unique clinical trials were included in this analysis, of which women were represented as PI in 76 (38%). Women were more likely to be a PI of trials funded by multiple sites than a single entity (RR = 1.80, 95% confidence interval (CI) 1.25, 2.61, p = 0.01), registered outside of Asia than those in Asia (RR = 1.78, 95% CI 1.11, 2.88, p = 0.02), and trials with multiple co-PIs than with one PI (RR = 1.78 (95% CI 1.18, 2.67), p = 0.01). Overall, women's representation as a PI increased by 3% annually (by year of registration, R2 = 0.61, p = 0.01). This increase was most evident in trials registered in multiple continents and Europe (both 4% annually). CONCLUSIONS: Women's representation as PIs in clinical trials has increased in the last decade. Trials funded by multiple sources outside of Asia have the highest proportion of PIs who are women. These trends may represent ongoing leadership and mentorship opportunities for women gynecologic oncologists.

Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization: the PASTIME protocol.

BACKGROUND: Multidisciplinary care of placenta accreta spectrum cases improves pregnancy outcomes, but the specific components of such a multidisciplinary collaboration varies between institutions. As experience with placenta accreta spectrum increases, it is crucial to assess new surgical techniques and protocols to help improve maternal outcomes and to advocate for hospital resources. OBJECTIVE: This study aimed to assess a novel multidisciplinary protocol for the treatment of placenta accreta spectrum that comprises cesarean delivery, multivessel uterine embolization, and hysterectomy in a single procedure within a hybrid operative suite. STUDY DESIGN: This was a matched prepost study of placenta accreta spectrum cases managed before (2010-2017) and after implementation of the Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol (2018-2021) at a tertiary medical center. Historical cases were managed with internal iliac artery balloon placement in selected cases with the decision to inflate the balloons intraoperatively at the discretion of the primary surgeon. Intraoperative Embolization cases were compared with historical cases in a 1:2 ratio matched on the basis of placenta accreta spectrum severity and surgical urgency. The primary outcome was a requirement for transfusion with packed red blood cells. Secondary outcomes included estimated surgical blood loss, operative and postoperative complications, procedural time, length of stay, and neonatal outcomes. RESULTS: A total of 15 Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization cases and 30 matched historical cases were included in the analysis. There were no demographic differences noted between the groups. A median (interquartile range) of 0 units (0-2 units) of packed red blood cells were transfused in the Intraoperative Embolization group compared with 2 units (0-4.5 units) in the historical group (P=.045); 5 of 15 (33.3%) Intraoperative Embolization cases required blood transfusions compared with 19 of 30 (63.3%) cases in the historical group (P=.11). The estimated blood loss was significantly less in the Intraoperative Embolization group with a median (interquartile range) of 750 mL (450-1050 mL) compared with 1750 mL (1050-2500 mL) in the historical group (P=.003). There were no cases requiring massive transfusion (≥10 red blood cell units in 24 hours) in the Intraoperative Embolization group compared with 5 of 30 (16.7%) cases in the historical group (P=.15). There were no intraoperative deaths from hemorrhagic shock using the Intraoperative Embolization protocol, whereas this occurred in 2 of the historical cases. The mean duration of the interventional radiology procedure was longer in the Intraoperative Embolization group (67.8 vs 34.1 minutes; P=.002). Intensive care unit admission and postpartum length of stay were similar, and surgical and postoperative complications were not significantly different between the groups. The gestational age and neonatal birthweights were similar; however, the neonatal length of stay was longer in the Intraoperative Embolization group (median duration, 32 days vs 15 days; P=.02) with a trend toward low Apgar scores. Incidence of arterial umbilical cord blood pH <7.2 and respiratory distress syndrome and intubation rates were not statistically different between the groups. CONCLUSION: A multidisciplinary pathway including a single-surgery protocol with multivessel uterine embolization is associated with a decrease in blood transfusion requirements and estimated blood loss with no increase in operative complications. The Placenta Accreta Spectrum Treatment With Intraoperative Multivessel Embolization protocol provides a definitive surgical method that warrants consideration by other centers specializing in placenta accreta spectrum treatment.

Unanticipated 30-day readmission following rectosigmoid resection at the time of cytoreductive surgery in patients with advanced stage ovarian cancer.

The objective of this study was to examine the rate of and indications for readmission in patients with advanced staged ovarian cancer undergoing rectosigmoid resection and primary anastomosis, an important quality metric. A retrospective review was conducted of patients with primary ovarian cancer who underwent rectosigmoid resection as part of cytoreductive surgery between July 2003 and July 2014. Univariate analysis identified rates and predictors of readmission. Fifty patients were eligible for analysis. The unanticipated 30-day readmission rate was 18% (n = 9). Of those readmitted less than 30 days from date of discharge, 3 were readmitted more than once, making 14 total readmissions. A total of 21 indications for readmission were reported, with the most common being: infection (23.8%, n = 5); thromboembolic events (19%, n = 4); and severe malnutrition (14.3%, n = 3). The median time to readmission was 14 days (range, 2-26). There were no deaths within 30 days of surgery in this cohort.IMPACT STATEMENTWhat is already known about the subject? Unanticipated 30-day readmission rates are reported to be between 12 and 20% among patients undergoing cytoreductive surgery for the management of ovarian cancer. The relative contribution of rectosigmoid resection at the time of cytoreductive surgery to readmission is not well studied.What do the results of this study add? In the examined cohort, the unanticipated 30-day readmission rate following rectosigmoid resection with primary reanastomosis at the time of cytoreductive surgery is 18%, similar to the readmission rate for patients undergoing cytoreductive surgery, in general. While the sample size is limited, the perioperative complications in this cohort appear similar to those of patients undergoing cytoreductive surgery.What are the implications of these findings for clinical practice and/or further research? Efforts to reduce unanticipated 30-day readmission following cytoreductive surgery is warranted. Future studies may benefit from multi-centre approaches and prospective data collection, while simultaneously assessing the impact of enhanced recovery programs. Ultimately, identification of risk factors, and programmatic initiatives to drive down readmission will be important across surgical platforms, and the opportunity exists in patients with advanced stage ovarian cancer.

Rapid dissemination of practice-changing information: A longitudinal analysis of real-world rates of minimally invasive radical hysterectomy before and after presentation of the LACC trial.

OBJECTIVE: Characterize change in rates of minimally invasive (MIS) radical hysterectomy after presentation of the LACC trial. METHODS: Longitudinal analysis of data from Vizient® database for surgically treated patients with invasive cervical cancer from April 2017-March 2019. Covariates studied included patient demographic and obesity categories, dates of LACC trial presentation and publication, and hospital characteristics. RESULTS: 2102 cervical cancer patients had surgery at 201 hospitals. Most were age 31-50 (51.2%), White (64.8%), and had public (49.2%) health insurance. Annual rates of MIS fell from 51.9% to 27.1% after the LACC trial presentation (RR 0.52, 95% CI 0.47, 0.58; p < 0.0001). Adjusting for within hospital correlation, the odds of MIS dropped by 13% per month (OR = 0.872 per month, 95% CI 0.852, 0.891; p < 0.001), without further change in rates of MIS after the peer-review publication (OR = 1.033 per month, 95% CI 0.897, 1.189; p = 0.65). Rates of MIS declined across all demographics (RR = 0.32-0.65; p < 0.01), except in morbidly obese women (RR = 0.90; p = 0.60). Applying mixed effects model, rates of MIS fell by 3% per month in morbidly obese women versus 18% per month if body mass index<40 kg/m2. NCCN member hospitals and hospitals with gynecologic oncology fellowship training programs significantly reduced rates of MIS radical hysterectomy faster, but not earlier, than other hospitals. CONCLUSIONS: Rates of MIS radical hysterectomy fell dramatically and pervasively after the LACC trial presentation, despite ongoing substantive controversy. Practice pattern changes were not significant in morbidly obese women.

Current status of hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer in the United States.

OBJECTIVES: 1.) To compare frequency of HIPEC use in ovarian cancer treatment before and after publication of the phase III study by van Driel et al. in January 2018. 2.) To compare associated rates of hospital-based outcomes, including length of stay, intensive care unit (ICU) admission, complications, and costs in ovarian cancer surgery with or without HIPEC. METHODS: We queried Vizient's administrative claims database of 550 US hospitals for ovarian cancer surgeries from January 2016-January 2020 using ICD-10 diagnosis and procedure codes. Sodium thiosulfate administration was used to identify HIPEC cases according to the published protocol. Student t-tests and relative risk (RR) were used to compare continuous variables and contingency tables, respectively. RESULTS: 152 ovarian cancer patients had HIPEC at 39 hospitals, and 20,014 ovarian cancer patients had surgery without HIPEC at 256 hospitals. Following the trial publication, 97% of HIPEC cases occurred. During the index admission, HIPEC patients had longer median length of stay (8.4 vs. 5.7 days, p < 0.001) and higher percentage of ICU admissions (63.1% vs. 11.0%, p < 0.001) and complication rates (RR = 1.87, p = 0.002). Index admission direct costs ($21,825 vs. $12,038, p < 0.001) and direct cost index (observed/expected costs) (1.87 vs. 1.11, p < 0.001) were also greater in the HIPEC patients. No inpatient deaths or 30-day readmissions were identified after HIPEC. CONCLUSIONS: Use of HIPEC for ovarian cancer increased in the US after publication of a phase III clinical trial in a high-impact journal, though the absolute number of cases remains modest. Incorporation of HIPEC was associated with increased cost, hospital length of stay, ICU admission, and hospital-acquired complication rates. Further studies are needed in order to evaluate long-term outcomes, including morbidity and survival.

Correlation between Surgeon's assessment and radiographic evaluation of residual disease in women with advanced stage ovarian cancer reported to have undergone optimal surgical cytoreduction: An NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: We sought to determine the level of concordance among surgeons' assessment of residual disease (RD) and pre-treatment computed tomography (CT) findings among women who underwent optimal surgical cytoreduction for advanced stage ovarian cancer. METHODS: This is a post-trial ad hoc analysis of a phase 3 randomized clinical trial evaluating the impact of bevacizumab in primary and maintenance therapy for patients with advanced stage ovarian cancer following surgical cytoreduction. All subjects underwent imaging of the chest/abdomen/pelvis to establish a post-surgical baseline prior to the initiation of chemotherapy. Information collected on trial was utilized to compare surgeon's operative assessment of RD, to pre-treatment imaging. RESULTS: Of 1873 enrolled patients, surgical outcome was described as optimal (RD≤1cm) in 639 subjects. Twelve patients were excluded as they did not have a baseline, pretreatment imaging, leaving 627 participants for analysis. The average interval from surgery to baseline scan was 26days (range: 1-109). In 251 cases (40%), the post-operative scan was discordant with surgeon assessment, demonstrating RD>1cm in size. RD>1cm was most commonly identified in the right upper quadrant (28.4%), retroperitoneal para-aortic lymph nodes (RD>1.5cm; 28.2%) and the left upper quadrant (10.7%). Patients with RD>1cm on pre-treatment CT (discordant) exhibited a significantly greater risk of disease progression (HR 1.30; 95% CI 1.08-1.56; p=0.0059). CONCLUSIONS: Among patients reported to have undergone optimal cytoreduction, 40% were found to have lesions >1cm on postoperative, pretreatment imaging. Although inflammatory changes and/or rapid tumor regrowth could account for the discordance, the impact on PFS and distribution of RD may suggest underestimation by the operating surgeon.

Expression Patterns of the Wnt Pathway Inhibitors Dickkopf3 and Secreted Frizzled-Related Proteins 1 and 4 in Endometrial Endometrioid Adenocarcinoma: An NRG Oncology/Gynecologic Oncology Group Study.

OBJECTIVE: The aim of the study was to determine the differential expression patterns of the wingless-type (Wnt) pathway inhibitors Dkk3 (Dickkopf 3), SFRP1 (secreted frizzled-related protein 1), and SFRP4 in normal müllerian tissue and endometrial endometrioid adenocarcinoma specimens. METHODS: Messenger RNA (mRNA) and protein levels of the Wnt pathway inhibitors Dkk3, SFRP1, and SFRP4 were evaluated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. A total of 87 human tissue specimens were obtained from 60 women who participated in Gynecologic Oncology Group protocol 210. Twenty-seven normal müllerian tissues, 32 early-stage, and 28 advanced-stage endometrial endometrioid cancer specimens were analyzed. RESULTS: Median age for this cohort was 60 years, with median body mass index of 32 kg/m. There was a difference in Dkk3 protein expression between normal müllerian tissues and primary endometrial endometrioid adenocarcinoma samples (P = 0.05). There was down-regulation of Dkk3, SFRP1, and SFRP4 mRNA expression in patients with high-grade disease (P = 0.08, 0.06, and 0.05, respectfully). Furthermore, a decrease in SFRP1 and SFPR4 mRNA expression was noted in patients with a diagnosis of locoregional and distant disease recurrence. Lastly, a trend toward decreased progression-free survival in patients with low Dkk3, SFRP1, and SFRP4 mRNA expression levels was noted. CONCLUSIONS: Wnt pathway inhibitor (Dkk3, sFRP1, and/or sFRP4) expression was down-regulated in patients with high-grade disease and was associated with locoregional and distant disease recurrence. Despite sample size (power) limitations, these results support previous preclinical studies and may suggest a therapeutic role for Wnt signaling in endometrial cancer.

Development of bevacizumab in advanced cervical cancer: pharmacodynamic modeling, survival impact and toxicology.

Historically, patients with metastatic, persistent or recurrent cervical cancer had limited therapeutic options. Despite several Phase II/III clinical trials, the combination of cisplatin and paclitaxel remained the most effective chemotherapeutic regimen. In 2014, publication of Gynecologic Oncology Group 240 represented the emergence of an alternate and effective therapeutic option. This prospective, randomized, Phase III clinical trial explored the impact of adding the antiangiogenic agent bevacizumab to two separate cytotoxic chemotherapy backbones. Importantly, the study met its primary end point, showing a survival advantage of approximately 4 months without detriment in quality of life. As such, a review of bevacizumab and its application in patients with advanced-stage cervical cancer is warranted.