Management of a complete mole and coexisting fetus in post-dobbs world.

BACKGROUND: Twin pregnancies consisting of a complete hydatidiform mole and a coexistent fetus (CMCF) are rare and associated with a high rate of maternal-fetal morbidity and mortality. Management of these pregnancies remains controversial and increasingly challenging following the Dobbs versus Jackson Women's Health decision given the viability of the coexisting twin fetus. CASE: This case looks at the diagnosis, management, and maternal-fetal outcomes of a viable fetus coexisting molar pregnancy at a large academic center in an abortion-restricted state. CONCLUSION: CMCF pregnancies are associated with a high risk of morbidity and mortality and are increasingly difficult to manage following the Dobbs decision. Testing platforms, which identify genetic abnormalities in the first trimester, are increasingly important as access to abortion care in the United States is restricted.

Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations.

PURPOSE: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations. EXPERIMENTAL DESIGN: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan-Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). RESULTS: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. CONCLUSIONS: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

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.

Sociodemographic characteristics and cervical cancer survival in different regions of the United States: a National Cancer Database study.

OBJECTIVE: To determine how sociodemographic factors impact cervical cancer survival in different geographic locations in the USA. METHODS: A retrospective cohort of patients with cervical cancer from January 1, 2004 to December 31, 2015 in the National Cancer Database (NCDB) was identified. Tumor characteristics as well as race, income, insurance type, and treating facility types were compared among nine geographic regions. χ2 tests and Cox regression were used to compare differences between regions; p values <0.05 were considered significant. RESULTS: A total of 48 787 patients were included. Survival was inferior in seven of nine regions for underinsured patients. In six regions survival was inferior for Medicaid and Medicare patients, respectively: Middle Atlantic: hazard ratio (HR) 1.25 and 1.22; South Atlantic: HR 1.41 and HR 1.22; East North Central: HR 1.36 and HR 1.25; East South Central: HR 1.37 and HR 1.25; West North Central: HR 1.67 and HR 1.42; West South Central: HR 1.44 and HR 1.46. In the Pacific region survival was inferior for Medicare patients (HR 1.35) but not inferior for Medicaid patients. Being uninsured was associated with worse survival in the South Atlantic (HR 1.23), East North Central (HR 1.23), East South Central (HR 1.56), and West South Central (HR 1.31) regions. Annual income level under $38 000 was associated with worse survival in the Middle Atlantic (HR 1.24), South Atlantic (HR 1.35), and East North Central (HR 1.49) regions. Lastly, when compared with academic research institutions, comprehensive community cancer centers had significantly worse survival in four of the nine regions. CONCLUSIONS: Cervical cancer mortality is higher for women with a low income, underinsured (Medicaid or Medicare) or uninsured status, and decreased access to academic institutions in most US regions. An increase in cervical cancer mortality was associated with underinsured or uninsured populations in regions mainly located in the South and Midwest.

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

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.

Inhibition of AXL and VEGF-A Has Improved Therapeutic Efficacy in Uterine Serous Cancer.

Endometrial cancer remains the most prevalent gynecologic cancer with continued rising incidence. A less common form of this cancer is uterine serous cancer, which represents 10% of endometrial cancer cases. However, this is the most aggressive cancer. The objective was to assess whether inhibiting the receptor tyrosine kinase AXL with AVB-500 in combination with bevacizumab would improve response in uterine serous cancer. To prove this, we conducted multiple angiogenesis assays including tube formation assays and angiogenesis invasion assays. In addition, we utilized mouse models with multiple cells lines and subsequently analyzed harvested tissue through immunohistochemistry CD31 staining to assess microvessel density. The combination treatment arms demonstrated decreased angiogenic potential in each assay. In addition, intraperitoneal mouse models demonstrated a significant decrease in tumor burden in two cell lines. The combination of AVB-500 and bevacizumab reduced tumor burden in vivo and reduced morphogenesis and migration in vitro which are vital to the process of angiogenesis.

New Treatments for Recurrent Uterine Cancer.

PURPOSE OF REVIEW: Endometrial cancer is a highly treatable cancer; however, 13 to 15% of cases recur. Traditional cytotoxic chemotherapies have produced modest results, but new treatments show promise. This information was compiled from an extensive literature search, which was completed in order to summarize current data in this review. Our objective was to describe new therapies for recurrent endometrial cancer in the last 5 years. RECENT FINDINGS: New targeted therapies are being identified for advanced and recurrent endometrial cancer. Within the last 5 years, pembrolizumab and lenvatinib have improved survival in advanced or recurrent endometrial cancer. Similarly, trastuzumab has shown efficacy in HER2-producing uterine serous cancer. Patients with recurrent endometrial cancer are often difficult to salvage. Traditional chemotherapy has produced poor response rates. Both immunotherapy and other targeted therapies have shown promise in recurrent disease.

Uterine carcinosarcomas: From pathology to practice.

OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare but aggressive cancer. In early-stage disease data guiding treatment is sparse. The purpose of this review is to summarize the findings from the 2019 NRG oncology group summer symposium meeting as well as a review of the current literature, with a particular focus on molecular targets, ongoing clinical trials, and treatment of early and advanced/recurrent disease. METHODS: A combination of expert presentations and an extensive literature search was undertaken to summarize the literature in this review. MEDLINE was queried for peer-reviewed publications on UCS. This search was not limited by year or study design, but was limited to English language publications. ClinicalTrials.gov was queried for ongoing trials in UCS. RESULTS: UCS is a rare cancer that is biphasic, with the carcinomatous component driving its aggressive nature. Level 3 evidence regarding early stage disease is lacking, but retrospective data suggests adjuvant therapy is warranted. The recent results of GOG 261 have contributed valuable information towards treatment strategy, including use of paclitaxel and carboplatin for UCS. Clinical trials are ongoing to investigate new targeted agents in UCS. CONCLUSION: Ongoing endometrial cancer clinical trials now include UCS patients. In combination with advances in molecular profiling, this will provide patients with UCS improved therapeutic options. Until that time, surgical resection and traditional cytotoxic chemotherapy remains standard of care.

Reducing emergency department (ED) computed tomography (CT) utilization in women treated for gynecologic cancers.

OBJECTIVES: The objective of this quality improvement (QI) project was to decrease the rate of low-value computed tomography (CT) imaging in established gynecologic oncology patients presenting to the emergency department (ED). METHODS: This was a cohort study with a before and after design that evaluated implementation of a QI project designed to decrease CT utilization in established gynecologic oncology patients in the ED. The pre-intervention cohort included patients admitted through the ED from 4/1/17 to 5/31/18, while the post-intervention cohort was from 6/1/18 to 5/31/19. The intervention included gynecologic oncology consultation before CT on patients who had imaging within the prior 3 weeks. Details regarding CT, ED length of stay (LOS), and oncologic history were abstracted. The value of CT was determined by consensus from 2 reviewers. Prospective data monitoring evaluated for patient safety. RESULTS: Prior to intervention, there were 129 unique ED encounters in gynecologic oncology patients leading to admission. CT scans were performed in 101 (78.3%) encounters, 57.7% of which were deemed to be of low-value. Following implementation, the CT utilization rate decreased significantly from median monthly rate of 75.2% to 49.1% (p < 0.00001), and the ED LOS decreased from 8.1 to 6.9 h (p = 0.0102). The number of CT scans deemed to be low-value in the post-intervention group decreased to 2 (3.8%). CONCLUSIONS: Implementation of an early consultation policy and imaging guidelines led to a significant decrease in unnecessary CT utilization and shorter ED LOS in gynecologic oncology patients presenting to the ED.

Vulvar Cancer as a Result of GATA2 Deficiency, a Rare Genetic Immunodeficiency Syndrome.

BACKGROUND: Vulvar cancer has become more prevalent, and its causes include chronic dermatoses and human papillomavirus (HPV)-mediated disease. Younger immunocompromised women can also be affected. We describe a case of vulvar carcinoma as a result of GATA2 deficiency. CASE: A 19-year-old woman presented to our gynecologic oncology clinic for management of a large vulvar mass. She was diagnosed with stage IB vulvar carcinoma after vulvectomy. GATA2 deficiency was the contributing factor causing vulvar carcinoma. CONCLUSION: GATA2 deficiency causes immunodeficiency in young women, and patients with early-onset HPV-related disease, a family or personal history of leukemia, recurrent infection, or immune irregularities should be screened. Health care providers for these women are often obstetrician-gynecologists, who can provide diagnosis, treatment, referral, and prevention of HPV-related diseases.

Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm.

The treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy often includes the combination of gemcitabine and docetaxel with or without doxorubicin in first-line systemic therapy, but these cytotoxic agents only provide patients with advanced disease a 5-year survival <30%. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uLMS. Critical ongoing studies investigating novel approaches including immunotherapeutics and genetic alterations also will be discussed. IMPLICATIONS FOR PRACTICE: Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these compounds. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uterine leoimyosarcoma.

Predictors of Unplanned Reoperation for Ovarian Cancer Patients From the National Surgical Quality Improvement Program Database.

OBJECTIVES: The aim of this study was to determine preoperative risk factors associated with unplanned reoperation within 30 days for patients undergoing major surgery for primary ovarian cancer using the National Surgical Quality Improvement Program database. METHODS: We conducted a retrospective cohort study utilizing the National Surgical Quality Improvement Program database to identify patients undergoing primary ovarian cancer surgery from 2012 to 2014. Patients who had a reoperation within 30 days of their primary surgery were identified. Demographics and clinical covariates were calculated. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariate logistic regression approaches to assess the association. RESULTS: A total of 4260 patients were identified during the study period. One hundred forty-eight patients (3.5%) underwent a reoperation within 30 days of their primary surgery. In univariate analysis, preoperative creatinine 1.5 mg/dL or greater (P = 0.010), smoking (P = 0.003), and both insulin-dependent (P = 0.029) and non-insulin-dependent diabetes mellitus (P = 0.048) were predictive of a reoperation. Multivariate analysis noted that smoking (OR, 1.94; 95% CI, 1.26-2.99), insulin-dependent diabetes mellitus (OR, 2.18; 95% CI, 1.08-4.40), non-insulin-dependent diabetes mellitus (OR, 1.65; 95% CI, 1.01-2.72), and preoperative creatinine (OR, 2.65; 95% CI, 1.26-5.58) were predictive of a reoperation. Age 50 to 60 years was protective against reoperation when compared with age younger than 50 years (OR, 0.54; 95% CI, 0.32-0.90). CONCLUSIONS: Efforts to reduce reoperation rates should focus on identifying high-risk patients by utilizing objective preoperative data. Optimizing their medical status prior to surgery may decrease the reoperation rate in patients with ovarian cancer, thereby improving outcomes and providing a probable cost benefit.

Malignant Brenner tumor associated with a germline BRCA2 mutation.

•The first woman with a Malignant Brenner tumor and a BRCA2 mutation is described.•Not all women with epithelial ovarian cancers are referred for genetic counseling.•Women should be referred for genetics regardless of how rare the histology.

Contributing factors for menopausal symptoms after surgical staging for endometrial cancer.

OBJECTIVE: The aim of the study was to examine contributing factors associated with developing menopausal symptoms after surgical staging in women with endometrial cancer. METHODS: This is a retrospective study examining patients with endometrial cancer who were premenopausal at the time of hysterectomy-based surgical staging including bilateral oophorectomy between January 2000 and October 2013. Cox proportional hazard regression model was used to evaluate demographics, medical comorbidity, liver function tests, tumor factors, and medication history for menopausal symptoms. RESULTS: There were 269 premenopausal women who were eligible. Mean age was 44.5 years, and the majority had endometrioid histology (91.1%), grade 1 tumor (60.2%), and stage I disease (65.8%). Postoperatively, 73 (27.1%) women developed menopausal symptoms, with hot flushes (20.1%) being the most common symptom followed by night sweats (4.1%). On multivariate analysis, younger age was independently associated with increased risk of developing menopausal symptoms (hazard ratio per unit 0.91, 95% CI 0.88-0.94, P < 0.01). In addition, lower albumin level remained an independent predictor for decreased risk of developing menopausal symptoms (hazard ratio per unit 2.16, 95% CI 1.19-3.93, P = 0.012). Lower albumin level was associated with medical comorbidity (hypertension and diabetes mellitus), use of antihypertensive/glycemic agents (angiotensin-converting enzyme inhibitors or receptor blocker, hydrochlorothiazide, sulfonylurea, and insulin), aggressive tumor (high cancer antigen 125 level, nonendometrioid histology, and advanced stage), and abnormal liver function (high alkaline phosphatase level and low total protein level; all, P < 0.05). CONCLUSIONS: Assessing albumin level, medical comorbidity, and medication type for the development of postoperative menopausal symptoms is a valuable step in the preoperative management of women with endometrial cancer.