Glycosaminoglycan modifications of betaglycan regulate ectodomain shedding to fine-tune TGF-ß signaling responses in ovarian cancer.

In pathologies including cancer, aberrant Transforming Growth Factor-ß (TGF-ß) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-ß responses. Betaglycan/type III TGF-ß receptor (TßRIII), is an established co-receptor for the TGF-ß superfamily known to bind directly to TGF-ßs 1-3 and inhibin A/B. Betaglycan can be membrane-bound and also undergo ectodomain cleavage to produce soluble-betaglycan that can sequester its ligands. Its extracellular domain undergoes heparan sulfate and chondroitin sulfate glycosaminoglycan modifications, transforming betaglycan into a proteoglycan. We report the unexpected discovery that the heparan sulfate glycosaminoglycan chains on betaglycan are critical for the ectodomain shedding. In the absence of such glycosaminoglycan chains betaglycan is not shed, a feature indispensable for the ability of betaglycan to suppress TGF-ß signaling and the cells' responses to exogenous TGF-ß ligands. Using unbiased transcriptomics, we identified TIMP3 as a key inhibitor of betaglycan shedding thereby influencing TGF-ß signaling. Our results bear significant clinical relevance as modified betaglycan is present in the ascites of patients with ovarian cancer and can serve as a marker for predicting patient outcomes and TGF-ß signaling responses. These studies are the first to demonstrate a unique reliance on the glycosaminoglycan chains of betaglycan for shedding and influence on TGF-ß signaling responses. Dysregulated shedding of TGF-ß receptors plays a vital role in determining the response and availability of TGF-ßs', which is crucial for prognostic predictions and understanding of TGF-ß signaling dynamics.

A spatial proteomic study of platinum refractory HGSOC implicates dual AKT and WNT activity linked to an immunosuppressive tumor microenvironment.

OBJECTIVE: Advanced-stage high-grade serous ovarian cancer (HGSOC) remains a deadly gynecologic malignancy with high rates of disease recurrence and limited, effective therapeutic options for patients. There is a significant need to better stratify HGSOC patients into platinum refractory (PRF) vs. sensitive (PS) cohorts at baseline to improve therapeutic responses and survival outcomes for PRF HGSOC. METHODS: We performed NanoString for GeoMx Digital Spatial Profile (G-DSP) multiplex protein analysis on PRF and PS tissue microarrays (TMAs) to study the bidirectional communication of cancer cells with immune cells in the tumor microenvironment (TME) of HGSOC. We demonstrate robust stratification of PRF and PS tumors at baseline using multiplex spatial proteomic biomarkers with implications for tailoring subsequent therapy. RESULTS: PS patients had elevated apoptotic and anti-tumor immune profiles, while PRF patients had dual AKT1 and WNT signaling with immunosuppressive profiles. We found that dual activity of AKT1 and WNT signaling supported the exclusion of immune cells, specifically tumor infiltrating lymphocytes (TILs), from the TME in PRF tumors, and this was not observed in PS tumors. The exclusion of immune cells from the TME of PRF tumors corresponded to abnormal endothelial cell structure in tumors with dual AKT1 and WNT signaling activity. CONCLUSIONS: We believe our findings provide improved understanding of tumor-immune crosstalk in HGSOC TME highlighting the importance of the relationship between AKT and WNT pathways, immune cell function, and platinum response in HGSOC.

Dedicated financial hardship screening adds value to routine distress screening among gynecologic cancer patients.

OBJECTIVES: To evaluate existing distress screening to identify patients with financial hardship (FH) compared to dedicated FH screening and assess patient attitudes toward FH screening. METHODS: We screened gynecologic cancer patients starting a new line of therapy. Existing screening included: (1) Moderate/severe distress defined as Distress Thermometer score ≥ 4, (2) practical concerns identified from Problem Checklist, and (3) a single question assessing trouble paying for medications. FH screening included: (1) Comprehensive Score for Financial Toxicity (COST) tool and (2) 10-item Financial Needs Checklist to guide referrals. FH was defined as COST score < 26. We calculated sensitivity (patients with moderate/severe distress + FH over total patients with FH) and specificity (patients with no/mild distress + no FH over total patients with no FH) to assess the extent distress screening could capture FH. Surveys and exit interviews assessed patient perspectives toward screening. RESULTS: Of 364 patients screened for distress, average age was 62 years, 25% were Black, 45% were Medicare beneficiaries, 32% had moderate/severe distress, 15% reported ≥1 practical concern, and 0 reported trouble paying for medications. Most (n = 357, 98%) patients also completed FH screening: of them, 24% screened positive for FH, 32% reported ≥1 financial need. Distress screening had 57% sensitivity and 77% specificity for FH. Based on 79 surveys and 43 exit interviews, FH screening was acceptable with feedback to improve the timing and setting of screening. CONCLUSIONS: Dedicated FH screening was feasible and acceptable, but sensitivity was low. Importantly, 40% of women with FH would not have been identified with distress screening alone.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Uterine cancer incidence trends and 5-year relative survival by race/ethnicity and histology among women under 50 years.

BACKGROUND: Uterine cancers diagnosed before age 50 years are increasing in the U.S., but changes in clinical characteristics and survival over time across racial/ethnic groups have not been previously described. OBJECTIVE: To investigate age-adjusted, hysterectomy corrected incidence rates and trends, and 5-year relative survival rates of uterine cancer in women aged <50 years, overall and stratified by race/ethnicity and histology. STUDY DESIGN: We included microscopically confirmed uterine cancer cases (diagnosed 2000-2019) in women aged 20 to 49 years from the Surveillance, Epidemiology, and End Results Program. Age-adjusted incidence and 5-year relative survival rates, and 95% confidence intervals were computed using Surveillance, Epidemiology, and End Results (SEER) ∗Stat and compared across time periods (2000-2009 and 2010-2019). Incidence rates were adjusted for hysterectomy prevalence using Behavioral Risk Factor Surveillance System data, and trends were computed using the Joinpoint regression program. RESULTS: We included 57,128 uterine cancer cases. The incidence of uterine cancer increased from 10.1 per 100,000 in 2000-2009 to 12.0 per 100,000 in 2010-2019, increasing at an annual rate of 1.7%/y for the entire period. Rising trends were more pronounced among women <40 years (3.0%/y and 3.3%/y in 20-29 and 30-39 years, respectively) than in those 40 to 49 years (1.3%/y), and among underrepresented racial/ethnic groups (Hispanic 2.8%/y, non-Hispanic-Black 2.7%, non-Hispanic-Asian/Pacific Islander 2.1%) than in non-Hispanic-White (0.9%/y). Recent (2010-2019) incidence rates were highest for endometrioid (9.6 per 100,000), followed by sarcomas (1.2), and nonendometrioid subtypes (0.9). Rates increased significantly for endometrioid subtypes at 1.9%/y from 2000 to 2019. Recent endometrioid and nonendometrioid rates were highest in non-Hispanic-Native American/Alaska Native (15.2 and 1.4 per 100,000), followed by Hispanic (10.9 and 1.0), non-Hispanic-Asian/Pacific Islander (10.2 and 0.9), non-Hispanic-White (9.4 and 0.8), and lowest in non-Hispanic-Black women (6.4 and 0.8). Sarcoma rates were highest in non-Hispanic-Black women (1.8 per 100,000). The 5-year relative survival remained unchanged over time for women with endometrioid (from 93.4% in 2000-2009 to 93.9% in 2010-2019, P≥.05) and nonendometrioid subtypes (from 73.2% to 73.2%, P≥.05) but decreased for women with sarcoma from 69.8% (2000-2009) to 66.4% (2010-2019, P<.05). CONCLUSION: Uterine cancer incidence rates in women <50 years have increased from 2000 to 2019 while survival has remained relatively unchanged. Incidence trends can be primarily attributed to increasing rates of cancers with endometrioid histology, with the greatest increases observed among non-Hispanic-Black, Hispanic, and non-Hispanic-Asian/Pacific Islander. Sarcomas, while much rarer, were the second most common type of uterine cancer among women <50 years and have poor prognosis and apparent decreasing survival over time. Rising rates of uterine cancer and the distinct epidemiologic patterns among women <50 years highlight the need for effective prevention and early detection strategies for uterine cancer in this age group.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

Emerging perspectives on growth factor metabolic relationships in the ovarian cancer ascites environment.

The ascites ecosystem in ovarian cancer is inhabited by complex cell types and is bathed in an environment rich in cytokines, chemokines, and growth factors that directly and indirectly impact metabolism of cancer cells and tumor associated cells. This milieu of malignant ascites, provides a 'rich' environment for the disease to thrive, contributing to every aspect of advanced ovarian cancer, a devastating gynecological cancer with a significant gap in targeted therapeutics. In this perspective we focus our discussions on the 'acellular' constituents of this liquid malignant tumor microenvironment, and how they influence metabolic pathways. Growth factors, chemokines and cytokines are known modulators of metabolism and have been shown to impact nutrient uptake and metabolic flexibility of tumors, yet few studies have explored how their enrichment in malignant ascites of ovarian cancer patients contributes to the metabolic requirements of ascites-resident cells. We focus here on TGF-ßs, VEGF and ILs, which are frequently elevated in ovarian cancer ascites and have all been described to have direct or indirect effects on metabolism, often through gene regulation of metabolic enzymes. We summarize what is known, describe gaps in knowledge, and provide examples from other tumor types to infer potential unexplored roles and mechanisms for ovarian cancer. The distribution and variation in acellular ascites components between patients poses both a challenge and opportunity to further understand how the ascites may contribute to disease heterogeneity. The review also highlights opportunities for studies on ascites-derived factors in regulating the ascites metabolic environment that could act as a unique signature in aiding clinical decisions in the future.

Evolving roles of activins and inhibins in ovarian cancer pathophysiology.

Activins and inhibins are unique members of the transforming growth factor-ß (TGFß) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.

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.

DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.

PURPOSE: Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations. METHODS: We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression. RESULTS: DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel. CONCLUSIONS: Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.

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

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

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Associations between geography, decision-making style, and interest in cancer clinical trial participation.

BACKGROUND: Clinical trials offer novel treatments, which are essential to high quality cancer care. Patients living in rural areas are often underrepresented in clinical trials due to several factors. This study evaluated the association between rurality and interest in clinical trial participation, change in interest, and treatment decision-making style preference. METHODS: This cohort study included patients with cancer receiving oncology care at the University of Alabama at Birmingham from 2017 to 2019. Associations between treatment decision-making preference and the interaction between rurality and area deprivation were analyzed using multinomial logistic regression. Initial interest in clinical trial participation and change in interest were analyzed using modified Poisson regressions with robust standard errors. Initial interest model was stratified by Area Deprivation Index (ADI; higher vs. lower disadvantaged). RESULTS: In adjusted models, patients in rural versus urban areas had similar initial interest in clinical trials, both those in higher (40% vs. 50%) and lower disadvantaged settings (54% vs. 62%). Additionally, rural versus urban patients had similar change of clinical trial interest for both those who changed from uninterested-to-interested (31% vs. 26%) and interested-to-uninterested (47% vs. 42%). CONCLUSION: This study compares the interest in clinical trial participation among patients living in rural and urban settings. Lack of interest may be secondary to barriers that patients in rural areas face (e.g., transportation, financial, access). Most rural patients prefer a shared treatment decision-making style, which should be considered when identifying interventions to increase enrollment of underserved rural patients in clinical trials.

Homologous Recombination Deficiency: Concepts, Definitions, and Assays.

BACKGROUND: Homologous recombination deficiency (HRD) is a phenotype that is characterized by the inability of a cell to effectively repair DNA double-strand breaks using the homologous recombination repair (HRR) pathway. Loss-of-function genes involved in this pathway can sensitize tumors to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy, which target the destruction of cancer cells by working in concert with HRD through synthetic lethality. However, to identify patients with these tumors, it is vital to understand how to best measure homologous repair (HR) status and to characterize the level of alignment in these measurements across different diagnostic platforms. A key current challenge is that there is no standardized method to define, measure, and report HR status using diagnostics in the clinical setting. METHODS: Friends of Cancer Research convened a consortium of project partners from key healthcare sectors to address concerns about the lack of consistency in the way HRD is defined and methods for measuring HR status. RESULTS: This publication provides findings from the group's discussions that identified opportunities to align the definition of HRD and the parameters that contribute to the determination of HR status. The consortium proposed recommendations and best practices to benefit the broader cancer community. CONCLUSION: Overall, this publication provides additional perspectives for scientist, physician, laboratory, and patient communities to contextualize the definition of HRD and various platforms that are used to measure HRD in tumors.

Genomic profiling in low grade serous ovarian cancer: Identification of novel markers for disease diagnosis and therapy.

OBJECTIVES: Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort. METHODS: Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens. RESULTS: Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent. CONCLUSION: BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents.

Sequential modulation of the Wnt/ß-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance.

BACKGROUND: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/ß-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/ß-catenin modulation facilitates a more immunotherapy-favorable TME. METHODS: Human tumor samples and in vivo patient-derived xenograft and syngeneic murine models were administered Wnt/ß-catenin modulating agents DKN-01 and CGX-1321 individually or in sequence. Analytical methods included immunohistochemistry, flow cytometry, multiplex cytokine/chemokine array, and RNA sequencing. RESULTS: DKK1 blockade via DKN-01 increased HLA/MHC expression in human and murine tissues, correlating with heightened expression of known MHC I regulators: NFkB, IL-1, LPS, and IFNy. PORCN inhibition via CGX-1321 increased production of T cell chemoattractant CXCL10, providing a mechanism for observed increases in intra-tumoral T cells. Diverse leukocyte recruitment was noted with elevations in B cells and macrophages, with increased tumor expression of population-specific chemokines. Sequential DKK1 blockade and PORCN inhibition decreased tumor burden as evidenced by reduced omental weights. CONCLUSIONS: Wnt/ß-catenin pathway modulation increases MHC I expression and promotes tumor leukocytic infiltration, facilitating a pro-immune TME associated with decreased tumor burden. This intervention overcomes common tumor immune-evasion mechanisms and may render ovarian tumors susceptible to immunotherapy.

High-intermediate risk endometrial cancer: moving toward a molecularly based risk assessment profile.

In the USA, endometrial cancer (EMCA) incidence is increasing as the risk factors of obesity, diabetes, and hypertension become more prevalent. Although most EMCA is detected at an early stage and surgical intervention is curative, a subset of patients termed 'high-intermediate risk' (H-IR) experience an increased rate of recurrence. Unfortunately, adjuvant therapies in patients with H-IR EMCA have yet to increase overall survival. Historically, stratification of these patients from their low-risk counterparts incorporated clinical and pathologic findings. However, due to developments in molecular testing and genomic sequencing, tumor biomarkers are now being incorporated into the risk-assessment criteria in the hope of finding molecular profile(s) that could highlight treatment regimens that will increase patient survival. Since modern research aims to accurately identify patients with a higher risk of recurrence and develop effective interventions to improve patient survival, these molecular-based analyses could allow for an enhanced understanding of a patient's true risk of recurrence to facilitate the rise of personalized medicine. This review summarizes key clinical trials and recent advances in molecular and genomic profiles that have influenced current treatment regimens for patients with H-IR EMCA and laid the foundation for subsequent research.

Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study.

BACKGROUND: Both incidence and mortality of uterine cancer are on the rise and mortality is higher for African American women. The aim of our study was to evaluate how Next Generation Sequencing (NGS) may facilitate identification of and intervention for treatment disparities when integrated into clinical workflows. RESULTS: Our cohort included 159 uterine cancer patients with recurrent/progressive and newly diagnosed advanced stage and/or high-risk histology. The most common tumor histological subtypes included EEC (n = 67), SEC (n = 34), UCS (n = 20), and mixed (n = 14). Black patients were most likely to present with aggressive histology: (SEC, 34.0%) and carcinosarcoma (UCS, 14.0%). The four most common mutations across all subtypes were TP53, PIK3CA, PTEN, and ARID1A. There was racial disparity between Black versus non-Black patients who were initiated on targeted therapy (28.2% vs. 38.2%, respectively) and clinical trial (15% vs. 22.6%, respectively). Compared to non-Black patients, Black patients had a significantly higher percentage TP53 mutations (p < 0.05) and a significantly lower percentage ARID1A mutations (p < 0.05). CONCLUSIONS: NGS for uterine malignancies provides actionable information for targetable mutations and/or clinical trial enrollment in most patients; further investigation is necessary to identify potentially modifiable factors contributing to current disparities that may improve targeted therapy uptake and clinical trial participation.

Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.

INTRODUCTION: In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress. MANUSCRIPT DEVELOPMENT PROCESS: The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication. The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines [1] using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.