For the majority of patients with endometrial cancer who are diagnosed at an early stage, high-quality evidence directs mainstay initial surgical treatment, which confers excellent long-term survival. Conversely, the 8%-15% of endometrial cancers diagnosed at a clinically advanced stage with primary metastatic disease have a significantly worse prognosis and a 5-year relative survival rate of 15%-20%. The management of primary advanced endometrial cancer is understudied with the majority of relevant evidence being retrospective, single institution, and in heterogenous populations (combined with management of recurrent endometrial cancer), and there are few prospective studies that focus solely on primary advanced disease. It appears that hysterectomy and surgical cytoreduction may improve long-term survival in metastatic endometrial cancer; however, it remains unclear which patients are most likely to benefit. Furthermore, the new integration of molecular classifications to the management of endometrial cancer has opened up new prognosis and treatment perspectives; however, the majority of current trials investigating new management paradigms based on molecular features exclude advanced-stage disease, so the implications for practice regarding this patient group are understudied. This review analyzes the current available evidence regarding surgical management of primary metastatic endometrial cancer, including current international guideline recommendations, evidence for primary cytoreductive surgery and neoadjuvant systemic treatment followed by surgery, surgical resection of distant metastases, and lymph node management.

This study aimed to explore differences in disease extent based on the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classification and to establish personalized staging surgery strategies in patients with preoperatively presumed uterus-confined endometrial cancer.

In this retrospective, single-center study, we reviewed the medical records of patients with endometrial cancer. These patients were classified according to the ProMisE classification based on tissue samples obtained from dilation and curettage or staging surgeries, and the disease extent was analyzed based on pathologic reports.

A total of 345 patients were clinically estimated to be in stage 1/2 before staging surgery, with immunohistochemistry (IHC) results available. This cohort included 332 patients (96.2%) with clinical stage 1 and 13 patients (3.8%) with stage 2 based on the 2009 FIGO staging system. Among these, 81 patients (23.5%) were assigned to an mismatch repair deficient group (MMRd), 33 (9.6%) to an abnormal p53 group, and 123 (71.1%) to a no specific molecular profile (NSMP) group. Overall, 13 patients had nodal metastasis, with a higher rate observed in the abnormal p53 group (1.2%, 12.1%, and 2.2% for the MMRd, abnormal p53, and NSMP groups, respectively, p=0.013). One patient (0.3%) had parametrial metastasis and four (1.1%) had peritoneal metastasis.

Patients with abnormal p53 IHC results exhibited a higher likelihood of lymph node metastasis, even when initially presumed to be at an early stage. For the abnormal p53 group, proactive lymphadenectomy surgery appears beneficial for accurate staging and establishing a subsequent treatment plan.

Endometrial cancer (EC) is the most common gynecologic cancer in the United States with rising incidence and mortality. Despite optimal treatment, 15%-20% of all patients will recur. To better select patients for adjuvant therapy, it is important to accurately predict patients at risk for recurrence. Our objective was to train, validate, and test models of EC recurrence using lasso regression and other machine learning (ML) and deep learning (DL) analytics in a large, comprehensive data set.

Data from patients with EC were downloaded from the Oncology Research Information Exchange Network database and stratified into low risk, The International Federation of Gynecology and Obstetrics (FIGO) grade 1 and 2, stage I (N = 329); high risk, or FIGO grade 3 or stages II, III, IV (N = 324); and nonendometrioid histology (N = 239) groups. Clinical, pathologic, genomic, and genetic data were used for the analysis. Genomic data included microRNA, long noncoding RNA, isoforms, and pseudogene expressions. Genetic variation included single-nucleotide variation (SNV) and copy-number variation (CNV). In the discovery phase, we selected variables informative for recurrence (P < .05), using univariate analyses of variance. Then, we trained, validated, and tested multivariate models using selected variables and lasso regression, MATLAB (ML), and TensorFlow (DL).

Recurrence clinic models for low-risk, high-risk, and high-risk nonendometrioid histology had AUCs of 56%, 70%, and 65%, respectively. For training, we selected models with AUC >80%: five for the low-risk group, 20 models for the high-risk group, and 20 for the nonendometrioid group. The two best low-risk models included clinical data and CNVs. For the high-risk group, three of the five best-performing models included pseudogene expression. For the nonendometrioid group, pseudogene expression and SNV were overrepresented in the best models.

Prediction models of EC recurrence built with ML and DL analytics had better performance than models with clinical and pathologic data alone. Prospective validation is required to determine clinical utility.

Uterine clear cell carcinoma (UCCC) is a rare but aggressive histologic type of endometrial cancer. Recommendations for adjuvant treatment of early-stage UCCC remain vague. The objective of this study is to assess the impact of adjuvant treatment on survival outcomes of patients with stage I UCCC.

Using the Surveillance, Epidemiology and End Results database (SEER), patients with stage I UCCC were identified. Disease-specific survival (DSS) as well as overall survival (OS) for patients who underwent observation alone versus adjuvant treatment with either chemotherapy alone, radiotherapy (RT) alone, or chemotherapy plus RT, were analyzed by Kaplan-Meier (K-M) survival estimates and multivariate Cox proportion hazards model.

The study included 881 patients with stage I UCCC. Kaplan-Meier estimates showed no difference in DSS among those who underwent observation versus adjuvant treatment. In the multivariate model for DSS, tumor size ≥40 mm was associated with an increased risk of death (HR 2.02, p = 0.0267) while living in a metropolitan county decreased the risk of death (HR 0.46, p = 0.009). The K-M curve for OS showed a significant difference among the four treatment groups (p = 0.0475), with a 10-year OS of 61 % for patients who received no adjuvant treatment versus 74 % for those receiving chemotherapy plus radiation. However, this difference was not significant in the multivariate analysis.

In this study of stage I UCCC, the use of adjuvant treatment did not confer a survival advantage. Observation may be considered an acceptable option although prospective research is needed.

Endometrial cancer is the most common gynecological malignancy in high-income countries. While early-stage endometrial cancer generally has a favorable prognosis, a small proportion of low-risk patients experience unexpected recurrence. This study aimed to identify molecular factors contributing to recurrence in stage 1 A grade 1-2 low-risk endometrioid endometrial cancer.

We performed next-generation sequencing (NGS) on tumor samples from 19 patients who experienced recurrence despite favorable clinicopathological features and compared them with six control patients without recurrence. Results were also compared to a matched cohort of low-risk endometrial cancers from The Cancer Genome Atlas (TCGA) database.

Mutations in PTEN, PIK3CA, ARID1A, and FGFR2 were the most frequent in the recurrence group. FGFR2 mutations were exclusive to the recurrence group (9/19, 47.4 %) and absent in the non-recurrent group (0/6), a difference approaching statistical significance (p = 0.0571). FGFR2 mutations were also significantly more prevalent in the recurrence cohort compared to the TCGA low-risk cohort (p = 0.0039). Prominent FGFR2 missense mutations included S252W, K659E, and N549K, which may drive oncogenesis and tumor progression. Among the recurrence group, a rare POLE-mutated tumor recurred unexpectedly and proved fatal, highlighting the potential for poor outcomes even in typically favorable molecular subtypes.

FGFR2 mutations may play a role in tumor recurrence in a subset of low-risk endometrial cancers, underscoring the importance of molecular profiling in identifying patients at risk. FGFR2 represents a potential therapeutic target, warranting further validation in larger cohorts to establish its clinical utility.

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.

In various missing data problems, values are not entirely missing, but are coarsened. For coarsened observations, instead of observing the true value, a subset of values - strictly smaller than the full sample space of the variable - is observed to which the true value belongs. In our motivating example for patients with endometrial carcinoma, the degree of lymphovascular space invasion (LVSI) can be either absent, focally present, or substantially present. For a subset of individuals, however, LVSI is reported as being present, which includes both non-absent options. In the analysis of such a dataset, difficulties arise when coarsened observations are to be used in an imputation procedure. To our knowledge, no clear-cut method has been described in the literature on how to handle an observed subset of values, and treating them as entirely missing could lead to biased estimates. Therefore, in this paper, we evaluated the best strategy to deal with coarsened and missing data in multiple imputation. We tested a number of plausible ad hoc approaches, possibly already in use by statisticians. Additionally, we propose a principled approach to this problem, consisting of an adaptation of the SMC-FCS algorithm (SMC-FCS  CoCo $$ {}_{\mathrm{CoCo}} $$ : Coarsening compatible), that ensures that imputed values adhere to the coarsening information. These methods were compared in a simulation study. This comparison shows that methods that prevent imputations of incompatible values, like the SMC-FCS  CoCo $$ {}_{\mathrm{CoCo}} $$ method, perform consistently better in terms of a lower bias and RMSE, and achieve better coverage than methods that ignore coarsening or handle it in a more naïve way. The analysis of the motivating example shows that the way the coarsening information is handled can matter substantially, leading to different conclusions across methods. Overall, our proposed SMC-FCS  CoCo $$ {}_{\mathrm{CoCo}} $$ method outperforms other methods in handling coarsened data, requires limited additional computation cost and is easily extendable to other scenarios.

Clear cell ovarian and endometrial carcinomas are rare and aggressive gynecologic malignancies that present unique challenges owing to their underrepresentation in clinical trials and limited prospective data. In this report, we aimed to explore 3 major controversies in the management of clear cell ovarian and endometrial carcinomas, highlighting areas that require further investigation. First, we addressed the unique phenotypic characteristics of clear cell ovarian carcinoma and clear cell endometrial carcinoma and whether they should be considered a unified disease entity or a distinct disease. Recent trials grouped these carcinomas, potentially expanding their therapeutic options. However, emerging molecular data underscores the significant differences between clear cell ovarian carcinoma and clear cell endometrial carcinoma, raising questions regarding this combined approach. This distinction is critical in guiding tailored treatment strategies. Second, we examined the management of localized diseases. Although early-stage diagnoses are common in clear cell carcinomas, optimal surgical and adjuvant treatment strategies remain uncertain. Current practice often relies on data from broader studies with limited inclusion of clear cell histology. This review underscores the need for more specific evidence to refine treatment protocols and balance efficacy with the minimization of treatment-related morbidity. Third, we explored novel therapeutic strategies for the treatment of recurrent diseases. Advances in the understanding of the biology of clear cell carcinomas have identified potential targets in the immune microenvironment, cellular processes, and metabolism. Ongoing clinical trials are investigating these approaches, which hold promise in transforming the treatment landscape and outcomes. In conclusion, this review emphasizes the necessity for international collaboration and the inclusion of diverse patient populations to address the challenges posed by cell carcinomas. By focusing on these controversies, we aim to stimulate further research and support more evidence-based personalized approaches for the management of these rare but challenging cancers.

The Thai Gynecologic Cancer Society (TGCS) continues its efforts to elevate the standard of practice of gynecologic oncologists across all regions of Thailand. A key initiative involves collaborating with the Royal Thai College of Obstetricians and Gynaecologists and the National Cancer Institute, Thailand to regularly update and release clinical practice guidelines (CPGs) for gynecologic cancer. The TGCS released the first CPG for endometrial cancer (EMC) in 2011. Following significant advancements in disease understanding and the major revision of EMC staging by the International Federation of Gynecology and Obstetrics in 2023, national experts collaborated to update the guideline for EMC. The key components of the CPG for EMC covered screening, diagnostic indications and methods, primary treatment including surgical approaches and procedures, pathological processes, adjuvant therapies, and the management of recurrent and advanced diseases through medical or surgical means. The guideline was based on scientific evidence, recommendations from international organizations, and the unique healthcare context of Thailand. The final version reflects a consensus reached through extensive discussions among TGCS members. To share our work with international organizations and healthcare professionals, an English version of the CPG was developed. While it mirrors the content of the Thai version, it differs in length and level of detail. The English version additionally included the level of evidence and a recommendation summary for each section, reflecting common domestic practices, available resources, and coverage under health reimbursement systems.

Of the 4 molecular subtypes of endometrial cancer (EC), p53-abnormal (p53abn) EC is associated with abundant copy number alterations and the worst clinical outcome. Patients with p53abn EC have the highest risk of disease recurrence and death, independent of tumor grade and histologic subtype. Currently, all invasive p53abn ECs are considered high risk, and no prognostic biomarkers have yet been found that can aid in clinical management. Here, we aimed to test whether loss of retinoblastoma (RB) protein expression using immunohistochemistry has the potential for prognostic refinement of p53abn EC. A large cohort of 227 p53abn ECs collected from the PORTEC-1/2/3 clinical trials and the Medisch Spectrum Twente cohort study was investigated, and RB loss was identified in 7.0% (n = 16/227). RB-lost p53abn ECs were predominantly high-grade endometrioid ECs (n = 6, 37.5%) and carcinosarcomas with endometrioid-type epithelial component (n = 5, 31.3%). Histologically, RB-lost p53abn ECs were typified by high-grade nuclear atypia (n = 16, 100%), predominantly solid growth pattern (n = 15/16, 93.8%), and polypoid growth (n = 9/16, 56.3%). Copy number loss involving the RB1 locus was identified in the majority of RB-lost p53abn EC (n = 13/14, 92.9%), explaining the loss of RB expression. Comparative analysis also showed that RB-lost p53abn ECs were diagnosed at earlier stages than RB-retained p53abn EC (P = .014). Interestingly, RB-lost p53abn EC showed prolonged time to overall recurrence (P = .038), even within stage I alone (P = .040). These findings highlight distinct morphomolecular features in RB-lost p53abn ECs and confirm the utility of RB immunohistochemistry as a surrogate for underlying molecular RB1 alterations. To our knowledge, this is the first study to show the potential use of RB in prognostic refinement of p53abn EC, although validation is warranted.

The ratio of harvested lymph nodes to the number of metastatic nodes is known as the lymph node ratio (LNR) and its prognostic significance was investigated in many types of cancer.

However, until now, the therapeutic role of lymphadenectomy in the management of endometrial cancer (EC) has remained controversial.

The search strategy involved the Medline, Scopus, Clinicaltrials.gov, Cochrane Central Register of Controlled Trials CENTRAL, and Google Scholar databases.

We included prospective and retrospective observational studies.

The current systematic review includes seven studies with a total of 6050 patients. From Cox regression analyses, pooled hazard ratios (HRs) were obtained to reduce the confounding effect of other factors that affect the survival outcomes.

The meta-analysis revealed a significant difference in progression-free survival in patients with LNR below the cut-off point in comparison to individuals with LNR above the cut-off point (HR 2.06, 95% CI 1.57-2.71, data from 6 studies). Similarly, a significantly smaller overall survival was observed among patients with LNR above the cut-off value (HR 1.99, 95% CI 1.53-2.60; data from five studies).

The results of this systematic review provide strong evidence that LNR could be a prognostic factor for EC patients regarding the need for adjuvant therapy and survival rate. Further studies should focus on the specific cut-off levels of LNR and the role of the molecular markers in assessing the prognosis of EC patients.

Cancer treatment using systemic therapy and radiotherapy may cause post-therapy complications, resulting in increased unplanned hospitalisation. The evidence on such complications, their impact on unplanned hospitalisations, and associated costs is scant in Australia. We aimed to estimate the prevalence of post-therapy complications, evaluate their impact on unplanned hospitalisation, length of stay (LOS) and investigate the associated medical costs. A retrospective cohort study was conducted among 8,633 cancer patients (1.03 million emergency hospital admissions) in Victoria, Australia from July 2006 to June 2020, from the Australian healthcare system perspective. Multivariate generalised linear regression models were employed to estimate the adjusted association between post-therapy complications and clinical characteristics with hospital LOS and associated hospitalisation medical costs. Approximately 52% of patients were male with an average patient age of 59.9 years. Annually, post-therapy complications leading to unplanned hospitalisations increased by 7.25%, outpacing the growth in overall hospitalisation admissions, which was 5.66% for overall hospitalisation admissions. A significant proportion of patients (71%) experienced multiple complications, with the most common being anemia (26%), sepsis (15%), nausea and vomiting (14%), and neutropenia (11%). Patients undergoing combined systemic and radiotherapy exhibited higher odds of post-therapy complications (OR = 8.24, 95%CI: 7.48 to 9.08) compared with those who only received systemic therapy. Mean hospital stay among patients who experienced post-therapy complications was 2.23 days per admission (360 days per patient), an extra 1.72 days per admission [95%CI: 1.68 to 1.76; 354 days per patient, 95%CI: 336 to 371 days] longer than patients without complications (0.51 days per admission and 6.48 days per patients). Overall, per-admission medical hospitalisation costs among patients with post-therapy complications were $8,791 higher than for patients who did not experience complications ($11,418 vs. $2,627 per admission, 95%CI: $8,685 to $8,897). Per-patient costs for unplanned hospitalisation due to post-therapy complications were significantly $1.82 million higher among patients than those without complications ($1.86 million vs. $33,599 per patient, 95%CI: $1.71 million to $1.94 million). The cost and hospitalisation stay (in days) varied by the type of therapy and cancer type. The study results indicate that post-therapy complications in cancer patients varied by the type of cancer and increased over the study period, leading to longer unplanned hospital stays and higher hospitalisation medical costs. The results highlight the need for better-customized treatment delivery strategies to address this burden and optimise resources in cancer care.

To evaluate changes in physical function (PF) for older women with endometrial cancer (EC) + / - adjuvant therapy in the Women's Health Initiative Life and Longevity after Cancer cohort.

This study examined women ≥ 70 years of age with EC with available treatment records. Change in PF was measured using the RAND-36 and compared between groups using Wilcoxon rank-sum tests. Multivariable median regression was used to compare the changes in scores while adjusting for confounding variables.

Included in the study were 287 women, 150 (52.3%) women who did not receive adjuvant therapy and 137 (47.7%) who received adjuvant therapy. When comparing PF scores, there was a statistically significant difference in the median percent change in functional decline, with a greater decline in those who received adjuvant therapy (- 5.9% [- 23.5 to 0%]) compared to those who did not (0 [- 18.8 to + 6.7%]), p = 0.02). Results were not statistically significant after multivariable adjustment, but women who underwent chemotherapy had a greater percent change (median ∆ - 13.8% [- 35.5 to 0%]) compared to those who received radiation alone (median ∆ - 5.9% [- 31.3 to 0%]) or chemotherapy and radiation (median ∆ - 6.5% [- 25.8 to + 5.7%].

Older women with EC who received adjuvant therapy experienced greater change in PF than those who did not receive adjuvant therapy, particularly women who received chemotherapy. These results were not statistically significant on multivariate analysis.

EC survivors may experience changes in PF because of chemotherapy and/or radiation therapy. Additional supportive care may need to be provided to older women to mitigate functional decline.

Recent success of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features.

HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status.

HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value.

A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

Interstitial brachytherapy (ISBT) is a known treatment for vaginal recurrence of endometrial cancer. This study reviews a large tertiary institution's ISBT experience and outcomes for vaginal recurrences.

Patients who underwent salvage ISBT for vaginal recurrence of endometrial cancer from January 1, 2014 to August 31, 2021, were identified. Initial and salvage disease factors and treatments were recorded. Outcomes were calculated including overall survival, local, and distant failure.

Thirty-nine patients were included; thirty received external beam radiotherapy and interstitial brachytherapy (EBRT + ISBT) while 9 received ISBT alone. At initial diagnosis, the ISBT alone group had an older median age, with stage IA-IV disease, frequently receiving adjuvant treatment, compared to the EBRT with ISBT group with mainly stage IA disease who did not. Median follow up was 22 months and median time to recurrence 14 months (16.5 months in EBRT + ISBT group and 14 in the ISBT alone group). Two-year overall survival was 85% for all patients, 85.6% and 83.3%in the EBRT + ISBT and ISBT alone groups, respectively. Local failure was 22.7% for all patients, 16.7% in the EBRT + ISBT group and 11.1% in the ISBT alone group. Median HRCTV D90 (EQD2) was 76.8 Gy in the EBRT + ISBT group, and 57.9 Gy in the ISBT alone group. Late grade 3 or higher toxicity occurred in only 3 patients.

EBRT + ISBT is an effective treatment for endometrial cancer vaginal recurrence, with acceptable toxicity. ISBT alone is an option for patients with contraindications to or with previous treatment of pelvic radiation.

During the last decades, the introduction of immune checkpoint inhibitors has radically changed the treatment landscape of several cancer types, improving the prognosis and the quality of life of cancer patients. Even for gynecological cancers, where the prognosis has historically been poor despite advancements in surgery, radiotherapy and oncological treatment, immunotherapy has represented a significant leap forward. In cervical and endometrial cancer, the introduction of immunotherapy has radically changed the treatment algorithm, especially for advanced disease. However, the scenario remains less promising for ovarian cancer, where, despite extensive research efforts, no consistent positive results have been achieved with immune checkpoint inhibitors, except for a few cases in rarer histological subtypes Here, we present a narrative review summarizing the most important practice-changing studies involving immune checkpoint inhibitors in gynecological cancers, particularly in cervical, endometrial, ovarian and vulvar cancer.

This study aimed to identify the magnetic resonance imaging (MRI)-based radiomics phenotypes of intermediate-to-high-risk endometrial cancers (ECs), explore their association with histopathologic features, and compare their prognostic ability with the International Federation of Gynecology and Obstetrics (FIGO) stage.

This study retrospectively recruited 355 patients with pathologically confirmed EC from 01/2016 to 06/2023. 166(46.8%) were classified as intermediate-to-high-risk ECs according to the European Society for Medical Oncology guidelines. Radiomics clustering analysis was performed on preoperative MRI to identify the radiomics phenotype of intermediate-to-high-risk ECs. The association between the radiomics phenotypes and the clinicopathologic information was explored, and the added value in predicting the recurrence was also evaluated using concordance index (C-index).

Of the included 166 patients (average age 56.83 ± 9.25 years), 23 were recurrent patients. The corresponding tumors in various clusters were assigned to phenotypes 1 and 2. Larger tumor diameter (P < .01), cervical mucosa invasion [30(36.15%) vs 15(18.07%), P = .01], deep myometrial infiltration [51(61.45%) vs 31(37.35%), P = .00], and histologic subtype [17(20.48%) vs 5(6.02%), P = .01] were associated with subtype 1. The risk of recurrence (P = .01) was higher in phenotype 1, and the FIGO stage could further differentiate higher recurrence risk in phenotype 1 (P < .01). The C-index was 0.66 for the radiomics phenotype model, 0.69 for the FIGO stage model, and 0.72 for the combined model.

MRI-based radiomics consensus clustering enabled the identification of associations between radiomics features and histopathologic features in intermediate-to-high-risk EC. The FIGO stage could further elevate the prediction ability of recurrence risk.

In early-stage endometrial cancer (EC), the treatment of aggressive histological subtypes (endometrioid carcinoma grade 3, serous carcinoma, clear-cell carcinoma, undifferentiated carcinoma, mixed carcinoma, and carcinosarcoma) is controversial. We aimed to investigate the treatment of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IC and stage IIC EC according to the 2023 classification.

We retrospectively identified patients with FIGO 2023 stage IC, IIC-intermediate risk (IIC-I), and IIC-high risk (IIC-H) EC who underwent adjuvant therapy or observation after surgery at eight medical institutions from 2004 to 2023. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and univariate and multivariate analyses.

The PFS and OS were significantly worse in patients with FIGO 2023 stage IIC-H EC than in those with FIGO 2023 stage IIC-I EC (PFS: p = 0.008 and OS: p = 0.006). According to the FIGO 2023 stage IIC-H classification, lymphadenectomy and chemotherapy resulted in better prognoses regarding both PFS and OS (p < 0.001 for both) than other treatments. Our findings suggest that lymphadenectomy and chemotherapy effectively reduced vaginal stump and lymph node metastases in FIGO 2023 stage IIC-H EC (p < 0.001 and p = 0.008, respectively). Furthermore, in the multivariate analysis, not undergoing lymphadenectomy or chemotherapy were independent predictors of recurrence and poor prognoses in patients with FIGO 2023 stage IIC-H EC (p < 0.001 and p = 0.031, respectively).

Lymphadenectomy and chemotherapy resulted in better prognoses regarding both recurrence and survival in patients with FIGO 2023 stage IIC high-risk EC.

Approximately 10-15 % of endometrial cancer patients with tumors confined to the uterus (FIGO 2009 stage I) demonstrate recurrence and the oncologic outcomes are highly related to recurrence patterns. This study aimed to verify whether the FIGO 2023 staging system could discriminate outcomes.

Between January 2010 and March 2019, 536 FIGO 2009 stage I patients were eligible for this retrospective cohort study. Patient characteristics and clinicopathological data were retrieved from electronic medical records. The patients were reclassified according to the FIGO 2023 staging criteria. Oncological outcomes included the recurrence rate, recurrence pattern, and overall survival.

Among the 536 eligible patients, the (sub)stage migration rate was 23.5 % from the FIGO 2009 to the FIGO 2023 stage system. FIGO 2023 staging system resulted in (sub)stage up-migration, mostly owing to aggressive histological types. A higher recurrence rate was detected in the FIGO 2023 stage II patients (12.3 %) compared to the stage I patients (6.9 %). In comparison to the FIGO 2023 stage I patients, the stage II patients had a higher distant recurrence rate (8.8 % vs. 2.6 %) and poorer overall survival (38.0 vs 69.0 months, p = 0.02).

Patients who are upstaged are prone to worse oncological outcomes, including distant recurrence and mortality. Therefore, comprehensive adjuvant treatment strategies based on each FIGO 2023 substage are imperative.

This study aimed to identify the recurrence and survival rates according to the mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) status in patients with advanced and recurrent endometrial cancer (EC) receiving systemic chemotherapy.

This single-center retrospective cohort study included chemotherapy-naïve patients with advanced-stage (III/IV) or recurrent EC between January 2015 and June 2022 (n = 156), who were administered chemotherapy as adjuvant therapy or first-line palliative treatment. MMR and p53 status were assessed, and L1CAM was tested using immunohistochemistry in the p53-wild and MMR-proficient (p53wt/pMMR) group. The primary outcomes were progression-free survival (PFS) and overall survival (OS).

Of the 156 patients, 62 (39.7%), 53 (34.0%), and 41 (26.3%) had p53wt/pMMR, abnormal p53 (p53abn), and MMR-deficient (dMMR) tumors, respectively. PFS and OS were longest in dMMR, followed by p53wt/pMMR, and were the least in p53abn tumors (PFS: p = 0.0006, OS: p = 0.0013). After p53wt/pMMR was classified according to positive or negative L1CAM status, the L1CAM negative group exhibited significantly shorter survival rates than the L1CAM positive group (PFS: p = 0.0001, OS: p = 0.0027). p53abn tumors were independent prognostic factors for poor PFS (PFS: p = 0.039 on multivariable analysis).

In chemotherapy-naïve patients with advanced and recurrent EC, there was a better prognosis in the order of MMR-D, p53wt/pMMR, and p53abn tumors after chemotherapy. L1CAM status is useful as a new marker to stratify p53wt/pMMR in advanced and recurrent groups.

Objectives. The aim was to evaluate the cost-effectiveness of sentinel lymph node (SLN) mapping in comparison to routine pelvic lymphadenectomy for lymph node assessment in patients with high-risk endometrial cancer (EC). Methods. A decision-analytic model was developed to compare SLN mapping with pelvic lymphadenectomy for guiding adjuvant therapy in patients with high-risk endometrioid and non-endometrioid EC, focusing on costs and health outcomes. The input data were obtained from systematic literature searches and expert consensus. Quality-adjusted life years (QALYs) was utilized as the measure of effectiveness. The model was constructed from a healthcare perspective, and the impact of uncertainty was evaluated through sensitivity analyses. Results. The base case analysis indicated that sentinel lymph node mapping is the dominant strategy for lymph node assessment in patients with high-risk endometrial cancer, as it was found to be both more effective and less costly than lymphadenectomy. The improved outcomes and reduced costs associated with SLN mapping primarily result from a decrease in the side effects related to lymph node assessment. Sensitivity analyses demonstrated that the outcome of the model was robust to variations in input values. Conclusion. SLN mapping is the most cost-effective strategy to determine the need for adjuvant therapy in patients with high-risk endometrioid and non-endometrioid endometrial cancer.

Endometrial cancer is a kind of gynaecological cancer. S100A2 is a newfound biomarker to diagnose endometrial cancer. This study was to investigate the role of S100A2 on regulating migration and invasion of endometrial cancer.

The mRNA and protein levels of S100A2 were obtained by quantitative real-time polymerase chain reaction, immunohistochemistry and western blot methods. Cell viability was measured by the Cell Counting Kit-8 assay. Cell migration and invasion were quantified using transwell assays. Western blot assay was conducted to quantify protein expressions of epithelial to mesenchymal transition-related proteins (N-cadherin and E-cadherin). Furthermore, in vivo tumour formation experiments were performed to evaluate the role of S100A2 on tumour xenografts.

S100A2 was significantly up-regulated in endometrial cancer tissues. Knockdown of S100A2 inhibited cell viability, migration and invasion of endometrial cancer cells. Meanwhile, STING pathway was activated by the inhibited S100A2. STING inhibitor C-176 significantly reversed the effects of S100A2 knockdown on aggressive behaviours of endometrial cancer cells. Inhibition of S100A2 dramatically suppresses the tumour growth in vivo.

S100A2 functions as an oncogene in endometrial cancer. Targeting S100A2 may be a promising therapeutic method to treat endometrial carcinoma.

This study defined a retrospective cohort of patients in England with primary advanced or recurrent (A/R) endometrial cancer (EC) who may have been eligible for clinical trials evaluating immune checkpoint inhibitors (ICIs) in the first-line (1L) setting within a real-world dataset, and described the characteristics, treatment patterns and outcomes within this cohort.

This was a retrospective, population-based study.

Routine population-level data from the National Cancer Registration and Analysis Service in England were used. Patients diagnosed with A/R EC between 1 January 2013 and 31 December 2019 were included (follow-up until 23 August 2021). ICI-eligible patients who received any 1L therapy (defined as first systemic treatment for A/R EC with or without radiotherapy) and met key eligibility criteria for the RUBY trial (NCT03981796; 1L cohort) were included. A subpopulation who solely received carboplatin-paclitaxel at 1L (carboplatin-paclitaxel subcohort) was identified.

Demographics, characteristics and therapy received were reported. Overall survival (OS), time to next treatment (TTNT) and time to treatment discontinuation (TTD) from 1L chemotherapy initiation were assessed using Kaplan-Meier methodology.

Of 13 954 patients identified, 2376 ICI-eligible patients were included in the 1L cohort (median [range] age: 67.9 [26.7-94.0] years); 902 patients received solely carboplatin-paclitaxel at 1L. Demographics and disease characteristics were generally similar between cohorts. Median (95% CI) OS, TTNT and TTD from 1L chemotherapy were 27.2 (24.7, 30.2), 16.9 (15.8, 18.5) and 3.4 (3.4, 3.4) months, respectively, in the 1L cohort, and 17.2 (15.5, 19.0), 12.4 (11.6, 13.5) and 3.4 (3.4, 3.4) months, respectively, in the carboplatin-paclitaxel subcohort.

Long-term outcomes were poor for both cohorts, particularly the carboplatin-paclitaxel subcohort, where patients did not receive radiotherapy and had predominantly metastatic disease. This reflects the unmet need for more durable treatment options to prevent relapse and prolong survival in this patient population. This real-world study will help contextualise outcomes from ongoing phase III clinical trials investigating 1L ICI treatments.

The traditional histopathological analysis of endometrial cancer (EC) is the main risk group classification tool (low, intermediate, high-intermediate, and high) for the implementation of adjuvant treatment. The International Federation of Gynecology and Obstetrics staging system of EC has incorporated a new molecular classification that serves as a new triage tool for optimal treatment planning for these patients. Our study aimed to investigate the prognostic role of the new molecular classification in EC.

A prospective study was conducted in the 1st Department of Obstetrics and Gynecology from January 1, 2022, to March 30, 2024, and included all new EC cases that presented the multidisciplinary tumor (MDT) board after surgery. We considered the traditional pathologic analysis and new molecular classification after performing tests on microsatellite instability (MSI), DNA polymerase epsilon (POLE) mutation, and p53 immunohistochemistry testing.

The study included 65 patients with presumed early endometrial. All patients underwent surgery and subsequent molecular testing. Among the patients, 35 (54%) had a "positive" result in all of the three markers of molecular classification: 14 patients presented with MSI-H, 5 with POLE gene mutation, and 17 with p53 abnormal expression. One case of multiple classifiers was presented. After the integration of molecular classification, a change was observed in the final MDT board decision in 23 cases (35.4%), including six cases of overtreatment and 17 cases of undertreatment, with statistical significance (P = 0.03469).

The data suggest that the new molecular classification, that is, testing for POLE mutation, MSI, and p53 mutation and for endometrial carcinoma, is a valuable tool for the recurrence risk prognosis and improved planning of adjuvant treatment for EC.

The effect of overall survival (OS) with adjuvant radiotherapy in stage III endometrial cancer (EC) remains controversial, and the adverse invents were unignorable.

A total of 4,064 stage III EC patients who underwent adjuvant chemotherapy post-operatively were selected from Surveillance, Epidemiology, and End Results (SEER) Program. Independent risk factors were identified through Cox regression models. A nomogram was developed accordingly to predict OS. The concordance index (C-index), calibration, and Receiver Operating Characteristic (ROC) curves were applied to assess the model. Patients were divided into the low- and high-risk groups based on the optimal risk cutoff. Stratified analysis was conducted by radiation in both groups, and interactions between radiation and the risk groups were conducted to explore if any benefit less from adjuvant radiotherapy.

A total of five candidate factors were identified from the model showing good calibration and consistency discriminative power in the training (C-index: 0.73; 95% CI: 0.70-0.75), testing (C-index: 0.73; 95% CI: 0.69-0.77), and external validation cohorts (C-index: 0.88, 95% CI, 0.78-0.97). Patients were categorized into the low- and high-risk groups based on the optimal risk cutoff of 2.1048630. The women in the high-risk group experience significantly less (42% vs. 63% reduction) or none (0 vs. 63%) benefit (p-interaction = 0.049 vs. 0.016 in training and testing cohorts, respectively).

A nomogram incorporating five variables was established to predict OS in stage III EC patients with adjuvant chemotherapy. The high-risk groups benefit less or none from adjuvant radiotherapy, which may serve as a useful reference for better guidance of radiotherapy in stage III EC patients.

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians (FIGO) staging model. Furthermore, we provide an overview of disease management in the first-line and recurrent disease settings. With increasing use of molecular profiling and updates in treatment paradigms, we also summarize new developments in this rapidly changing treatment landscape.

The clinical landscape for endometrial cancer in the UK is evolving to include new management guidelines and targeted treatment options. An understanding of current treatment and management practices in the UK will help services plan and adapt to upcoming changes.

The purpose of this survey was to understand current and anticipated real-world practices for endometrial cancer care in the UK and potential areas for optimisation.

Telephone interviews were conducted in November/December 2021 with UK-based healthcare professionals involved in endometrial cancer management. Questions were aligned with the British Gynaecological Cancer Society/European Society for Medical Oncology recommendations, covering the pathway from diagnosis and treatment to follow-up.

A total of 63 healthcare professionals (HCPs) involved in the management of patients with endometrial cancer participated in telephone interviews. The results highlighted variations in management and treatment practices for endometrial cancer and suggest that current UK practice appears to diverge from national and international guidance in some instances. While somatic mismatch repair deficiency testing was used by 89.7% of respondents as mainstream testing, the survey highlighted a lack of access to other key molecular biomarker tests, such as polymerase epsilon (POLE) sequencing (used by only 9.8% of HCPs at the time of the survey).

The results highlighted several perceived practical barriers to the swift adoption of new therapeutic options, including funding access, limited staff, treatment-related resources, staff education, and support. Our findings support the need for better access to biomarkers that could enable more effective and targeted treatments.

Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery.

We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population.

A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred.

Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable.

ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17.

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Identifying clinical features that are associated with recurrence of endometrioid endometrial carcinoma (EEC) in patients with diabetes mellitus (DM).

A single-center retrospective cohort study was performed on patients with a diagnosis of both DM and Stage I EEC. Clinical and pathologic features were analyzed in relation to 5-year progression free survival (PFS). Kaplan-Meier Curves and Cox proportional hazard ratios were utilized to assess effect on 5-year PFS.

A total of 539 patients were included, with biopsy proven recurrence in 86 (18 %), and 456 (82 %) with no evidence of recurrence. Age, BMI, HgbA1c, metformin use, number of antihyperglycemic medications, use of adjuvant radiation, and surgical approach were not associated with differences in PFS. Presence of end-organ complications associated with diabetes was correlated with worse PFS (HR 1.78, 95 % CI 1.1-2.9, P = 0.02), and specifically diabetic neuropathy was associated with higher rates of recurrence (HR 3.6, 95 % CI 2.1-6.2, P < 0.01). In this cohort, PFS was independently associated with extent of myoinvasion (HR 2.33, 95 % CI 1.4-3.7, P < 0.01) as well as both microsatellite instability (HR 3.43, 95 % CI 1.8-6.6, P < 0.01), and no specific molecular profile (HR 0.3, 95 % CI 0.2-0.6, P < 0.01) molecular subtypes.

In patients with DM and EEC, extent of myoinvasion and TCGA molecular subtype correlated with worse PFS. Control of DM as evidenced by HgbA1c, BMI, and use of antihyperglycemic medications did not correlate with PFS in our cohort of patients with Stage I EEC, while the presence of diabetic neuropathy was associated with a higher risk of recurrence. These results highlight importance of evaluating diabetes severity and molecular subtype in endometrial cancer patients.

Our objective was to describe the use of intraoperative radiation therapy (IORT) for the treatment of recurrent/persistent cervical or endometrial cancer and assess predictors of postoperative complications and 3-year mortality.

In this multi-site retrospective study, data were abstracted for recurrent/persistent endometrial or cervical cancer patients who underwent IORT from June 2004 to May 2021. Complications were graded on the six-point Accordion scale. Variables associated with complications were analyzed with univariate logistic regression, while variables associated with death within 3 years were analyzed with Cox proportional hazards modeling. Survival was analyzed with the Kaplan-Meier method.

Eighty patients had planned IORT for recurrent/persistent endometrial (n = 35) or cervical cancer (n = 45). The mean age of the cohort was 56.8 years (SD = 13.7), and the median disease-free interval from primary disease to recurrence was 20.0 months (IQR 10.0-63.1). The overall survival at 3 years was 48.6% (95% CI: 38.3-61.6%) with a median survival of 2.8 years. Within 30 days postoperative, 16 patients (20.1%) had grade 3-5 complications and one death (1.3%) occurred. Factors associated with grade 3+ complication included ECOG PS 2-3 (OR 18.00, p = 0.04), neoadjuvant chemotherapy and/or immunotherapy (OR 6.98, p < 0.01), and pelvic sidewall involvement (OR 8.80, p = 0.04). Factors associated with death within 3 years of surgery included ECOG PS 2-3 (HR 8.97, p < 0.01), neoadjuvant chemotherapy and/or immunotherapy (HR 2.34, p = 0.03), whether exenteration was performed (HR 2.64, p = 0.01), and positive resection margin (HR 3.37, p < 0.01).

In well-selected patients, IORT is a feasible and safe option for the treatment of recurrent/persistent gynecologic malignancy with an appreciable survival benefit.

This study aimed to compare survival and complications between minimally invasive surgery and open surgery and evaluate related risk factors in patients with non-endometrioid endometrial cancer.

Clinicopathologic characteristics; survival outcomes; complications; and prognostic factors associated with progression-free survival and overall survival were compared among patients with non-endometrioid endometrial cancer who underwent primary staging surgery using laparoscopic, robotic, or open abdominal surgery (2004-2017).

In total, 91 patients were included: 41 and 50 underwent minimally invasive surgery and open surgery, respectively. The minimally invasive surgery and open surgery groups showed similar progression-free survival (5-year progression-free survival rate, 58.7 % vs. 58.5 %; P = .925) and overall survival (5-year overall survival rate, 73.6 % vs. 80.3 %; P = .834). Intraoperative (7.2 % vs. 6.0 %; P = .111) and postoperative surgical complications (14.6 % vs. 26.0 %; P = .165) were similar between the groups. However, blood loss was lower (mean, 305.1 vs. 561.2 ml, P < .001) and hospital stay was shorter (mean, 8.2 vs. 15.4 days, P < .001) in the minimally invasive surgery group. Using multivariate analysis, lymphovascular space invasion was identified as poor prognostic factor for progression-free survival (adjusted hazard ratio [HR], 3.054; 95 % confidence interval [CI], 1.521-6.132; P = .002) and overall survival (adjusted HR, 3.918; 95 % CI, 1.455-10.551; P = .007), whereas age ≥ 60 years was poor prognostic factor for only overall survival (adjusted HR, 5.0953; 95 % CI, 1.660-15.378; P = .004).

Surgical outcomes did not differ between the minimally invasive and open surgery group in patients with non-endometrioid endometrial cancer. Lymphovascular space invasion was a significant survival factor in this context.