Differential levels of circulating RNAs prior to endometrial cancer diagnosis.

Endometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17-47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR-155-5p, miR-200b-3p, miR-589-5p, miR-151a-5p, miR-543, miR-485-5p, miR-625-p, and miR-671-3p. miR-200b-3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR-223-3p and miR-29b-3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q-value 4.39-6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll-like receptor, and VEGF had the strongest associations.

Clinical characteristics and radiation therapy modality of younger patients with early-stage endometrial cancer, a multicenter study in China's real world.

BACKGROUND: Endometrial cancer is a prevalent gynecologic malignancy found in postmenopausal women. However, in the last two decades, the incidence of early-stage has doubled in women under 40 years old. This study aimed to investigate the clinical and pathological characteristics and adjuvant therapeutic modalities of both young and not -young patients with early-stage endometrial cancer in China's real world. METHODS: This retrospective study analyzed patients with early-stage endometrial cancer at 13 medical institutions in China from 1999 to 2015. The patients were divided into two groups: young (≤ 45 years old) and non-young (> 45 years old). Statistical comparisons were conducted between the two groups for clinical characteristics, pathological features, and survival. The study also identified factors that affect local recurrence-free survival (LRFS) using Cox proportional risk regression analysis. Propensity score matching (1:1) was used to compare the effects of local control between vaginal brachytherapy (VBT) alone and pelvic external beam radiotherapy (EBRT) ± VBT. RESULTS: The study involved 1,280 patients, 150 of whom were 45 years old or younger. The young group exhibited a significantly higher proportion of stage II, low-risk, lower uterine segment infiltration (LUSI), and cervical invasion compared to the non-young group. Additionally, the young patients had significantly larger maximum tumor diameters. The young group also had a significantly higher five-year overall survival (OS) and a five-year LRFS. Age is an independent risk factor for LRFS. There was no significant difference in LRFS between young patients with intermediate- to high-risk early-stage endometrial cancer who received EBRT ± VBT and those who received VBT alone. CONCLUSIONS: In the present study, young patients had better characteristics than the non-young group, while they exhibited higher levels of aggressiveness in certain aspects. The LRFS and OS outcomes were better in young patients. Age is an independent risk factor for LRFS. Additionally, VBT alone may be a suitable option for patients under 45 years of age with intermediate- to high-risk early-stage endometrial cancer, as it reduces the risk of toxic reactions and future second cancers while maintaining similar local control as EBRT.

Intrauterine manipulator during hysterectomy for endometrial cancer: a systematic review and meta-analysis of oncologic outcomes.

OBJECTIVE: This study aimed to assess the effects on oncologic outcomes of intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer. DATA SOURCES: A systematic literature search was performed by an expert librarian in multiple electronic databases from inception to January 31, 2023. STUDY ELIGIBILITY CRITERIA: We included all studies in the English language that compared oncologic outcomes (recurrence-free, cause-specific, or overall survival) between endometrial cancer patients who underwent total laparoscopic or robotic hysterectomy for endometrial cancer with vs without the use of an intrauterine manipulator. Studies comparing only peritoneal cytology status or lymphovascular space invasion were summarized for completeness. No selection criteria were applied to the study design. METHODS: Four reviewers independently reviewed studies for inclusion, assessed their risk of bias, and extracted data. Pooled hazard ratios with 95% confidence intervals were estimated for oncologic outcomes using the random effect model. Heterogeneity was quantified using the I2 tests. Publication bias was assessed by funnel plot and Egger test. RESULTS: Out of 350 identified references, we included 2 randomized controlled trials and 12 observational studies for a total of 14 studies and 5,019 patients. The use of an intrauterine manipulator during hysterectomy for endometrial cancer was associated with a pooled hazard ratio for recurrence of 1.52 (95% confidence interval, 0.99-2.33; P=.05; I2=31%; chi square P value=.22). Pooled hazard ratio for recurrence was 1.48 (95% confidence interval, 0.25-8.76; P=.62; I2=67%; chi square P value=.08) when only randomized controlled trials were considered. Pooled hazard ratio for overall survival was 1.07 (95% confidence interval, 0.65-1.76; P=0.79; I2=44%; chi square P value=.17). The rate of positive peritoneal cytology or lymphovascular space invasion did not differ using an intrauterine manipulator. CONCLUSION: Intrauterine manipulator use during hysterectomy for endometrial cancer was neither significantly associated with recurrence-free and overall survival nor with positive peritoneal cytology or lymphovascular space invasion, but further prospective studies are needed.

Evaluating the quality of radiomics-based studies for endometrial cancer using RQS and METRICS tools.

OBJECTIVE: To assess the methodological quality of radiomics-based models in endometrial cancer using the radiomics quality score (RQS) and METhodological radiomICs score (METRICS). METHODS: We systematically reviewed studies published by October 30th, 2023. Inclusion criteria were original radiomics studies on endometrial cancer using CT, MRI, PET, or ultrasound. Articles underwent a quality assessment by novice and expert radiologists using RQS and METRICS. The inter-rater reliability for RQS and METRICS among radiologists with varying expertise was determined. Subgroup analyses were performed to assess whether scores varied according to study topic, imaging technique, publication year, and journal quartile. RESULTS: Sixty-eight studies were analysed, with a median RQS of 11 (IQR, 9-14) and METRICS score of 67.6% (IQR, 58.8-76.0); two different articles reached maximum RQS of 19 and METRICS of 90.7%, respectively. Most studies utilised MRI (82.3%) and machine learning methods (88.2%). Characterisation and recurrence risk stratification were the most explored outcomes, featured in 35.3% and 19.1% of articles, respectively. High inter-rater reliability was observed for both RQS (ICC: 0.897; 95% CI: 0.821, 0.946) and METRICS (ICC: 0.959; 95% CI: 0.928, 0.979). Methodological limitations such as lack of external validation suggest areas for improvement. At subgroup analyses, no statistically significant difference was noted. CONCLUSIONS: Whilst using RQS, the quality of endometrial cancer radiomics research was apparently unsatisfactory, METRICS depicts a good overall quality. Our study highlights the need for strict compliance with quality metrics. Adhering to these quality measures can increase the consistency of radiomics towards clinical application in the pre-operative management of endometrial cancer. CLINICAL RELEVANCE STATEMENT: Both the RQS and METRICS can function as instrumental tools for identifying different methodological deficiencies in endometrial cancer radiomics research. However, METRICS also reflected a focus on the practical applicability and clarity of documentation. KEY POINTS: The topic of radiomics currently lacks standardisation, limiting clinical implementation. METRICS scores were generally higher than the RQS, reflecting differences in the development process and methodological content. A positive trend in METRICS score may suggest growing attention to methodological aspects in radiomics research.

Are micro-RNA 21 and 143 indicative as prognostic biomarkers in dedifferentiated endometrial adenocarcinoma?

AIM: Dedifferentiated endometrial adenocarcinoma (DEAC) is a rare, aggressive subtype, accounting for 2% of all endometrial cancers. Poor survival in DEAC prompts the need for effective treatment modalities through better prognostic classification. MicroRNAs (miRNA) have essential roles in tumor angiogenesis, which might enable their use as novel biomarkers. In this study, we aimed to reveal the relationship between the expression of miRNA-21 and miRNA-143, which are associated with angiogenesis, and the prognosis of DEAC. METHOD: The study included six cases diagnosed with DEAC. The expression levels of miRNA-21 and miRNA-143 were detected by quantitative real-time PCR. Microvascular density (MVD) was measured by CD34 staining. All data and effects on survival were compared for statistical significance. RESULTS: Six cases diagnosed with DEAC were included in the study. The percentage of undifferentiated components ranged from 50 to 90%. The second component of differentiated carcinoma was detected as endometrioid (3/5 grade I, 1/5 grade II, 1/5 grade III) in five cases and serous in one case. The mean MVD was 27 (range 17-44, SD 9.4). In three cases, miRNA-21 expression was down-regulated in neoplastic areas compared to non-neoplastic areas. On the contrary, it was found to be up-regulated in the remaining three cases. MiRNA-143 expression decreased in four cases and increased in two cases. CONCLUSIONS: Based on these findings, we found a significant irregular expression of miRNA-21 in DEACs. As in other cancers, angiogenesis is significantly associated with survival in DEACs. This study provides initial data for revealing possible implications of miRNAs as prognostic indicators in DEAC.

Estimating risk of endometrial malignancy and other intracavitary uterine pathology in women without abnormal uterine bleeding using IETA-1 multinomial regression model: validation study.

OBJECTIVES: To assess the ability of the International Endometrial Tumor Analysis (IETA)-1 polynomial regression model to estimate the risk of endometrial cancer (EC) and other intracavitary uterine pathology in women without abnormal uterine bleeding. METHODS: This was a retrospective study, in which we validated the IETA-1 model on the IETA-3 study cohort (n = 1745). The IETA-3 study is a prospective observational multicenter study. It includes women without vaginal bleeding who underwent a standardized transvaginal ultrasound examination in one of seven ultrasound centers between January 2011 and December 2018. The ultrasonography was performed either as part of a routine gynecological examination, during follow-up of non-endometrial pathology, in the work-up before fertility treatment or before treatment for uterine prolapse or ovarian pathology. Ultrasonographic findings were described using IETA terminology and were compared with histology, or with results of clinical and ultrasound follow-up of at least 1 year if endometrial sampling was not performed. The IETA-1 model, which was created using data from patients with abnormal uterine bleeding, predicts four histological outcomes: (1) EC or endometrial intraepithelial neoplasia (EIN); (2) endometrial polyp or intracavitary myoma; (3) proliferative or secretory endometrium, endometritis, or endometrial hyperplasia without atypia; and (4) endometrial atrophy. The predictors in the model are age, body mass index and seven ultrasound variables (visibility of the endometrium, endometrial thickness, color score, cysts in the endometrium, non-uniform echogenicity of the endometrium, presence of a bright edge, presence of a single dominant vessel). We analyzed the discriminative ability of the model (area under the receiver-operating-characteristics curve (AUC); polytomous discrimination index (PDI)) and evaluated calibration of its risk estimates (observed/expected ratio). RESULTS: The median age of the women in the IETA-3 cohort was 51 (range, 20-85) years and 51% (887/1745) of the women were postmenopausal. Histology showed EC or EIN in 29 (2%) women, endometrial polyps or intracavitary myomas in 1094 (63%), proliferative or secretory endometrium, endometritis, or hyperplasia without atypia in 144 (8%) and endometrial atrophy in 265 (15%) women. The endometrial sample had insufficient material in five (0.3%) cases. In 208 (12%) women who did not undergo endometrial sampling but were followed up for at least 1 year without clinical or ultrasound signs of endometrial malignancy, the outcome was classified as benign. The IETA-1 model had an AUC of 0.81 (95% CI, 0.73-0.89, n = 1745) for discrimination between malignant (EC or EIN) and benign endometrium, and the observed/expected ratio for EC or EIN was 0.51 (95% CI, 0.32-0.82). The model was able to categorize the four histological outcomes with considerable accuracy: the PDI of the model was 0.68 (95% CI, 0.62-0.73) (n = 1532). The IETA-1 model discriminated very well between endometrial atrophy and all other intracavitary uterine conditions, with an AUC of 0.96 (95% CI, 0.95-0.98). Including only patients in whom the endometrium was measurable (n = 1689), the model's AUC was 0.83 (95% CI, 0.75-0.91), compared with 0.62 (95% CI, 0.52-0.73) when using endometrial thickness alone to predict malignancy (difference in AUC, 0.21; 95% CI, 0.08-0.32). In postmenopausal women with measurable endometrial thickness (n = 848), the IETA-1 model gave an AUC of 0.81 (95% CI, 0.71-0.91), while endometrial thickness alone gave an AUC of 0.70 (95% CI, 0.60-0.81) (difference in AUC, 0.11; 95% CI, 0.01-0.20). CONCLUSION: The IETA-1 model discriminates well between benign and malignant conditions in the uterine cavity in patients without abnormal bleeding, but it overestimates the risk of malignancy. It also discriminates well between the four histological outcome categories. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

A qualitative systematic review of the significance of adjuvant therapy in patients with low-risk endometrial cancer presenting positive peritoneal cytology: a relevant study to the guideline update for endometrial cancer by the Japan society of gynecologic oncology guideline committee.

In association with an update of the Japan Society of Gynecologic Oncology clinical practice guidelines for endometrial cancer in 2023, a systematic review was conducted about the therapeutic benefit of adjuvant therapy on patients with early-stage endometrial carcinoma, who presented positive peritoneal cytology (PPC) without the risk factors for recurrence. The systematic review only included two eligible retrospective studies. Both studies included patients with risk factors for recurrence. A nationwide study in the United States reported that adjuvant chemotherapy was associated with the reduced risk of death among patients with stages I-II endometrial cancer with PPC by multivariate, propensity score-adjusted analysis. Another single-center study in Japan reported no association between adjuvant chemotherapy and relapse-free survival among patients with stage IA endometrial cancer by univariate analysis. This systematic review identified that evidence was limited with conflicting results. Continuous evaluation is warranted to address this clinical question.

Mismatch repair status and surgical approach in apparent early-stage endometrial cancer.

OBJECTIVE: To test the hypothesis that mismatch repair (MMR) status (as an accurate surrogate marker for microsatellite stability) modifies the effect of surgical approach on oncological outcome for apparent early-stage endometrial cancer. METHODS: Observational data from a large prospective population study on endometrial cancer were analyzed using target trial methodology and doubly robust methods, including propensity score matching and adjusted regression analyses. Laparoscopy was compared with laparotomy, stratified by MMR status on outcomes of recurrence and site, and recurrence-free, overall, and disease-specific survival. RESULTS: After matching, there were 400 patients for analysis, with 200 in each treatment group. The mean age was 62 years and mean body mass index was 32 kg/m2. Most patients had early-stage disease (stage I n=362 (90%)) and endometrioid histology (n=363 (91%)). Adjuvant pelvic radiation was administered to 11%, adjuvant vaginal brachytherapy to 13% and adjuvant chemotherapy to 5% of patients. Five-year recurrence-free survival did not differ significantly between modes of surgery across the cohort (p=0.7) or within MMR strata (MMR-proficient p=0.9, MMR-deficient p=0.6). Similarly, there was no significant difference in overall or disease-specific survival by mode of surgery across the cohort or within MMR strata. There was no significant difference in the HR for recurrence for those treated with laparoscopy stratified by MMR status (MMR-proficient HR=0.99 (95% CI 0.28 to 3.58); MMR-deficient HR=0.83 (95% CI 0.24 to 2.87)), even when restricted to endometrioid subtype. CONCLUSION: In this study, there was no evidence of a difference in survival outcomes according to mode of surgery and MMR status.

DNA methylation detection is a significant biomarker for screening endometrial cancer in premenopausal women with abnormal uterine bleeding.

OBJECTIVE: The aim of our study was to explore the value of DNA (CDO1m/CELF4m) methylation detection in exfoliated cervical cells collected for screening endometrial cancer in premenopausal women with abnormal uterine bleeding. METHODS: A total of 296 premenopausal women with abnormal uterine bleeding admitted to the Department of Obstetrics and Gynecology at the Third Xiangya Hospital of Central South University from November 2021 to October 2022 were selected. Clinical characteristics, endometrial thickness measured by transvaginal ultrasound and serum CA125 were collected. Exfoliated cervical cells from the thinPrep cytogic test were collected for DNA (CDO1m/CELF4m) methylation testing. Endometrial tissue was collected under hysteroscopy for pathological diagnosis as the gold standard. A univariate logistic regression model was used to analyze risk factors for endometrial cancer. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to measure the diagnostic efficacy of DNA methylation detection in endometrial cancer screening of women with abnormal uterine bleeding. RESULTS: Univariate logistic regression analysis showed that age, body mass index (BMI) ≥25 kg/m2, endometrial thickness ≥11 mm, CDO1 methylation (CDO1mΔCt≤8.4), CELF4 methylation (CELF4mΔCt≤8.8), and dual gene methylation (CDO1mΔCt≤8.4 or CELF4mΔCt≤8.8) were independent risk factors for endometrial cancer in women with abnormal uterine bleeding. The odds ratio (OR) values (95% confidence interval (CI) were 0.87 (0.80-0.95), 4.76 (1.89-11.96), 8.41 (3.13-22.59), 64.49 (20.46-203.33), 12.79 (4.91-33.30), and 42.53 (11.90-152.04), respectively. Among these indicators, dual gene methylation had the higher sensitivity and specificity for endometrial cancer screening (85.7% and 87.6%). Moreover, dual gene methylation combined with BMI or endometrial thickness could further improve the screening efficiency of endometrial cancer in women with abnormal uterine bleeding. CONCLUSIONS: In premenopausal women with abnormal uterine bleeding, the clinical efficacy of DNA (CDO1m/CELF4m) methylation detection in exfoliated cervical cells for endometrial cancer screening was better than that of other noninvasive clinical indicators. In addition, dual gene methylation combined with BMI or endometrial thickness was a good predictor of endometrial cancer screening.

Intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer: association for pathological factors and oncologic outcomes.

OBJECTIVE: To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. METHODS: This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. RESULTS: Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). CONCLUSION: This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.

The clinical landscape of antibody-drug conjugates in endometrial cancer.

Clinical outcomes remain challenging in advanced or recurrent endometrial cancer due to tumor heterogeneity and therapy resistance. Antibody-drug conjugates are a novel class of cancer therapeutics, representing a promising treatment option for endometrial cancer. Antibody-drug conjugates consist of a high-affinity antibody linked to a cytotoxic payload through a stable linker. After binding to specific antigens on tumor cells, the drug is internalized, and the payload is released. In addition, the free intracellular drug may be released outside the target cell through a 'bystander effect' and kill neighboring cells, which is crucial in treating malignancies characterized by heterogeneous biomarker expression like endometrial cancer.This article aims to provide a comprehensive overview of the current clinical landscape of antibody-drug conjugates in the treatment of endometrial cancer. We conducted a thorough analysis of recent clinical trials focusing on efficacy, safety profiles, and the mechanisms by which antibody-drug conjugates target endometrial cancer. We focused particularly on the most promising antibody-drug conjugate targets in endometrial cancer under clinical investigation, such as human epidermal growth factor receptor 2 (HER2), folate receptor alpha (FRα), trophoblast cell-surface antigen-2 (TROP2), and B7-H4. We also briefly comment on the challenges, including the emergence of resistance mechanisms, and future development directions (especially agents targeting multiple antigens, combinatorial strategies, and sequential use of agents targeting the same antigen but using different payloads) in antibody-drug conjugate therapy for endometrial cancer.

PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer.

OBJECTIVE: There is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer. METHODS: In this phase II, open-label study, eligible patients had histologically or cytologically confirmed endometrial cancer, documented progressive disease, and a WHO performance status of ≤2. All participants received treatment with pazopanib 800 mg once daily until progression, unacceptable toxicity, or patient refusal. The primary endpoint was progression-free survival at 3 months, with secondary outcomes of overall response rate, progression-free survival, overall survival, and toxicity. The study was powered to demonstrate 50% progression-free survival at 3 months with α=0.05 and ß=80%. RESULTS: Between January 2011 and February 2016, 60 eligible patients were included (intention-to-treat population). Median age was 68 (range, 53-85) years. Previous treatment included pelvic radiotherapy (58%), chemotherapy (90%), and hormonal therapy (43%). Three-month progression-free survival was 63.3% in the intention-to-treat population, with median progression-free survival and overall survival of 3.4 and 7.5 months, respectively. Overall response rate was 8.3%, and median follow-up 7.6 months. The most common grade 3 or higher adverse events were gastrointestinal toxicity in 21% of participants, including two patients with a gut perforation, one fatal gastrointestinal hemorrhage, one enterocutaneous fistula, and one fatal enterovaginal fistula. Extensive peritoneal disease existed in 80% of the patients with severe gastrointestinal toxicity. A definite correlation with previous radiotherapy could not be established. CONCLUSIONS: Pazopanib met its primary endpoint of 3 months' progression-free survival in advanced endometrial cancer (63.3%), but response rates were modest. There may be a correlation for rare but severe gastrointestinal toxicity with previous treatments and/or disease site that has yet to be elucidated.

Low-dose lenvatinib and anti-programmed cell death protein-1 combination therapy in patients with heavily pre-treated recurrent ovarian and endometrial cancer: a pilot study.

OBJECTIVE: Treatment options for heavily pre-treated recurrent ovarian and endometrial cancer are limited. Lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has been efficacious in advanced endometrial cancer, but at the recommended dose level, high-grade adverse events occur and lead to drug discontinuation. This study evaluated the feasibility of low-dose lenvatinib plus anti-PD-1 therapy in patients with recurrent ovarian and endometrial cancer. METHODS: This is a single-arm, protocol-based pilot study. Patients with recurrent ovarian cancer or endometrial cancer who had at least one line of previous therapy were included and given lenvatinib 8 or 12 mg daily (based on the patient's weight) and anti-PD-1 therapy. The primary endpoint was the objective response rate. RESULTS: Twenty-one patients were enrolled, including 15 with ovarian cancer and six with endometrial cancer. All patients were pre-treated, and the median number of lines of previous treatment of the ovarian and endometrial cancer cohorts was three and two, respectively. After a median follow-up of 11.0 months (range 6.8-23.9), the objective response rate for the ovarian cancer and endometrial cancer cohorts was 46.7% (95% CI 21.3% to 73.4%) and 66.7% (95% CI 22.3% to 95.7%), respectively. The median duration of response for the ovarian cancer and endometrial cancer cohorts was 5.3 (95% CI 0 to 11.7) and 6.1 (95% CI 2.4 to 9.8) months, respectively. The median progression-free survival for the ovarian cancer and endometrial cancer cohorts was 4.1 (95% CI 2.6 to 5.6) and 6.6 (95% CI 1.7 to 11.5) months, respectively. No grade 4 or 5 adverse events occurred. Eight (38.1%) patients had a lenvatinib dose reduction. There was no discontinuation of lenvatinib alone, and only one patient discontinued both drugs due to adverse events. CONCLUSION: Low-dose lenvatinib in combination with anti-PD-1 therapy showed promising efficacy and favorable tolerability in patients with heavily pre-treated ovarian and endometrial cancer.

Lymph node dissection after neoadjuvant chemotherapy improves overall survival in clinical stage III endometrial cancer.

OBJECTIVE: To investigate whether performing a lymph node dissection during hysterectomy improves overall survival in patients with clinical stage III endometrial cancer who received neoadjuvant chemotherapy. METHODS: The National Cancer Database was queried to identify all patients with clinical stage III endometrial cancer who had undergone pre-operative chemotherapy as first course of treatment followed by hysterectomy with or without lymph node dissection between the years 2004 and 2020. Univariable and multivariable models were performed to investigate prognostic factors on overall survival. RESULTS: This study analyzed 2882 patients with clinical stage III endometrial cancer who received upfront chemotherapy. Among those who underwent lymph node dissection, 38% had positive lymph nodes. Factors found to be independently associated with improved survival included lymph node dissection (p<0.001), adjuvant radiation (p<0.001), histology (p<0.001), tumor grade (p<0.001), pathologic node status (p<0.001), age (p<0.001), type of insurance (p=0.027), and race (p<0.001). Patients who underwent lymph node dissection at time of hysterectomy had a significantly better overall survival (107 vs 85 months; p<0.001). Multivariate and propensity score analyses robustly demonstrated that lymph node dissection significantly improved overall survival (HR 0.69, 95% CI 0.57 to 0.84, p<0.001), even among patients with pathologically negative lymph nodes. CONCLUSION: Our study suggests that performing lymph node dissection at the time of hysterectomy is associated with improved overall survival in all patients with stage III endometrial cancer who receive upfront chemotherapy, regardless of age, race, insurance status, histologic subtype, tumor grade, pathologic node status, adjuvant radiation or chemotherapy. Notably, patients with high-risk disease may particularly benefit from this approach.

Prognosis of isolated tumor cells and use of molecular classification in early stage endometrioid endometrial cancer.

OBJECTIVE: We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease. METHODS: Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol. Patients with cytokeratin positive cells, micrometastases, and macrometastases were excluded. Clinical, pathology, and molecular subtype data were reviewed. RESULTS: Overall, 1214 patients with early stage endometrioid endometrial cancer met the inclusion criteria, of whom 1089 (90%) had node negative disease and 125 (10%) had isolated tumor cells. Compared with node negative disease, the presence of isolated tumor cells had a greater association with deep myometrial invasion, lymphovascular space invasion, receipt of adjuvant therapy, and adjuvant chemotherapy with or without radiation (p<0.01). There was no significant difference in survival rates between patients with isolated tumor cells and node negative disease (3 year progression free survival rate 94% vs 91%, respectively, p=0.21; 3 year overall survival rate 98% vs 96%, respectively, p=0.45). Progression free survival did not significantly differ among patients with isolated tumor cells who received no adjuvant therapy or chemotherapy with or without radiation (p=0.31). There was no difference in the distribution of molecular subtypes between patients with isolated tumor cells (n=28) and node negative disease (n=194; p=0.26). Three year overall survival rates differed significantly when stratifying the entire cohort by molecular subtype (p=0.04). CONCLUSIONS: Patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with patients with nodenegative disease. Among the available data, molecular classification did not have a significant association with the presence of isolated tumor cells, although copy number-high status was a poor prognostic indicator in early stage endometrioid endometrial cancer.

Best original research presented at the 24th European Congress on Gynaecological Oncology-Best of ESGO 2023.

The 'Best of ESGO 2023' manuscript comprises a compilation of the best original research presented during the European Society of Gynaecologic Oncology annual congress held in Istanbul between September 28 and October 1, 2023. Out of 1030 submitted abstracts, 33 studies presented during the Best Oral Sessions, Mini Oral Sessions, and Young Investigator Session were selected by the ESGO Abstract Committee and the European Network of Young Gynae Oncologists (ENYGO) authors. There was a strong focus on surgical de-escalation, immunotherapy, maintenance therapy, and molecular profiling in gynecologic oncology. With this manuscript, ENYGO and ESGO aim to disseminate the valuable research results to readers interested in our field.

Impact of molecular classification on recurrence risk in endometrial cancer patients with lymph node metastasis: multicenter retrospective study.

OBJECTIVE: To assess the distribution of molecular classes and their impact on the risk of recurrence in endometrial cancer patients with lymph node metastasis at the time of primary surgery. METHODS: Endometrial cancer patients with lymph node micrometastasis or macrometastasis (International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIIC) after surgical staging at five referral centers worldwide from October 2013 to September 2022 who underwent molecular classification were identified. Endometrial cancers were categorized into four molecular classes: POLE mutated, mismatch repair deficient, p53 abnormal, and no specific molecular profile. Survival analyses using Kaplan-Meier and Cox models (univariate and multivariate) were conducted to evaluate the relationship between molecular class and 5-year recurrence free survival. RESULTS: 131 patients were included: 55 (42.0%) no specific molecular profile, 46 (35.1%) mismatch repair deficient, 1 (0.8%) POLE mutated, and 29 (22.1%) p53 abnormal. During a 5 year follow-up period, 50 (38.2%) patients experienced a recurrence with a median time of 1.2 years (interquartile range (IQR) 0.5-1.8). Median follow-up for the remaining 81 patients was 3.1 years (IQR 1.3-4.5). Survival analysis revealed a significant difference in recurrence-free survival between no specific molecular profile, mismatch repair deficient, and p53 abnormal classes (log rank p<0.01). In a model adjusted for type of lymph node metastasis and tumor grade, the molecular class did not retain significance (p=0.13), while in a model adjusted for type of lymph node metastasis and adjuvant therapy, the molecular class retained significance (p<0.01). CONCLUSION: Among patients with stage IIIC endometrial cancer, POLE mutated tumors exhibited an extremely low prevalence, with no specific molecular profile emerging as the largest molecular subgroup. Despite the significant difference in recurrence-free survival between molecular classes, conventional histopathologic parameters retained crucial prognostic value. Our findings highlight the necessity of integrating molecular classes with pathological characteristics, rather than considering them in isolation as crucial prognostic factors in stage IIIC endometrial cancer.

SENECA study: staging endometrial cancer based on molecular classification.

OBJECTIVE: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification. METHODS: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens. RESULTS: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001). CONCLUSIONS: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Management of endometrial cancer in Latin America: raising the standard of care and optimizing outcomes.

Molecular characterization of endometrial cancer is allowing for increased understanding of the natural history of tumors and paving a more solid pathway for novel therapies. It is becoming increasingly apparent that molecular classification is superior to histological classification in terms of reproducibility and prognostic discrimination. In particular, the Proactive Molecular Risk Classifier for Endometrial Cancer allows classification of endometrial cancer into groups very close to those determined by the Cancer Genome Atlas Research Network-that is, DNA polymerase epsilon-mutated, mismatch repair-deficient, p53 abnormal, and non-specific molecular profile tumors. The transition from the chemotherapy era to the age of targeted agents and immunotherapy, which started later in endometrial cancer than in many other tumor types, requires widespread availability of specialized pathology and access to novel agents. Likewise, surgical expertise and state-of-the-art radiotherapy modalities are required to ensure adequate care. Nevertheless, Latin American countries still face considerable barriers to implementation of international guidelines. As we witness the dawn of precision medicine as applied to endometrial cancer, we must make continued efforts towards improving the quality of care in this region. The current article discusses some of these challenges and possible solutions.