Early-stage Endometrial Cancer Research Articles

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

ObjectiveTo 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...

Abstract PR003: The combination of the glucagon like peptide-1 receptor agonist semaglutide and the progestin levonorgestrel is highly effective in preclinical studies of endometrial cancer

Abstract Obesity is a major risk factor for endometrial cancer (EC), and glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss during conservative treatment or for EC prevention. Progestins such as levonorgestrel are effective in preventing or treating early-stage EC. However, better and more durable response rates could be achieved using combinatorial therapeutic regimens of well tolerated agents with the potential to enhance progestin effectiveness. We theorized that the combination of semaglutide and levonorgestrel would be useful as a novel treatment or prevention regimen and tested this hypothesis using EC cell lines, patient-derived organoids, and RNA-sequencing from patient samples. From the molecular perspective, EC cell lines, organoids, and tissues express GLP-1R as determined by both qPCR and Western blotting, and GLP-1R agonist treatment induces GLP-1R mRNA transcription through positive feedback mechanisms in EC cell models. Preclinical studies in 6 patient-derived organoid models of EC demonstrated the promising therapeutic effects of the combination of semaglutide and levonorgestrel on endometrial cell viability. Specifically, patient-derived organoids from grade 1 endometrial carcinomas were treated with progesterone, levonorgestrel, semaglutide, or levonorgestrel + semaglutide at drug concentrations of 100 nM for 72 hours. Multiple models demonstrated a significant reduction in viability in response to combinatorial treatment. Most interesting was the induction of not only the membrane GLP-1 receptor with treatment, but also the significant upregulation of nuclear and membrane progesterone receptors, PR and PGRMC1/2, respectively, indicating a positive feedback loop between semaglutide and progestins such as levonorgestrel. In addition, other steroid hormone receptor mRNAs such as the estrogen, androgen and mineralocorticoid receptors (ER, AR, and MR) were similarly upregulated. In these studies, we identify synergistic molecular crosstalk between the GLP-1R and steroid hormone receptor pathways with the potential to enhance the anti-cancer activity of semaglutide and levonorgestrel when combined. Future studies are aimed at testing this regimen in patients conservatively managed for atypical endometrial hyperplasia or low-grade endometrial cancers. Citation Format: Kimberly K. Leslie, Andrea Hagemann, Kristina Thiel, Ian Hagemann, David Mutch, Eric Devor, Paige Malmrose. The combination of the glucagon like peptide-1 receptor agonist semaglutide and the progestin levonorgestrel is highly effective in preclinical studies of endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr PR003.

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

End-to-end deep learning method for predicting hormonal treatment response in women with atypical endometrial hyperplasia or endometrial cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and atypical endometrial hyperplasia (AEH) is considered a high-risk precursor to EC. Hormone therapies and hysterectomy are practical treatment options for AEH and early-stage EC. Some patients prefer hormone therapies for reasons such as fertility preservation or being poor surgical candidates. However, accurate prediction of an individual patient's response to hormonal treatment would allow for personalized and potentially improved recommendations for these conditions. This study aims to explore the feasibility of using deep learning models on whole slide images (WSI) of endometrial tissue samples to predict the patient's response to hormonal treatment. We curated a clinical WSI dataset of 112 patients from two clinical sites. An expert pathologist annotated these images by outlining AEH/EC regions. We developed an end-to-end machine learning model with mixed supervision. The model is based on image patches extracted from pathologist-annotated AEH/EC regions. Either an unsupervised deep learning architecture (Autoencoder or ResNet50), or non-deep learning (radiomics feature extraction) is used to embed the images into a low-dimensional space, followed by fully connected layers for binary prediction, which was trained with binary responder/non-responder labels established by pathologists. We used stratified sampling to partition the dataset into a development set and a test set for internal validation of the performance of our models. The autoencoder model yielded an AUROC of 0.80 with 95% CI [0.63, 0.95] on the independent test set for the task of predicting a patient with AEH/EC as a responder vs non-responder to hormonal treatment. These findings demonstrate the potential of using mixed supervised machine learning models on WSIs for predicting the response to hormonal treatment in AEH/EC patients.

Additional Value of FDG-PET/MRI Complementary to Sentinel Lymphonodectomy for Minimal Invasive Lymph Node Staging in Patients with Endometrial Cancer: A Prospective Study.

Lymph node metastases (LNM) are rare in early-stage endometrial cancer, but a diagnostic systematic lymphadenectomy (LNE) is often performed to achieve reliable N-staging. Therefore, this prospective study aimed to evaluate the benefit of [18F]-Fluorodeoxyglucose (FDG) PET/MRI complementary to SPECT/CT guided sentinel lymphonodectomy (SLNE) for a less invasive N-staging Methods: 79 patients underwent a whole-body FDG-PET/MRI, SLN mapping with 99mTc-Nanocolloid SPECT/CT and indocyanine green (ICG) fluoroscopy followed by LNE which served as ground truth. FDG-PET/MRI was highly specific in N-staging (97.2%) but revealed limited sensitivity (66.7%) due to missed micrometastases. In contrast, bilateral SLN mapping failed more often in patients with macrometastases. The combination of SLN mapping and FDG-PET/MRI increased the sensitivity from 66.7% to 77.8%. Additional SLN labeling with dye (ICG) revealed a complete SLN mapping in 80% (8/10) of patients with failed or incomplete SLN detection in SPECT/CT, reducing the need for diagnostic systematic LNE up to 87%. FDG-PET/MRI detected para-aortic LNM in three out of four cases and a liver metastasis. The combination of FDG-PET/MRI and SLNE can reduce the need for diagnostic systematic LNE by up to 87%. PET/MRI complements the SLN technique particularly in the detection of para-aortic LNM and occasional distant metastases.

Assessment of sentinel Lymph node mapping with different volumes of Indocyanine green in early-stage ENdometrial cancer: the ALIEN study

ObjectiveTo evaluate the impact of different volumes of indocyanine green (ICG) on the detection rate and bilateral mapping of sentinel lymph nodes in patients with apparent uterine-confined endometrial cancer.MethodsAll patients...

Sentinel lymph node biopsy with carbon dye in endometrial cancer: a single center, prospective cohort study.

Many agents have been used for the detection of sentinel lymph nodes in endometrial cancer. Carbon dye, which has a strong staining ability and high contrast due to its dark black color, identifies the lymph nodes efficiently. Our aim was to evaluate the safety and efficacy of carbon dye for the detection of sentinel lymph nodes in endometrial cancer. We conducted a single-center, prospective, cohort study in 89 patients with early-stage endometrial cancer between September 2021 and August 2022. The procedure was performed under laparoscopy. The sensitivity and negative predictive value of the sentinel lymph node biopsy (SLNB) with carbon dye injection were 83.3% and 98.8%, respectively. Mapping identified at least one sentinel lymph node in 84 patients (94.4%) on one pelvic side and at least one sentinel lymph node in 73 patients (82.0%) on each pelvic side out of 89 patients. In addition, no carbon dye-associated allergic reaction was detected. Carbon dye is a non-allergenic, inexpensive, and effective agent for SLNB with a satisfying sensitivity and a negative predictive value. In addition, both unilateral and bilateral detection rates were sufficient. Accordingly, carbon dye may be a promising tracer and a considerable option, particularly for low-income countries.

Prognostic Effect of Mismatch Repair Status in Early-Stage Endometrial Cancer Treated With Adjuvant Radiation: A Multi-institutional Analysis

The aim of this work was to report the effect of mismatch repair (MMR) status on outcomes of patients with stage I-II endometrioid endometrial adenocarcinoma (EEC) who receive adjuvant radiation therapy. This is a multi-institutional retrospective cohort study across 11 institutions in North America. Patients with known MMR status and stage I-II EEC status postsurgical staging were included. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated via the Kaplan-Meier method. Univariable and multivariable analyses were performed via Cox proportional hazard models for RFS and OS. Statistical analyses were conducted using SPSS version 27. In total, 744 patients with a median age at diagnosis of 65 years (IQR, 58-71) were included. Most patients were White (69.4%) and had Federation of Obstetrics and Gynecology 2009 stage I (84%) and Federation of Obstetrics and Gynecology grade 1 to 2 (73%). MMR deficiency was reported in 234 patients (31.5%), whereas 510 patients (68.5%) had preserved MMR. External beam radiation therapy with or without vaginal brachytherapy was delivered to 186 patients (25%), whereas 558 patients (75%) received vaginal brachytherapy alone. At a median follow-up of 43.5 months, the estimated crude OS and RFS rates for the entire cohort were 92.5% and 84%, respectively. MMR status was significantly correlated with RFS. RFS was inferior for MMR deficiency compared with preserved MMR (74.3% vs 88.6%, P < .001). However, no difference in OS was seen (90.8% vs 93.2%, P = .5). On multivariable analysis, MMR deficiency status was associated with worse RFS (hazard ratio, 1.86; P = .001) but not OS. MMR status was independently associated with RFS but not OS in patients with early-stage EEC who were treated with adjuvant radiation therapy. These findings suggest that differential approaches to surveillance and/or treatment based on MMR status could be warranted.

Effect of time interval between surgery and the initiation of adjuvant therapy on the oncologic outcomes of early-stage endometrial cancer.

To identify the impact of time interval between surgery and initial adjuvant radiotherapy on oncologic outcomes in early-stage endometrial cancer. This retrospective cohort study included patients with stage I/II endometrial cancer who underwent surgical staging and adjuvant therapy at Songklanagarind Hospital from January 1, 2007, to December 31, 2017. Patients were categorized into two groups: TI <6 weeks and TI ≥6 weeks. The effects of TI and clinicopathological factors on recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox proportional-hazards regression. In total, 177 patients were enrolled, with 52% receiving adjuvant radiotherapy at <6 weeks (overall median TI 5.7 weeks). The recurrence and death rates were 13% and 10.2%, respectively. The median follow-up time was 46.6 months. The overall 3-year RFS and OS rates were 88.2% and 85.2%, respectively. The TI significantly affected the 3-year RFS (94.4% vs 81.2%; P = 0.008) and 3-year OS (95.5% vs 83.2%; P = 0.012) in patients with TI <6 and ≥6 weeks, respectively. In multivariate analysis, the depth of myometrial invasion (MI), presence of lymphovascular space invasion, and TI were independent prognostic factors for both RFS and OS. Delaying the TI (≥6 weeks) was significantly associated with a worse RFS (hazard ratio [HR] 3.70; 95% confidence interval [CI]: 1.34-10.22; P = 0.012) and an inferior OS (HR 3.80; 95% CI: 1.23-11.69; P = 0.02). A delay in the TI between surgery and the initiation of adjuvant radiotherapy of ≥6 weeks negatively affected the oncologic outcomes in early-stage endometrial cancer.

Prognosis of Stage I Endometrial Cancer According to the FIGO 2023 Classification Taking into Account Molecular Changes.

Optimum risk stratification in an early stage of endometrial cancer (EC) combines molecular and clinicopathological features. The purpose of the study was to determine the prognostic value of molecular classification and traditional pathological factors in a sample group of patients with stage I EC according to the FIGO 2023 criteria, to achieve a more personalized approach to patient care and treatment. The immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain and clinicopathological parameters, including disease disease-free survival (DFS) and overall survival (OS) in 139 patients, were analyzed. It has been shown that the independent recurrence risk factors are stage IC (p < 0.001), aggressive histological types EC (p < 0.001), and the presence of p53abn protein immunoexpression (p = 0.009). Stage IC (p = 0.018), aggressive histological types EC (p = 0.025) and the presence of p53abn protein immunoexpression (p = 0.010) were all significantly associated with lower 5-year OS rates. Our research studies confirm that the molecular category corresponds to a different prognosis in clinical stage I EC according to the new 2023 FIGO classification, with POLEmut cases presenting the best outcomes and p53abn cases showing the worst outcomes. Beyond the previous routine clinicopathological assessment, the new EC staging system represents an important step toward improving our ability to stratify IC stage EC risk.

Impact of sentinel lymph node mapping on survival in patients with high-risk endometrial cancer in the early stage: A matched cohort study.

The aim of this study was to compare patient survival using sentinel lymph node (SLN) procedure and pelvic lymphadenectomy for stating early-stage high risk endometrial cancer. Patients who underwent surgery for early-stage high risk endometrial cancer between 2010 and 2017 were extracted from the incidence registry of the SEER program. We identified patients who underwent SLN mapping. Patients who initially underwent pelvic lymphadenectomy were selected as the comparison group. One-to-one matching was performed according to age, ethnicity, histology, extension and grade. The primary outcome was disease-specific survival. The secondary outcome was overall survival. A total of 326 patients who underwent SLN mapping and 326 who underwent pelvic lymphadenectomy initially were included in the study. The three-year analysis did not find a significant difference between the SLN and lymphadenectomy groups on disease-specific survival probability (88.2% vs 82.7, P = 0.07) and on overall survival probability (82.7% vs 78.2%, P = 0.57). Patients who underwent SLN mapping had a lower mean number of lymph nodes removed (mean 3 vs 16, P < 0.001) and there was a higher rate of patients with positive pelvic lymph nodes (18% vs 14%, P = 0.04). Following adjustment for confounding factors, disease-specific survival did not vary according to the lymph node intervention performed (P = 0.056), but the SLN group had better overall survival than those in the lymphadenectomy group (P = 0.047). The SLN technique was not associated with poorer disease-specific survival than pelvic lymphadenectomy even after adjustment. These results suggest that SLN is an acceptable and safe procedure in surgical staging for early-stage high-risk endometrial cancer.

THE SYSTEMATIC REVIEW OPEN SURGERY VS MINIMALLY INVASIVE IN HIGH RISK ENDOMETRIAL CANCER

Background: When treated with minimally invasive surgery (MIS), women with early-stage endometrial cancer recover more quickly from surgery than when they have open operations; nevertheless, there is no discernible difference in terms of overall survival or progression-free survival. Aims : This systematic review is to review the comparison of open surgery and minimally invasive in high risk endometrial cancer Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2014 and 2024 were taken into account. Several different online reference sources, like Pubmed and SCIENCE DIRECT, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 144 articles, whereas the results of our search on SCIENCE DIRECT brought up 588 articles. The results of the search conducted for the last year of 2014 yielded a total 121 articles for PubMed and 175 articles for SCIENCE DIRECT. In the end, we compiled a total of 5 papers, 4 of which came from PubMed and 1 of which came from SCIENCE DIRECT. We included five research that met the criteria. Conclusion: In summary, this systematic review of observational studies showed that the prognosis of endometrial cancer patients with high risk histology was unaffected by minimally invasive surgery and might confirm the findings of this rare but lethal malignancy.

Development of a long term, ex vivo, patient-derived explant model of endometrial cancer.

Incidence of endometrial cancer (EC) is rising in the developed world. The current standard of care, hysterectomy, is often infeasible for younger patients and those with high body mass index. There are limited non-surgical treatment options and a lack of biologically relevant research models to investigate novel alternatives to surgery for EC. The aim of the present study was to develop a long-term, patient-derived explant (PDE) model of early-stage EC and demonstrate its use for investigating predictive biomarkers for a current non-surgical treatment option, the levonorgestrel intra-uterine system (LNG-IUS). Fresh tumour specimens were obtained from patients with early-stage endometrioid EC. Tumours were cut into explants, cultured on media-soaked gelatin sponges for up to 21 days and treated with LNG. Formalin-fixed, paraffin embedded (FFPE) blocks were generated for each explant after 21 days in culture. Tumour architecture and integrity were assessed by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). IHC was additionally performed for the expression of five candidate biomarkers of LNG resistance. The developed ex vivo PDE model is capable of culturing explants from early-stage EC tumours long-term (21 Days). This model can complement existing models and may serve as a tool to validate results obtained in higher-throughput in vitro studies. Our study provides the foundation to validate the extent to which EC PDEs reflect patient response in future research.

Effect of 3D laparoscopy versus traditional laparotomy on serum tumor markers and coagulation function in patients with early-stage endometrial cancer

ObjectivesTo investigate the impact of Three-Dimensional (3D) laparoscopy compared to traditional laparotomy on serum tumor markers and coagulation function in patients diagnosed with early-stage Endometrial Cancer (EC). MethodThe authors retrospectively analyzed the clinical data of 75 patients diagnosed with early-stage EC and categorized them into two groups based on the surgical techniques employed. The 3D group consisted of 36 patients who underwent 3D laparoscopic surgery, while the Laparotomy group comprised 39 patients who underwent traditional laparotomy. The authors then compared the alterations in serum tumor markers and coagulation function between the two groups. ResultsPostoperatively, serum levels of CA125, CA199, and HE4 were notably reduced in both groups on the third day, with the levels being more diminished in the 3D group than in the Laparotomy Group (p < 0.05). Conversely, FIB levels escalated significantly in both groups on the third-day post-surgery, with a more pronounced increase in the 3D group. Additionally, PT and APTT durations were reduced and were more so in the 3D group than in the laparotomy group (p < 0.05). ConclusionsWhen juxtaposed with traditional laparotomy, 3D laparoscopic surgery for early-stage EC appears to be more efficacious, characterized by reduced complications, and expedited recovery. It can effectively mitigate serum tumor marker levels, attenuate the inflammatory response and damage to immune function, foster urinary function recovery, and enhance the quality of life. However, it exerts a more significant influence on the patient's coagulation parameters, necessitating meticulous prevention and treatment strategies for thromboembolic events in clinical settings.

Prognostic values of tumor size and location in early stage endometrial cancer patients who received radiotherapy.

To investigate the correlation between tumor size, tumor location, and prognosis in patients with early-stage endometrial cancer (EC) receiving adjuvant radiotherapy. Data of patients who had been treated for stage I-II EC from March 1999 to September 2017 in 13 tertiary hospitals in China was screened. Cox regression analysis was performed to investigate associations between tumor size, tumor location, and other clinical or pathological factors with cancer-specific survival (CSS) and distant metastasis failure-free survival (DMFS). The relationship between tumor size as a continuous variable and prognosis was demonstrated by restricted cubic splines. Prognostic models were constructed as nomograms and evaluated by Harrell's C-index, calibration curves and receiver operating characteristic (ROC) curves. The study cohort comprised 805 patients with a median follow-up of 61 months and a median tumor size of 3.0 cm (range 0.2-15.0 cm). Lower uterine segment involvement (LUSI) was found in 243 patients (30.2%). Tumor size and LUSI were identified to be independent prognostic factors for CSS. Further, tumor size was an independent predictor of DMFS. A broadly positive relationship between poor survival and tumor size as a continuous variable was visualized in terms of hazard ratios. Nomograms constructed and evaluated for CSS and DMFS had satisfactory calibration curves and C-indexes of 0.847 and 0.716, respectively. The area under the ROC curves for 3- and 5-year ROC ranged from 0.718 to 0.890. Tumor size and LUSI are independent prognostic factors in early-stage EC patients who have received radiotherapy. Integrating these variables into prognostic models would improve predictive ability.

Diagnostic value of ICG for sentinel lymph node mapping in patients with stage I endometrial cancer

Background. Lymphatic spread is the main route of metastasis in early stage endometrial cancer. Considering its significance, three risk factors of lymph node metastasis were identified. At a high risk of lymph node metastasis in patients with stage I endometrial cancer, pelvic and lumbar lymph node dissection is recommended. In low-risk patients, lymph node dissection is not performed. Lymph node dissection in medium-risk patients is considered as a staging procedure. However, in patients with aggravating factors that prevent extended hysterectomy, lymph node biopsy with ICG mapping and subsequent microstaging may be an alternative to lymph node dissection. Purpose of the study: to analyze the effectiveness of surgical approaches for staging endometrial cancer at different risk factors for lymphatic metastasis.Material and Methods. The treatment outcomes were retrospectively analyzed in 565 patients with stage I endometrial cancer treated at the gynecological oncology department of Botkin City Clinical Hospital and at the gynecological oncology department of Kaluga Regional Clinical Oncology Center from 2021 to 2023. All women were divided into three groups according to the risk factors of lymph node metastasis. Patients underwent hysterectomy, hysterectomy combined with pelvic or pelvic and lumbar lymphadenectomy, as well as hysterectomy with ICG mapping and sentinel lymph node biopsy.Results. A total of 334 endometrial cancer patients underwent surgery at Botkin City Clinical Hospital. In the medium-risk group patients (n=94), who underwent hysterectomy with pelvic (n=36) and pelvic + lumbar lymphadenectomy (n=31), lymph node metastases were detected in 4 (11.1 %) and 6 (19.4 %) patients, respectively. In the high-risk group (n=50) with similar surgeries, metastatic lymph nodes were identified in 2 (10.5 %, n=19) and 6 (26.1 %, n=23) patients, respectively. At Kaluga Regional Oncology Center, 231 patients underwent hysterectomy with sentinel lymph node biopsy. The low-risk group, the medium-risk group, and the high-risk group showed lymph node metastases in 7 (5.47 %), 6 (10.2 %), and 6 (13.6 %) patients, respectively.Conclusion. In stage I endometrial cancer patients with a low risk of lymph node metastasis, hysterectomy with sentinel lymph node biopsy is recommended. For medium-and high-risk groups, hysterectomy with systemic lymphadenectomy is recommended. If it is not possible to remove the pelvic and lumbar lymph nodes, their biopsy with ICG mapping and microstaging can be recommended. A combination of systemic lymphadenectomy with sentinel lymph node biopsy is a promising technique that could hypothetically demonstrate better results in terms of disease staging.

Retroperitoneal sentinel lymph node biopsy by transvaginal natural orifice transluminal endoscopic surgery in early-stage endometrial cancer.

Retroperitoneal sentinel lymph node biopsy by transvaginal natural orifice transluminal endoscopic surgery in early-stage endometrial cancer.

Comparison between laparoscopy and laparotomy for systematic pelvic lymphadenectomy in patients with early-stage endometrial cancer

Comparison between laparoscopy and laparotomy for systematic pelvic lymphadenectomy in patients with early-stage endometrial cancer

Metformin as an Adjunct to Progestin Therapy in Endometrial Hyperplasia and Early-Stage Endometrial Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Metformin has been studied for its anti-proliferative effects on endometrial cells, and it is hypothesized to have a synergistic effect with progestin therapy in suppressing endometrial cell proliferation. This systematic review and meta-analysis aimed to determine the efficacy of adjunctive metformin in the clinical regression of endometrial hyperplasia and early-stage endometrial carcinoma. There have been previous systematic reviews that investigated the role of metformin with progesterone for endometrial hyperplasia and endometrial cancer, but they have included retrospective cohorts, and are thus have higher risk of bias. This meta-analysis followed the Cochrane methodology and adhered to the PRISMA 2020 guidelines. Randomized controlled trials (RCTs) were included if they enrolled reproductive-aged women with endometrial hyperplasia (with and without atypia) and endometrial carcinoma who were treated with progestin and metformin. The primary outcome was the complete response rate at 12-16 weeks, and secondary outcomes included relapse rate, clinical pregnancy rate, and live birth rate. Subgroup analysis of endometrial hyperplasia without atypia vs hyperplasia with atypia and early endometrial cancer was also included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for dichotomous data. Six RCTs were included. The addition of metformin to progestin therapy may increase the complete response rate of endometrial hyperplasia without atypia (OR 5.12, 95% CI 1.17 to 22.41; n = 102) and live birth rates (OR 2.51, 95% CI 1.34 to 4.69; n = 188) compared to progestin therapy alone, but the certainty of the evidence is low. Metformin did not have a significant effect on the clinical response of endometrial hyperplasia with atypia and endometrial carcinoma, relapse rates, and clinical pregnancy rates. Current evidence is uncertain on the potential benefit of metformin with progestin in endometrial hyperplasia and carcinoma. Future high-quality randomized controlled trials with larger sample sizes and longer follow-up periods are needed to support practice recommendations.

Impact of adjuvant treatment on survival in patients with 2023 FIGO stage IIC endometrial cancer: a retrospective analysis from two tertiary centers in Korea and Taiwan.

In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors.