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Landscape of endometrial cancer: molecular mechanisms, biomarkers, and target therapy.

Simple Summary

1. introduction, 2. molecular mechanisms involved in the pathogenesis of endometrial cancers, 2.1. genetic mutations, 2.2. defects in dna mismatch repair genes, 2.3. hormonal signaling, 2.4. epigenetic modifications, 2.5. angiogenesis, 3. biomarkers in endometrial cancer, prognostic biomarkers are indicators that predict the course or outcome of a disease, 4. endometrial cancer therapy between standard approaches and future directions, 4.1. standard therapy, 4.2. targeted therapy strategies in endometrial cancer, 4.2.1. targeting the pi3k/akt/mtor signaling pathway, 4.2.2. targeting angiogenesis, 4.2.3. targeting her2-receptors, 4.2.4. immunotherapy, 4.2.5. targeting mirnas, 5. conclusions, author contributions, conflicts of interest.

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Share and Cite

Bostan, I.-S.; Mihaila, M.; Roman, V.; Radu, N.; Neagu, M.T.; Bostan, M.; Mehedintu, C. Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy. Cancers 2024 , 16 , 2027. https://doi.org/10.3390/cancers16112027

Bostan I-S, Mihaila M, Roman V, Radu N, Neagu MT, Bostan M, Mehedintu C. Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy. Cancers . 2024; 16(11):2027. https://doi.org/10.3390/cancers16112027

Bostan, Ioana-Stefania, Mirela Mihaila, Viviana Roman, Nicoleta Radu, Monica Teodora Neagu, Marinela Bostan, and Claudia Mehedintu. 2024. "Landscape of Endometrial Cancer: Molecular Mechanisms, Biomarkers, and Target Therapy" Cancers 16, no. 11: 2027. https://doi.org/10.3390/cancers16112027

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Endometrial cancer

Affiliations.

• 1 Gynaecological Oncology Research Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK; Department of Obstetrics and Gynaecology, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: [email protected].
• 2 Gynaecological Oncology Research Group, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.
• 3 Department of Obstetrics and Gynaecology, Division of Gynecologic Oncology, University of British Columbia and BC Cancer, Vancouver, BC, Canada.
• 4 Kolkata Gynecological Oncology Trials and Translational Research Group, Chittaranjan National Cancer Institute, Kolkata, India; Department of Gynaecological Oncology, James Cook University Hospital, Middlesbrough, UK; Department of Gynaecological Oncology, Newcastle University, Newcastle upon Tyne, UK.
• 5 Department of Clinical Oncology, Barts and The London NHS Trust, London, UK.
• 6 Department of Anatomic Pathology, Vancouver General Hospital, Vancouver, BC, Canada.
• PMID: 35397864
• DOI: 10.1016/S0140-6736(22)00323-3

Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more research is needed to offer primary prevention to high-risk women and to optimise endometrial cancer survivorship. Early presentation with postmenopausal bleeding ensures most endometrial cancers are cured by hysterectomy but those with advanced disease have a poor prognosis. Minimally invasive surgical staging and sentinel-lymph-node biopsy provides a low morbidity alternative to historical surgical management without compromising oncological outcomes. Adjuvant radiotherapy reduces loco-regional recurrence in intermediate-risk and high-risk cases. Advances in our understanding of the molecular biology of endometrial cancer have paved the way for targeted chemotherapeutic strategies, and clinical trials will establish their benefit in adjuvant, advanced, and recurrent disease settings in the coming years.

Copyright © 2022 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Declaration of interests EJC received fees for participation in a GlaxoSmithKline advisory board in 2020. JNM received grants from the Michael Smith Foundation for Health Research, the Canadian Cancer Society and the Canadian Institute for Health Research, outside the submitted work. She is named as one of the inventors on a US provisional patent application, but this is not being pursued and no payments have been received. AM received royalty payments to her institution for her role in the development of the PARP inhibitor rucaparib, the proceedings of which were donated to women's cancer research in low-income and middle-income countries. NS received honoraria for participation in advisory boards for GlaxoSmithKline and AstraZeneca-Merck-Sharp & Dohme. The other authors declare no competing interests.

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Endometrial cancer articles from across Nature Portfolio

Endometrial cancer is a type of tumour that arises in the tissue lining the uterus. Most endometrial cancers are adenocarcinomas; that is, cancers formed from cells that make and release mucus and other fluids.

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Vrede SW , Kasius J , Bulten J, et al. Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer. JAMA Netw Open. 2022;5(12):e2247372. doi:10.1001/jamanetworkopen.2022.47372

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Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer

• 1 Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands
• 2 Department of Obstetrics and Gynecology, Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands
• 3 Department of Gynecologic Oncology, Amsterdam Medical Centers and Center of Gynecologic Oncology Amsterdam, Amsterdam, the Netherlands
• 4 Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands
• 5 Department of Health Evidence, Radboud University Medial Center, Nijmegen, the Netherlands
• 6 Department of Pathology, University of Turku, Turku, Finland
• 7 Biomedical Research Group in Gynecology, Vall Hebron Institute of Research, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red Cáncer, Barcelona, Spain
• 8 Gynecological Department, Vall Hebron University Hospital, Centro de Investigación Biomédica en Red Cáncer, Barcelona, Spain
• 9 Pathology Department, Vall Hebron University Hospital, Centro de Investigación Biomédica en Red Cáncer, Barcelona, Spain
• 10 Department of Obstetrics and Gynecology, Catharina Hospital Eindhoven, the Netherlands
• 11 Departement of Obstetrics and Gynecology, Elisabeth-Tweesteden Hospital, the Netherlands
• 12 Department of Obstetrics and Gynecology, Medical Center–University of Freiburg, Freiburg, Germany
• 13 Department of Oncology, KU Leuven, Leuven, Belgium
• 14 Department of Gynaecologic Oncology, Netherlands Cancer Institute and Amsterdam Medical Centers, Amsterdam, the Netherlands
• 15 Department of Pathology, Stichting Laboratory for Pathology and Medical Microbiology, Eindhoven, the Netherlands
• 16 Department of Pathology, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands
• 17 Department of Obstetrics and Gynecology, School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands
• 18 Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, Institut de Recerca Biomèdica de Lleida, Centro de Investigación Biomédica en Red Cáncer, Lleida, Spain
• 19 Department of Obstetrics and Gynecology, University Hospital in Brno and Masaryk University, Brno, Czechia
• 20 Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands

Question   Is tumor molecular profile associated with outcomes among patients with low-grade endometrial cancer?

Findings   In this retrospective multicenter cohort study of 393 patients, outcomes for patients with low-grade endometrial cancer were not associated with molecular subgroup.

Meaning   These findings do not support routine molecular profiling in patients with low-grade endometrial cancer.

Importance   Patients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear.

Objective   To determine the association of molecular profiling with outcomes among patients with low-grade EC.

Design, Setting, and Participants   This retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon ( POLE)- altered, microsatellite instable (MSI), tumor protein p53 ( TP53)- altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022.

Exposures   Molecular testing of the 4 molecular subgroups.

Main Outcomes and Measures   The main outcome was disease-specific survival (DSS) within the molecular subgroups.

Results   A total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE- altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53 -altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% ( P  < .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P  < .001), TP53 -altered (HR, 1.76; 95% CI, 1.04-2.95; P  = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P  < .001) disease were independently associated with reduced DSS.

Conclusions and Relevance   This cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

More than 85% of patients with endometrial cancer (EC) present with low-grade histology (ie, grade 1-2) and International Federation of Gynecology and Obstetrics (FIGO) early-stage (ie, I-II) endometrioid EC and have a favorable prognosis, with a 5-year overall survival of 95%. 1 , 2 Standard treatment is hysterectomy with bilateral salpingo-oophorectomy, including lymph node staging for patients with substantial risk of lymph node metastasis. 2

The Cancer Genome Atlas defined 4 important prognostic molecular subgroups in EC based on integrated genomic data: ultramutated tumors with polymerase epsilon ( POLE ; OMIM 174762) alteration, microsatellite instability (MSI), copy-number-high with frequent tumor protein p53 ( TP53 ; OMIM 191170) alteration, and copy-number-low (also known as no specific molecular profile [NSMP]). These subgroups increase insight in biological tumor behavior based on molecular signature beyond current morphological classification. 3 Patients with TP53 -altered tumors have the worst outcome, representing 15% of all EC diagnoses and responsible for 50% to 70% of all EC-related mortality. 4 , 5

For decades, tumor grading and FIGO staging have been used to guide primary and adjuvant treatment. 6 Currently, with incorporation of the molecular classification to guide adjuvant treatment, the prognostic relevance of tumor grading has gained less attention. 7 Molecular profiling has been shown to improve prognostication mainly in patients with high-grade EC, probably due to poor interobserver reproducibility of morphological classification and the prognostic and intratumoral heterogeneity of high-grade ECs. 5 , 8 To our knowledge, no data have been reported about the prognostic relevance of molecular profiling specifically in patients with low-grade EC. The aim of this study is to determine the prognostic relevance of molecular profiling within low-grade EC. As most patients present with low-grade EC and have an excellent outcome, we hypothesized that molecular profiling might be less useful in these patients.

This cohort study was approved by the institutional review board of Radboud University Medical Center and the institutional review boards of all participating centers. Data used in this study were from previous published studies by our research group; therefore, informed consent was waived for participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

This retrospective European multicenter study used data from 4 previously published studies 9 - 12 and 1 study that has not been published yet, all published by our research group. A baseline overview and flowchart of the included studies are shown in eTable 1 and eFigure 1 in Supplement 1 .

All patients were surgically treated between 1994 and 2018 (median, 2006). Inclusion criteria for this study were: patients diagnosed with primary EC with all histological subtypes and FIGO stages, with available EC tissue samples, from which tumors were successfully classified according molecular profiling or the Proactive Molecular Risk Classifier for Endometrial Cancer 13 classification. The exclusion criterion was unknown lymph node status in FIGO early-stage disease.

Patients were classified into 1 of 4 molecular subgroups according to the diagnostic algorithm ( Figure 1 ): POLE- altered, MSI, TP53 -altered, and NSMP. Multiple-classifiers were classified as the molecular subgroup with the best prognosis. 14

Representative areas of EC in the surgical specimen were marked and selected for formalin-fixed paraffin-embedded 20-μm thick sections. Slides were cut from these formalin-fixed paraffin-embedded sections and stained with hematoxylin and eosin. Tumor areas were marked on these slides, and the tumor cell percentage was estimated. These specimens were digested overnight at 56 °C in TET-lysis buffer (10 mmol/L Tris/hydrochloride, pH 8.5; 1 mmol/L ethylenediaminetetraacetic acid, pH 8.0; and 0.01% polysorbate 20 [Tween-20; Thermo Fisher]) with 5% Chelex-100 (Bio-Rad) and 0.2% proteinase K, with subsequent inactivation at 95 °C for 10 minutes. After this was centrifugated, the supernatant was transferred into a clean tube. DNA concentration was determined using the Qubit Broad Range Kit (Thermo Fisher Scientific).

Samples were analyzed with single-molecule molecular inversion probes (smMIPs). The design (Integrated DNA Technologies), as well as the library preparation, were previously published. 15 Further detailed information on smMIP design, library preparation, and sequencing are provided in the eMethods in Supplement 1 .

Detailed information about the immunohistochemical staining for p53 and mismatch repair endonucleases PMS2 and MSH6 can be found in the eMethods in Supplement 1 and original published studies. 9 , 10 In brief, staining for p53 was considered outside reference range when more than 80% of tumor cell nuclei showed strong expression (overexpression) or when there was complete absence of nuclear staining (null expression). Mismatch repair deficiency was defined as total loss of nuclear staining of PMS2 or MSH6 in the presence of a positive internal control.

Early-stage disease was defined as FIGO stage I or II, and advanced-stage was defined as FIGO III or IV. Low-grade EC was defined as grade 1 and grade 2 EC, and high-grade EC was defined as grade 3 endometrioid EC and nonendometrioid EC, according to the latest European Society of Gynaecological Oncology, European Society for Radiotherapy and Oncology, and European Society of Pathology and World Health Organization guidelines. 2 , 16 The included patients in our retrospective cohort received either full lymphadenectomy or no lymphadenectomy, as sentinel lymph node procedure was not routinely incorporated yet.

Statistical analyses were performed on SPSS version 25.0 (IBM) using χ 2 , Fisher exact test, Mann-Whitney U test, Kaplan-Meier survival analysis, and univariable and multivariable Cox regression analysis. For survival curves, including Hall-Wellner confidence bands, we used SAS version 9.4 (SAS Institute). Two-tailed P  < .05 was considered statistically significant. The assumption of proportionality for the included variables was tested with log-minus-log curves and time-dependent covariate (time × covariate). Disease-specific survival (DSS) was defined as time from date of surgery to date of death from EC, all censored by date of last contact. We validated our data with the open access database of Kandoth et al 3 by performing Kaplan-Meier analysis. Method and baseline characteristics can be found in the original article. 3 Data were analyzed February 20 to June 16, 2022.

In total, 689 patients were available with successful DNA analysis, of whom 296 (42.9%) were excluded based on unknown lymph node status in FIGO early-stage disease (eFigure 1 in Supplement 1 ) . Baseline characteristics of the included vs excluded patients are shown in eTable 2 in Supplement 1 . Of 393 included patients, median (range) age was 64.0 (31.0-86.0) years, and median (range) body mass index (calculated as weight in kilograms divided by height in meters squared) was 29.1 (18.0-58.3) ( Table 1 ). Baseline characteristics of the included patients according to the 4 molecular subgroups are shown in Table 1 . Molecular subgroup distribution was 33 patients (8.4%) with POLE -altered disease, 78 patients (19.8%) with MSI disease, 72 patients (18.3%) with TP53 -altered tumors, and 210 patients (53.4%) with NSMP. Low- and high-grade EC were equally distributed in patients with POLE- altered and MSI tumors. Most patients with TP53 -altered tumors had high-grade EC, and most NSMP tumors were low-grade EC ( Table 1 ). The EC-related mortality was highest in the TP53 -altered subgroup (33 patients [45.8%]) compared with the other molecular subgroups (NSMP: 33 patients [15.7%], MSI: 6 patients [7.7%]; POLE -altered: 1 patients [3.0%]). Excluded patients had similarly favorable DSS outcomes for all molecular subgroups within low-grade EC.

For the independent variables in Cox regression models, the proportional hazard assumption was checked. Results of testing the proportional hazard assumption show that all the variables were satisfied.

The 5-year DSS of the included study cohort was worst for TP53 -altered tumors and best for POLE- altered tumors ( Figure 2 A). Across all molecular subgroups, patients with low-grade EC had an outstanding 5-year DSS compared with patients with high-grade EC, varying between 90% to 100% vs 41% to 90% ( P  < .001) ( Figure 2 B). For all the molecular subgroups in patients with grade 1 EC, excellent 5-year DSSs were observed ( Figure 2 C). Patients with grade 2 EC and TP53 -altered or NSMP had 5-year DSSs of 85% to 95% ( Figure 2 D). Within the external validation cohort of 373 patients, survival outcomes were similarly distributed across all the molecular subgroups, with 5-year DSSs varying between 98% to 100% in low-grade EC and 62% to 100% in high-grade EC ( P  = .02) (eFigure 2 in Supplement 1 ).

In multivariable analysis of the entire cohort, high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P  < .001), TP53 -altered (HR, 1.76; 95% CI, 1.04-2.95; P  = .03), and FIGO advanced-stage (HR, 4.26; 95% CI, 2.50-7.26; P  < .001) disease were independently associated with reduced DSS. Among patients with low-grade EC, FIGO advanced stage was independently associated with a reduced DSS, but none of the of molecular subgroups were. However, the number of events was low and the estimated HR’s were of similar magnitude as in the entire cohort ( Table 2 ). Among patients with high-grade EC, only FIGO advanced-stage remained associated as an independent prognostic factor for a reduced DSS (eTable 3 in Supplement 1 ). Including the diagnostic year in the multivariable Cox regression analyses did not change the results of the Cox regression analyses.

This cohort study assessed whether molecular profiling is associated with outcomes in patients with low-grade EC. Interestingly, patients with low-grade EC had very favorable 5-year DSSs independent of the molecular subgroups compared with patients with high-grade EC. Furthermore, high-grade EC, as well as TP53 -altered tumors and FIGO advanced-stage disease, were independently associated with decreased DSS. Among patients with low-grade EC, none of the molecular subgroups were independently associated with reduced DSS.

Our study supported previous findings 3 , 13 regarding the excellent prognosis for POLE -altered EC, good or intermediate prognosis for MSI and NSMP EC, and poor prognosis for TP53 -altered tumors when analyzing all histological subtypes. Moreover, this study illustrated that the molecular subgroups were mainly discriminative among high-grade EC. 3 , 8 To our knowledge, no previous studies have evaluated outcomes for the molecular subgroups within patients with low-grade EC. We analyzed the open access data of Kandoth et al 3 to validate our results.

Molecular profiling has been proposed to be performed routinely in all patients with EC. 2 , 17 However, as most patients with EC are diagnosed with low-grade disease, it is questioned whether this strategy is beneficial and cost-effective. Our data on low-grade EC demonstrate that full molecular profiling may not be necessary (except for screening for Lynch syndrome). 18 Multivariate analyses did not show any statistically significant association of the molecular subgroups among patients with low-grade EC. However, the number of events was low in this subgroup analysis. Analyzing the HRs, the high HR of TP53 -altered tumors could still be associated with a reduced DSS in patients with low-grade EC. We question whether this is mainly attributable to grade 2 EC, as shown in the DSS curve of TP53 -altered tumors within grade 2 EC. Poor interobserver reproducibility is mainly observed within grade 2 and 3 EC; in these patients, the use of immunohistochemical or molecular markers could be recommended, eg, TP53 genomic or expression analysis in patients with doubtful low-grade (grade 2) EC. 4 , 8 , 19 , 20 In this way, binary grading (low vs high) with molecular profiling or immunohistochemistry could be optimized with respect to reproducibility. 2

Molecular profiling is demanding for health care facilities and comes with high costs, which can be especially challenging in low-income countries. Therefore, primary clinical management of EC should be guided based on morphological tumor characteristics, consideration of immunohistochemistry in doubtful cases, and selective molecular profiling in patients with high-grade or advanced-stage disease to guide adjuvant treatment decisions. 21

To our knowledge, this is the first study to address the prognostic relevance of molecular profiling in low-grade EC. Our study consisted of a large study population, with known lymph node status in FIGO early-stage disease to prevent bias by undiagnosed stage III. Furthermore, our results are comparable with the data of the Cancer Genome Atlas research network. 3

This study has a few limitations, including those owing its retrospective design. First, differences in the methods between the included studies exist. More than 80% of the cohort was assessed with complete molecular profiling and less than 20% with the immunohistochemistry surrogates of molecular profiling according to the Proactive Molecular Risk Classifier for Endometrial Cancer criteria. However, immunohistochemistry surrogate analysis has been established as a reliable alternative for molecular profiling. 13 Second, the original diagnosis was used without centralized pathology review; however, slides were from large referral hospitals, and diagnoses were made by expert gynecological pathologists. This makes our study applicable to daily practice. Third, race and ethnicity have not been reported in our study. Although we fully agree that these patients’ race and ethnicity might impact outcomes in several diseases, within Europe they are not routinely documented in patient files. 22 To evaluate whether race and ethnicity might have impacted our results, we performed additional analyses within the Kandoth et al open access database. 3 Race was not statistically different between patients with low- vs high-grade EC or between EC-related mortality. 3 However, in patients with Black race, TP53 -altered tumors was more frequently present, supporting previous findings of a study by Lu et al 23 that these women more often were diagnosed with nonendometrioid EC. Therefore, it seems probable that molecular subgroups override the prognostic relevance of race. Fourth, patients were diagnosed between 1994 and 2018, a time spanning more than 24 years, and this could have biased the survival findings because of different treatment strategies over time. Including the diagnostic year in the multivariable Cox regression analyses did not change the results of the Cox regression analyses. Furthermore, although there were significantly more patients with low-grade EC among the excluded patients, the DSS for excluded patients showed similar favorable outcomes for all molecular subgroups within low-grade EC.

The findings of this cohort study suggest that routine molecular profiling would not be beneficial in patients with low-grade EC due to their excellent prognosis independent of molecular subgroup. Our data demonstrate the importance of primary diagnostic tumor grading and do not support routine molecular profiling in low-grade EC as a cost-effective approach.

Accepted for Publication: October 21, 2022.

Published: December 16, 2022. doi:10.1001/jamanetworkopen.2022.47372

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Vrede SW et al. JAMA Network Open .

Corresponding Author: Johanna M. A. Pijnenborg, MD, PhD, Department of Obstetrics and Gynaecology, Radboud University Medical Center, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB, Nijmegen, the Netherlands ( [email protected] ).

Author Contributions: Drs Vrede and Pijnenborg had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vrede, Kasius, Boll, van Weelden, van der Putten, Reijnen, Pijnenborg.

Acquisition, analysis, or interpretation of data: Vrede, Kasius, Bulten, Huvila, Colas, Gil-Moreno, Vos, van Altena, Asberger, Sweegers, van Weelden, van der Putten, Amant, Visser, Snijders, Küsters-Vandevelde, Kruitwagen, Matias-Guiu, Weinberger, Reijnen, Pijnenborg.

Drafting of the manuscript: Vrede, Sweegers, Kruitwagen, Reijnen, Pijnenborg.

Critical revision of the manuscript for important intellectual content: Vrede, Kasius, Bulten, Huvila, Colas, Gil-Moreno, Boll, Vos, van Altena, Asberger, van Weelden, van der Putten, Amant, Visser, Snijders, Küsters-Vandevelde, Matias-Guiu, Weinberger, Reijnen, Pijnenborg.

Statistical analysis: Vrede, Reijnen.

Administrative, technical, or material support: Vrede, Huvila, Colas, van Altena, Asberger, Sweegers, van Weelden, van der Putten, Snijders, Küsters-Vandevelde, Matias-Guiu, Reijnen, Pijnenborg.

Supervision: Kasius, Bulten, Gil-Moreno, Boll, van der Putten, Amant, Kruitwagen, Matias-Guiu, Weinberger, Pijnenborg.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: Astrid Eijkelenboom, PhD (Tumor Genetics, Radboud University Medical Center) helped with the interpretation of complex cases of molecular profiling and was not compensated for this work.

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Advances in Endometrial Cancer Research

Researchers are testing certain targeted therapies for some types of endometrial cancer.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat endometrial cancer , which is a type of uterine cancer . The other type,  uterine sarcoma , is much less common and can be more aggressive and harder to treat.

There are two main subtypes of endometrial cancers: endometrioid and non-endometrioid. Both occur in the inner lining of the uterus, but they look different under a microscope.

• Endometrioid tumors are more common (they make up 75% to 80% of uterine cancers), are typically diagnosed at an early stage, and may have a favorable prognosis .
• Non-endometrioid tumors (including serous , clear cell , carcinosarcoma , and other, rarer types of endometrial cancer) are often more aggressive and have a poor prognosis.

This page highlights some of the latest research in endometrial cancer, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Endometrial Cancer

There is no standard screening test for endometrial cancer. Researchers are exploring a variety of ways to detect endometrial cancer before symptoms develop. This includes studying genetic risk factors that increase the risk of endometrial and other cancers.

Abnormal bleeding: Early-stage endometrial cancer and even atypical hyperplasia of the endometrium (which is not cancer but can become cancer) can cause vaginal bleeding in postmenopausal women. Although bleeding can have many causes, research shows that most postmenopausal women with endometrial cancer had abnormal vaginal bleeding before diagnosis. This confirms the value of follow-up testing in women who have this symptom.

New biomarkers: Scientists are looking at potential biomarkers to further improve diagnosis of early endometrial cancer. A biomarker is a molecule found in blood or other tissues that is a sign of a condition or disease. Research has shown that it's possible to detect endometrial cancer biomarkers from minimally invasive, lower genital tract samples. 

In the  DETECT Study , for example,  researchers from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) are studying ways to detect endometrial cancer in samples collected using vaginal tampons. Scientists are comparing biomarkers in both tissue and tampon samples collected from women who are having a hysterectomy for endometrial cancer, and from women having a hysterectomy for an unrelated benign condition. Researchers hope to find biomarkers that may eventually lead to noninvasive early detection approaches. This study is also designed to reach a racially diverse group of women.

Researchers funded by NCI’s Early Detection Research Network (EDRN) , a network of institutions developing biomarkers to detect cancer in its early stages, designed a test called PapSEEK that analyzes cells from the lining of the uterus. In a research study, the test identified cancer-related DNA alterations in most women with known endometrial cancer, but also in a few women without the disease.

More studies of PapSEEK are needed before the test will be ready for use in patient care.

Familial genetic risk: Lynch syndrome is an inherited DNA repair disorder in which people have a higher-than-normal risk of developing certain cancers, including endometrial cancer, colon cancer, and, less frequently, ovarian cancer. About 5% of endometrial cancers are caused by Lynch syndrome. It is recommended that all women diagnosed with endometrial cancer be tested for this disorder. This will aid in treatment decisions and also help with prevention and screening of other cancers in the patient and their blood relatives.

Advances in Endometrial Cancer Treatment

Surgery is the standard treatment for early-stage endometrial cancer. Additional treatment, depending on the stage of disease and other factors, may include radiation with or without chemotherapy , hormone therapy , immunotherapy , and some targeted therapies. Several new treatments for advanced disease have become available. (For a complete list of all currently approved drugs, see Drugs Approved for Endometrial Cancer .)

Molecular Subtypes

One area that is changing practice is determining the molecular subtype s of cancers and deciding treatment according to type. Funded by the Cancer Genome Atlas Program , researchers have found that there are four molecular subtypes of endometrial cancer . These subtypes differ in how likely it is that the cancer will come back after treatment.

Doctors are now using these subtypes to help choose the best treatments for certain patients with endometrial cancer. Molecular analysis of endometrial cancers is now recommended for all newly diagnosed patients and can be used to guide treatment decisions in selected subtypes. This includes intensifying treatment where needed, or reducing the intensity of treatment if it's shown to be safe and equally effective.

Immunotherapy

Immunotherapies help the immune system to better fight cancer. Immune checkpoint inhibitor s, a type of immunotherapy, have shown promise in treating certain forms of endometrial cancer. 

These drugs are especially useful in tumors that have defects in a specific DNA repair process, called mismatch repair. Tumors with  mismatch repair deficiency ( dMMR ) develop a large number of DNA  mutations , a condition called high microsatellite instability ( MSI -H). Such tumors are particularly vulnerable to treatment with immunotherapy alone or immunotherapy in combination with other therapies.

Endometrial cancers that develop in people with Lynch syndrome  are dMMR/MSI-H. In addition, around one-third of people with endometrial cancer that is not due to an inherited defect in DNA repair also have dMMR/MSI-H cancers. 

Role of Immunotherapy in Treating Endometrial Cancer Expands

Adding immune checkpoint inhibitors to standard treatment provides substantial benefits.

The immune checkpoint inhibitor   pembrolizumab (Keytruda) has been approved for treating patients with advanced endometrial cancer that is dMMR or MSI-H, cannot be removed surgically, and has gotten worse after other treatments. A different immune checkpoint inhibitor, dostarlimab , is also used for advanced endometrial cancer that is dMMR and is not responding to chemotherapy. 

When combined with chemotherapy, both drugs have been shown to extend the time until disease recurs . This applies to patients with newly diagnosed advanced stage endometrial cancer or those with a first recurrence after radiation therapy. 

The chemotherapy/dostarlimab combination was approved for use in patients with dMMR cancers. It is expected that the NCI-sponsored trial of chemotherapy/pembrolizumab will be approved for dMMR patients.  The pembrolizumab study suggests there may also be benefit of the combination for patients who do not have dMMR cancers, but conclusions are pending.

Other advances include:

• An NCI-sponsored study is testing whether combining the drugs nivolumab and ipilimumab is better than nivolumab alone in shrinking tumors in patients with recurrent endometrial carcinoma that has progressed after earlier treatment with an immune checkpoint inhibitor. The combination of these two drugs has been found to shrink or stabilize other dMMR cancers, but this has not been studied in endometrial cancer until now.
• Pembrolizumab has also been approved to be used together with the targeted therapy lenvatinib (Lenvima) for some patients with advanced endometrial cancer that is not MSI-H or dMMR and has gotten worse after other treatments. A 2022 clinical trial showed that combining the two drugs led to longer progression-free survival and overall survival among patients than using chemotherapy.
• Researchers are also examining the role of adding pembrolizumab to standard radiation therapy for early-stage endometrial cancer that is MSI-H or dMMR.

Targeted Therapy

Targeted therapies are drugs or other substances that interfere with specific molecules , or targets, to block the growth and spread of cancer with less harm to normal cells.

Several targeted therapies are being studied for treating advanced endometrial cancer. Some examples include:

• One NCI-sponsored trial is studying how well the drugs olaparib (Lynparza) and cediranib maleate (Recentin) work in treating patients with endometrial cancer that has come back, does not respond to treatment, or has spread elsewhere in the body. These drugs may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase 2 clinical trial is now testing three additional combinations of targeted therapies .
• A new trial is testing the combination of olaparib with the chemotherapy drug temozolomide in people with a type of uterine sarcoma called leiomyosarcoma . The hope is that using both drugs together will work better to treat the disease than giving either drug alone. 
• Another trial is  testing whether adding certain targeted therapies to chemotherapy will shrink tumors in patients with one of two rare types of endometrial cancer that have excess amounts of a protein called HER2 (also called HER2 positive cancer). The treatment will target the HER2 protein and will be given in a new form, a subcutaneous shot (under the skin), rather than patients having another IV infusion .

Treatment Combinations

Radiation therapy and cisplatin: An NCI randomized phase 2 trial is comparing the combination of radiation therapy and cisplatin with radiation therapy alone in treating patients with endometrial cancer that has come back. The trial is now closed and researchers are analyzing the results.

Surgery and chemotherapy versus surgery and chemoradiation : An NCI-funded study found that, among women with  locally advanced endometrial cancer, those who received radiation in addition to chemotherapy (chemoradiation) after surgery had the same rate of cancer recurrence as those who received chemotherapy without radiation. More research is needed to determine whether specific groups of patients would benefit from radiation.

Rising Endometrial Cancer Rates and Disparities

Unlike most other cancers in the United States, endometrial cancer has increased in both incidence and death rates in recent years. These changes reflect increases in aggressive (non-endometrioid) subtypes of uterine cancer, with rates of endometrioid subtypes having remained fairly stable.

Recent studies have shown that these increases are seen in all racial and ethnic groups. However, a 2019 study from NCI showed that Black women have the highest incidence rates and poorer survival than women in other racial and ethnic groups . In a 2022 NCI study, Black women had more than twice the rate of deaths from uterine cancer overall compared with other racial and ethnic groups . This may be due to a higher frequency of the serous subtype of endometrial cancer in Black women, but scientists are studying why this might be the case.

The reasons for the increases in non-endometrioid subtypes and the disparities across groups are not clear, but NCI-funded studies are seeking to understand their origin. For example:

• In addition to studying biomarkers in tampon specimens, the aforementioned DETECT study has expanded their aims to investigate possible sources of these disparities, such as differences in risk factors, in molecular markers and in care delays.
• As part of NCI's Cancer Moonshot Program , researchers at Ohio State University will examine the genomics of 350 Black and 350 white women with higher risk endometrial cancers. Scientists hope to get a better understanding of the underlying biology of these tumors in order to better personalize treatment.
• The Social Interventions for Support During Treatment for Patients with Endometrial Cancer (SISTER Study) will compare whether weekly support groups led by peer supporters, 1-on-1 peer support check-ins, or enhanced usual care work better to support Black patients with endometrial cancer during treatment. Researchers hope to see if social interventions can provide support and improve the well-being and quality of life of patients with endometrial cancer.
• In the NIH-funded, Multilevel determinants of racial disparities in receipt of guideline-concordant endometrial cancer treatment , researchers at Ohio State University will analyze data from NCI’s Surveillance, Epidemiology, and End Results (SEER)  Medicare database and conduct interviews with Black women with endometrial cancer. They hope to find out what causes the differences in how this group gets treated compared to the recommended guidelines for treatment. 
• The Carolina Endometrial Cancer Study seeks to address this gap by analyzing endometrial tumors to identify genetic details and guide treatment strategies. Women from across the state of North Carolina are being recruited, with a goal of half the participants being Black.

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and the world, are seeking ways to address uterine cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes.

• The Endometrial Specialized Programs of Research Excellence (SPOREs) promotes collaborative translational cancer research. This group works to improve prevention and treatment approaches, along with molecular diagnostics, in the clinical setting to help patients with endometrial cancer.
• NCI”s Division of Cancer Prevention (DCP) is addressing rising endometrial cancer rates by supporting gynecologic cancer prevention research and developing concepts for future studies. 
• Approaches to Identify and Care for Individuals with Inherited Cancer Syndromes seeks the best approaches to identify those with an inherited cancer syndrome and provide appropriate follow-up care.
• The NCI-funded  Colon Cancer Family Registry has established an international cohort of thousands of colorectal cancer patients, their relatives, and other individuals at increased risk of colorectal and other cancers, including endometrial cancer. More than 10,000 families from the United States, Canada, Australia, and New Zealand have been registered. The database includes more than 2,000 individuals with Lynch syndrome from 781 families. 
• The Epidemiology of Endometrial Cancer Consortium (E2C2) is an NCI-supported consortium studying the causes and origins of this cancer through collaboration among investigators. The goal of E2C2 is to combine data across studies to better understand endometrial cancer.

Clinical Trials for Uterine Cancer

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for the treatment of both endometrial cancer and uterine sarcoma .

Endometrial Cancer Research Results

The following are some of our latest news articles on endometrial cancer research:

• Immunotherapy’s Role in Treating Endometrial Cancer Expected to Grow
• Uterine Cancer Death Rates Rising, Highest Among Black Women in the United States
• Trastuzumab May Improve Survival in Women with Rare Endometrial Cancer
• Women Experience More Side Effects from Pelvic Radiation than Realized
• Can Some Women Treated for Endometrial Cancer Forgo Radiation after Surgery?
• Study Shows Incidence Rates of Aggressive Subtypes of Uterine Cancer Rising

View the full list of Uterine Cancer Research Results and Study Updates .

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Major clinical research advances in gynecologic cancer in 2021

Jeong-yeol park.

1 Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Jung-Yun Lee

2 Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Korea.

Yoo-Young Lee

3 Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Seung-Hyuk Shim

4 Department of Obstetrics and Gynecology, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea.

Dong Hoon Suh

5 Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea.

Jae-Weon Kim

6 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea.

Associated Data

In the 2021 series, we not only summarized the major clinical research advances in gynecologic oncology but also added discussions to every part, based on communications at the conference. A review of cervical cancer included adjuvant treatments such as radiation and chemoradiation (concurrent or sequential) after radical hysterectomy in early cervical cancer, and immune checkpoint inhibitors in advanced, recurrent, and metastatic disease. Ovarian cancer research included studies of secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer, and various trials of immune checkpoint inhibitors with or without vascular endothelial growth factor inhibitors and conventional chemotherapy. The rechallenge of poly (ADP-ribose) polymerase inhibitor maintenance in heavily pretreated ovarian cancer were also addressed. For uterine corpus cancer, dostarlimab (anti-programmed cell death protein 1 antibody) alone, or a tyrosine kinase inhibitor in combination with pembrolizumab for advanced, metastatic, or recurrent endometrial cancer were reviewed. The survival differences between the intensive and minimalist follow-up protocols were also described. In this review, we compared salpingectomy with delayed oophorectomy and salpingo-oophorectomy in terms of quality of life in BRCA 1 and 2 pathogenic variant carriers.

INTRODUCTION

The Journal of Gynecologic Oncology review group has held a conference and compiled a list of major clinical studies on gynecologic cancer since 2020. With support from the Asian Society of Gynecologic Oncology (ASGO), a review course titled, “Major Clinical Advances in Gynecologic Cancer” was held at Daeyang AI Center at Sejong University on December 11, 2021 ( Table S1 ).

In this review, we summarized and discussed the major clinical research on gynecologic cancer in 2021 ( Table 1 ).

ATR, ataxia-telangiectasia and Rad3-related; DESKTOP, Descriptive Evaluation of preoperative Selection KriTeria for Operability; MMRd, mismatch repair-deficient; MMRp, mismatch repair-proficient; MSI-H, microsatellite instability-high; OS, overall survival; PARPi, poly (ADP-ribose) polymerase inhibitor.

CERVICAL CANCER

The major cervical cancer research findings reported in 2021 can be summarized in the following five categories:

• 1) The STARS trial investigated the role of adjuvant therapy after radical hysterectomy [ 1 ].
• 2) The OUTBACK trial examined outback chemotherapy after concurrent chemoradiation therapy (CCRT) in locally advanced cervical cancer [ 2 ].
• 3) The KN826 [ 3 ] & EMPOWER trials [ 4 ] explored the role of immunotherapy in first- and second-line chemotherapy.
• 4) The innovaTV 204 [ 5 ] study aimed to find a new target agent with a higher response rate in advanced, metastatic, and recurrent cervical cancer.
• 5) The CONCERV trial prospectively evaluated the feasibility of conservative surgery in early-stage, low-risk cervical cancer [ 6 ].

1. STARS trial

The STARS trial was a phase III randomized controlled trial that compared the effects of adjuvant radiation therapy (RT), CCRT, and sequential chemoradiation therapy (SCRT) in the International Federation of Gynaecology and Obstetrics (FIGO) stage IB–IIB patients with one or more risk factors for recurrence after radical hysterectomy [ 1 ]. The histological types included squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. The risk factors included lymph node metastasis, positive parametrium, positive margins, lymphovascular space involvement, and deep stromal invasion. It was possible to participate in the study if the patient had one or more risk factors. In this study. a total of 1,048 patients were enrolled and randomized into the RT, CCRT, and SCRT groups, in a ratio of 1:1:1. The primary endpoint was disease-free survival (DFS). In the intention-to-treat and per-protocol populations, the SCRT group had significantly better DFS than the RT group. Moreover, the overall survival (OS) of the SCRT group was significantly better than that of the RT group. However, there were no significant differences in DFS and OS between the CCRT and RT groups. There were also no significant differences in DFS and OS between the SCRT and CCRT groups. Therefore, the authors concluded that SCRT had a greater survival benefit than RT for post-radical hysterectomy and high-risk cervical cancer.

Efforts to find appropriate adjuvant therapy in intermediate- and high-risk groups after radical hysterectomy for early-stage cervical cancer have been ongoing for a long time. Regarding adjuvant therapy in the high-risk group, CCRT with 5-fluorouracil+cisplatin showed a significant improvement in survival compared to RT in the Intergroup trial 0107/GOG 109/SWOG-8797 study in the early 2000s [ 7 ]. The survival benefit of CCRT was reconfirmed in a population-based cohort study using the National Cancer Database [ 8 ]. In recent years, CCRT has become the standard adjuvant therapy for high-risk patients undergoing radical hysterectomy. The NOGGO-AGO intergroup study compared CCRT with cisplatin and SCRT composed of 4 cycles of paclitaxel + carboplatin followed by RT [ 9 ]. In that study, there was no difference in the survival rate between the CCRT and SCRT groups. However, CCRT and SCRT show different toxicity profiles. To date, SCRT has not yet been able to replace CCRT. In the STARS trial, SCRT reduced the risk of recurrence by 48% and 35% compared with RT and CCRT, respectively. Adverse events in the SCRT group were not different from those in the CCRT group, and gastrointestinal adverse events were fewer in the SCRT group than in the CCRT group [ 1 ]. One of the possible mechanisms for better survival in SCRT compared with RT or CCRT is the short interval between surgery and adjuvant treatment. Another mechanism suggested that paclitaxel + cisplatin is a better regimen for decreasing distant failure because weekly cisplatin is a radiosensitizer and has no advantage for distant control. Of note, the STARS trial had several limitations. First, the study design was problematic. The primary endpoint was not that CCRT and SCRT were compared, but that CCRT or SCRT would have a survival benefit compared to RT. Second, stratification according to risks was not performed when patients were randomized to three groups (RT, CCRT, and SCRT). Third, approximately 20% of patients received neoadjuvant chemotherapy. Fourth, the completion rate of treatment was 62% in the CCRT group, which was much lower than the 73% in the SCRT group. Owing to these problems, the authors also commented that SCRT may be a good treatment strategy and suggested that chemotherapy should be performed first, followed by RT, especially in a resource-limited country where the waiting time for RT is long because of a lack of RT resources. Further studies comparing the roles of CCRT and SCRT are necessary because the intermediate- and high-risk groups are mixed in the STARS trial. The NRG 0724 study comparing CCRT with cisplatin and CCRT with cisplatin followed by four cycles of paclitaxel + carboplatin, as adjuvant therapy for high-risk groups, and the GOG 263/KGOG 1008 study comparing adjuvant RT and CCRT with cisplatin in the intermediate-risk group are both still ongoing. Appropriate adjuvant therapy after radical hysterectomy will have to wait for the results of these studies.

2. OUTBACK trial

The OUTBACK trial was a phase III randomized controlled trial evaluating the role of outback chemotherapy after CCRT in locally advanced cervical cancer patients with FIGO stage IB1 with lymph node metastasis, IB2, II, IIIB, and IVA, by randomizing them into a group receiving CCRT only and additional adjuvant therapy after CCRT [ 2 ]. Patients with nodal metastasis in the L3-L4 para-aortic area were excluded from the study. The histological types included squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. Additional chemotherapy (ACT) was 4 cycles of paclitaxel (155 mg/m 2 ) and carboplatin (AUC 5) every 3 weeks. A total of 926 patients were randomized 1:1 to receive CCRT and ACT. The primary endpoint was OS, and there were no significant intergroup differences between the two groups.

The primary concern with CCRT, the standard treatment for locally advanced cervical cancer, is the possibility of distant failure. Therefore, adjuvant systemic chemotherapy (outback chemotherapy) has been considered a solution to reduce distant failure after CCRT. In a randomized controlled trial published in 2011, CCRT with gemcitabine + cisplatin followed by gemcitabine + cisplatin showed a significantly improved survival rate compared to CCRT with gemcitabine + cisplatin [ 10 ]. Grade 3 and 4 toxicities were significantly higher in the ACT group. In contrast, outback chemotherapy did not improve patient survival in the OUTBACK trial. OUTBACK trials have several limitations. First, the rate of failure to implement adjuvant chemotherapy is high. For example, 22% of the patients did not start adjuvant chemotherapy, and 38% did not complete adjuvant chemotherapy. Moreover, since only four cycles of adjuvant chemotherapy are used, low-dose intensity is also a potential concern. One strategy to reduce distant failure after CCRT in the future is the use of immunotherapy during and after CCRT. A study comparing CCRT and CCRT + durvalumab (CALLA trial) has completed patient registration, and a study comparing CCRT and CCRT + pembrolizumab (KEYNOTE-A18/ENGO-cx11) is currently ongoing.

3. KeyNote-826 trial

Following the positive results of the GOG-240 trial, showing a significant improvement in survival by adding bevacizumab to first-line chemotherapy for persistent, recurrent, and metastatic cervical cancer, platinum-based chemotherapy plus bevacizumab has become standard care. Although the response rate of immune checkpoint inhibitors in persistent, recurrent, and metastatic cervical cancer has been reported in several studies, there have been no phase III studies showing improved survival following treatment. The KeyNote-826 study is the first phase III study to show that when immune checkpoint inhibitors are added to standard care for persistent, recurrent, and metastatic cervical cancer, a significant improvement in survival is found. The results of this study will likely lead to a significant change in the treatment of cervical cancer. The KeyNote-826 trial was a phase III randomized controlled trial showing an additional improvement in survival rate by adding immunotherapy to standard care [ 3 ]. A total of 617 patients with persistent, recurrent, and metastatic cervical cancer were randomized to receive paclitaxel + cisplatin/carboplatin ± bevacizumab, or paclitaxel + cisplatin/carboplatin ± bevacizumab + pembrolizumab (up to 35 cycles). DFS and OS were significantly improved in the pembrolizumab group in the all-comers population. The safety profile was manageable by adding pembrolizumab.

4. EMPOWER trial

In the treatment of cervical cancer, the activity of immune checkpoint inhibitors as a second-line, or higher, chemotherapy has been introduced through several studies, but there has not been a phase III study showing the superiority of immune checkpoint inhibitors compared to cytotoxic chemotherapy corresponding to the current standard of care. The EMPOWER trial is the first phase III study to show the superiority of immune checkpoint inhibitors over second-line treatment in the treatment of recurrent, metastatic cervical cancer. The results of this study will likely lead to a paradigm shift in the treatment of cervical cancer. The EMPOWER trial is a phase III randomized controlled trial that showed the efficacy of immunotherapy in recurrent, metastatic cervical cancer resistant to platinum-based chemotherapy previously performed for persistent, metastatic, and recurrent cervical cancer [ 4 ]. The histological types included squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. A total of 608 patients were randomized 1:1 to either cemiplimab or physician-choice chemotherapy. Chemotherapy included pemetrexed, gemcitabine, topotecan, and irinotecan. The primary endpoint was OS. Compared to chemotherapy, cemiplimab demonstrated significant improvement in OS in all populations, including squamous cell and adenocarcinoma populations.

5. InnovaTV 204 trial

Tisotumab vedotin (TV) is another drug that has recently shown promising activities in the treatment of cervical cancer. TV is an antibody-drug conjugate that targets tissue factors. This was evaluated in the Innova TV 204 phase II trial [ 5 ]. Patients included in the study had recurrent or extrapelvic metastatic cervical cancer and had received two or fewer at least two prior systemic chemotherapy regimens for recurrent or metastatic disease. Patients had progressive disease during or after doublet chemotherapy (paclitaxel plus either platinum or topotecan) with bevacizumab, if eligible. The histological types included squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. A total of 101 patients were evaluated, with an objective response rate (ORR) of 24%. The complete response, partial response, and stable disease rates were 7%, 17%, and 49%, respectively. Most tumor responses were rapid, with a median response of 1.4 months. The median duration of response (DOR) was 8.3 months (95% confidence interval [CI]=4.2-not reached) and the median progression-free survival (PFS) was 4.2 months (95% CI=3.0–4.4 months). Furthermore, TV had a manageable safety profile.

6. ConCerv trial

The ConCerv trial evaluated the feasibility of conservative surgery in women with early- stage, low-risk cervical cancer [ 6 ]. This study included women with FIGO 2009 stage IA2-IB1 cervical cancer ≤2 cm, without lymphovascular space invasion, a depth of invasion ≤10 mm, and a negative conization margin. Conservative surgery was conization followed by lymph node assessment for women wishing to preserve fertility, and simple hysterectomy with lymph node assessment for women who did not want to preserve fertility. A total of 100 patients were included in this study. The surgery types were conization followed by lymph node dissection in 44 women, simple hysterectomy with lymph node evaluation in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Three patients experienced recurrence within 2 years following surgery, and the cumulative incidence of recurrence was 3.5%.

OVARIAN CANCER

1. secondary cytoreductive surgery (scs) in recurrent ovarian cancer.

The role of SCS in patients with platinum-sensitive recurrent ovarian cancer is controversial. The findings of three multicenter, randomized, phase III trials (DESKTOP III [ {"type":"clinical-trial","attrs":{"text":"NCT01611766","term_id":"NCT01611766"}} NCT01611766 ], GOG-213 [ {"type":"clinical-trial","attrs":{"text":"NCT00565851","term_id":"NCT00565851"}} NCT00565851 ], and SOC-1 [ {"type":"clinical-trial","attrs":{"text":"NCT01611766","term_id":"NCT01611766"}} NCT01611766 ]) have been published [ 11 , 12 , 13 ]. All three trials were distinct in terms of the patient cohort, eligibility criteria for surgery, and center selection ( Table 2 ).

PARP, poly (ADP-ribose) polymerase; DESKTOP, Descriptive Evaluation of preoperative Selection KriTeria for Operability; GOG, Gynecologic Oncology Group; SOC, Surgery or chemotherapy in recurrent Ovarian Cancer.

We noted inconsistent results from the three studies (DESKTOP III and SOC-1 trials vs. GOG-213 trial). One explanation may be related to the difference in bevacizumab usage. In the GOG 213 trial, 84% of patients received bevacizumab. In contrast, in the DESKTOP III and SOC-1 trials, only 23% and 1% of patients received bevacizumab, respectively. Another explanation may be the different processes used in each trial for selecting patients and centers.

The final analysis from DESKTOP III was published in the New England Journal of Medicine in 2021 [ 12 ]. The primary endpoint analysis of the DESKTOP III trial reported a median OS of 53.7 months with surgery and 46.0 months without surgery (p=0.02).

DESKTOP III is the first surgical study to demonstrate a meaningful survival benefit among patients with ovarian cancer, with an acceptable incidence of complications and without a detrimental effect on the quality of life, based on the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score.

The authors emphasized that all patients with a first relapse after a platinum-free interval of at least 6 months should be assessed to determine if surgery is an option, and that the AGO score should be incorporated into the evaluation.

2. Unsatisfactory results from front-line chemo-immunotherapy

Two randomized phase III studies failed to show the benefit of adding immune checkpoint inhibitors to chemotherapy as first-line therapy and for maintenance in patients with newly diagnosed ovarian cancer [ 14 , 15 ].

In IMagyn 050, adding atezolizumab to a chemotherapy plus bevacizumab backbone did not improve PFS compared with chemotherapy plus bevacizumab alone in either the intention-to-treat or programmed death-ligand 1 (PD-L1) positive (immune cells [IC>1%) populations. Exploratory PFS analyses in the PD-L1 IC ≥5% subgroup showed a trend toward atezolizumab (PFS: hazard ratio [HR]=0.64, 95% CI=0.43–0.96).

The JAVELIN Ovarian 100 study did not meet either of its two primary objectives of improving PFS with two avelumab regimens with chemotherapy versus chemotherapy alone. PD-L1 status did not predict the benefit of avelumab treatment, either as maintenance therapy or in combination with chemotherapy. These findings did not concur with results from the JAVELIN Ovarian 200 study. In these two studies, the addition of PD-L1 inhibitors was unsatisfactory. Current attention is focused on doublet or triplet combination trials, including the DUO-O [ 16 ], FIRST/ENGOT-ov44 [ 17 ], KEYLINK-001/ENGOT-ov43 [ 18 ], and ATHENA [ 19 ] studies, which investigated immune checkpoint inhibitors with PARP inhibitors and/or bevacizumab in the first-line setting.

3. Overcoming PARP inhibitor resistance

As more patients receive PARP inhibitors as maintenance therapy as part of first- or second-line treatment, resistance to platinum agents and PARP inhibitors is inevitable. The EFFORT [ 20 ] and CAPRI [ 21 , 22 ] studies use targeting agents involved in DNA damage responses (DDR). OReO ( {"type":"clinical-trial","attrs":{"text":"NCT03106987","term_id":"NCT03106987"}} NCT03106987 ) evaluated PARP inhibitor retreatment in PARP inhibitor responders [ 23 ]. Various DDR inhibitors have been developed for anticancer therapy. PARP, ataxia-telangiectasia, Rad3-related (ATR), and WEE1 are the key components of different DDR pathways. PARP inhibitors are the best-studied class of DDR inhibitors. ATR inhibitors and WEE1 inhibitors are currently being investigated in clinical trials, especially in PARPi-resistant settings. In this review, the results of two phase II studies (EFFORT: WEE1 inhibitor, CAPRI: ATR inhibitor) and one phase III study (olaparib rechallenge with maintenance Olaparib [OReO]) were reviewed.

EFFORT showed that adavosertib (WEE1 inhibitor) alone and in combination with olaparib demonstrated efficacy in patients with PARP inhibitor-resistant ovarian cancer irrespective of BRCA status (ORR 29% from adavosertib+olaparib, ORR 23% from adavosertib alone) [ 20 ]. CAPRI evaluated the combination of a PARP inhibitor (olaparib) and ATR inhibitor (ceralasertib) in patients who were on a PARP inhibitor and experienced disease progression [ 22 ]. They showed that olaparib and ceralasertib were well-tolerated (no grade 4/5 toxicities) and showed clinical activity (ORR 46%) in platinum-sensitive patients who had progression with prior PARP inhibitors. However, there was no objective response in 12 platinum-resistant patients [ 21 ].

OReO/ENGOT Ov-38 is a randomized, double-blind trial, and the first phase III study to evaluate PARPi maintenance rechallenge. Patients enrolled in the BRCA1/2 mutated (BRCAm) (≥18 months [m] first-line [1 L] or ≥12 m 2 L + prior PARPi exposure [PPE]) and non-BRCAm (≥12 m 1 L or 6 m 2 L + PPE) cohorts were randomized (2:1; stratified by prior bevacizumab [yes vs. no] and prior lines of PBC [≤3 vs. ≥4]) to olaparib (O) tablets (300 mg bid [or 250 if 300 not previously tolerated]) or placebo (P) until progression. The primary endpoint was investigator-assessed PFS using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. OReO showed that, in a heavily pretreated ovarian cancer population, rechallenge with maintenance olaparib following response to platinum-based chemotherapy provided a statistically significant improvement in PFS compared with placebo, regardless of the BRCAm cohort (HR=0.57, 95% CI=0.37–0.87; nonBRCAm cohort: HR=0.43, 95% CI=0.26–0.71).

Future studies must investigate the following questions: 1) Who will benefit from PARP inhibitor retreatment? 2) Is the current “cut-off” of the previous PARP inhibitor duration the most appropriate? 3) Can we expect the same responses between women with progression prior to PARP inhibitors and those who progress after completion of the PARP inhibitor? 4) Are there several different effects if the PARP inhibitor is changed, for example, olaparib to olaparib/niraparib to olaparib?

UTERINE CORPUS CANCER

The incidence and mortality of endometrial cancer have been increasing [ 24 , 25 , 26 ]. The mortality rate is projected to rise by 19% between 2014 and 2035, and to 9 deaths per 100,000 females by 2035 [ 27 ]. The majority of endometrial cancers are diagnosed in the early stages and have a favorable prognosis. Survivorship has been highlighted and many gynecologic oncologists have enquired about the optimal follow-up protocol for patients with endometrial cancer. Routine cytology is not conducted as part of pelvic examination during follow-up [ 28 ] and the role of ultrasound, tumor markers, or computed tomography (CT) scans has also been questioned. To date, evidence for the ideal follow-up intervals is lacking. The TOTEM study compared the OS of an intensive (INT) vs. minimalist (MIN) 5-year follow-up regimen for endometrial cancer [ 29 ].

Endometrial cancer with unfavorable biomarkers, such as p53 abnormality [ 30 ], HER2 overexpression [ 31 ] or recurrent endometrial cancer, are the main reasons for the increased mortality among patients with endometrial cancer. Additionally, the search for effective new treatment has been met with limited success [ 32 , 33 ]. Significant improvement in recurrence-free survival among patients with high-risk endometrial tumors with p53 abnormality is achieved by adding chemotherapy during and after adjuvant radiation [ 34 ], regardless of the histologic type. The NRG Oncology GY-026 study investigated the treatment of HER2 positive endometrial cancer by adding trastuzumab to paclitaxel and carboplatin and found that it increased OS [ 32 ]. The GY-026 study is an international three-arm, phase III study of women with primary stage I–IV, HER2-positive endometrial cancer. The study examined the role of mono (trastuzumab) or dual inhibition of HER2 (trastuzumab/pertuzumab) in addition to cytotoxic chemotherapy.

In addition to p53 abnormality and HER2 overexpression, patients with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), DNA polymerase epsilon (POLE) mutation, and nonspecific molecular profile (NSMP) are also considered distinct subgroups of endometrial cancer [ 35 ]. In contrast to other solid tumors, endometrial cancer is believed to be an ideal target for immunotherapy because of the unique immune landscape of the tumors, including a higher tumor mutation burden. Moreover, dMMR or MSI-H are surrogate markers for high tumor mutations, and are considered a predictive marker for immunotherapy. Consequently, several clinical trials have focused on dMMR or MSI-H tumors treated with immune checkpoint inhibitors in solid tumors, including endometrial cancer [ 36 ]. Recently, the GARNET and KEYNOTE 775 [ 37 ] trials have shown promising results in patients with recurrent endometrial cancer and also dMMR or MSI-H.

In endometrial cancer, only a few randomized controlled trials have been conducted to assess the role of a reduced number of scheduled visits. The contribution of routine serum, cytological, or imaging follow-up in improving OS or quality of life has not been observed. The TOTEM study is a multicenter randomized controlled clinical trial involving two follow-up regimens with different test intensities for endometrial cancer [ 29 ]. Patients with surgically treated endometrial cancer and who were in complete clinical remission as confirmed by imaging and FIGO stages I-IV were included. The patients were stratified by centers and low- or high-risk of recurrence, and then randomized to INT or MIN hospital-based follow-up regimens. In total, 1847 patients were included in the final analysis between 2008 and 2018.

Regarding follow-up protocols for the low-risk group defined as FIGO stage 1A and low-grade, one of the biggest differences between the MIN and INT arms was the lack of routine Pap smear and CT scans in the MIN arm. Routine CT scans were obtained in the 12 th and 24 th months after randomization during the 5-year follow-up in INT arm. The MIN arm was followed up every 6 months for 5 years. The INT arm was followed up every 4 months for the first 2 years, and every 6 months for the latter 3 years. For the high-risk group defined as FIGO stage IA with grade 3 or IB or above, no routine Pap smear, ultrasound, or tumor markers were planned in the MIN arm. However, routine CT scans in the 12 th and 24 th month after randomization were identical between the two arms. In all patients, unscheduled examinations were arranged if there were abnormal test results or clinical suspicion.

Overall compliance with the scheduled follow-up visits was 75.3% (INT 74.7% vs. MIN 75.9%). On the contrary, the mean number of recorded exams (laboratory or imaging) was significantly higher in the INT than in the MIN arms (9.7% vs. 2.9%, p<0.0001). After a median follow-up of 66 months, the 5-year OS rate was 91.3%, 90.6% in the INT arm and 91.9% in the MIN arm, respectively (HR=1.12, 95% CI=0.85–1.48, p=0.429). According to recurrence risk, the 5-year OS rate was 94.1% (INT) and 96.8% (MIN) (HR=1.48, 95% CI=0.92–2.37, p=0.104) in the low-risk group, and 85.3% (INT) and 84.7% (MIN) (HR=0.96, 95% CI=0.68–1.36, p=0.814) in the high-risk group. Health-related quality of life (HRQoL) data were available only for a subgroup of patients (50% at baseline) and did not differ between the arms. As a result, the INT follow-up protocol did not improve OS, even in high-risk patients, nor did it influence HRQoL. Based on these results, the authors suggested that the frequent routine use of imaging and laboratory examinations in these patients should be discouraged.

These findings may be applicable in patients with a low risk of recurrence. However, concerns remain for the high-risk patients. In the TOTEM study, patients with aggressive histology and/or advanced disease accounted for approximately 10% of the entire cohort, which appears to be too underpowered to draw any conclusions. Other limitations include the lack of molecular classification and incomplete data on lymphovascular space invasion and HRQoL. Of note, 80.4% of relapses in the low-risk group were diagnosed with clinical examination combined with other examinations, and 53.2% of relapses were identified with clinical examination and CT scan. This means that imaging and laboratory examinations still play a role in detecting recurrence, but should not be used for routine testing. There are three ongoing clinical trials (ENDCAT [ 38 ], ENSURE [ 39 , 40 ], and OPAL [ 41 ]) that are determining the optimal follow-up protocol for endometrial cancer. However, only patients with stage I or low/intermediate risk are eligible, which means that uncertainty for optimal follow-up in high-risk endometrial cancer may continue unless a new clinical trial for high-risk patients is developed.

Dostarlimab is an anti-programmed cell death protein 1 (PD-1) antibody, and GARNET is a phase I single-arm study of dostarlimab monotherapy in expanded cohorts of multiple tumor types [ 42 ]. The endometrial cancer cohort (A1, A2) included patients with recurrent/advanced dMMR/MSI-H (A1) or MMR-proficient (pMMR)/microsatellite instability-stable (MSS) (A2) endometrial cancer who had ≤2 prior lines of treatment for recurrent or advanced disease, and progression after platinum doublet therapy. Patients received 500 mg Q3W of dostarlimab for the first four cycles, followed by 1,000 mg Q6W, until disease progression or discontinuation. The primary endpoints were ORR and DOR using RECIST. irRECIST was the secondary endpoint.

In the interim analysis [ 43 ], 129 and 161 patients were enrolled in A1 and A2, respectively. pMMR/MSS patients had more aggressive histology (type II, 77.6% vs. 34.3%) and were more heavily pretreated (2 or above prior lines of chemotherapy, 53.8% vs. 36.1%) than dMMR/MSI-H patients. Radiation history was similar between the two groups. Based on RECIST, the ORRs in the dMMR/MSI-H and pMMR/MSS cohorts were 43.5% and 14.1%, respectively. Disease control rates in the dMMR/MSI-H and pMMR/MSS groups were 55.6% and 34.6%, respectively. The median DOR was not reached in either arm at the time of the analysis. The irORR was 44.8% in patients with dMMR/MSI-H and 14.4% in patients with pMMR/MSS. Overall, the efficacy results based on irRECIST were similar to those of RECIST. Most treatment-emergent adverse events were grade 1–2 (75.5%), with 5.5% discontinuation. The manageable toxicity profiles have been reported previously. In August 2021, the FDA approved dostarlimab for adult patients with dMMR recurrent or advanced solid tumors, including endometrial cancer.

Currently, dostarlimab is being evaluated in a phase III clinical trial (RUBY) in combination with standard chemotherapy in patients with recurrent or primary advanced endometrial cancer [ 44 ]. Another PD-1 inhibitor, pembrolizumab, is also being studied in a different phase III clinical trial (NRG GY-018) [ 45 ]. The NRG GY-018 study aimed to determine the efficacy of pembrolizumab in combination with paclitaxel and carboplatin in patients with advanced disease stages (measurable stage III or IVA, stage IVB, and recurrent endometrial cancer stratified by MMR status). A clinical trial with a PD-L1 inhibitor is also ongoing. The AtTEnd/ENGOT-en7 is a multicenter phase III double-blind randomized controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer [ 46 , 47 ].

3. Keynote 775

The Keynote 775 study is a multicenter, open-label, randomized, phase III trial that compared the efficacy and safety of lenvatinib plus pembrolizumab versus treatment of physician’s choice in patients with advanced, metastatic, or recurrent endometrial cancer after one prior platinum-based chemotherapy [ 37 ]. Patients were randomized to receive lenvatinib 20 mg orally QD plus pembrolizumab 200 mg IV Q3W or treatment of the physician’s choice (doxorubicin, 60 mg/m 2 IV Q3W or paclitaxel, 80 mg/m 2 IV Q 3wk on/1wk off). Randomization was stratified by MMR status, and patients with pMMR tumors were further stratified by ECOG performance status, geographic region, and history of pelvic radiation. The primary endpoints were PFS and OS.

In total, 827 patients (697 with pMMR and 130 with dMMR) were randomly assigned to receive either lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median PFS was longer in patients with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months, HR=0.60, 95% CI=0.50–0.72, p<0.001; dMMR population: 10.7 vs. 3.7 months, HR=0.36, 95% CI=0.23–0.57, p<0.001; overall: 7.2 vs. 3.8 months, HR=0.56, 95% CI=0.47–0.66, p<0.001). The median OS was better with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months, HR=0.68, 95% CI=0.56–0.84, p<0.001; dMMR population: not reached vs. 8.6 months, HR=0.37, 95% CI=0.11–0.62, p<0.001; overall: 18.3 vs. 11.4 months, HR=0.62, 95% CI=0.51–0.75, p<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab, and 72.7% of those who received chemotherapy.

This is the first clinical trial showing that a combination of immune checkpoint inhibitors and tyrosine kinase inhibitors led to superior survival rate compared to chemotherapy among patients with recurrent endometrial cancer with prior platinum-based chemotherapy, regardless of MMR status. The benefit appeared to be more prominent in patients with dMMR. In the dMMR subgroup in the Keynote 775 study, 40% of ORR with lenvatinib plus pembrolizumab was observed, which was significantly higher than the 12.3% observed in the chemotherapy group. KEYNOTE 146 [ 48 ] is a baseline study for KEYNOTE 775. It is a multinational, open-label, single-arm study of lenvatinib plus pembrolizumab in patients with selected solid tumors, including endometrial cancer. Among 118 patients with endometrial cancer in this study, 11 showed dMMR with a 63.6% ORR at the 24 th week. Although this was a very promising result, further verification is warranted because of the study’s small sample size. The clinically meaningful activity of lenvatinib plus pembrolizumab was confirmed in the KEYNOTE 775 study. The safety profile of dMMR patients was generally consistent with that of the full study population. Treatment-related adverse events of grade 3 or above were relatively high at 95.3%. Dose reduction, interruption, and discontinuation were observed in 64.1%, 71.9%, and 43.8% of dMMR patients, respectively. Hypothyroidism and hypertension were the most common symptoms observed. The combination of lenvatinib plus pembrolizumab was approved by the FDA only for patients with pMMR or MSS in July 2021. Currently, the combination of lenvatinib and pembrolizumab is being evaluated as a frontline treatment in patients with endometrial cancer. ENGOT-en9/LEAP-001 is a phase III study investigating first-line lenvatinib plus pembrolizumab versus chemotherapy in newly diagnosed patients with stage III, IV, or recurrent endometrial cancer [ 49 , 50 ].

In summary, the strong activity of dostarlimab, an anti PD-1 antibody, was observed in the GARNET study regardless of previous lines of therapy for patients with dMMR endometrial cancer. In the KEYNOTE 775 study, superior OS and PFS with lenvatinib plus pembrolizumab over chemotherapy were observed across all patient subgroups, including MMR status. Multiple studies on immune checkpoint inhibitors in the presence or absence of multiple kinases are ongoing, which may change the standard of treatment for endometrial cancer in the future.

PREVENTION OF GYNECOLOGIC CANCER

The major research results related to the prevention of gynecological cancer reported in 2021 can be summarized into two categories as follows:

• 1) Long-term follow-up results of the UKCTOCS study that evaluated the effectiveness of early ovarian cancer detection [ 51 ].
• 2) A TUBA trial compared salpingectomy with delayed oophorectomy and salpingo-oophorectomy in terms of quality of life in BRCA 1 and 2 pathogenic variant carriers [ 52 ].

1. UKCTOCS trial

The UKCTOCS trial was a randomized controlled trial to determine whether ovarian cancer population screening can reduce deaths due to ovarian cancer [ 51 ]. In this trial, 202,638 women from the general population were randomly assigned to two annual screening groups and a no screening group. One of the annual screening modalities was multimodal screening which consisted of longitudinal CA 125 and second-line transvaginal ultrasonography. The other was ultrasound screening. In the initial report of this trial in 2015, multimodal screening was associated with an increased number of patients diagnosed with stage I-II ovarian cancer, but neither of the two screening methods reduced the risk of ovarian cancer. In 2021, the long-term mortality effects of ovarian cancer screening in the UKCTOCS showed a reduction in stage III or IV disease incidence in the multimodal screening group. However, this reduction did not translate into a reduction in ovarian cancer mortality. Based on this study, general population screening for ovarian cancer is not recommended.

2. TUBA trial

Prophylactic bilateral salpingo-oophorectomy in BRCA 1 and 2 pathogenic mutation carriers has been shown to reduce the risk of ovarian cancer by 96%. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended for patients in their late 30s who are BRCA 1 pathogenic carriers, and patients in their early 40s who are BRCA 2 pathogenic carriers. However, in this case, early menopause is problematic and may lead to a decrease in the quality of life. Recently, based on the theory that high-grade serous carcinoma, the most common type of epithelial ovarian cancer, is of tubal origin, a preventive strategy of first performing only salpingectomy and later performing oophorectomy in BRCA 1 and 2 pathogenic carriers was proposed. Whether this strategy sufficiently reduces the risk of ovarian cancer has not yet been investigated in prospective trials. The TUBA trial was a prospective non-randomized trial that compared the menopause-related quality of life of risk-reducing salpingectomy with delayed oophorectomy and RRSO in BRCA 1 and 2 pathogenic carriers [ 52 ]. This study included 577 BRCA 1 and 2 pathogenic carriers. Of these, 394 underwent risk-reducing salpingectomy, and 154 had RRSO. The menopause-related quality of life was improved in patients who underwent risk-reducing salpingectomy compared to those who underwent RRSO regardless of hormone replacement therapy. Additional follow-up studies are required to determine the oncologic safety of risk-reducing salpingectomies.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to the ‘2021 Team for Major Clinical Research Review’ as follows.

Soon-Beom Kang (Seoul National University, Seoul), Young Tae Kim (Yonsei University, Seoul), Joo-Hyun Nam (University of Ulsan, Seoul), Myong Cheol Lim (National Cancer Center, Goyang), Hee-Sug Ryu (Ajou University, Suwon), Byoung-Gie Kim (Sungkyunkwan University, Seoul) for organizing the review course. Sokbom Kang (National Cancer Center, Goyang), Hee Seung Kim (Seoul National University, Seoul), Maria Lee (Seoul National University, Seoul), Joseph J Noh (Sungkyunkwan University, Seoul), Soo Jin Park (Seoul National University, Seoul), So-Hyun Nam (University of Ulsan, Seoul) for reviewing cervical cancer. Jae Kwan Lee (Korea University, Seoul), Ju Won Roh (CHA University, Goyang), Sung Jong Lee (The Catholic University of Korea, Seoul), Tae Hun Kim (Seoul National University, Seoul), Sang Il Kim (The Catholic University of Korea, Suwon), Hyun-Woong Cho (Korea University, Korea) for prevention. Dae-Yeon Kim (University of Ulsan, Seoul), Seob Jeon (Soonchunhyang University, Cheoan), Kyung Jin Eoh (Yonsei University, Yongin), Woo Yeon Hwang (Seoul National University, Seongnam), Se Ik Kim (Seoul National University, Seoul), Kyeong-A So (Konkuk University, Seoul) for reviewing uterine corpus cancer. Suk-Joon Chang (Ajou University, Suwon), Sook Hee Hong (The Catholic University, Seoul), Tae-Wook Kong (Ajou University, Suwon), Hyun-Jin Choi (Chung-Ang University, Seoul), In Hee Lee (Daegu Catholic University, Daegu), Junsik Park (Yonsei University, Seoul) for reviewing ovarian cancer.

Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Author Contributions:

• Conceptualization: S.D.H., K.J.W.
• Methodology: P.J.Y., L.J.Y., L.Y.Y., S.S.H., S.D.H.
• Project administration: S.D.H., K.J.W.
• Supervision: K.J.W.
• Visualization: S.D.H.
• Writing - original draft: P.J.Y., L.J.Y., L.Y.Y., S.D.H.
• Writing - review & editing: P.J.Y., L.J.Y., L.Y.Y., S.S.H., S.D.H. K.J.W.

SUPPLEMENTARY MATERIAL

Asian Society of Gynecologic Oncology (ASGO) Review Course 2021: major clinical advances in gynecologic cancer

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29F - Worried about endometrial/uterine cancer and have been waiting to see a specialist for 9 months. "Lots of uterine polyps, all over" according to my doctor, plus a whole list of other symptoms, and he still won't take me seriously. Am I overreacting?? Help/advice please!

I have been experiencing a wide range of symptoms and am worried that I might have uterine/endometrial cancer, but my doctor won't take my symptoms seriously. I don't want to jump to the worst-case scenario, but I also don't want to ignore a potentially serious problem. What do I do??

I have always had heavy/painful periods and cramps, but in the past few years, they have been getting worse. About 4-5 years ago, I started having about 1-inch wide blood clots consistently throughout my period as well as a dull aching pain in my right ovary area. I had an internal and external ultrasound done and both came back clear. However, these clots have gotten MUCH larger in the past year and are now about the size of a golf ball on average, and sometimes as large as half of my palm. My periods are VERY heavy now and I have about a dozen of these clots per day.

In October of 2023, I started spotting almost every day for a month and went to a walk-in clinic to ask for more testing as I do not have a family doctor. I also told him about the blood clots and pain. The (older male) doctor told me "I shouldn't worry about it" and that it was "probably stress". Frustrated, I went to another walk-in clinic and wrote down ALL of my symptoms ahead of time so that I wouldn't forget anything. AGAIN, this (male) doctor told me "it's probably nothing", but finally agreed to send me for a transvaginal ultrasound after I pushed for testing.

The waitlist in Canada is very long for these procedures, so their next appointment was in February of 2024. They found evidence of a possible polyp and sent me for a sonohysterogram in March where they found "lots of polyps all over, swollen ovaries, and likely PCOS" according to the doctor who relayed the results to me.

When I asked what I can do and what my next steps should be, he told me that there was "basically nothing we can do" and that he'd refer me to a gynecologist but that I'd "probably never get an appointment because the health care system in Canada is broken" (his words). By this point, it had already been about 5 months since my first appointment, and I had been spotting/bleeding almost every day since then. I was super frustrated about his attitude, but left feeling at least relieved that he'd be sending my information over to a gynecologist and I'd be done dealing with him.

About 2 weeks ago (late May 2024), I called the office back as I STILL hadn't heard anything from the referral in March. They told me that they DID send the referral in March but that they just hadn't heard back. Then a week ago I was in so much pain during my period that I nearly threw up and ended up passing a HUGE blood clot so we called again to check in on the referral and they told me that the referral had been denied/rejected....?!?! I suspect that it was never sent in the first place, but they have assured me that they have "re-sent" it now. I can't imagine why it would be denied as I feel like my symptoms are reason for alarm.

The symptoms I'm currently experiencing are:

spotting or bleeding most days since October 2023

uterine/abdominal pain/cramping almost daily (not just on my period)

full/heavy feeling in my lower abdomen

daily bloating/frequent nausea

about 50lb mostly unintentional weight loss within the last year (I was 250 pounds and am now 200, so the doctor only sees the weight loss as a positive thing)

bleeding after sex

pain and discomfort during sex (in my uterus/abdomen area)

multiple uterine polyps "with vascularity" (diagnosed in the sonohysterogram)

swollen ovaries

dizziness/blacking out (but never passing out) when I stand up

achy pain from my pelvis down my thighs (that gets worse when I have my period)

heavy periods with lots of large blood clots

On top of this, I have never been pregn@nt and they suspect that I have PCOS, both of which I know increase your chances of polyps being cancerous.

It has now been about 9 months since my first appointment and my symptoms feel like they are getting worse. I am starting to feel super defeated because these doctors keep telling me not to worry, but I feel like something is seriously wrong and that it will continue getting worse the longer this process takes. Am I just overreacting? What else could this be? Are the doctors right that it's "probably nothing" and I'm stressed for no reason? What do I do?!

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Researcher discovers that endometriosis tricks the immune system in the same way cancer does

by Claes Björnberg, Umea University

Treatment options for those suffering from endometriosis are currently few, but research at Umeå University provides new opportunities to understand the disease. A new thesis answers the question of how cells, which are normally found inside the uterus, can gain a foothold in the abdomen and evade the immune system. The results can hopefully contribute to new treatments.

Endometriosis is a benign, chronic disease, in which tissue similar to the lining of the uterus attaches to places in the body other than inside the uterus and causes pain.

Emma Björk, Department of Clinical Sciences, has shown in her research that endometriosis secretes so-called exosomes that trick the immune system into inactivity in the same way that cancer does.

Endometriosis also secretes something called cytokines, which produce an immune response that counteracts the removal of the endometriotic cells.

"It is known that the immune system's so-called natural killer cells do not function optimally in endometriosis and therefore do not kill the endometriotic cells, but it has not been known why," says Björk.

These exosomes carry molecules that inhibit the activity of natural killer cells and increase programmed cell death in active immune cells. These two mechanisms give the endometriotic tissue the opportunity to both persist and grow in the body.

Similar experiments were carried out in ovarian cancer , and it turned out that ovarian cancer also secretes exosomes with molecules that inactivate natural killer cells.

Björk's thesis also investigates the expression of cytokines, i.e., small proteins that are used for communication between cells. Among other things, an immunosuppressive cytokine response was observed, and microscopy showed an increased number of immune cells of a type that inhibits the activity of natural killer cells in the endometriotic tissue.

The study demonstrates several mechanisms affecting the function of natural killer cells in endometriosis . This new knowledge contributes to the understanding of how the disease can arise and further develop. Hopefully, the results can contribute to new treatments and diagnostic possibilities.

"At present, it takes several years to be diagnosed, and the treatments available often cause side effects. Exosomes will probably lead to ways to diagnose many different diseases in the future more easily," says Björk.

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