May 2026 brought notable published research on uterine and endometrial cancer, with studies spanning molecular tumor classification, fertility-sparing treatment, epigenetic resistance, survivorship disparities, and hormonal management. A high-profile comprehensive review of endometrial cancer appeared in JAMA this month, and an ancillary analysis of the GOG-0249 trial clarified how molecular subtypes track with survival in patients with early-stage disease. Several other clinically significant papers also published in May, but this digest includes only papers published under open-access licenses. *The papers highlighted here represent a selection of those published during the month. The papers were selected and summarized by AI. Accuracy of the summaries was confirmed by a scientist.* This digest incorporates only open-access research articles that are free to be read by the entire community and that are explicitly licensed to be shared and reused. --- **Your tumor's molecular "type" now predicts more than just prognosis - it may define your treatment** The core message from multiple strands of May's research is that molecular classification of endometrial cancer has become a practical clinical tool, and the details of that classification increasingly shape decisions about treatment intensity and surveillance. - A large genomic study analyzing 2,901 endometrial carcinomas across two independent datasets (the MSK-IMPACT clinical cohort and The Cancer Genome Atlas) reinforced that all four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) confer equivalently favorable survival outcomes when mutated. This means that for purposes of deciding whether a patient might benefit from immunotherapy (drugs that help the immune system attack cancer), it doesn't matter which specific repair gene is affected, dMMR (mismatch repair-deficient) status as a whole class is what matters. The study also found that the very favorable prognosis associated with POLE-ultramutated tumors applies only to a specific type of POLE change called a canonical exonuclease-domain mutation; patients with POLE variants of uncertain significance had outcomes more similar to the NSMP (no specific molecular profile) group. This has direct relevance for genetic testing interpretation. ([Read the full paper](https://doi.org/10.3390/genes17050591)) --- **Unscheduled bleeding on HRT: most cases are early and manageable, but timing matters** For postmenopausal people experiencing unexpected bleeding while on hormone replacement therapy (HRT), a retrospective NHS cohort study offers some reassurance alongside a new clinical observation. - Among 343 women who underwent investigation for unscheduled bleeding while on HRT, only 1.2% (4 patients) had endometrial cancer and all four cases were caught at the earliest stage (Stage IA), requiring no additional treatment beyond surgery. The study also observed an intriguing pattern: 89% of all abnormal findings, including hyperplasia, occurred within the first two years of starting HRT, with no cases of endometrial pathology found among the 45 women who had used systemic HRT for more than five years. The authors suggest this temporal clustering raises the hypothesis that early unscheduled bleeding may be unmasking pre-existing endometrial conditions rather than HRT-induced ones, though they emphasize that this is only a hypothesis and the data come from a selected group already presenting for investigation. If you are on HRT and experiencing bleeding, especially in the first two years, this research supports promptly getting it evaluated. ([Read the full paper](https://doi.org/10.3390/curroncol33050284)) --- **Epigenetic regulation: a new lens on why some endometrial cancers become treatment-resistant** Beyond the four established molecular subtypes, researchers are exploring the role of epigenetic changes (modifications to how genes are switched on or off, without changing the underlying DNA sequence) in driving treatment resistance. - A published review proposes what the authors call an Epigenetic State-Response Framework for endometrial cancer: the idea that tumors exist in dynamic epigenetic "states" that determine whether they will respond to chemotherapy, immunotherapy, or hormone therapy and that these states can potentially be reversed. The review surveys evidence for how DNA methylation patterns, histone modifications, and small RNA molecules shape treatment sensitivity, and discusses how drugs that target these processes (including DNA methyltransferase inhibitors and histone deacetylase inhibitors) might be combined with existing treatments to restore drug sensitivity in resistant tumors. This is a review paper synthesizing preclinical evidence rather than a clinical trial, so its implications are not yet practice-ready. However, for those whose cancer has stopped responding to standard therapies, epigenetic targeting is an active research area worth watching. ([Read the full paper](https://doi.org/10.3390/ijms27104371)) --- **Fertility-preserving treatment: your tumor's molecular profile may predict whether progesterone therapy will work and what might help when it doesn't** For younger people who want to preserve fertility and are being treated with progesterone therapy instead of surgery, May's research adds clarity and, potentially, hope for new approaches. - A laboratory study from Shanghai identified a specific molecular mechanism by which some endometrial cancers develop resistance to medroxyprogesterone acetate (MPA), the most commonly used progesterone-based fertility-sparing treatment. The researchers found that a protein called AMBRA1 binds to the progesterone receptor (PR, the cellular "antenna" that progesterone therapy relies on) and tags it for destruction, effectively turning off the treatment's ability to work. By blocking the enzyme complex that AMBRA1 uses (called CRL4) with a drug called MLN4924, the researchers restored progesterone sensitivity in cell lines and patient-derived organoid (lab-grown mini-tumor) models. This is preclinical work and MLN4924 is not currently approved for this indication, but it illuminates a targetable pathway that could eventually inform new approaches to overcoming resistance. ([Read the full paper](https://doi.org/10.7150/ijbs.133072)) - A case report from China described a patient with advanced endometrial cancer who was unable to tolerate standard chemotherapy and had such extensive pelvic tumor progression that surgery was not possible. Treated with a combination of anlotinib (a multi-target tyrosine kinase inhibitor that cuts off blood supply to tumors by blocking multiple growth signals) and envafolimab (a PD-L1 antibody - a type of immunotherapy), the patient achieved enough tumor shrinkage that surgery became possible. She underwent laparoscopic hysterectomy and remained disease-free at follow-up. This is a single case report and not generalizable, but it illustrates the potential of this combination as a conversion therapy in highly selected patients who have exhausted other options. ([Read the full paper](https://doi.org/10.1080/21645515.2026.2664297)) --- **When standard treatment options are exhausted: an emerging immunotherapy target in uterine sarcoma** Uterine sarcomas (a rare subtype of uterine cancer arising from the muscle or connective tissue of the uterus rather than the lining) are among the most challenging to treat, with few approved options after standard chemotherapy fails. - A Phase 1 multicenter trial tested an antibody called S095029, which targets a protein called NKG2A that acts as a "brake" on immune cells. In a small study of 41 heavily pretreated patients with various advanced solid tumors, the combination of S095029 with an anti-PD-1 immunotherapy (Sym021) produced confirmed partial responses in two patients, one with uterine sarcoma and one with leiomyosarcoma. These are early findings from a first-in-human trial with very small numbers, and no conclusions about effectiveness in uterine sarcoma can be drawn from this data alone. The study is noted here as a signal that NKG2A-targeting approaches may have activity in these rare tumors and warrant further investigation. ([Read the full paper](https://doi.org/10.1136/jitc-2025-014325)) --- **Lab science: two molecular pathways in endometrial cancer that researchers are working to understand** Researchers this month identified two distinct molecular mechanisms that promote endometrial cancer cell growth and spread. - A laboratory study using cell lines to study the AURKA/TPX2 pathway identified that a protein called RBM15B stabilizes another protein, FOXM1, through a chemical modification called m6A methylation. This in turn activates a cascade that promotes endometrial cancer cell proliferation and invasion. The study is preclinical work in cell lines and points to a potential therapeutic target, though it remains far from clinical application. ([Read the full paper](https://doi.org/10.1080/19336918.2026.2674357)) --- **What Does This Mean for Me?** **Should I ask about molecular testing for my tumor?** May's research continues to reinforce that knowing your tumor's molecular subtype, particularly whether it is mismatch repair-deficient (dMMR), POLE-mutated, p53-abnormal, or "no specific molecular profile" (NSMP), is becoming an increasingly important part of personalized treatment planning. The dual-cohort genomic study this month confirmed that all dMMR tumors, regardless of which repair gene is affected, appear to share the same favorable prognosis and the same potential to respond to immunotherapy. If your care team hasn't discussed molecular tumor testing with you, it may be worth asking: "Has my tumor been tested for mismatch repair deficiency, POLE mutations, and p53 status? And how might those results affect my treatment plan?" **I'm on HRT and experienced unexpected bleeding. Do I need to be worried?** This month's NHS cohort study found that the vast majority of people investigated for unscheduled bleeding while on HRT did not have endometrial cancer (only 1.2% did), and all who did were caught at the earliest and most treatable stage. The research also found that bleeding occurring within the first two years of starting HRT accounted for nearly all abnormal findings. The most important takeaway is: don't ignore unscheduled bleeding, and do get it evaluated promptly - not because the risk is high, but because when cancer is present, earlier detection makes a real difference. Reporting it quickly is the right call. **I'm being treated with progesterone therapy to preserve my fertility, and my doctor says I'm not responding well. Are there any options?** Progesterone resistance is one of the most challenging problems in fertility-sparing management of endometrial cancer, and May's preclinical research identified a specific molecular mechanism that can shut down the progesterone receptor in resistant tumors. This research is not yet clinical; the drug it points to (MLN4924) is not approved for this use, but it does suggest that the biology of resistance is being mapped out in detail. If you're not responding to progesterone therapy, talking with your gynecologic oncologist about whether molecular profiling of your tumor (including p53 and MMR status) could help explain the resistance and guide next steps would be a reasonable conversation to have. Clinical trials targeting resistance mechanisms may also be worth exploring. If you’ve been diagnosed with uterine or endometrial cancer and are looking for support and community, consider attending OCRA’s [uterine cancer Staying Connected](https://ocrahope.org/resources-support/staying-connected-support-series/) group, which meets virtually every Monday at 3pm ET. *This digest is prepared by OCRA (Ovarian Cancer Research Alliance) for patients, caregivers, and advocates. It is intended to inform, not to guide individual treatment decisions. Please speak with your care team about what research findings may mean for your specific situation.* --- **Sources** **Directly Referenced in This Digest** 1. Sertesen Çamöz E, et al. "Beyond Histology: A Dual-Cohort Genomic Analysis of 2901 Endometrial Carcinomas Reveals Class-Level Mismatch Repair Effects and Refines Molecular Classification." *Genes (Basel).* May 21, 2026. PMID 42195047. 2. Abdelaziz MAM, et al. "Temporal Clustering of Endometrial Cancer and Hyperplasia in HRT Users with Unscheduled Bleeding: A Retrospective NHS Cohort Study." *Current Oncology.* May 12, 2026. PMID 42187601. 3. Srivastava M, et al. "From Epigenetic Dysregulation to Therapeutic Reprogramming in Endometrial Cancer: A State-Response Framework for Treatment Resistance." *International Journal of Molecular Sciences.* May 14, 2026. PMID 42196351. 4. Sheng Y, et al. "CRL4-mediated progesterone receptor degradation drives progestin resistance and represents a therapeutic vulnerability in endometrial cancer." *International Journal of Biological Sciences.* May 1, 2026. PMID 42157930. 5. Naing A, et al. "Phase 1 multicenter study of the NKG2A targeting antibody S095029 as a single agent and in combination with anti-PD-1 in patients with advanced malignancies." *Journal for Immunotherapy of Cancer.* May 8, 2026. PMID 42103356. 6. Xu J, et al. "Anlotinib plus envafolimab as neoadjuvant therapy in a patient with chemotherapy-refractory advanced endometrial cancer: A case report." *Human Vaccines & Immunotherapeutics.* May 4, 2026. PMID 42077092. 7. Zhang L, Wu P. "RBM15B-mediated m6A modification of FOXM1 activates the AURKA/TPX2 axis to promote epithelial-mesenchymal transition-driven endometrial cancer progression." *Cell Adhesion & Migration.* May 18, 2026. PMID 42148505. **Additional Open-Access Papers Published in May 2026 on Related Topics** 8. Chen CH, et al. "Transcriptomic Evidence of Immune-Tumor Uncoupling Defines a High-Risk State in Uterine Corpus Endometrial Carcinoma." *International Journal of Molecular Sciences.* May 7, 2026. PMID 42196154. *(Bioinformatics analysis identifying a 28-gene transcriptomic risk signature associated with a state in which immune signaling is preserved but fails to translate into effective anti-tumor activity; validated in independent cohorts.)* **Papers Excluded Due to Licensing Restrictions** 8. D'Angelo G, et al. "Sentinel Lymph Node Mapping with Indocyanine Green in Endometrial Cancer: Does the Minimally Invasive Platform Matter?" *Journal of Investigative Surgery.* May 19, 2026. PMID 42157366. *(Excluded: License not confirmed; subscription/hybrid journal. Topic: Comparison of sentinel lymph node mapping success rates between laparoscopic and robotic-assisted surgery in early-stage endometrial cancer.)* 9. Frerichs HD, et al. "Type 2 diabetes remission in gynaecologic oncology patients completing an acute preoperative weight loss protocol: a case series." *Journal of Obstetrics and Gynaecology.* May 18, 2026. PMID 42145191. *(Excluded: License not confirmed; subscription/hybrid journal. Topic: Outcomes of a preoperative weight loss protocol including diabetes remission rates in gynecologic oncology patients, predominantly endometrial cancer.)* 10. Abacjew-Chmylko A, et al. "Decoding the 2023 FIGO Staging System in Endometrial Cancer: A Practical, Visually Guided Framework for Molecular Risk-Adapted Care Incorporating the 2025 Risk Group Update." *Current Oncology Reports.* May 29, 2026. PMID 42209822. *(Excluded: License not confirmed; Springer hybrid journal. Topic: Comprehensive educational review of FIGO 2023 endometrial cancer staging, integrating molecular classification and 2025 ESGO-ESTRO-ESP estrogen receptor guidance.)* 11. Barmayehvar B, et al. "Role of overdiagnosis in the rising incidence of endometrial cancer: a population-based ecological study." *BMJ Evidence-Based Medicine.* May 21, 2026. PMID 40707171. *(Excluded: BMJ Group proprietary license, no open-access license confirmed. Topic: Population-based study from Norway examining whether overdiagnosis and transvaginal ultrasound use explain rising endometrial cancer incidence.)* 12. Srivastava M, et al. "From Epigenetic Dysregulation to Therapeutic Reprogramming in Endometrial Cancer: A State-Response Framework for Treatment Resistance." \[See #3 above\] 13. Yu H, et al. "The influence of robotic-assisted systems on the surgical approach and outcomes in hysterectomy for benign and malignant diseases." *Journal of Robotic Surgery.* May 12, 2026. PMID 42115535. *(Excluded: License not confirmed; Springer exclusive license. Topic: Retrospective study of 4,821 hysterectomies finding robotic surgery reduces operative time for endometrial cancer cases with lymph node dissection and improves outcomes in radical hysterectomy for cervical cancer.)* 14. Park SK, et al. "Functional dissection of SPOP at the amino acid level reveals a comprehensive functional landscape of variants during tumorigenesis." *Proceedings of the National Academy of Sciences.* May 6, 2026. PMID 42090249. *(Excluded: CC BY-NC-ND. Topic: Deep mutational screening of the SPOP protein — which plays opposing roles in endometrial and prostate cancers — revealing functional consequences of 7,933 single amino acid variants.)* 15. Mager KL, McLean K. "Endometrial Cancer: A Review." *JAMA.* May 12, 2026. PMID 41973450. *(Excluded: License not confirmed; JAMA subscription journal. Topic: Comprehensive clinical review of endometrial cancer covering epidemiology, diagnosis, staging, molecular classification, and treatment — including updated U.S. incidence data showing endometrial cancer as the fourth most common cancer in women.)* 16. Chen CH, et al. \[See #7 above — in Additional Open-Access Papers section\] 17. Lei H, et al. "Expression and clinical significance of cytochrome b561 in endometrial cancer." *Journal of Cancer Research and Clinical Oncology.* May 4, 2026. PMID 42082769. *(Excluded: License not confirmed; Springer hybrid journal. Topic: Immunohistochemical study of 195 endometrial carcinoma tissues finding that high CYB561 expression is independently associated with improved survival.)* 18. Salameh A, et al. "Behind the bleeding: rare and relentless uterine lymphoma ending in chemotherapy toxicity." *BMJ Case Reports.* May 4, 2026. PMID 42082264. *(Excluded: BMJ Group proprietary license. Topic: Case report of primary endometrial diffuse large B-cell lymphoma initially misdiagnosed as endometrial stromal sarcoma.)* 19. Brown JA, et al. "Neighborhood Socioeconomic Deprivation and Perceived Discrimination Among Endometrial Cancer Survivors." *Psycho-Oncology.* May 2026. PMID 42185225. *(Excluded: License not confirmed; Wiley proprietary license. Topic: Cross-sectional study of 901 endometrial cancer survivors finding that neighborhood deprivation is associated with perceived discrimination in racially patterned ways, with distinct patterns for Black and White survivors.)* 20. Kuroki LM, et al. "Molecular classification and association with survival outcomes in high-intermediate and high-risk early-stage endometrial cancers: Ancillary analysis of GOG-0249." *Gynecologic Oncology.* May 26, 2026. PMID 42190623. *(Excluded: Elsevier all rights reserved. Topic: Ancillary analysis of the GOG-0249 randomized trial showing that p53-abnormal endometrial cancers have 4-fold higher risk of recurrence and nearly 10-fold higher risk of death than p53 wild-type, and that molecular subtype did not predict differential benefit from vaginal brachytherapy plus chemotherapy versus pelvic radiation.)* 21. Sun X, et al. "miR-26a/b-5p-STAT3-YKL-40 regulatory axis on proliferation, migration, and invasion of endometrial cancer cells." *Oncology Reports.* May 15, 2026. PMID 42138189. *(Excluded: CC BY-NC-ND. Topic: Preclinical study demonstrating that STAT3 promotes endometrial cancer cell proliferation and that miR-26a/b-5p acts as an upstream suppressor; STAT3 also binds and activates YKL-40.)* 22. Xu J, et al. \[See #6 above — Directly Referenced in This Digest. This paper carries a CC BY-NC 4.0 license.\] 23. Tian C, et al. "A Novel Nomogram Incorporating the Aggregate Index of Systemic Inflammation, Clinicopathological Parameters and Molecular Classification to Predict Recurrence of Endometrial Cancer." *Cancer Medicine.* May 2026. PMID 42033057. *(Excluded: License not confirmed; Wiley/Cancer Medicine hybrid. Topic: Multi-center retrospective study of 1,557 EC patients developing a recurrence-prediction nomogram incorporating 8 factors including systemic inflammation index and p53 status.)* 24. Techasontichai M, et al. "A prognostic performance of 2023 FIGO for early-stage endometrial cancer staging." *Taiwanese Journal of Obstetrics & Gynecology.* May 2026. PMID 42036184. *(Excluded: License not confirmed; Elsevier proprietary license. Topic: Retrospective cohort of 364 early-stage patients comparing 2009 and 2023 FIGO staging systems, finding the 2023 system better distinguishes clinically meaningful subgroups even without molecular data.)* 25. Qian XQ, et al. "Efficacy of Fertility-Sparing Treatment With Progestin Is Associated With Different Molecular Classification in Endometrial Carcinoma and Atypical Endometrial Hyperplasia." *Cancer Medicine.* May 2026. PMID 42068048. *(Excluded: License not confirmed; Wiley/Cancer Medicine hybrid. Topic: Retrospective study of 74 cases finding that NSMP patients had 100% complete response rate to progestin, compared to 83% for MMRd and 33% for p53-abnormal tumors; pregnancy rates were highest in NSMP group.)* 26. Lee J, et al. "Anthracotic Right Supraclavicular Lymph Node Mimicking Metastasis on FDG-PET/CT in Endometrial Carcinosarcoma: A Case Report." *In Vivo.* 2026. PMID 42049432. *(Excluded: All rights reserved — International Institute of Anticancer Research. Topic: Case report highlighting false-positive PET findings due to nodal anthracosis in endometrial carcinosarcoma.)* 27. Zhang T, et al. "Comparison of the EORTC QLQ-EN24, FACT-En, and FEnSI-23 for assessing quality of life in endometrial cancer: a systematic review." *Current Opinion in Supportive and Palliative Care.* May 28, 2026. PMID 42213858. *(Excluded: Wolters Kluwer all rights reserved. Topic: Systematic review comparing three endometrial cancer-specific quality-of-life instruments, with guidance on instrument selection for different research purposes.)* 28. Bergerot C, et al. "Understanding Contemporary Challenges in the Care of Patients With Early-Onset Cancer: Epidemiologic Trends, Patient Well-Being, Oncofertility, and Cancer Survivorship." *ASCO Educational Book.* May 28, 2026. PMID 42208006. *(Excluded: License not confirmed. Topic: Review including rising endometrial cancer incidence in younger adults, psychosocial burden, and fertility-related challenges in adolescents and young adults.)* 29. Cuello MA, et al. "Advancing equity in endometrial cancer: A narrative synthesis using a cluster-informed framework for resource-stratified implementation." *International Journal of Gynaecology and Obstetrics.* May 15, 2026. PMID 42138708. *(Excluded: License not confirmed; IFGO/Wiley proprietary license. Topic: Narrative review applying a 68-country system-readiness framework to identify implementation gaps in endometrial cancer staging, molecular pathology, surgery, and survivorship care.)* 30. Sun BJ, et al. "Efficacy and Safety of Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Recurrent Uterine Leiomyosarcoma: Results of a Phase 2 Study." *Annals of Surgical Oncology.* May 8, 2026. PMID 42104036. *(Excluded: License not confirmed; Springer/Society of Surgical Oncology proprietary license. Topic: Single-arm phase 2 study of cytoreductive surgery plus HIPEC with gemcitabine in 17 recurrent uterine leiomyosarcoma patients, finding median progression-free survival of 11 months compared to historical control of 3 months.)* 31. Yang L, et al. "Deciphering the predictors of endometrial nonbenign lesions in asymptomatic postmenopausal women via explainable machine learning." *Menopause.* May 1, 2026. PMID 41589874. *(Excluded: License not confirmed; Wolters Kluwer proprietary license. Topic: Machine learning model using 5 clinical predictors to identify endometrial malignancy risk in 971 asymptomatic postmenopausal women with endometrial thickening.)* 32. Zhang J, et al. "Multiparametric MRI for preoperative identification of aggressive type endometrial carcinoma in FIGO 2023." *British Journal of Radiology.* May 1, 2026. PMID 41729871. *(Excluded: All rights reserved; Oxford University Press. Topic: Prospective dataset analysis developing and validating a multiparametric MRI model to distinguish aggressive from non-aggressive endometrial carcinoma subtypes before surgery.)* 33. Saleem Z. "Association of endometrial pathologies with infertility and malignant potential in pre- and postmenopausal women — a systematic review." *British Journal of Radiology.* May 1, 2026. PMID 41671103. *(Excluded: All rights reserved; Oxford University Press. Topic: Systematic review on the malignant potential and infertility risk of endometrial pathologies, emphasizing the value of transvaginal ultrasound.)* 34. Zaheer S, et al. "Exploring synchronous endometrial and ovarian cancers." *BMJ Case Reports.* May 29, 2026. PMID 42215058. *(Excluded: BMJ Group proprietary license. Topic: Three case reports of synchronous primary endometrial and ovarian carcinomas, distinguishing them from metastatic disease.)* 35. Lin Q, et al. "The Predictive Value of Lactate Dehydrogenase (LDH) for Lymphovascular Invasion in Endometrial Cancer: a Retrospective Cohort Study." *Clinical Laboratory.* May 1, 2026. PMID 42159128. *(Excluded: License not confirmed. Topic: Retrospective study of 147 endometrial cancer patients finding elevated LDH independently predicts survival but showing only modest accuracy for lymphovascular invasion detection.)* 36. Lin M, et al. "Leiomyosarcoma of uterus in pregnancy: A case report." *Medicine (Baltimore).* May 8, 2026. PMID 42116313. *(Excluded: License not confirmed; Wolters Kluwer proprietary license. Topic: Case report of uterine leiomyosarcoma incidentally diagnosed during cesarean section, emphasizing diagnostic challenges during pregnancy.)* 37. Kouri A, et al. "Uterine Sarcomas: Clinical Management and a Review of Systemic Therapy." *Obstetrical & Gynecological Survey.* May 7, 2026. PMID 42096621. *(Excluded: All rights reserved; Wolters Kluwer. Topic: Comprehensive review of uterine sarcoma subtypes including leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, and adenosarcoma — covering histology-specific management and emerging systemic therapies.)*

This Month in Uterine Cancer Research

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