Recurrent Endometrial Carcinoma Research Articles

ENGOT-EN20/GOG-3083/XPORT-EC-042 – A phase III, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with p53 wild-type, advanced, or recurrent endometrial carcinoma: rationale, methods, and trial design

BackgroundPatients with advanced/recurrent endometrial cancer have a poor prognosis and limited treatment options. Biomarkers such as tumor protein 53 (TP53) in endometrial cancer can integrate novel strategies for improved and...

Cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy for treating previously treated advanced endometrial cancer in Sweden

Objective Pembrolizumab plus lenvatinib was recently approved for the treatment of advanced or recurrent endometrial carcinoma in women with disease progression on or following prior treatment with a platinum‑containing therapy in any setting, and who are not candidates for curative surgery or radiation (KEYNOTE-775/Study-309; NCT03517449). The objective was to assess the cost effectiveness of pembrolizumab plus lenvatinib compared with chemotherapy from a Swedish healthcare perspective. Materials and methods A lifetime partitioned-survival model with three health states (progression free, progressed disease, death) was constructed. Chemotherapy was represented by paclitaxel or doxorubicin. Overall survival, progression-free survival, time on treatment, and utility data were obtained from KEYNOTE-775 (database lock: March 1, 2022). Costs (in 2020 Swedish Krona [SEK]) included drug acquisition and administration, health state, end of life, adverse event management, subsequent treatment, and societal (scenario analysis). Outcomes were calculated as quality-adjusted life-years (QALY) and life-years. Model results were presented as incremental cost-effectiveness ratios for all-comers, patients with proficient mismatch repair tumors, and deficient mismatch repair tumors. Deterministic and probabilistic sensitivity analyses were conducted. Results Pembrolizumab plus lenvatinib is a cost-effective treatment when compared with chemotherapy, with estimated deterministic and probabilistic incremental cost-effectiveness ratios of SEK 795,712 and 819,757 per QALY gained. Pembrolizumab plus lenvatinib was associated with a large incremental QALY and life-year gain per person versus chemotherapy over the model time horizon (1.49 and 1.76). Limitations Time-to-event data were incomplete and semiparametric and parametric curves were utilized for lifetime extrapolation. Willingness-to-pay thresholds, costs, and utility weights vary by country, which would vary the treatment’s cost effectiveness in different countries. Conclusions This partitioned survival analysis suggests that pembrolizumab plus lenvatinib is cost effective compared with chemotherapy in Sweden for women with advanced or recurrent endometrial carcinoma following previous systemic therapy. Results were robust to mismatch repair status and to changes in parameters/assumptions.

Early-stage endometrial carcinoma; risk factors for recurrence

Background: Endometrial carcinoma (EC) is the most common gynecological malignancy in developed countries. The overall prognosis is excellent, as most cases are diagnosed at an early stage with low-grade histology, but once the recurrence occurs, the median survival decreases severely. Aims and Objectives: The aim of this study was to identify the risk factors associated with recurrence in early-stage EC and explore their impact on overall survival (OS) after recurrence. Materials and Methods: Records from patients diagnosed with EC were retrospectively reviewed. 220 patients were identified as early-stage, low-risk EC who underwent primary surgical treatment between January 2010 and December 2022, and their baseline characteristics were analyzed. Cox regression analysis was used to identify various factors for tumor recurrence. Survival analysis was done using the Kaplan-Meier method. Results: In a cohort of 220 patients, we observed tumor recurrence in 44 (20%) patients and 34 (15.45%) deaths over a median follow-up of 72 months (range, 12–144 months). Multivariate analysis confirmed two risk factors: myometrial invasion (MMI) of any depth and lymphovascular invasion (LVI) as independent predictors of recurrence. The prognosis was worse for patients with recurrence than for those without. The OS for the recurrent group was 38.6%, compared to 96.0% in the non-recurrent group. In our study, the median time to recurrence was 19 months (confidence interval 18–30) months. Conclusion: The presence of MMI and LVI are important predictors for recurrence in early-stage low-risk EC.

Abstract A018: A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer

Abstract Introduction/Objective: This trial in progress is designed to evaluate the anti-tumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative treatment options, particularly for advanced or recurrent EEC remain necessary. Dysregulation of mammalian target of rapamycin (mTOR) signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EC. nab-Sirolimus, a nanoparticle injectable form of mTORi, is approved in the USA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that nab-sirolimus in combination with letrozole may produce synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemo-based regimen, Eastern Cooperative Oncology Group performance status score 0 or 1, naïve to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. The relationship between biomarkers and response outcomes is an exploratory endpoint. Citation Format: Lauren E. Dockery, Anna Priebe, Linda Duska, Angela K. Green, Cara Mathews, Fernanda Musa, David O'Malley, Allison Puechl, Li Ding, Anita N. Schmid, Willis H. Navarro, Brian Slomovitz, Kathleen Moore. A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A018.

Prognostic factors of patients with recurrent uterine malignancies undergoing secondary cytoreductive surgery.

Several studies have demonstrated that secondary cytoreductive surgery (SCS) for patients with recurrent uterine malignancies may improve the survival. However, the selection criteria for SCS remain to be defined. This study aimed to assess the outcome of SCS and to explore factors that may influence the prognosis. Data of patients with recurrent uterine malignancies who received SCS in our hospital between January 2005 and January 2015 were retrospectively analyzed. Patients were assigned into endometrial carcinoma (EC) group and uterine sarcoma (US) group. 84 cases in total were involved in the study, including 47 cases with recurrent EC and 37 cases with recurrent US. The 5-year survival of cases with recurrent EC and recurrent US was 59.6% and 33.3%, respectively. Recurrent EC cases with a lower tumor grade (G1/G1-G2/G2), size of the largest tumor ≤ 6cm, single recurrent tumor, a history of adjuvant therapy, as well as recurrent US cases with younger age, a longer disease-free interval (DFI) before SCS (≥ 12 months), no peritoneal dissemination, and a history of complete cytoreduction were associated with a longer survival. The number of recurrent tumors was found as an independent prognostic factor of SCS. Recurrent EC cases with a lower tumor grade, smaller tumor size, single tumor, a history of adjuvant therapy, as well as recurrent US cases with younger age, a longer DFI before SCS, no peritoneal dissemination, and a history of complete cytoreduction were more likely to benefit from SCS.

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma

BackgroundEndometrial carcinoma is the most common gynecologic cancer, with increasing incidence and mortality. Combination endocrine therapy comprised of tamoxifen and progestational agents has demonstrated promising results in treating recurrent disease. This case report describes the prolonged clinical benefit of treatment with tamoxifen and megestrol acetate in a woman with recurrent, metastatic endometrial endometrioid carcinoma positive for estrogen (ER) and progesterone receptors (PR).CaseA 71-year-old gravida 1 para 1 woman presented with postmenopausal bleeding and vaginal discharge. Pelvic ultrasound and magnetic resonance imaging confirmed a 4.7 cm endometrial mass. The patient underwent a total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy; pathology revealed a FIGO stage IA grade 1 ER/PR-positive endometroid endometrial adenocarcinoma. She continued under active surveillance for approximately 42 months until she experienced bone metastases in her pelvis, for which she received radiation therapy. Five months later, pulmonary metastases were detected, and she received six cycles of carboplatin and paclitaxel. She then started megestrol acetate and tamoxifen and has remained clinically stable with minimal side effects and reasonable quality of life for approximately 57 months.ConclusionOur case suggests that combination endocrine therapy has the potential to provide substantial long-term clinical benefit in women with recurrent endometrial cancer and bone metastases, despite multiple prior treatments, allowing patients to experience stable disease and quality of life. In patients with recurrent endometrioid, ER/PR-positive disease, endocrine therapy alone or in combination with other targeted therapies are regimens that may be considered due to their low overall toxicity.

CHMP4B and VSP4A reverse GSDMD-mediated pyroptosis by cell membrane remodeling in endometrial carcinoma

BackgroundIn advanced and recurrent endometrial carcinoma (EC), the current state of immuno- or targeted therapy remains in the clinical research phase. Our study aimed to explore the role of the ESCRT machinery in maintaining cell membrane integrity and reversing pyroptotic cell death. MethodsImmunohistochemistry, western blotting, and co-immunoprecipitation were performed to determine the expression and relationship between GSDMD, CHMP4B, and VPS4A. We employed techniques such as FITC Annexin V/propidium iodide staining, Ca2+ fluorescence intensity, IL-1β enzyme-linked immunosorbent assay, and lactate dehydrogenase release assay to detect pyroptosis in endometrial cancer cells. Plasma membrane perforations and CHMP4B/VPS4A puncta were observed through electron and fluorescence confocal microscopy. ResultsWe showed that GSDMD, CHMP4B, and VPS4A were differentially expressed in the pyroptotic EC xenograft mouse model group, as well as high, moderate, and mild expression in EC cells treated with LPS and nigericin compared to endometrial epithelial cells. Co-IP confirmed the interaction between GSDMD, CHMP4B, and VPS4A. We found that GSDMD knockdown reduced PI-positive cells, Ca2+ efflux, IL-1β, and LDH release, while CHMP4B and VPS4A depletion enhanced these indicators in HEC1A and AN3CA cells. Electron microscopy showed membrane perforations correspondingly decreased with inactivated GSDMD and increased or decreased after CHMP4B and VPS4A depletion or overexpression in EC cells. Fluorescence confocal microscopy detected CHMP4B protein puncta associated with VPS4A at the injured plasma membrane in GSDMDNT cells. ConclusionsWe preliminary evidenced that CHMP4B and VPS4A reverses GSDMD-mediated pyroptosis by facilitating cell membrane remodeling in endometrial carcinoma. Targeting CHMP4B related proteins may promote pyroptosis in endometrial tumors.

[Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles].

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.

CHMP4B and VSP4A reverse GSDMD-mediated pyroptosis by cell membrane remodeling in endometrial carcinoma

BackgroundIn advanced and recurrent endometrial carcinoma (EC), the current state of immuno- or targeted therapy remains in the clinical research phase. Our study aimed to explore the role of the ESCRT machinery in maintaining cell membrane integrity and reversing pyroptotic cell death. MethodsImmunohistochemistry, western blotting, and co-immunoprecipitation were performed to determine the expression and relationship between GSDMD, CHMP4B, and VPS4A. We employed techniques such as FITC Annexin V/propidium iodide staining, Ca2+ fluorescence intensity, IL-1β enzyme-linked immunosorbent assay, and lactate dehydrogenase release assay to detect pyroptosis in endometrial cancer cells. Plasma membrane perforations and CHMP4B/VPS4A puncta were observed through electron and fluorescence confocal microscopy. ResultsWe showed that GSDMD, CHMP4B, and VPS4A were differentially expressed in the pyroptotic EC xenograft mouse model group, as well as high, moderate, and mild expression in EC cells treated with LPS and nigericin compared to endometrial epithelial cells. Co-IP confirmed the interaction between GSDMD, CHMP4B, and VPS4A. We found that GSDMD knockdown reduced PI-positive cells, Ca2+ efflux, IL-1β, and LDH release, while CHMP4B and VPS4A depletion enhanced these indicators in HEC1A and AN3CA cells. Electron microscopy showed membrane perforations correspondingly decreased with inactivated GSDMD and increased or decreased after CHMP4B and VPS4A depletion or overexpression in EC cells. Fluorescence confocal microscopy detected CHMP4B protein puncta associated with VPS4A at the injured plasma membrane in GSDMDNT cells. ConclusionsWe preliminary evidenced that CHMP4B and VPS4A reverses GSDMD-mediated pyroptosis by facilitating cell membrane remodeling in endometrial carcinoma. Targeting CHMP4B related proteins may promote pyroptosis in endometrial tumors.

ENGOT-EN20/GOG-3083/XPORT-EC-042 A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients (pts) with P53 wild-type, advanced or recurrent endometrial carcinoma (1246)

ENGOT-EN20/GOG-3083/XPORT-EC-042 A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients (pts) with P53 wild-type, advanced or recurrent endometrial carcinoma (1246)

The crucial value of serum ferritin in assessing high-risk factors and prognosis for patients with endometrial carcinoma

BackgroundEndometrial carcinoma is a common malignant tumor in female reproductive system. At present, there is no effective and economic prognostic index. This study aimed to investigate the effect of serum ferritin levels on the prognosis of endometrial carcinoma.MethodsData of 367 patients who diagnosed with endometrial carcinoma at the First Affiliated Hospital of Chongqing Medical University between January 2012 and August 2018 was retrospectively analyzed. The prediction accuracy was evaluated by receiver operating characteristics curves and Youden's J statistics. Hosmer–lemeshow test was used to confirm the goodness of fit of the model. The prognostic value of serum ferritin on disease free survival (DFS) and overall survival (OS) of endometrial carcinoma was evaluated by univariate log-rank tests and multivariate cox regression models.ResultsPreoperative high serum ferritin was correlated with older age, high grade, specific histological subtypes and recurrence of endometrial carcinoma (P < 0.05). The DFS and OS of 198 patients with elevated serum ferritin levels were significantly lower than those with low serum ferritin levels (P = 0.001 and P = 0.002, respectively). In multivariate analysis, serum ferritin was an independent prognostic factor for DFS and OS in endometrial carcinoma (P = 0.012, P = 0.028).ConclusionThrough our research, we found that the high expression of serum ferritin level was not only related to low DFS and OS in patients with endometrial carcinoma, but also related to the high-risk factors of endometrial carcinoma recurrence. So serum ferritin levels may be used to predict the poor prognosis of patients with endometrial carcinoma.

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the “cluster” pattern of G-ITH, whereas the “mosaic” pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.

Clinical Relevance of Red Blood Cell Distribution Width (RDW) in Endometrial Cancer: A Retrospective Single-Center Experience from Korea.

Red blood cell distribution width (RDW) is a standard parameter of complete blood count and indicates the variability in red blood cell size. This study aimed to determine whether preoperative RDW can be used to predict the recurrence and prognosis of endometrial carcinoma. The medical records of 431 patients diagnosed with endometrial carcinoma were retrospectively reviewed between May 2006 and June 2018. In addition to RDW, the clinicopathological factors, survival curves, and prognoses of the patients with endometrial carcinoma were compared between the high (n = 213) and low (n = 218) groups according to the median RDW value (12.8%). The patients with high RDW had significantly advanced-stage (p = 0.00) pelvic lymph node metastasis (p = 0.01) and recurrence (p = 0.01) compared to those in the low-RDW group. In univariate analysis with DFS as the endpoint, surgical stage, type II histology, grade, RDW, and lymph node metastasis were independently associated with survival. Patients with high RDW values had significantly shorter disease-free survival and overall survival than those with low RDW values (log-rank p = 0.03, log-rank p = 0.04, respectively). Our results demonstrate that RDW is a simple and convenient indicator of endometrial carcinoma recurrence. Prospective studies are needed to validate the findings of the current study.

Should we abandon hormonal therapy in endometrial cancer? Outcomes of recurrent and metastatic endometrial cancer treated with systemic progestins.

The objective of this study is to determine primary survival endpoints in women with recurrent and metastatic endometrial carcinoma (RMEC) treated with progestins. A retrospective chart review was conducted at The Ottawa Hospital using electronic medical records. Inclusion criteria were a diagnosis of RMEC between 2000 and 2019, endometrioid histology, and ≥one line of progestin treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Of 2342 cases reviewed, 74 met inclusion criteria. Sixty-six (88.0%) patients received megestrol acetate and 9 (12.0%) received a progestin alternative. The distribution of tumors by grade was: 1: 25 (33.3%), 2: 30 (40.0%), and 3: 20 (26.7%). The PFS and OS for the entire study sample was 14.3 months (95% CI 6.2-17.9) and 23.3 months (14.8-36.8), respectively. The PFS for patients with Grade 1-2 RMEC was 15.7 months (8.0, 19.5), compared to 5.0 months (3.0, 23.0) with Grade 3 disease. The OS for patients with Grade 1-2 versus Grade 3, was 25.9 months (15.3, 40.3) versus 12.5 months (5.7, 35.9), respectively. Thirty-four (45.9%) and 40 (54.1%) patients were treated with 0 and ≥1 line of chemotherapy. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed. This real-world data on RMEC suggests there is a role for progestins in select subgroups of women. The PFS for chemotherapy-naïve patients was 17.9 months (14.3, 27.0), versus 6.2 months (3.9, 14.8) following ≥1 line of treatment. The OS was 29.1 months (17.9, 61.1) for chemotherapy-OS was 29.1 months (17.9, 61.1) for chemotherapy-naïve patients versus 23.0 months (10.5, 37.6) for patients previously exposed.

A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283

ObjectiveGynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma. MethodsWe conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes. ResultsTwenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors. ConclusionsDasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.

Correlation Analysis of Immune Cell Infiltration in Recurrent Endometrial Carcinoma

Numerous studies have established a close relationship between tumor progression, prognosis, and the infiltration of immune cells in the tumor microenvironment. This study aimed to investigate the differences in infiltrating immune cells between recurrent endometrial cancer and non-recurrent endometrial cancer. Firstly, gene expression data of endometrial cancer were obtained from the GEO database. Differential gene analysis using Geo2R identified significant gene expression differences, and KEGG and GO analyses were conducted on the qualified differential genes. Subsequently, CIBERSORT was employed to analyze the infiltration of 22 immune cell types in the tumor microenvironment, identifying differential immune cells. The results revealed significant differences in gene expression between recurrent and non-recurrent endometrial carcinoma. Interestingly, CIBERSORT analysis demonstrated a significant increase in monocyte infiltration in recurrent endometrial cancer compared to non-recurrent cases. Monocyte infiltration was found to play a crucial role in the progression of endometrial cancer recurrence. These findings provide valuable insights for clinicians to develop personalized treatment strategies for patients with recurrent endometrial cancer.

Retracted: Analysis of Prognostic Factors and Treatment Modes of Patients with Recurrent Endometrial Carcinoma.

[This retracts the article DOI: 10.1155/2021/8793187.].

Preliminary results of a phase II trial with sacituzumab govitecan-hziy in patients with recurrent endometrial carcinoma overexpressing Trop-2.

5599 Background: Despite recent advances, there remains a significant need for targeted, efficacious treatments for advanced and recurrent endometrial carcinoma (EC). Trop-2 has been demonstrated to be overexpressed in several EC including grade 3 endometrioid adenocarcinoma (96%), and uterine serous carcinoma (65%). Trop-2 overexpression has been found to confer a worse prognosis and predicts disease recurrence. Sacituzumab govitecan-hziy (SG) is an antibody-drug conjugate comprised of a humanized anti-Trop-2 antibody conjugated with the active metabolite of irinotecan, a topoisomerase-I inhibitor. SG is currently FDA-approved for use in metastatic urothelial cancer and metastatic triple-negative breast cancer. Methods: We report results from the stage 1 of an open-label non-randomized phase 2 trial (NCT04251416) established to evaluate the clinical activity of SG in patients with persistent or recurrent EC of epithelial origin with Trop-2 overexpression. Criteria for study participation included radiographically confirmed and measurable persistent or recurrent EC, progression after or during platinum-based chemotherapy, and at least 2+ staining of Trop-2. One target lesion by RECIST v1.1 and adequate bone marrow, renal, and hepatic function were required. Patients were at least two weeks beyond prior treatment, major surgery, or high dose systemic corticosteroid use. Patients were given 10mg/kg of SG administered as an intravenous infusion once weekly on days 1 and 8 of 21-day treatment cycles. This 3-week cycle was continued without rest until disease progression or unacceptable toxicity. Results: Twenty-one patients were enrolled into stage 1. Ten patients (48%) had uterine serous carcinoma, seven (33%) had endometrioid adenocarcinoma, three (14%) had carcinosarcoma, and one patient had mixed serous and clear cell histology. All patients received at least one prior line of chemotherapy, (median 3 lines, range 1-6). At the time of submission, 20 patients were response-evaluable (Table); seven (35%) achieved objective response (5 out of 7 confirmed). Eighteen patients were evaluable for durable disease control; 7 (39%) achieved it. Follow-up durations had a median (IQR) of 15.6 (5.7–22.5) months. Median OS was 22.5 months, and median PFS was 5.7 months. The treatment was well-tolerated with no new or unexpected safety signals reported. Conclusions: Sacituzumab govitecan shows remarkable clinical activity against some of the most historically challenging and chemotherapy-resistant endometrial pathologies and demonstrates a favorable safety profile. With these promising results, we will begin the stage 2 expansion of this phase 2 trial. Clinical trial information: NCT04251416 . [Table: see text]

ENGOT-EN20/GOG-3083/xport-EC-042: A phase 3, randomized, placebo-controlled, double-blind, multicenter trial of selinexor in maintenance therapy after systemic therapy for patients with P53 wild-type, advanced or recurrent endometrial carcinoma.

TPS5627 Background: Patients (pts) with first-line metastatic or recurrent endometrial cancer (EC) have a poor prognosis. Selinexor is an oral XPO1 inhibitor, which leads to nuclear accumulation of tumor suppressor proteins, including p53. Selinexor is FDA-approved for use in multiple myeloma and diffuse large B-cell lymphoma, and has shown clinical activity in previously treated, advanced EC. Molecular characterization of EC is critical in directing treatment for advanced and recurrent disease. Of the EC molecular subtypes, TP53 wild type (wt) tumors represent 50% of advanced and recurrent tumors. A recent phase 3 study in maintenance after chemotherapy found that, despite the primary endpoint (PFS) not reaching statistical significance, prolonged PFS of oral once-weekly selinexor versus placebo (13.7 months and 3.7 months, respectively) was observed in a prespecified exploratory subgroup analysis of patients with advanced or recurrent TP53wt EC. Methods: XPORT-EC-042 (NCT05611931) is a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of selinexor as maintenance therapy in pts with TP53wt advanced or recurrent EC, who have achieved a partial response or complete response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 after completing at least 12 weeks of platinum combination chemotherapy ±immunotherapy for primary stage IV or recurrent disease. Eligible pts must be ≥18 years of age, have histologically confirmed EC, and TP53 wt disease based on NGS sequencing assessed by Foundation Medicine. Pts will be randomized 1:1 with either selinexor 60 mg or placebo once weekly in 28-day cycles until progressive disease, toxicity, or 3 years if in complete response. A total of 220 pts will be enrolled at sites across the United States, Canada, Europe, and Israel. The primary objective is to compare PFS in pts treated with selinexor compared to placebo based on RECIST v1.1 criteria as assessed by the Investigator. Key secondary objective is overall survival. Other secondary objectives are safety, time to first subsequent therapy, time to second subsequent therapy, time from randomization until the second progression event (PFS2), and PFS by a blinded independent central review. Patient enrollment is ongoing. Clinical trial information: NCT05611931 .

A Risk-scoring Model for Predicting Post-recurrence Survival in Patients With Endometrial Carcinoma

AimsThe survival time of patients with recurrent endometrial carcinoma is generally short. However, considerable interindividual variation exists. We developed a risk-scoring model for predicting post-recurrence survival in patients with endometrial carcinoma. Materials and methodsPatients with endometrial carcinoma treated at a single institution between 2007 and 2013 were identified. Pearson chi-squared analyses were used to compute odds ratios for the associations between risk factors and short survival after cancer recurrence. The results for biochemical analyses represented values at diagnosis of disease recurrence or values at initial diagnosis for those patients who had a primary refractory disease. Logistic regression models were constructed for the identification of variables that independently predict short post-recurrence survival. The models were used to assign points based on odds ratios for risk factors and risk scores were derived. ResultsIn total, 236 patients with recurrent endometrial carcinoma were included in the study. Based on overall survival analysis, 12 months was selected as the cut-off for short post-recurrence survival. Factors associated with short post-recurrence survival were platelet count, serum CA125 concentration and progression-free survival. A risk-scoring model with an area under the receiver operating characteristic curve (AUC) of 0.782 (95% confidence interval 0.713–0.851) was developed in patients without missing data (n = 182). When patients with a primary refractory disease were excluded, age and blood haemoglobin concentration were identified as additional predictors of short post-recurrence survival. For this subpopulation (n = 152), a risk-scoring model with an AUC of 0.821 (95% confidence interval 0.750–0.892) was developed. ConclusionsWe report a risk-scoring model that shows acceptable to excellent accuracy in predicting post-recurrence survival in patients with endometrial carcinoma, with primary refractory diseases included or excluded. This model has potential applications in precision medicine in patients with endometrial carcinoma.