ABSTRACTIntroductionHead and neck squamous cell carcinoma (HNSCC) accounts for approximately 5% of cancer cases worldwide, with more than half of patients presenting with locally advanced (LA) disease. Treatment of LA HNSCC is multimodal and may include concomitant cisplatin-based chemoradiotherapy (CRT) or surgery; however, recurrence rates are high, and there is an unmet need for new treatments. Immune checkpoint inhibitors that target programmed death receptor-1 (PD-1) are standard of care for recurrent/metastatic HNSCC, but outcomes for anti-PD-1 and anti-PD-(ligand [L])1 therapies with CRT in LA HNSCC have been variable. Dostarlimab, an anti-PD-1 therapy approved in advanced endometrial cancer and mismatch repair-deficient solid tumors is being investigated across other tumor types, including HNSCC. JADE is a global, multicenter, double-blind, placebo-controlled, randomized phase 3 study evaluating the efficacy and safety of dostarlimab as post-cisplatin-based CRT sequential therapy in patients with LA unresected PD-L1-expressing HNSCC. JADE seeks to overcome the limitations of previous studies by incorporating both PD-L1 selection and solely sequential administration of dostarlimab soon after CRT.MethodsThe primary endpoint is event-free survival, with overall survival as a key secondary endpoint; safety and tolerability, pharmacokinetics, immunogenicity, biomarkers, and patient-reported outcomes will also be assessed.Clinical trial registrationwww.clinicaltrials.gov identifier is NCT06256588.

Recommendations for clinical practice Nice-Saint Paul de Vence 2024-2025: Management of advanced/relapsing endometrial cancer

Despite the introduction of novel therapeutic options, the prognosis of advanced endometrial cancer remains poor. In recent years, increasing attention has been directed toward the molecular characterization of endometrial cancer. However, data specifically focusing on advanced-stage disease are still limited. In our single-center, retrospective, exploratory study with a limited sample size, we analyzed 32 patients with advanced or recurrent endometrial cancer treated at the Modena Cancer Center. Comprehensive molecular profiling was performed to assess DNA mutations, copy number variations, and RNA expression. We characterized the molecular landscape of this cohort, evaluated selected genomic alterations across predefined clinical subgroups, and explored their association with overall survival. Consistent with previous reports, a high prevalence of PTEN and PIK3CA mutations were observed. Patients experiencing relapse more than six months after diagnosis were more likely to harbor CTNNB1 mutations. KRAS mutations were more frequently detected in younger patients and in those with endometrioid histology, whereas PPP2R1A and TP53 mutations were enriched in tumors with non-endometrioid histology. Notably, CTNNB1 mutations were associated with a favorable prognostic impact, while KRAS mutations correlated with poorer overall survival. Our findings underscore the need for further investigation into the molecular landscape of advanced endometrial cancer, particularly in the context of therapeutic implications. Combinatorial treatment strategies targeting specific molecular alterations, such as KRAS, in combination with other targeted agents or therapeutic approaches, warrant further exploration.

(1) Background: Advance-stage endometrial cancer is a rare disease that encompasses a heterogeneous group of patients. Primary surgery is the treatment of choice, while neoadjuvant chemotherapy (NACT) seems to be an alternative option for inoperable frail patients. The aim of this study was to identify possible prognostic factors for advance-stage endometrial cancer patients. (2) Methods: We retrospectively analyzed the records of patients with endometrial cancer that underwent surgery in the 1st Department of Obstetrics-Gynecology from 2012 to 2023. Patients with advance-stage disease (FIGO stage III-IV) were included, while those with incidental microscopic lymph node metastases after staging lymphadenectomy were excluded. (3) Results: The population of this study consisted of 89 women. Patients were obese, with moderate comorbidities and a median age of 64 years old. The majority of them (75.3%) had FIGO stage IIIC disease, while one-fourth (24.7%) presented with peritoneal metastases (FIGO stage IV). Most patients had endometrioid, high-grade tumors, with substantial lymphovascular space invasion (LVSI) and deep myometrial invasion. Complete gross resection was achieved in 92.1% of the patients. NACT was administrated in 14.6% of the population. Deep myometrial invasion and non-endometrioid histology were recognized as independent prognostic factors for worse PFS, but no association was found for OS. Concerning survival rates, the median progression-free (PFS) and overall (OS) survival were 44 and 70 months, respectively. (4) Conclusions: Myometrial invasion and histological subtypes seem to affect the recurrence rate of advanced endometrial cancer patients. NACT could likely be an alternative for primarily inoperable and frail patients, but does not appear to alter survival rates.

Abstract Objectives: Indocyanine green (ICG) sentinel lymph node (SLN) mapping has been used in endometrial cancer. We aimed to report our experience in the lymph node detection rate, negative predictive value (NPV), distribution, and risk factors of laparoscopic ICG SLN mapping in patients with endometrial cancer. Materials and Methods: We retrospectively analyzed patients with endometrial cancer who underwent laparoscopic staging surgery with ICG SLN mapping between January 2019 and July 2023. Thirty-one patients were included. ICG was injected into the cervix at 2–4 points. The outcomes were detecting and mapping failure rates and subsequent adjuvant therapy. Kruskal–Wallis and Chi-square tests were used for continuous and categorical variables. Statistical significance was set at P < 0.05. Results: The overall detection rate of SLN was 80.6% (25/31). Both NPV and sensitivity were 100%. Bilateral SLN was detected in 52% (13/25) of cases. The right and left sides were visualized in 84% (21/25) and 68% (17/25) cases, respectively. Complete pelvic lymph node dissection was done when SLN mapping failed. The most common SLN locations were the right and left external iliac regions. SLN detection in the para-aortic area was observed in 20% (5/25) cases. Twenty-five patients had positive SLN mapping. Two patients (8%) had positive lymph node metastasis: one underwent bilateral pelvic sentinel lymphadenectomy plus para-aortic sentinel lymphadenectomy with the final histologic type of Grade 2 endometrioid carcinoma (Stage IIIC1), and the other underwent bilateral pelvic lymphadenectomy with the final histologic type of serous carcinoma (Stage IIIC1). Sixteen patients had high-grade stage IA or above; five received postoperative adjuvant chemotherapy, five received postoperative radiotherapy, four received chemotherapy with radiotherapy, and two were followed up. Conclusion: The NPV and sensitivity of ICG application in our study were high. The metastatic status of the lymph nodes is important for future therapeutic planning for advanced endometrial cancer.

Although recent clinical trials proved survival benefit from the addition of immune checkpoint inhibitors to standard chemotherapy, treatment of mismatch repair-proficient (pMMR) advanced or recurrent endometrial cancer (arEC) is challenging. As poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effects of immune checkpoint inhibitors when combined, improvement of survival is expected by dual maintenance in this population. The PENELOPE trial will investigate the efficacy and safety of dual maintenance with nesuparib, an orally active PARP1/2 and tankyrase 1/2 inhibitor, and pembrolizumab after paclitaxel/carboplatin plus pembrolizumab (TCP) treatment in patients with pMMR arEC. In this multicenter, randomized, open-label, non-comparative phase II trial, patients with pMMR arEC, naïve to first-line chemotherapy, will be enrolled. Six patients will be enrolled in stage 1 (safety run-in) and treated with TCP for 6 cycles followed by dual maintenance with nesuparib and pembrolizumab. The study will proceed to stage 2 (dose expansion) if less than 33% of patients in stage 1 experience a dose-limiting toxicity. Otherwise, additional patients will be enrolled in stage 1 at a lower dose level. In stage 2, 80 patients will be randomized (1:1) to: arm A) TCP followed by maintenance with pembrolizumab; arm B) TCP followed by dual maintenance with nesuparib and pembrolizumab. Patients are planned to receive maintenance treatment up to 14 cycles every 6 weeks. Primary endpoint is investigator-assessed progression-free survival (Response Evaluation Criteria in Solid Tumors 1.1) of each arm vs. historical control, which is the placebo arm for pMMR patients in the NRG-GY018 study, and key secondary endpoints are overall survival, overall response rate, disease control rate, duration of response, and safety. Enrollment began in Q4 2024. ClinicalTrials.gov Identifier: NCT06502743.

Associations between obesity and outcomes in pembrolizumab-treated endometrial cancer.

Executive Summary of the American Radium Society™ (ARS) Appropriate Use Criteria (AUC) for Management of Locally Advanced Endometrial Cancer.

Phase I Clinical Trial of De-escalated Conformal Radiation Expedited Sequentially with Chemotherapy for Advanced Endometrial Cancer (DeCRESCEndo).

Evidence on neoadjuvant chemotherapy in clinically advanced endometrial cancer is limited, with most of the data from high-income countries. To address this gap, we evaluated the treatment responses and survival outcomes in these patients at a tertiary cancer center in India. This retrospective study included patients with International Federation of Gynecology and Obstetrics 2009 stage III to IVB endometrial cancer treated at Gujarat Cancer Research Institute between January 1, 2017 and December 31, 2022. Patients deemed unfit for primary surgery and who received neoadjuvant chemotherapy were analyzed. Data collected included age, Eastern Cooperative Oncology Group performance status, tumor histology, CA125 levels, and chemotherapy regimens. Radiologic response to neoadjuvant chemotherapy was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria. Interval debulking surgery outcomes were categorized as optimal (residual tumor ≤1 cm) or sub-optimal. Post-operative therapies and survival outcomes were evaluated. The median overall survival was estimated using the Kaplan-Meier method. A total of 41 patients met inclusion criteria. The mean age was 55.6 years (standard deviation 12.1), and the majority (83%) had endometrioid histology. Most patients had stage III disease (78%). The primary reason for inoperability was parametrial invasion (46.3%). After neoadjuvant chemotherapy, 22 patients (53.7%) underwent interval debulking, 14 of these (63.6%) achieved optimal cytoreduction. Based on RECIST, complete response occurred in 6 patients (14.6%) and progressive disease in 10 (24.4%). Overall, 39% experienced recurrence. The 5-year overall survival rate was 58.2% (95% confidence interval 41.75% to 81.3%). Patients who underwent surgery had significantly better survival than those who received chemoradiotherapy (5-year overall survival 77.1% vs 26.1%) (95% confidence interval 58.90% to 100%, p = .014). Neoadjuvant chemotherapy, followed by interval debulking surgery, is a feasible and effective treatment approach with unresectable advanced-stage endometrial cancer. Although a small sample size, favorable survival outcomes are observed, particularly, in patients achieving optimal cytoreduction. Further prospective studies are needed to validate these findings and refine patient selection.

The development of antitumor strategies aimed at restoring systemic and local immune regulation is considered one of the most promising directions. Technologies based on dendritic cell vaccines (DCVs), characterized by minimal toxicity and alignment with fundamental immunological mechanisms of antitumor resistance, are of particular interest. Purpose of the study . Is to evaluate the effectiveness of immunotherapeutic approaches for gynecologic malignancies using DCVs and to outline promising directions for further development. Materials and methods. A literature search was conducted in the bibliographic registers MEDLINE, ClinicalTrial.gov., eLIBRARY and CyberLeninka, using the search systems PubMed, Google Scholar. The vast majority of the identified sources are indexed in Scopus and Web of Science. The review includes more than 60 publications in Russian and English, over 50 % of which were published within the past five years. Results. The analysis summarizes data on the clinical outcomes of DCV-based therapy in advanced cervical cancer, endometrial cancer, and ovarian cancer. Reported beneficial effects include temporary disease stabilization, improved overall survival and quality of life in advanced malignancies, enhanced efficacy of subsequent chemotherapy, and occasional cases of partial or complete remission. The review also addresses potential reasons for the limited efficacy of DCVs, as well as possible combinations of this technology with other immunotherapeutic modalities and traditional anticancer treatments. The currently modest therapeutic effectiveness of DCVs in gynecologic cancers may be attributed both to the insufficient maturity of the technology and to inherent mechanisms of tumor immune evasion. Conclusion. The therapeutic potential of DCVs has not yet been fully realized. Advances in immunotherapy, molecular biology, nanotechnology, and strategies for activating systemic and local antitumor resistance mechanisms provide a foundation for defining future research priorities aimed at improving the efficacy of DCVs as an important component of multimodal treatment for gynecologic malignancies.

Background/Objectives: Although the binarism between type I and II endometrial cancer was dismissed and substituted with molecular classification, histopathological features remain of paramount importance. Hence, analysing survival outcomes according to histological type, our aim is to clarify whether the morphological features of the tumour retain prognostic relevance in the context of advanced disease. Methods: This is a retrospective analysis led within the Thames Valley Cancer Alliance Network. Results: We include 148 FIGO 2009 stage III–IV patients affected by endometrioid endometrial cancer (EEC) G1, G2, and G3, carcinosarcoma (CS), serous carcinoma (SC), and clear cell carcinoma (CCC) of the uterus. Five year overall survival (OS) is distinct among the histological groups (p-value < 0.001), being 73.3% for G2 endometrioid, 49.2% for G3 endometrioid, 8.3% for CS, and 28.4% for SC. The divergence was marked also for 5 year progression-free survival (PFS) (p-value < 0.001) as follows: for G2 endometrioid, was 76.4%; for G3 endometrioid, 52.7%; and for carcinosarcoma, 5.9%. PFS after 18 months for serous carcinoma was 5.7%. The multivariate analysis found G3 endometrioid (HR 2.91, 95% CI 1.20–7.11, p-value 0.018), carcinosarcoma (HR 12.15, 95% CI 5.07–29.11, p-value < 0.001), and serous carcinoma (HR 4.84, 95% CI 2.16–10.83, p-value < 0.001) as independent predictors of poor survival, as well as cervical invasion (HR 1.83, 95% CI 1.10–3.05, p-value 0.020) as the only histopathological feature confirmed. Regarding progression-free only carcinosarcoma (HR 14.91, 95% CI 5.28–41.11) and serous carcinoma (HR 17.68, 95% CI 6.41–48.75) were associated with an increased risk of recurrence. Conclusions: Our findings testify that, beyond the disease stage, histological subtype remains a major determinant of survival outcome. Cervical involvement is associated with a more aggressive disease, possibly correlated to death beyond relapse. Prospective trials involving advanced stage endometrial cancer, stratified by histological subtype and integrated with the molecular classification, are required.

Endometrial cancer is the sixth most common cancer in women worldwide and the fourth most common cancer in women in the United States. In the United States, its incidence and mortality rates have continued to increase since the late 1990s. Endometrial cancer comprises most uterine corpus carcinomas and represents a heterogeneous group of cancers varying in pathology, histology, molecular biology, immunogenicity, and prognosis. Recently, the advancement of molecular classification and subsequent clinical trials have led to new FDA approvals for the use of immune checkpoint inhibitors in endometrial cancer. However, recurrent and advanced-stage endometrial cancer continues to demonstrate high morbidity and mortality, denoting an unmet need for innovative immunotherapeutic strategies. This review explores current concepts in the endometrial cancer tumor immune microenvironment, comparing antigenicity, immunosurveillance, and immunoregulation among molecular and histologic subtypes and providing insight into which subtypes may be particularly responsive to immunotherapy. Novel immunotherapeutic strategies targeting cancer antigens, emerging immune checkpoints, immunomodulatory cytokines, and tumor-infiltrating immune cells are described, and corresponding clinical trials are presented. Integrated approaches such as immunogenic modulation, which enhances tumor susceptibility to immune attack, and immune subset conditioning, which modifies suppressive immune components within the tumor immune microenvironment, are presented as promising avenues to render "cold" tumors responsive. Together, the immunotherapies reviewed here offer potential strategies for treating patients with advanced or refractory endometrial cancer.

Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial.

Surgically inoperable locally advanced endometrial cancer is associated with poor prognosis. The optimal treatment strategy remains controversial. In this study, we report the treatment outcomes and adverse effects of neoadjuvant radiotherapy followed by definitive surgery for locally advanced surgically inoperable endometrial cancer in our institution. Between January 2010 and June 2024, patients with locally advanced upfront inoperable endometrial cancer who received neoadjuvant radiotherapy were retrospectively reviewed. Margin status, pathological response, and toxicities were reported. Kaplan-Meier analysis was performed to estimate progression-free survival and overall survival. A total of 37 consecutive patients were included. All had cervical involvement. A total of 26 patients (70%) had parametrial involvement, and 10 patients (27%) had nodal involvement. After external beam radiotherapy, 33 patients (89%) received brachytherapy. Among the patients, 24 (65%) had concurrent platinum-based chemotherapy. After neoadjuvant radiotherapy, 33 patients (89%) were deemed operable. Definitive surgery was eventually performed in 31 patients (84%). The complete resection rate was 100% (n = 31). A pathological complete response was achieved in 9 patients (29%), while 7 patients (23%) had microscopic disease only. Downstaging to stage I or below occurred in 19 patients (61%). The median follow-up was 74 months. The 5-year progression-free survival and overall survival rates were 71.9% and 73.4% respectively. One patient experienced grade 3 diarrhea during radiotherapy. Surgical complications of grade 2 to 3 severity occurred in 3 patients (10%). Chronic radiotherapy toxicities of grade 3 or higher were also observed in 3 patients (10%). Neoadjuvant radiotherapy is feasible for locally advanced endometrial cancer, with high complete resection, pathological complete response, and locoregional control rates in a single center. Further research is warranted to optimize treatment efficacy and toxicities in the image-guided brachytherapy era.

626P The impact of platinum-free interval on the efficacy of lenvatinib/pembrolizumab in advanced or recurrent endometrial cancer

For many years, drug therapy for endometrial cancer has centered on chemotherapy regimens such as adriamycin+cisplatin(AP)or paclitaxel+carboplatin(TC). In recent years, however, the introduction of immune checkpoint inhibitors(ICIs)has dramatically changed the treatment landscape. Multiple phase Ⅲ trials(eg, NRG-GY018, DUO-E)have demonstrated that adding ICIs to TC chemotherapy improves prognosis, and in 2024 combination therapies with pembrolizumab or durvalumab were approved in Japan for advanced or recurrent endometrial cancer. Additionally, development of antibody-drug conjugates(ADCs)is underway, and ADCs targeting HER2, TROP2, and other tumor-specific antigens are anticipated to become new therapeutic options.

627eP Survey of current treatment patterns among Chinese physicians for advanced endometrial cancer that progressed on platinum treatment

Investigate the utilization and oncologic outcomes of the sentinel lymph node algorithm for patients with locally advanced endometrial cancer (involvement of the cervix, vagina, ovary, or parametria) (International Federation of Gynecology and Obstetrics stage II-IIIB). Patients diagnosed between 2012 and 2015 with endometrial carcinoma who underwent minimally invasive hysterectomy and had endocervical (T2), serosal/adnexal (T3A), or vaginal/parametrial involvement (T3B) and no distant metastases (M0) were identified in the National Cancer Database. Those who underwent sentinel lymph node biopsy (with or without lymphadenectomy) or systematic lymphadenectomy alone (defined as at least 20 lymph nodes removed) were included. Based on pathology reports, the incidence of lymph node metastases was compared with the χ2 test. Overall survival was evaluated using Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. A total of 2108 patients were identified; 1786 (84.7%) had systematic lymphadenectomy (of whom 78.1% had para-aortic lymphadenectomy) with a median of 26 lymph nodes removed, while 322 (15.3%) patients underwent sentinel lymph node biopsy. The rate of lymph node metastases was 35.8% in the systematic lymphadenectomy group and 32.6% in the sentinel lymph node biopsy group, P = .27. Rates of adjuvant chemotherapy (59.7% vs 62.4%, p = .36) and radiation therapy (61.5% vs 58.7%, p = .34) were comparable. Patients who had systematic lymphadenectomy were less likely to be discharged within 1 day of surgery (66.4% vs 78.6%, p < .001). There was no overall survival difference between patients who had sentinel lymph node biopsy and those who had systematic lymphadenectomy (p = .60; 4-year overall survival rates were 71.5% and 73.9%, respectively), even after controlling for confounders (HR 1.08, 95% CI 0.82 to 1.41). Patients with locally advanced endometrial cancer have a high incidence of lymph node metastases. For these patients, sentinel lymph node biopsy is associated with overall survival similar to that of systematic lymphadenectomy.

Endometrial cancers (ECs) are mainly adenocarcinomas arising from the uterine endometrium. In this work, we employed data-independent acquisition (DIA) mass spectrometry (MS)-based label-free quantification (LFQ-MS) proteomics to analyze the proteome of tissue washings collected from 25 control (CTRL) subjects, 25 patients with low-grade type 1 endometrial cancer (EC), and 24 patients with high-grade type 1 EC. Following quantification and statistical analysis, we identified 42 proteins able to discriminate CTRL from EC patients, and 151 proteins differentiating high-grade EC cases from low-grade EC cases. Notably, PRRC2A and SYDE2 effectively distinguished both EC patients from controls and advanced EC cases from low-grade EC cases. Validation by Western blot analysis in an independent cohort comprising 19 CTRL patients, 19 patients with low-grade EC, and 19 patients with high-grade EC confirmed the upregulation of PRRC2A and SYDE2. These proteins are implicated in the translocation of SLC2A4, the regulation of MECP2, and extracellular matrix (ECM) proteoglycan pathways, all of which are associated with tumor growth. Our results demonstrate that DIA-based proteomic analysis of tissue washings enables the identification of potential biomarkers for endometrial cancer (EC). Moreover, this study highlights tissue washings as a promising biological fluid for biomarker discovery in EC.