To explore why in large phase III randomized clinical trials TP53-mutated (TP53mut) endometrial cancer (EC) was the only tumor showing survival benefit to immune checkpoint inhibitors (ICIs) added to chemotherapy when compared with other low TMB TP53mut cancers, such as high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC). From 606 patients with one of the three mentioned cancers, "The Cancer Genome Atlas" data on clinical outcome, TMB and detailed composition of the tumor immune-microenvironment (TIME) (immune infiltrating cells, cytokines, and other immune-modulators) were compared using the Kruskal-Wallis test, followed by Pearson correlation. Prognostic value of studied variables was assessed by Kaplan-Meier and Cox-regression analyses. TMB was very low in all three TP53mut entities, being lowest in EC (median: 1.27 Mut/Mb; p < 0.001). Interestingly, high TMB was significantly associated with improved clinical outcome in every entity, whereby best discrimination for PFS was found in EC (HR: 0.52). Compared to EC, immune-suppressing regulatory T-cells were higher in HGSOC and TNBC (p < 0.001) and M2-like macrophages higher in HGSOC (p < 0.001). In contrast, immune-activating mDCs were more prominent in EC than in HGSOC (p < 0.001). Differential modulator expression analyses revealed highest discrimination for the immune-inhibiting FOXP3, C1QA and XBP1, which all exhibited lower levels in EC compared with HGSOC and TNBC (p < 0.001). Characteristics of TIME differ substantially among the assessed entities in terms that EC exhibits fewer immunosuppressive traits, expecting a higher likelihood for responding to ICIs, despite a very low TMB, whereas HGSOC and TNBC exhibit an immune hostile TIME.

Background/Objectives: This study aimed to characterize dendritic cell (DC) heterogeneity, immune associations, and prognostic relevance across three TP53-mutated tumor entities—high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and endometrial cancer—focusing on plasmacytoid DCs (pDCs) in HGSOC. Methods: RNA-sequencing and clinical data of 603 patients from The Cancer Genome Atlas were analyzed. DC subset abundance was assessed for cDC progenitor, conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), plasmacytoid DC (pDC), and mature DC by marker gene signatures. Differences in DC scores across tumors were analyzed using Kruskal–Wallis. Survival analyses were performed using Kaplan–Meier and Cox regression. Spearman’s correlation was used to determine associations between parameters. Results: HGSOC showed the lowest pDC abundance, yet high pDC scores were independently associated with shorter PFS (HR = 1.55, 95% CI: 1.05–2.27; p = 0.027), representing the only DC-subset-related prognostic signal observed across tumor types. pDCs correlated positively with neutrophils and negatively with monocytes, and pDCs, cDC2s, and cDC progenitors correlated inversely with TMB. No consistent link was found between pDC and TP53 mutation classes. However, tumors harboring specific TP53 mutations within established hotspot regions exhibited significantly lower pDC levels (p = 0.015). Conclusions: Our findings reveal distinct DC infiltration patterns and highlight the immunological vulnerability of TP53-mutated HGSOC. pDCs appear to exert a tumor-promoting, immune-evasive role, suggesting that DC function depends on their programming and tumor context. Selective targeting of DC subsets may offer novel therapeutic opportunities in TP53-mutated, low-TMB cancers.

The 2025 ESGO/ESTRO/ESP guideline for endometrial carcinoma (EC) integrates molecular classification into clinical decision-making and, for the first time, recommends the subdivision of carcinomas with no specific molecular profile (NSMP) according to estrogen receptor (ER) status and histological grading. However, NSMP carcinomas remain a highly heterogeneous subgroup, posing challenges in terms of diagnosis and therapy. We report the case of a 71-year-old female patient with low-grade NSMP EC. Due to ER-negativity and strong L1 cell adhesion molecule (L1CAM) expression, the German/Austrian/Swiss S3 guideline at that time required comprehensive histopathological reassessment, which reclassified the tumor as mesonephric-like adenocarcinoma. Extended molecular profiling further identified a KRAS mutation and the absence of common alterations in PTEN, PIK3CA, and PIK3R1. These features correspond to the aggressive “Cluster 3” subgroup of NSMP tumors, characterized by ER-negativity, L1CAM positivity, KRAS mutations, and frequent chromosome 1q gain. The patient therefore underwent adjuvant carboplatin/paclitaxel chemotherapy followed by vaginal brachytherapy and has remained recurrence-free for five years. This case demonstrates molecular classification of an unusual histological type of EC exhibiting an extremely short-term risk of early distant metastasis and its implication on aggressive adjuvant therapeutical approach. It, furthermore, exemplifies the pronounced heterogeneity of the NSMP subgroup.

Definitive radiochemotherapy with external beam radiotherapy and brachytherapy is standard for locally advanced cervical cancer (LACC). Advanced techniques

Non-surgical, fertility-sparing management using a levonorgestrel intra-uterine device is a de-escalation strategy for selected patients with early-stage endometrial adenocarcinoma or endometrial hyperplasia with atypia. Although the oncologic outcomes of the feMMe trial have been reported, long-term patient-reported outcomes remain insufficiently characterized. This study evaluated long-term quality of life, self-efficacy, social support, and patient-reported experiences following conservative management. The feMMe trial (open-label, randomized phase II study) includes three treatment arms: levonorgestrel intra-uterine device alone, levonorgestrel intra-uterine device plus weight loss, and levonorgestrel intra-uterine device plus metformin. Participants were contacted 15.8 to 130.2 months after trial entry. Quality of life was assessed using the Functional Assessment of Cancer Therapy-General questionnaire. Self-efficacy and social support regarding physical activity and diet were evaluated using the Self-Efficacy and Social Support questionnaire. Post-treatment experiences were collected using structured self-report items. Analyses were descriptive and included non-parametric group comparisons and correlation analyses. Forty-four participants completed long-term follow-up questionnaires. After a median follow-up of 63 months, overall quality of life was favorable; the mean (standard deviation) Functional Assessment of Cancer Therapy-General total score was 80.5 (16.4). Quality of life scores did not differ by treatment arm, baseline diagnosis, pathologic response, disease recurrence, or hysterectomy status. Self-efficacy for physical activity was more favorable among patients achieving pathologic complete response at trial completion (p =.002). Perceived social support for health-related behaviors was limited, with no significant correlations between self-efficacy and social support. A total of 32 (74.4%) of participants reported a positive treatment experience and 35 (85.4%) would recommend treatment with a levonorgestrel intra-uterine device. Long-term quality of life and patient-reported outcomes following non-surgical management of early-stage endometrial adenocarcinoma and endometrial hyperplasia with atypia are favorable and comparable across conservative treatment strategies. These findings contribute to the understanding of long-term patient-reported outcomes after conservative management and underscore the importance of integrating survivorship-focused outcomes into shared treatment decision-making.

Objective Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value. Methods Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1), its ligand (PDL1, encoded by CD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548). Results PD1, PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG. Increased expression of PD1, PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort. Conclusions Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in “hot tumors”, predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.