Purpose: The forkhead box transcription factor FoxP3 is specifically expressed in T cells with regulatory properties (Treg). Recently, high numbers of Treg were described to be associated with poor survival in different malignancies. The aim of the presented study was determine the prognostic effect of FoxP3 mRNA expression (reflecting the tissue content of Treg) in ovarian carcinoma and its relation with cytokines, such as IFN-γ. Experimental Design: Total RNA was isolated from 99 ovarian carcinoma and from 14 healthy ovarian biopsies. Real-time PCR for FoxP3 was done and correlated with IFN-γ-, CD3-, IRF-1-, SOCS-1-, HER-2-, and iNOS expression as well as patients' outcome. The mRNA data was corroborated by FoxP3 immunohistochemistry. Results: Quantitation of FoxP3 expression identified a patient subgroup (>81th percentile), which is characterized by a significantly worse prognosis in terms of overall survival (27.8 versus 77.3 months, P = 0.0034) and progression-free survival (18 versus 57.5 months; P = 0.0041). FoxP3 expression correlated with IFN-γ, IRF-1, and CD3 expression. High FoxP3 expression represents an independent prognostic factor for overall survival (P = 0.004) and progression-free survival (P = 0.004). Conclusions: High expression levels of FoxP3 might represent a surrogate marker for an immunosuppressive milieu contributing to tumor immune escape. Strategies selectively depleting Treg might improve the antitumor activity of endogenously arising tumor-reactive T cells and immunotherapies using vaccines or antibodies.

Background Despite the excellent prognosis of Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stage I, type I endometrial cancers, a substantial number of patients experience recurrence and die from this disease. We analyzed the value of immunohistochemical L1CAM determination to predict clinical outcome. Methods We conducted a retrospective multicenter cohort study to determine expression of L1CAM by immunohistochemistry in 1021 endometrial cancer specimens. The Kaplan–Meier method and Cox proportional hazard model were applied for survival and multivariable analyses. A machine-learning approach was used to validate variables for predicting recurrence and death. Results Of 1021 included cancers, 17.7% were rated L1CAM-positive. Of these L1CAM-positive cancers, 51.4% recurred during follow-up compared with 2.9% L1CAM-negative cancers. Patients bearing L1CAM-positive cancers had poorer disease-free and overall survival (two-sided Log-rank P < .001). Multivariable analyses revealed an increase in the likelihood of recurrence (hazard ratio [HR] = 16.33; 95% confidence interval [CI] = 10.55 to 25.28) and death (HR = 15.01; 95% CI = 9.28 to 24.26). In the L1CAM-negative cancers FIGO stage I subdivision, grading and risk assessment were irrelevant for predicting disease-free and overall survival. The prognostic relevance of these parameters was related strictly to L1CAM positivity. A classification and regression decision tree (CRT)identified L1CAM as the best variable for predicting recurrence (sensitivity = 0.74; specificity = 0.91) and death (sensitivity = 0.77; specificity = 0.89). Conclusions To our knowledge, L1CAM has been shown to be the best-ever published prognostic factor in FIGO stage I, type I endometrial cancers and shows clear superiority over the standardly used multifactor risk score. L1CAM expression in type I cancers indicates the need for adjuvant treatment. This adhesion molecule might serve as a treatment target for the fully humanized anti-L1CAM antibody currently under development for clinical use.

Recently, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer (EC) critically integrating new pathological and molecular features was published. The present study evaluated the clinical impact of the new 2023 FIGO staging system by comparing it to the previous 2009 system. This is an international, pooled retrospective study of 519 EC patients who underwent primary treatment (and molecular characterisation) at three European Society of Gynaecological Oncology (ESGO) accredited centres in Austria/Italy. Patients were categorised according to the 2009 and the 2023 FIGO staging systems. Stage shifts were analysed and (sub)stage specific 5-year progression-free (PFS) and overall survival (OS) rates were calculated and compared. Different statistical tests were applied to evaluate the prognostic precision of the two FIGO staging systems and to compare them to each other. (Sub)stage shifts occurred in 143/519 (27.6%) patients: 123 upshifts (23.7%) and 20 (3.9%) downshifts. 2023 FIGO staging system identified a stage I cohort with a notably higher 5-year PFS rate compared to 2009 (93.0% versus 87.4%, respectively). For stage II disease, the 5-year PFS rate was similar in the 2023 and the 2009 FIGO staging systems (70.2% versus 71.2%, respectively). The two new molecularly defined 2023 FIGO substages IAm_POLEmut and IICm_p53abn displayed distinct, particularly favourable and adverse oncologic outcomes within early stage disease, respectively. A remarkably lower 5-year PFS rate for stage III patients was revealed in the 2023 FIGO staging system compared to 2009 (44.4% versus 54.1%, respectively). All applied statistical tests confirmed a more accurate prediction of PFS and OS by the 2023 FIGO staging system compared to 2009. The new 2023 FIGO stating system led to a substantial stage shift in about one quarter of patients leading to a higher prognostic precision. In early stage disease, the new substages added further prognostic granularity and identified treatment relevant subgroups.

Through the last three decades, the combination of paclitaxel and carboplatin remains the standard of care chemotherapy in newly diagnosed epithelial ovarian cancer (EOC). Based on a single trial, first-line maintenance therapy with angiogenesis inhibitor bevacizumab was approved in Europe and widely applied. In 2018, based on a second trial bevacizumab was approved for first-line maintenance in the United States. Despite complete remission upon chemotherapy, the majority of the patients recur. A large number of randomized trials were conducted to explore the optimal front-line therapy regimen, but neither dose-densing, nor adding of a third chemotherapy agent or intraperitoneal administration could improve overall survival (OS). Also implementation of hyperthermic intraperitoneal chemotherapy (HIPEC) or the neoadjuvant approach failed to improve OS. Recently, maintenance therapy with PARP inhibitors showed encouraging results in patients with BRCA1/2 mutation. Further trials with targeted therapies are ongoing. Here we review the achievements of front-line therapy in primary advanced EOC through the last three decades and discuss future treatment strategies.

The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues (P=0.002, P<0.001, P<0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with BRCA1/2 mRNA-expression (BRCA1: miR34 b/c P=0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and BRCA2 mRNA-expression (P<0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in TP53-mutated compared with TP53-wild-type ovarian cancers (P<0.001, P=0.002, P=0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, P=0.033; miR-34b: HR 0.2, P=0.001 and miR-34c: HR 0.3, P=0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, P=0.016) and miR-34c (HR 0.6, P=0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.