Ovarian cancer (OC) has the highest mortality rate of all gynecological malignancies due to the high prevalence of advanced stages of diagnosis and the high rate of recurrence. Furthermore, the heterogeneity of OC tumors contributes to the rapid development of resistance to conventional chemotherapy. In recent years, in order to overcome these problems, targeted therapies have been introduced in various types of tumors, including gynecological cancer. However, the lack of predictive biomarkers showing different clinical benefits limits the effectiveness of these therapies. This requires the development of preclinical models that can replicate the histological and molecular characteristics of OC subtypes. In this scenario, organoids become an important preclinical model for personalized medicine. In fact, patient-derived organoids (PDO) recapture tumor heterogeneity with the possibility of performing drug screening. However, to best reproduce the patient’s characteristics, it is necessary to develop a specific extracellular matrix (ECM) and introduce a tumor microenvironment (TME), which both represent an actual object of study to improve drug screening, particularly when used in targeted therapy and immunotherapy to guide therapeutic decisions. In this review, we summarize the current state of the art for the screening of PDOs, ECM, TME, and drugs in the setting of OC, as well as discussing the clinical implications and future perspectives for the research of OC organoids.

Background/Objectives: Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases. This review evaluated PD-L1 and PD-1 expression as potential biomarkers for immunotherapy response in EC, focusing on their relationship with MSI status. Methods: A systematic review, adhering to PRISMA guidelines, analyzed studies from MEDLINE and Embase until February 2023 on PD-1/PD-L1 expression in EC stratified by MSI status, including diverse study designs but excluding conference abstracts, with independent screening, data extraction, and additional reference checks to ensure comprehensive coverage. Results: A systematic analysis of 10 studies found that PD-L1 expression was more frequently expressed in MSI tumors (49%) compared to microsatellite-stable tumors (MSS) (33.5%), while PD-1 was expressed in 58% of MSI cases and 48% of MSS cases. Despite these findings, the prognostic value of PD-L1/PD-1 remains uncertain, with conflicting results regarding their association with survival outcomes. PD-L1 expression varied across molecular subtypes, being highest in POLE-mutated tumors (76.56%) and serous carcinomas (73%). Differences in PD-L1 expression between primary and metastatic sites were also noted, complicating its use as a biomarker. Conclusions: The assessment of PD-L1 expression in EC could represent a valuable option for selecting patients who may benefit from immune checkpoint inhibitors (ICI), including those in the MSS cohort, thereby ensuring a more tailored and personalized treatment strategy.

(1) Background: Endometrial carcinoma (EC) classified as no specific molecular profile (NSMP) represents a heterogeneous group with variable prognoses. This retrospective, single-center study aims to further stratify NSMP ECs to tailor treatment strategies and improve outcomes. (2) Methods: From 2020 to 2023, we collected data on 51 patients diagnosed with NSMP EC following the introduction of molecular profiling at our institution. Patients were retrospectively analyzed for estrogen receptor (ER) status, histotype, and grade to identify potential prognostic subgroups. (3) Results: Our analysis identified two distinct subgroups within NSMP EC: low-risk and high-risk, based on ER status, histotype, and grade. The low-risk NSMP group demonstrated significantly better survival outcomes compared to the high-risk group. With a median follow-up time of 16 moths (IQR 13.0–29.7), the disease-free survival (DFS) and overall survival (OS) for the low-risk group were 100%. For the high-risk group, the DFS and OS were 71.4% and 78.6%, respectively, which showed a statistically significantly difference (Log-Rank Mantel-Cox < 0.001). In the high-risk group, four patients experienced recurrence, and three of these patients died. (4) Conclusions: Stratifying NSMP EC into low-risk and high-risk categories based on ER status, histotype, and grade can lead to more accurate prognostic assessments. In time, it may require tailored adjuvant therapies and a personalized treatment.

Objective: We aimed to compare the clinical utility and diagnostic accuracy of the ADNEX model, ROMA score, RMI I, and RMI IV, as well as two serum markers (CA125 and HE4) in preoperative discrimination between benign and malignant adnexal masses (AMs). Methods: We conducted a retrospective study extracting all consecutive patients with AMs seen at our Institution between January 2015 and December 2020. Accuracy metrics included sensitivity (SE), specificity (SP), and area under the receiver operating characteristic curve (AUC), and their 95% confidence intervals (CI) were calculated for basic discrimination between AMs. Model performance was evaluated in terms of discrimination ability and clinical utility (net benefit, NB). Results: A total of 581 women were included; 481 (82.8%) had a benign ovarian tumor and 100 (17.2%) had a malignant tumor. The SE and SP of CA125, HE4, ROMA score, RMI I, RMI IV, and ADNEX model were 0.60 (0.54–0.66) and 0.80 (0.76–0.83); 0.39 (0.30–0.49) and 0.96 (0.94–0.98); 0.59 (0.50–0.68) and 0.92 (0.88–0.95); 0.56 (0.46–0.65) and 0.98 (0.96–0.99); 0.54 (0.44–0.63) and 0.96 (0.94–0.98); 0.82 (0.73–0.88) and 0.91 (0.89–0.94), respectively. The overall AUC was 0.76 (0.74–0.79) for CA125, 0.81 (0.78–0.83) for HE4, 0.82 (0.80–0.85) for ROMA, 0.86 (0.84–0.88) for RMI I, 0.83 (0.81–0.86) for RMI IV, and 0.92 (0.90–0.94) for ADNEX. The NB for ADNEX was higher than other biomarkers and models across all decision thresholds between 5% and 50%. Conclusions: The ADNEX model showed a better discrimination ability and clinical utility when differentiating malignant from benign Ams, compared to CA125, HE4, ROMA score, RMI I, and RMI IV.

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

Homologous recombination deficiency (HRD) is a key biomarker associated with increased sensitivity to PARP inhibitors (PARPi) in advanced epithelial ovarian cancer. Accurate identification of HRD status is essential for selecting patients most likely to benefit from these therapies. Current diagnostic approaches combine sequencing to detect mutations in homologous recombination repair genes—particularly BRCA1 and BRCA2—with genome-wide analysis of structural genomic alterations indicative of HRD. This review briefly outlines the biological basis of HRD and its clinical significance and then focuses on currently available assays for HRD assessment. We compare their molecular strategies, including the use of targeted gene panels and genomic instability metrics such as loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions. The review also highlights the strengths and limitations of each platform and discusses their role in guiding clinical decision-making. Challenges related to dynamic tumor evolution and the interpretation of HRD status in recurrent disease settings are also addressed.