Andrés Redondo

PURPOSE: To evaluate atezolizumab combined with bevacizumab and non–platinum-based chemotherapy for recurrent ovarian cancer. METHODS: The double-blind randomized phase III AGO-OVAR 2.29/ENGOT-ov34 trial (ClinicalTrials.gov identifier: NCT03353831 ) enrolled patients with first or second relapse of ovarian cancer ≤6 months after completing platinum-based chemotherapy (or third relapse regardless of treatment-free interval). PD-L1 status was tested centrally (VENTANA SP142 assay) in recent (P = .06; median 14.2 months with atezolizumab and 13.0 months with placebo) and the hazard ratio for PFS was 0.87 (95% CI, 0.73 to 1.04; P = .12; median 6.4 v 6.7 months, respectively). OS hazard ratios were similar regardless of PD-L1 status. Grade ≥3 adverse events occurred in 72% of atezolizumab-treated and 69% of placebo patients. CONCLUSION: Combining atezolizumab with bevacizumab and chemotherapy did not significantly improve OS or PFS in patients with recurrent ovarian cancer ineligible for platinum. The safety profile was as expected from previous experience with these drugs.

Between 20% and 30% of endometrial cancer (EC) cases show mismatch repair deficiency (dMMR), and its characterisation is recommended in these tumours for molecular classification, screening of Lynch syndrome, and as a predictive biomarker for immunotherapy. The aim of this study was to explore two tests developed by Promega (OncoMate MSI Dx Analysis System and long mononucleotide repeat (LMR) microsatellite instability (MSI) analysis system). DNA from 126 EC tumours had been screened for MMR status by immunohistochemistry (IHC). Overall, 67 (53.2%) dMMRs and 59 (46.8%) proficient (pMMR) were included. The same cases were additionally explored for MMR genomic status, with 55 (43.7%) cases presenting an altered genomic pattern, and 69 (54.8%) with no genomic alterations. There were 71 (56.3%) microsatellite stability (MSS) cases for OncoMate and 69 (54.8%) for LMR, and 37 (29.4%) microsatellite instability (MSI) cases for OncoMate and 44 (34.9%) for LMR. Differences between the test assignments were significant (p < 0.001), with an increased proportion of correctly classified cases for the LMR assay, taking the IHC result as the reference. The respective sensitivity and specificity of the LMR assay was 95.5% and 68.1%, versus 86.5% and 53.5% for the OncoMate assay. In conclusion, the new LMR MSI Analysis System had a higher correlation with IHC, including cases that could be misdiagnosed due to minimal shifts, as well as higher sensitivity and specificity than the OncoMate panel. The best method regarding the use of dMMR/MSI as a response biomarker for immune checkpoint inhibitors requires further investigation.

Endometrial carcinoma is the most frequent gynecologic malignancy in western countries. In recent years, mutations in CTNNB1 have been associated with worse prognosis in low-risk carcinomas. However, there is a lack of understanding of the proteomic implications of CTNNB1 mutations in this type of tumor. In this study, we performed shotgun proteomics using Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples of CTNNB1 mutated and wild-type low-risk endometrial carcinomas. A publicly available proteomic and transcriptomic database was used to validate results. Differential protein expression and Gene Set Enrichment Analysis revealed dysregulation of pathways associated with cell keratinization, immune response modulation, and intracellular calcium regulation. CTNNB1 mutated tumors showed immune dysregulation at multiple levels including cytokine secretion, cell adhesion, and lymphocyte activation. These results were supported by tissue multiplex immunofluorescence analysis, demonstrating reduced CD8 tumor-infiltrating lymphocytes and different immune spatial interaction patterns. Intracellular calcium dysfunction was associated with key transcript dysregulation. We found an increased expression of CAMK2A and ROR2, suggesting a potential role for non-canonical Wnt pathway activation in CTNNB1 mutated tumors.

Soft tissue sarcomas (STSs) are a rare and highly heterogeneous group of tumours originating from mesenchymal cells, characterized by significant clinical and biological diversity. Due to this complexity, STSs present considerable challenges in both diagnosis and treatment, requiring an expert, multidisciplinary, and coordinated approach. To address these challenges, a multidisciplinary team of experts from the Spanish Group for Research in Sarcomas (GEIS) has developed a comprehensive, evidence-based consensus guideline that incorporates the latest advancements in biology, imaging techniques, and treatment options. The primary objective of this guideline is to provide clear and practical, up-to-date recommendations addressing the key questions that arise in the management of STSs. This approach aims to support therapeutic decision-making, enhance overall patient management, and ultimately improve clinical outcomes for patients affected by STSs. Key recommendations include the use of MRI as the preferred imaging modality prior to biopsy and ensuring that all patients are referred to specialised sarcoma centres with a multidisciplinary team for diagnosis and treatment.

Endometrial carcinoma is the most frequent gynecologic malignancy in western countries. In recent years, mutations in CTNNB1 have been associated with worse prognosis in low-risk carcinomas. However, there is a lack of understanding of the proteomic implications of CTNNB1 mutations in these tumors. In this study, we performed shotgun proteomics using Formalin Fixed Paraffin Embedded (FFPE) tissue samples of CTNNB1 mutated and wild-type low-risk endometrial carcinomas. A publicly available proteomic and transcriptomic database was used to validate results. Differential protein expression and Gene Set Enrichment Analysis revealed dysregulation of pathways associated with cell keratinization, immune response modulation, and intracellular calcium regulation. CTNNB1 mutated tumors showed immune dysregulation at multiple levels including cytokine secretion, cell adhesion, and lymphocyte activation. These results were supported by tissue multiplex immunofluorescence analysis, demonstrating reduced CD8 tumor infiltrating lymphocytes and different immune spatial interaction patterns. Intracellular calcium dysfunction was associated with key transcript dysregulation. We found an increased expression of CAMK2A and ROR2, suggesting a potential role for non-canonical Wnt pathway activation in CTNNB1 mutated tumors.

Harano K, et al. J Gynecol Oncol. 2025 Apr;36:e117. https://doi.org/10.3802/jgo.2025.36.e117

Background Granulosa cell ovarian tumors (GCTs) are a rare neoplasia characterized by a pathognomonic mutation in the FOXL2 gene. In vitro studies have demonstrated an overactivation of hormone activity due to this alteration. Thus, we aimed to determine the activity of orteronel, a CYP17 inhibitor, in advanced disease. Methods We designed a multicentric open-label phase II clinical trial. Eligible patients were adult woman with advanced or unresectable GCTs. Primary objective was clinical benefit rate, defined as the average of patients with radiological response plus stable disease longer than 6 months. Results From October 1, 2014 to May 20, 2016, ten patients were included in six participating institutions members of the GETTHI group. The study was terminated early due to a low recruitment rate. Up to 40% (CI 95% [9.6–70.4%]) cases presented a disease stabilization longer than 6 months and two of them, longer than 12 months. One patient continued on treatment at database closure 29 months after inclusion in the trial. No patient reached partial or complete response by RECIST criteria on the independent radiological review. The drug was well tolerated with nausea as the only grade 3 adverse event in one case. Conclusion Low accrual led to an early interruption of the study. However, orteronel achieved a promising clinical benefit rate that supports further development of new hormonotherapies in this tumor. ClinicalTrials.gov identifier NCT02101684.