Félix Blanc-Durand

Early Clinical and Molecular Biomarkers in Patients With Advanced Ovarian Cancer Undergoing Neoadjuvant Chemotherapy: CHIVA Phase II GINECO Trial

PURPOSE Platinum-based chemotherapy and surgery are pivotal in managing ovarian cancer (OC), yet prognosis remains poor, and early biomarkers for platinum resistance are needed. The neoadjuvant setting provides an opportunity to evaluate tumor responsiveness to platinum chemotherapy in vivo. This study evaluated whether early measures of platinum response combined with molecular alterations could predict surgical outcomes and survival in patients with OC treated with neoadjuvant chemotherapy (NACT). METHODS The CHIVA study enrolled stage III/IV OC patients eligible for three cycles NACT with or without nintedanib, followed by interval debulking surgery. Archival samples underwent extensive sequencing to detect clinically relevant variants and copy number alterations and calculate genomic instability (GIS). Early chemotherapy response measures—cancer antigen 125 kinetics by KELIM, major pathologic response, GIS status, tumor infiltrating lymphocytes (TILs) abundance, and genomic alterations—were correlated with surgery completeness and survival. RESULTS Among 127 patients, the overall response rate was 44%, and the complete cytoreduction (CC0) rate was 54.8%. Homologous recombination deficiency (HRD) was identified in 56% of patients and was associated with better survival. The median progression-free survival was 21.4, 20.5, and 14.4 months in the BRCAmut , BRCAwt /GIS-high, and BRCAwt /GIS-low subgroups, respectively ( P = .001). Unfavorable KELIM predicted lower objective response rate, CC0, and shorter survival, while low intraepithelial TILs (ieTILs) correlated with poor outcomes. Multivariate analysis confirmed KELIM, HRD status, and ieTILs as independent biomarkers. CCNE1 amplifications, observed in 20% of patients, were associated with moderate chemotherapy sensitivity. CONCLUSION HRD status, KELIM, and TILs are key independent biomarkers in advanced OC. CCNE1 amplifications, although typically associated with platinum resistance, were linked to moderate chemotherapy sensitivity, defining an intermediate prognostic subgroup.

Clearer Horizons: The latest advances in clear cell ovarian cancer treatment

This review aims to consolidate the current understanding of Clear Cell Ovarian Carcinoma (CCOC), a rare yet distinct subtype of epithelial ovarian cancer. CCOC exhibits unique epidemiological, clinical and molecular features, being one of the most frequent subtypes in East Asia, often diagnosed at an early stage and frequently affecting younger women. Its hallmark characteristics include high resistance to conventional chemotherapy, poor prognosis in advanced stage and a molecular profile distinct from high-grade serous histotype. Specifically, CCOC is characterized by a low prevalence of TP53 mutations, BRCA1/2 mutations and homologous-recombination deficiency, but a high frequency of ARID1A, along with other SWI/SNF alterations, and PIK3CA mutations, both of which represent promising therapeutic targets. Despite the absence of validated therapies for CCOC so far, significant advancements in preclinical research and emerging clinical strategies including immunotherapy combinations offer hope for improved outcomes. Given the rarity of this cancer type, collaborative research and global partnerships have enabled robust studies and the implementation of trials with innovative personalized therapeutic approaches. The objective of this report is to explore the epidemiology, clinical and molecular characteristics, current standard of care and evolving therapeutic strategies for CCOC patients. It will not only highlight the progress made so far, but most importantly identifies critical research priorities to optimizing patient outcomes.

Controversies in the management of mucinous ovarian tumors

Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer, comprising less than 5% of all cases, and distinguished by its unique molecular, histologic, and clinical features. Its rarity and marked differences from other ovarian cancer subtypes have led to significant controversies regarding its diagnosis, surgical strategies, and systemic therapies. Accurate differentiation between primary and metastatic MOCs remains a critical challenge because of their overlapping features with gastrointestinal cancers, often leading to misclassification. This can result in suboptimal management and impaired patient outcomes, thus highlighting the importance of high-quality pathologic reviews. The surgical approach to MOC is highly controversial. In early-stage disease, fertility-sparing surgery should be systematically considered in young patients, although its feasibility requires careful consideration. In addition, systematic staging lymphadenectomy, which has been de-escalated for patients with expansile MOC, is recommended for those with early-stage infiltrative MOC. In advanced-stage disease, where tumors are often bulky and chemoresistant, the benefits of extensive cytoreduction must be balanced against surgical morbidities. MOC poses significant challenges for systemic treatment owing to its poor response rate to standard ovarian cancer chemotherapy regimens. Alternative therapeutic strategies offer promise but lack robust clinical validation, including gastrointestinal-based regimens, HER2-targeted antibody-drug conjugates (eg, trastuzumab deruxtecan), and immune checkpoint inhibitors for microsatellite unstable MOC. Furthermore, pre-clinical and early phase trials have suggested the potential of combination strategies, including RAS pathway and WEE1 inhibitors. Addressing these controversies requires a multidisciplinary approach that underscores the importance of histologic subtyping and molecular profiling to guide personalized treatment. International collaboration is essential for overcoming the rarity of MOC by enabling larger studies and global registries. These efforts are pivotal for improving diagnostic accuracy, expanding therapeutic options, and, ultimately, enhancing outcomes in patients with this challenging malignancy.

Controversies in the management of clear cell carcinoma of the uterus and ovary

Clear cell ovarian and endometrial carcinomas are rare and aggressive gynecologic malignancies that present unique challenges owing to their underrepresentation in clinical trials and limited prospective data. In this report, we aimed to explore 3 major controversies in the management of clear cell ovarian and endometrial carcinomas, highlighting areas that require further investigation. First, we addressed the unique phenotypic characteristics of clear cell ovarian carcinoma and clear cell endometrial carcinoma and whether they should be considered a unified disease entity or a distinct disease. Recent trials grouped these carcinomas, potentially expanding their therapeutic options. However, emerging molecular data underscores the significant differences between clear cell ovarian carcinoma and clear cell endometrial carcinoma, raising questions regarding this combined approach. This distinction is critical in guiding tailored treatment strategies. Second, we examined the management of localized diseases. Although early-stage diagnoses are common in clear cell carcinomas, optimal surgical and adjuvant treatment strategies remain uncertain. Current practice often relies on data from broader studies with limited inclusion of clear cell histology. This review underscores the need for more specific evidence to refine treatment protocols and balance efficacy with the minimization of treatment-related morbidity. Third, we explored novel therapeutic strategies for the treatment of recurrent diseases. Advances in the understanding of the biology of clear cell carcinomas have identified potential targets in the immune microenvironment, cellular processes, and metabolism. Ongoing clinical trials are investigating these approaches, which hold promise in transforming the treatment landscape and outcomes. In conclusion, this review emphasizes the necessity for international collaboration and the inclusion of diverse patient populations to address the challenges posed by cell carcinomas. By focusing on these controversies, we aim to stimulate further research and support more evidence-based personalized approaches for the management of these rare but challenging cancers.

Targeting the immune microenvironment in ovarian cancer therapy—mission impossible?

Clinical and biological characteristics associated with loss-of-heterozygosity in endometrial cancer

Genomic instability has been identified in a subgroup of endometrial cancers (ECs) that are predominantly We conducted a retrospective analysis of EC patients from France and Singapore. All patients underwent comprehensive molecular profiling using the tumor based FoundationOne CDX panel. The degree of LOH was correlated with molecular and clinicopathologic findings. LOH-high, intermediate and low were defined as ≥14%, 4%-14%, and <4%, respectively. One hundred twelve patients were identified, including 66% Asian and 34% Caucasian. Fifty nine percent had International Federation of Gynecology and Obstetrics III/IV diseases, 34% low-grade endometrioid, 19% high-grade endometrioid, and 15% serous. The 63% and 50% of tumors expressed estrogen receptor (ER) and progesterone receptor (PR). One percent had a In this large multiethnic cohort, 17% of EC exhibited high LOH and correlated with hormone-receptor-negative tumors and poorer survival rates. LOH may serve as a tool for identifying EC cases with high genomic instability that could potentially benefit from PARP inhibitors.

Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer

AbstractBackgroundMolecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell‐free DNA (cfDNA) profiling in EC to identify targetable alterations.MethodsWomen with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT).ResultsA total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression‐free survival of 7.7 months.ConclusionscfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.

Spatial Profiling of Ovarian Carcinoma and Tumor Microenvironment Evolution under Neoadjuvant Chemotherapy

Abstract Purpose: This study investigates changes in CD8+ cells, CD8+/Foxp3 ratio, HLA I expression, and immune coregulator density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. Experimental Design: Multiplexed immune profiling and cell clustering analysis were performed on paired matched ovarian cancer samples to characterize the immune tumor microenvironment (iTME) at diagnosis and under NACT in patients enrolled in the CHIVA trial (NCT01583322). Results: Several immune cell (IC) subsets and immune coregulators were quantified pre/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA I+-enriched tumors were associated with a better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance, and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into four subsets: high Binf, enriched in B clusters; high Tinf and low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors were segregated into three clusters: high BinfTinf, low Tinf, and desert. The high BinfTinf, more diverse in IC composition encompassing T, B, and NK cells, correlated with improved survival. PDL1 was rarely expressed, whereas TIM3, LAG3, and IDO1 were more prevalent. Conclusions: Several iTMEs exist during tumor evolution, and the NACT impact on iTME is heterogeneous. Clustering analysis of patients unravels several IC subsets within ovarian cancer and can guide future personalized approaches. Targeting different checkpoints such as TIM3, LAG3, and IDO1, more prevalent than PDL1, could more effectively harness antitumor immunity in this anti-PDL1–resistant malignancy.

ESR1 Mutation in Endocrine Treatment-Naïve Endometrial Cancer: Prevalence, Characteristics, and Prognostic Implications, Results from the UTOLA Phase II GINECO Trial

Abstract Purpose: Aromatase inhibitors (AI) are used to treat estrogen receptor (ER)–positive low-grade endometrioid endometrial cancer. In breast cancer, ESR1 mutations are rare at diagnosis (&amp;lt;5%) but are frequently acquired in AI-resistant cases and are considered one of the major resistance mechanisms to endocrine therapy. This study aimed to assess the prevalence of ESR1 mutations in hormonotherapy-naïve endometrial cancer samples and correlate them with molecular profiles, ER expression, and clinical outcomes. Experimental Design: A total of 147 patients with advanced endometrial cancer who had responded to first-line chemotherapy were recruited into the UTOLA trial. Archival endometrial cancer tumor tissues underwent sequencing of 127 genes, including ESR1. Only hotspot mutations in the ligand-binding domain were evaluated. ESR1 mutation prevalence was validated in the Genomics England dataset. In UTOLA, tumors were classified as POLE, MMR deficient, TP53abn, or no specific molecular profiles (NSMP) based on the Proactive Molecular Risk Classifier for Endometrial Cancer (PROMISE) classification. Results: Of 147 patients, 137 had sufficient tumor material for sequencing. ESR1 mutations were identified in eight tumors (6%), including Y537S/C/N (n = 4), L536H/P (n = 2), and E380Q (n = 2). A similar prevalence (3.5%) was found among 1,311 tumors in the Genomics England dataset. All ESR1 mutation cases were low-grade endometrioid endometrial cancer, ER-positive, and PR-positive, and classified as NSMP. Among patients with metastatic NSMP low-grade endometrioid endometrial cancer, 22% (8/37) harbored ESR1 mutations. Survival outcomes after platinum chemotherapy were similar between patients with ESR1 mutation endometrial cancer and ESR1 wild type (median, not reached vs. 25.3 months; P = 0.114). Conclusions: ESR1 mutations, while rare overall in treatment-naïve endometrial cancer, are more prevalent in patients with NSMP low-grade endometrioid endometrial cancer, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.