Deciphering brain metastasis in epithelial ovarian cancer: multimodal analysis and potential biomarkers R. Trozzi, M. Salvi, M. Karimi, A. Minucci, G. Raspaglio, M. De Donato, M. Buttarelli, A. Piermattei, L. Vaccaro, A. Grimaldi, R. De Santis, M. Massa, F. Sillano, L. Giacò, L. Mastrantoni, V. Iacobelli, F. Camarda, M. Cesana, S. Duranti, M. C. Sassu, P. Mattogno, A. Fagotti, C. Marchetti, G. Scambia, C. Nero, D. Cacchiarelli Npj Precision Oncology, 2026 Epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy in developed countries, with recurrence and drug resistance posing significant clinical challenges. Brain metastases (BM) from epithelial ovarian cancer, once rare, are an increasing phenomenon and are characterised by a dismal prognosis. To explore the molecular underpinnings of BM in EOC, we conducted a multimodal genomics and transcriptomics analysis of matched primary tumour and brain metastases samples from a retrospective cohort. Our findings revealed high genomic concordance between primary tumour (PT) and BM, with alterations in key pathways such as MYC (MYC Proto-Oncogene, bHLH Transcription Factor) targets, extracellular matrix remodelling, and inflammatory signalling characterizing the BM. AFP (Alpha-fetoprotein) and GFAP (Glial Fibrillary Acidic Protein) emerged as potential biomarkers from the primary lesion for BM onset, while network analysis identified MET (MET Proto-Oncogene, Receptor Tyrosine Kinase), GDF15 (Growth Differentiation Factor 15), and S100A9 (S100 Calcium Binding Protein A9) as candidate mediators of tumour-brain crosstalk. These results offer new insights into EOC brain tropism, highlighting potential targets for therapeutic intervention and personalized patient management in the precision oncology era.
ESGO Consensus Statement on endometrial cancer prevention, risk reduction strategies, and management of women with Lynch syndrome Claudia Marchetti, Murat Gultekin, Carolina Maria Sassu, François Planchamp, Laura Burney Ellis, Sarah J Bowden, Vasilis Theodoulidis, Vesna Kesic, Beyhan Ataseven, Giovanni Scambia, Fabrice Lécuru, Maurizio Genuardi, Mev Dominguez-Valentin, Toni T. Seppälä, Frédéric Amant, Mihaela Grigore, Stephan Polterauer, Bilal Esat Temiz, Hasan Volkan Ege, Simona Duranti, Nicolò Bizzarri, Hélène Didelot, Nina Pauly, Veronika Seebacher-Shariat, Ranjit Manchanda, Maria Kyrgiou European Journal of Cancer, 2026 Lynch syndrome (LS) is a hereditary condition associated with an increased susceptibility to developing cancer, primarily colorectal and gynaecological cancer (endometrial cancer and ovarian cancer). The European Society of Gynaecological Oncology (ESGO) nominated fifteen practicing multidisciplinary clinicians with expertise in this field and ten gynaecological and oncological fellows with interest in the topics to develop evidence-based statements, sharing and standardizing the management of LS carriers. Published evidence was integrated with clinical experience to reach Consensus Statements through anonymous voting. In this Consensus, thirty-one statements based on the best available evidence and expert agreement are offered. They focused on genetic and cancer risk counseling principles, screening procedures, risk-reducing surgical and medical strategies, and address emerging topics such as reproductive issues for LS carriers, which are important in current practice. This manuscript reports the Statements that reached a consensus, their voting results, and a summary of supporting evidence.
Co-targeting hallmarks of cancer for therapeutic benefit in ovarian cancer: a scoping review Valentina Iacobelli, Floriana Camarda, Gloria Anderson, Marianna Buttarelli, Luca Mastrantoni, Miriam Grazia Ferrara, Rita Trozzi, Simona Duranti, Vanda Salutari, Giulia Sabetta, Giovanni Scambia, Anna Fagotti, Camilla Nero International Journal of Gynecological Cancer, 2026 The conceptualization of cancer characteristics into 14 hallmarks is now widely adopted. Simultaneous targeting of multiple cancer hallmarks represents a promising strategy to overcome therapeutic resistance and improve clinical outcomes. This approach is particularly relevant in epithelial ovarian cancer, which remains highly lethal despite significant advances in first-line treatment. This scoping review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines and included searches of Medline, Scopus, the Cochrane Library, and ClinicalTrials.gov for studies published up to September 30, 2024. To be eligible, trials were required to be phase I to III clinical trials (both completed and ongoing) enrolling patients with any histotype of epithelial ovarian cancer and to target ≥2 of the 14 cancer hallmarks. Studies were screened and data extracted independently by 3 reviewers. Out of 1461 records screened at the title and abstract level (data cutoff: September 30, 2024), 225 studies were identified, comprising 111 completed and 114 ongoing trials. The adoption of co-targeting strategies has notably increased, with a 3-fold increase in trials between 2007-2013 and 2021-2024. Among 94 trials reporting clinically meaningful benefits, the most frequent combination involved targeting "sustaining proliferative signaling" and "genome instability and mutations." In ongoing trials, 40 are focused on modulating "avoiding immune destruction." However, no clinical trials were identified for 4 of the 14 hallmarks: "unlocking phenotypic plasticity," "senescent cells," "non-mutational epigenetic re-programming," and "polymorphic microbiomes." These hallmarks remain underexplored, highlighting critical gaps and potential areas for future research. In conclusion, co-targeting approaches in epithelial ovarian cancer rely on combining genomic instability and angiogenesis inhibition with chemotherapy. Current research trends are shifting toward chemotherapy-free regimens and novel therapeutic targets, aiming to address resistance mechanisms and improve long-term outcomes.
Enhanced Detection of BRCA Copy Number Alterations Within a Commercial HRD Assay: Implications for Precision Oncology in Ovarian Cancer Maria De Bonis, Pierluigi Iapicca, Elisa De Paolis, Francesca Brisighelli, Jessica Evangelista, Alessia Perrucci, Claudio Ricciardi Tenore, Giulia Maneri, Paola Concolino, Alessia Piermattei, Iolanda Mozzetta, Tina Pasciuto, Alessia Preziosi, Luciano Giacò, Simona Duranti, Camilla Nero, Anna Fagotti, Angelo Minucci International Journal of Molecular Sciences, 2026 Large genomic rearrangements (LGRs), occurring as copy number alterations (CNAs), represent a clinically relevant class of pathogenic or likely pathogenic variants (P LPVs) in BRCA1/2 (BRCA) genes in ovarian cancer (OC). We evaluated the performance of a high-resolution algorithm integrated into a commercial homologous recombination deficiency (HRD) assay to improve the identification of clinically actionable CNAs in BRCA genes by formalin-fixed paraffin-embedded (FFPE) samples. A total of 760 OC samples were analyzed using a commercial HRD assay incorporating a bioinformatics algorithm for CNA detection. The algorithm was additionally applied to additional homologous recombination repair (HRR) genes, and associations between CNA events and genomic instability (GI) were evaluated. The algorithm demonstrated high sensitivity for both gene and exon-level CNA. The high correlation between CNA positivity cases and GI, in the absence of P/LPVs BRCA single-nucleotide or indels variants, emphasizes the value of integrating CNA detection into routine HRD testing workflows. The extended analysis of additional HRR genes enabled broader characterization of clinically relevant CNAs. This study enables reliable identification of clinically relevant BRCA LGRs from FFPE within HRD testing, supporting a tumor-first diagnostic strategy. This approach may expand the identification of OC patients potentially eligible for PARP inhibitor therapy.
Concordance Analysis of Microsatellite Instability via NGS and Mismatch Repair Deficiency via IHC in Endometrial and Colorectal Cancer Camilla Nero, Lisa Salvatore, Simona Duranti, Gloria Anderson, Luca Mastrantoni, Mina Karimi, Giulia Mantini, Angelo Minucci, Giulia Maneri, Luciano Giacò, Angela Santoro, Arianna Panfili, Alessia Piermattei, Ilenia Marino, Giulia Caira, Maria Alessandra Calegari, Giovanni Trovato, Valentina Iacobelli, Vanda Salutari, Nicola Normanno, Francesco Fanfani, Giovanni Scambia, Giampaolo Tortora Targeted Oncology, 2026 BACKGROUND: Assessment of mismatch repair (MMR) function provides critical guidance for diagnosis, prognosis, and therapeutic decision making in colorectal and endometrial cancers. Mismatch repair immunohistochemistry (IHC) is the routine clinical test for identifying MMR deficiency, while microsatellite instability (MSI) serves as its surrogate, detected by polymerase chain reaction or next-generation sequencing (NGS). Available data indicate a high concordance rate between these approaches in colon cancer, whereas a lower concordance has been reported in endometrial cancer. OBJECTIVE: We aimed to assess the concordance rate between MMR-IHC and MSI-NGS from patients with colorectal or endometrial cancer, using IHC as the gold standard. METHODS: A cohort of 520 patients (352 with endometrial cancer and 168 with colorectal cancer) were included. MMR‑IHC assessed MLH1, MSH2, MSH6, and PMS2 expression, while MSI‑NGS was determined by profiling 130 homopolymer repeat loci using the TruSight Oncology 500 panel from Illumina. RESULTS: While concordance was high in the colorectal cancer cohort (99%, 95% confidence interval 96-100), a lower level of agreement was observed in endometrial cancer cases (85%, 95% confidence interval 81-89). Fifty-two of 53 discordant cases exhibited MMR deficiency by IHC in the absence of detectable MSI. Forty percent of discordant cases could be explained by factors previously associated with reduced MSI levels, including mutations in DNA polymerase genes (n = 5), isolated MSH6 loss (n = 10), atypical IHC staining patterns (n = 8), and germline variants (n = 6). Additionally, the presence of genetic and epigenetic alterations (specifically, 19 cases with MLH1 promoter hypermethylation and ten with somatic or germline MMR variants) supports the interpretation that MSI calls were missed in a subset of cases. Finally, optimizing the MSI threshold enhanced detection accuracy in endometrial tumors. CONCLUSIONS: These findings confirm the lower concordance between MMR-IHC and MSI-NGS in endometrial cancer compared with colorectal cancer when broad panels are used, underscoring the importance of tumor-specific interpretation even within tumor-agnostic assays. Although cut-off optimization improved agreement, the evidence remains insufficient for clinical implementation, and further validation studies are needed.
Hereditary cancer syndromes with gynecological cancer risk: focus on prevention strategies Simona Duranti, Valentina Iacobelli, Rita Trozzi, Floriana Camarda, Arianna Panfili, Anna Fagotti, Francesco Fanfani, Claudia Marchetti, Camilla Nero Frontiers in Oncology, 2026 Background Hereditary cancer syndromes, including pathogenic variants in BRCA1/2 and mismatch-repair genes, confer a substantial risk of several malignancies, including ovarian, endometrial, and fallopian tube cancers. Given the limited efficacy of current screening strategies, particularly for ovarian cancer, a prevention-focused approach is required. This review synthesizes evidence on identification, risk stratification, surveillance, chemoprevention, and prophylactic surgery in women with inherited gynecologic cancer susceptibility, proposing a precision-prevention framework. Methods A structured search of MEDLINE, Embase, and the Cochrane Library was conducted through July 2025. Original studies, reviews, and guidelines in English were included following independent screening and full-text assessment by two authors. Results Expanded germline testing, universal mismatch-repair screening, and genomic profiling have improved carrier identification beyond family history–based criteria. Integrated counseling models enhance informed decision-making and access to care. Conventional surveillance tools show limited sensitivity; emerging strategies, including circulating tumor DNA assays and artificial intelligence, require further validation. Hormonal and anti-inflammatory agents demonstrate potential for risk reduction. Prophylactic surgery, including salpingo-oophorectomy, hysterectomy, or investigational salpingectomy with delayed oophorectomy, remains central, requiring multidisciplinary evaluation and attention to fertility, menopausal health, and patient preferences. Ethical and health-economic considerations remain critical in clinical practice and policy development. Further studies are warranted to better elucidate the potential role of liquid biopsy, microbiota, and targeted vaccination strategies. Conclusions Prevention of gynecologic cancers in genetically predisposed women requires an integrated strategy that includes comprehensive genetic assessment, risk-adapted surveillance, evidence-based risk-reduction interventions, and multidisciplinary coordination. Implementing and refining precision prevention frameworks is crucial to optimize outcomes and translate genetic risk into tailored preventive care.
Clinical features and surgical options of obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome: A systematic review and a meta-analysis of prevalence Emma Bonetti, Gloria Anderson, Simona Duranti, Federico Ferrari, Franco Odicino, Antonia Testa, Francesco Fanfani, Giovanni Scambia, Ursula Catena International Journal of Gynecology and Obstetrics, 2025 BackgroundOHVIRA syndrome, a urogenital malformation, lacks standardized management. Narrative reviews exist, but there is no a comprehensive meta‐analysis.ObjectivesThe aim of this first systematic review and meta‐analysis is to evaluate the current literature and inform management strategies.Search StrategyWe searched Scopus, Medline, Embase and Web of Science, up to March 2024.Selection CriteriaCase series, case reviews, and longitudinal studies on patients with OHVIRA syndrome.Data Collection and AnalysisData were extracted and meta‐analyzed using R software.Main ResultsIn all, 35 studies (1988–2022) with 526 patients were included. Average symptom onset was 14.45 years, and diagnosis at 16.36 years suggests potential delays. The most common symptoms were abdominal pain (67%, 95% CI 54–77, I2 = 66%) and dysmenorrhea (64%, 95% CI 55–72, I2 = 46%). Ultrasound (86%, 95% CI 76–92, I2 = 58%) and pelvic magnetic resonance imaging (61%, 95% CI 46–74, I2 = 72%) were primary imaging modalities. Hematocolpos (55%, 95% CI 42–67, I2 = 53%) and hematometra (53%, 95% CI 37–69, I2 = 70%) were frequent findings. Pelvic endometriosis, a major long‐term complication, affected 20% of patients. Vaginal septum resection (83%, 95% CI 75–89, I2 = 48%) was the most common surgical treatment, often accompanied by laparoscopic endometriosis excision. Hysteroscopic septum resection emerged as a minimally invasive option (78%, 95% CI 46–93, I2 = 54%), with high success rate.ConclusionsEarly diagnosis and surgery are crucial to prevent complications. Vaginal septum resection remains the gold standard, while hysteroscopy offers a promising minimally invasive alternative.
A Case Report to Reflect on the Origins of MMRd Mesonephric-like Ovarian Adenocarcinoma: Can It Be Defined as a Mϋllerian Neoplasm? Nicoletta D’Alessandris, Angela Santoro, Michele Valente, Giulia Scaglione, Giuseppe Angelico, Belen Padial Urtueta, Nadine Narducci, Simona Duranti, Francesca Addante, Angelo Minucci, Gian Franco Zannoni International Journal of Molecular Sciences, 2025 Mesonephric-like adenocarcinoma (MLA) of ovaries is a new and rare neoplastic entity, recently classified by the World Health Organization. Its morphological and immunohistochemical profile is similar to primitive cervical mesonephric adenocarcinoma, but its origin has not been determined yet. Some authors believe that this neoplasm originates from Wolffian remnants in the ovarian hilum, while others suggest an origin from the Mϋllerian epithelium, followed by a mesonephric trans-differentiation. Starting from a recently diagnosed mismatch repair-deficient ovarian MLA, we try to further develop this line of research. A detailed molecular analysis of the studied tumor helps clarify our ideas. In fact, the typical KRAS mutation was not present. We found mutations in numerous other genes, which are rarely described in the literature or are already described in the endometrioid histotype. We reached some interesting conclusions, which, if supported by future studies, will clarify the true nature of these tumors, allowing for better stratification and a better therapeutic framework.
Are all mismatch repair deficient endometrial cancers created equal? A large, retrospective, tertiary center experience Ilaria Capasso, Emanuele Perrone, Simona Duranti, Diana Giannarelli, Camilla Nero, Emanuela Lucci Cordisco, Maria Grazia Pomponi, Laura Remondini, Alessia Piermattei, Michele Valente, Angela Santoro, Giovanni Esposito, Giuseppe Parisi, Maria Consiglia Giuliano, Martina Corrado, Giovanni Scambia, Francesco Fanfani European Journal of Cancer, 2025 BACKGROUND: One third of endometrial carcinomas (ECs) presents with mismatch repair deficiency (MMRd). Of these, 70 % are caused by somatic hypermethylation of MLH1 promoter; the remaining cases are determined by Lynch syndrome or double somatic inactivation of MMR genes. Although associated with good-intermediate prognosis, heterogeneity in treatment response and survival has been reported among MMRd ECs. We aim to investigate differences in pathologic aggressiveness and event-free survival (EFS) among three MMRd EC subtypes, classified by immunohistochemistry (IHC) and MLH1 methylation analysis. METHODS: Subjects undergone surgical staging for EC were retrospectively included. IHC analysis was performed in all patients to assess MMR and p53 status. Methylation analysis was performed in MMRd patients with IHC-negative MLH1. The MMRd population was classified into: 1)MLH1-hypermethylated (MLH1-HyMet); 2)MLH1-unmethylated (MLH1-UnMet); 3)IHC-negative MSH2 and/or MSH6 or PMS2 alone (non-MLH1). RESULTS: Of 1171 patients undergoing surgical staging and IHC assessment, 362 (30.9 %) were classified as MMRd and included in the analysis. Among these, 59.7 % (n = 216) were MLH1-HyMet, 11 % (n = 40) MLH1-UnMet, and 29.3 % (n = 106) non-MLH1. Compared to MLH1-UnMet and non-MLH1, MLH1-HyMet was associated with older age, higher BMI, larger tumor size, deeper myometrial invasion, substantial lymphovascular space invasion, lower frequency of early-stage and low-risk disease. EFS was similar when comparing the MMRd subtypes, even after adjusting for stage and tumor histology. However, a trend of MLH1-HyMet toward poorer prognosis can be observed, particularly in the advanced/metastatic setting. CONCLUSIONS: MLH1-hypermethylated MMRd ECs display more aggressive clinicopathologic features compared to the other MMRd subgroups. However, although a suggestive trend toward poorer EFS was observed in the hypermethylated subset, particularly in the advanced setting, no significant differences in prognosis were detected among the MMRd subtypes.
Multigenic panels in breast cancer: Clinical utility and management of patients with pathogenic variants other than BRCA1/2 Alessandra Fabi, Laura Cortesi, Simona Duranti, Emanuela Lucci Cordisco, Alba Di Leone, Daniela Terribile, Ida Paris, Antonio Giulio de Belvis, Armando Orlandi, Fabio Marazzi, Margherita Muratore, Giorgia Garganese, Paola Fuso, Filippo Paoletti, Rossella Dell’Aquila, Angelo Minucci, Giovanni Scambia, Gianluca Franceschini, Riccardo Masetti, Maurizio Genuardi Critical Reviews in Oncology Hematology, 2024
Breast cancer drug approvals issued by EMA: A review of clinical trials Simona Duranti, Alessandra Fabi, Marco Filetti, Rosa Falcone, Pasquale Lombardi, Gennaro Daniele, Gianluca Franceschini, Luisa Carbognin, Antonella Palazzo, Giorgia Garganese, Ida Paris, Giovanni Scambia, Antonella Pietragalla Cancers, 2021
Erratum: The promher study: An observational Italian study on adjuvant therapy for her2-positive, pt1a-b pn0 breast cancer stefania gori (PLoS ONE (2015) 10:9 (e0139650) DOI: 10.1371/journal.pone.0139650) Stefania Gori, Alessandro Inno, Elena Fiorio, Jennifer Foglietta, Antonella Ferro, Marcella Gulisano, Graziella Pinotti, Marta Gubiotti, Maria Giovanna Cavazzini, Monica Turazza, Simona Duranti, Valeria De Simone, Laura Iezzi, Giancarlo Bisagni, Simon Spazzapan, Luigi Cavanna, Chiara Saggia, Emilio Bria, Elisabetta Cretella, Patrizia Vici, Daniele Santini, Alessandra Fabi, Ornella Garrone, Antonio Frassoldati, Laura Amaducci, Silvana Saracchini, Lucia Evangelisti, Sandro Barni, Teresa Gamucci, Lucia Mentuccia, Lucio Laudadio, Alessandra Zoboli, Fabiana Marchetti, Giuseppe Bogina, Gianluigi Lunardi, Luca Boni Plos One, 2015
The promher study: An observational Italian study on adjuvant therapy for her2-positive, pT1a-b pN0 breast cancer Stefania Gori, Alessandro Inno, Elena Fiorio, Jennifer Foglietta, Antonella Ferro, Marcella Gulisano, Graziella Pinotti, Marta Gubiotti, Maria Giovanna Cavazzini, Monica Turazza, Simona Duranti, Valeria De Simone, Laura Iezzi, Giancarlo Bisagni, Simon Spazzapan, Luigi Cavanna, Chiara Saggia, Emilio Bria, Elisabetta Cretella, Patrizia Vici, Daniele Santini, Alessandra Fabi, Ornella Garrone, Antonio Frassoldati, Laura Amaducci, Silvana Saracchini, Lucia Evangelisti, Sandro Barni, Teresa Gamucci, Lucia Mentuccia, Lucio Laudadio, Alessandra Zoboli, Fabiana Marchetti, Giuseppe Bogina, Gianluigi Lunardi, Luca Boni Plos One, 2015
