Coleman RL, Ray-Coquard I, Herzog TJ
… +7 more, González-Martín A, Slomovitz B, Harter P, Campbell-Simms K, Colombo N, Copeland LJ, GOG Foundation, Inc, and the European Network of Gynaecological Oncological Trial Groups
Int J Gynecol Cancer
· 2026 Jul · PMID 42391801
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Lou X, Wu Y, Fu Y
… +9 more, Liang S, Li Y, Li K, Xu D, Wu Y, Wang Y, Du Z, Fang H, Cui W
Int J Gynecol Cancer
· 2026 Jun · PMID 42391800
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OBJECTIVE: Current ovarian cancer biomarkers lack sensitivity for early detection and non-serous sub-types. PIWI-interacting RNAs have attracted growing interest as stable, circulating molecules with biomarker potential....OBJECTIVE: Current ovarian cancer biomarkers lack sensitivity for early detection and non-serous sub-types. PIWI-interacting RNAs have attracted growing interest as stable, circulating molecules with biomarker potential. To fully exploit their clinical value, this study aims to identify ovarian cancer-associated PIWI-interacting RNAs with clinical utility. METHODS: We analyzed 1120 participants, including 610 patients with ovarian cancer, across discovery and multi-center validation cohorts. Candidate PIWI-interacting RNAs were identified via sequencing and validated through reverse transcription quantitative polymerase chain reaction. Diagnostic performance was assessed using receiver operating characteristic analysis and machine learning algorithms. Functional mechanisms were explored via proliferation assays, flow cytometry, RNA-sequencing, fluorescence in situ hybridization, RNA pulldown assay, and mass spectrometry. RESULTS: We identified piR-hsa-8111406 as a novel biomarker significantly upregulated in the serum of patients with ovarian cancer. It exhibited robust diagnostic performance in distinguishing malignant from benign ovarian masses (area under the curve 0.892, 95% confidence interval 0.859 to 0.926), which was comparable to CA125 (area under the curve 0.874, 95% confidence interval 0.840 to 0.908). A Multilayer Perceptron model integrating piR-hsa-8111406 with conventional markers achieved higher overall precision (area under the curve 0.949, 95% confidence interval 0.928 to 0.975). Specifically, in stage I to II early detection, it achieved an area under the curve of 0.803 (95% confidence interval 0.720 to 0.886), performing consistently alongside standard markers such as CA125 (area under the curve 0.789, 95% confidence interval 0.709 to 0.868), Risk of Ovarian Malignancy Algorithm (area under the curve 0.789, 95% confidence interval 0.667 to 0.911), and HE4 (area under the curve 0.754, 95% confidence interval 0.633 to 0.874). Furthermore, it maintained stable performance across non-serous sub-types and was independent of menopausal status. Functionally, it promoted cancer cell proliferation and cell cycle progression. CONCLUSIONS: Serum piR-hsa-8111406 is a promising complementary biomarker for distinguishing ovarian cancer from benign masses, particularly in early-stage disease. Its stability and correlation with International Federation of Gynecology and Obstetrics stage and post-operative change support its potential for clinical triage. Preliminary in vitro experiments provide supportive biological evidence, showing an association with cell proliferation in ovarian cancer.
Int J Gynecol Cancer
· 2026 Jun · PMID 42391799
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OBJECTIVE: Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance demonstrated statistically significant and clinically meaningful benefits in progression-free and overall survival in the overall populati...OBJECTIVE: Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance demonstrated statistically significant and clinically meaningful benefits in progression-free and overall survival in the overall population of primary advanced/recurrent endometrial cancer versus chemotherapy alone in Part 1 of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial (NCT03981796). Part 2 evaluated the efficacy and safety of the addition of the poly(adenosine diphosphate-ribose) polymerase inhibitor niraparib to dostarlimab maintenance following dostarlimab+chemotherapy versus placebo maintenance following placebo+chemotherapy in primary advanced/recurrent endometrial cancer. METHODS: Patients were randomized 2:1 to dostarlimab+chemotherapy followed by niraparib+dostarlimab maintenance (niraparib+dostarlimab arm) or placebo+chemotherapy followed by placebo maintenance (control arm). Primary endpoint was progression-free survival in the overall and mismatch repair-proficient/micro-satellite stable populations. Overall survival (key secondary endpoint) and safety were assessed. RESULTS: In total, 291 patients were randomized (192 to niraparib+dostarlimab; 99 to control). With approximately 22 months of follow-up, the risk of progression or death was significantly reduced by 40% (hazard ratio 0.60, 95% confidence interval 0.43 to 0.82, p <.001) and 37% (hazard ratio 0.63, 95% confidence interval 0.44 to 0.91, p =.006) with niraparib+dostarlimab versus the control in the overall and mismatch repair-proficient/micro-satellite stable populations, respectively. At 36.2 months of follow-up, no overall survival benefit was observed with niraparib+dostarlimab versus the control (hazard ratio 1.2, 95% confidence interval 0.81 to 1.78). Grade ≥3 treatment-related adverse events occurred in 70.7% of patients in the niraparib+dostarlimab arm and 37.5% in the control arm; serious treatment-related adverse events occurred in 24.6% and 9.4%, respectively. Discontinuations due to adverse events occurred in 38.7% of patients in the niraparib+dostarlimab arm and 11.5% in the control arm. CONCLUSIONS: While the addition of niraparib to dostarlimab maintenance showed a significant improvement in progression-free survival, there was no observed overall survival benefit. Dostarlimab+carboplatin-paclitaxel followed by dostarlimab maintenance remains the only regimen to demonstrate significant overall survival benefit versus carboplatin-paclitaxel alone in primary advanced/recurrent endometrial cancer.
Wolswinkel JT, van Lenthe I, Maurits JSF
… +10 more, Aarts JWM, Bekkers RLM, Ten Eikelder MLG, Stroeken Y, Beltman JJ, Ter Kuile MM, Lok CAR, van Trommel NE, Kasius JC, Zusterzeel PLM
Int J Gynecol Cancer
· 2026 Jun · PMID 42385629
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OBJECTIVE: Fertility-sparing surgery offers the opportunity to preserve fertility but comes with higher oncologic and obstetric risks. This study aims to identify key factors influencing decision-making of women with ear...OBJECTIVE: Fertility-sparing surgery offers the opportunity to preserve fertility but comes with higher oncologic and obstetric risks. This study aims to identify key factors influencing decision-making of women with early-stage cervical cancer. METHODS: We conducted a vignette-based study involving former patients and gynecologic oncologists in the Netherlands. Eligible patients were aged 25-42 years at the time of surgery and underwent radical trachelectomy or radical hysterectomy for early-stage cervical cancer between 2014 and 2024. All Dutch gynecologic oncologists were invited. Four vignette attributes were selected based on literature and patients' and experts' opinions. Different risk percentages for these attributes were varied in 16 scenarios. Participants rated their preference on a 5-point Likert scale, where 1 indicated a strong preference for hysterectomy and 5 a strong preference for fertility-sparing surgery. Preferences were analyzed using linear mixed-effects models. RESULTS: A total of 58 out of 205 patients (28.3%) and 33 of 55 gynecologic oncologists (60%) participated. The mean preference for fertility-sparing surgery across all scenarios was 3.48 (95% confidence interval (CI) 3.22 to 3.74) for patients and 3.16 (95% CI 2.95 to 3.36) for gynecologic oncologists. All four attributes played significant roles in decision-making. For patients, the likelihood of achieving pregnancy was the most influential factor, increasing the preference score by 1.07 (scale 1 to 5) for an 85% chance of conception. For gynecologic oncologists, an increased risk of cancer-related death was the most decisive factor, resulting in a 1.84 decrease (scale 1 to 5) for a 10% additional risk of death. CONCLUSIONS: Patients and gynecologic oncologists showed a modest preference for fertility-sparing surgery over hysterectomy. Patients appeared to place relatively greater weight on likelihood of pregnancy and were less deterred than clinicians by hypothetical increases in cancer-related mortality risk. This underscores the importance of thoroughly involving patients in the decision-making process.
Fanfani F, Capasso I, Mauro J
… +22 more, Perrone E, Mueller M, Bruno V, Fruscio R, Imboden S, Garcia-Pineda V, Taskin S, Tripodi E, Restaino S, Grassi T, Raimondo D, Berretta R, Papadia A, Siegenthaler F, Casarin J, Chiantera V, Vizza E, Zapardiel I, Vizzielli G, Taskiran C, Gungor M, Buda A
Int J Gynecol Cancer
· 2026 Jun · PMID 42378721
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OBJECTIVE: The updated European Society of Gynaecological Oncology guidelines recommend routine molecular classification to refine risk assessment and guide adjuvant treatment. However, the prognostic impact of sentinel...OBJECTIVE: The updated European Society of Gynaecological Oncology guidelines recommend routine molecular classification to refine risk assessment and guide adjuvant treatment. However, the prognostic impact of sentinel lymph node involvement and molecular classification in apparent early-stage endometrial cancer remains incompletely defined. METHODS: PROMISE-EC is a multi-center retrospective study including patients with apparently uterine-confined endometrial cancer who underwent surgical staging with sentinel lymph node biopsy at 16 European institutions (January 2014-February 2024). Clinicopathologic characteristics, sentinel lymph node status, and Cancer Genome Atlas-based molecular classification were collected and analyzed. The primary endpoint was progression-free survival. RESULTS: Among 2732 records, 2003 patients met inclusion criteria. International Federation of Gynecology and Obstetrics 2009 stage I was observed in 1585 patients (79.4%). Sentinel lymph node involvement was present in 282 patients (14.1%). p53-abnormal tumors were associated with poorer progression-free survival (p <.0001), whereas patients with POLE-mutated tumors showed excellent outcomes, with no significant difference compared with non-specific molecular profile (p =.103). Patients with deficient mismatch repair tumors showed intermediate outcomes (p =.484). In unadjusted Kaplan-Meier analysis, progression-free survival worsened with increasing sentinel lymph node tumor burden (p =.047). In multi-variable analysis, high-grade disease (p =.003) and p53 abnormal status (p <.001) remained independent predictors of recurrence. The association between sentinel lymph node tumor burden and recurrence was attenuated, with only macrometastatic involvement retaining independent prognostic significance. In multi-variable logistic regression, lymphovascular space invasion was the strongest predictor of sentinel lymph node metastases (p <.00001), while patients with POLE-mutated tumors were less likely to harbor clinically relevant nodal involvement (p =.032). CONCLUSIONS: Our study supports the prognostic relevance of both sentinel lymph node assessment and molecular classification in early-stage endometrial cancer, with potential implications for post-operative risk stratification and management.
Tran HTT, Doan NH, Le DV
… +6 more, Shrestha R, Warring SK, Thomé SD, Wetter DA, Bakkum-Gamez JN, Nguyen GH
Int J Gynecol Cancer
· 2026 Jun · PMID 42349066
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OBJECTIVE: To characterize population-level excess mortality relative to the general U.S. population and cause-specific mortality patterns within a competing-risks framework among patients with vulvar squamous cell carci...OBJECTIVE: To characterize population-level excess mortality relative to the general U.S. population and cause-specific mortality patterns within a competing-risks framework among patients with vulvar squamous cell carcinoma. METHODS: We conducted a population-based study using the Surveillance, Epidemiology, and End Results program (2000-2022). Standardized mortality ratios and excess absolute risks were used to assess excess mortality. Cause-specific mortality was analyzed using cumulative incidence functions and Fine-Gray competing-risk models. RESULTS: Among 13,924 patients, 52.2% died during follow-up over 83,357 person-years at risk. Vulvar squamous cell carcinoma was the leading cause of death (21.9%), followed by cardiovascular disease (8.9%) and other malignancies (8.7%). Compared with the general population, patients had excess mortality not only from vulvar squamous cell carcinoma but also from second malignancies and non-cancer conditions, including cardiovascular disease, chronic obstructive pulmonary disease, infection, and diabetes. In competing-risk analyses, advanced stage was strongly associated with higher vulvar squamous cell carcinoma-specific mortality. Higher cardiovascular disease mortality was observed among Black patients, and higher cardiovascular disease and chronic obstructive pulmonary disease mortality among unmarried patients. CONCLUSIONS: Patients with vulvar squamous cell carcinoma experience substantial excess mortality beyond cancer. These findings highlight the importance of survivorship care addressing second malignancies, cardiopulmonary comorbidities, and social disparities.
Joura E, Chatzistamatiou K, Gultekin M
… +4 more, Sehouli J, Toth I, Toth R, European Society of Gynaecological Oncology (ESGO)
Int J Gynecol Cancer
· 2026 Jun · PMID 42341405
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The Risk-Based Screening for Cervical Cancer project was a 4-year Horizon 2020 European research consortium that developed and validated a risk-stratified approach to cervical cancer screening, moving away from the curre...The Risk-Based Screening for Cervical Cancer project was a 4-year Horizon 2020 European research consortium that developed and validated a risk-stratified approach to cervical cancer screening, moving away from the current one-size-fits-all model. The European Society of Gynecological Oncology and its network, the European Network of Gynecological Advocacy Groups, participated as partners, contributing their expertise from both professional medical society and patient advocacy perspectives. The project's key findings support replacing cytology with human papillomavirus (HPV) deoxyribonucleic acid testing as the primary screening modality, as it provides greater protection against invasive cervical cancer. Gender-neutral HPV vaccination is endorsed as a strategy to accelerate herd immunity, particularly where vaccination coverage falls short of the World Health Organization targets. HPV genotyping, alongside age and screening history, emerges as a critical tool for individualizing risk assessment, while methylation tests might be useful tools to significantly reduce unnecessary colposcopy referrals within a fully molecular approach to cervical cancer screening. For vaccinated cohorts specifically, the evidence supports longer screening intervals, more conservative management of high-grade lesions caused by non-vaccine HPV types, and the potential substitution of HPV genotyping for standard HPV testing. Self-sampling combined with polymerase chain reaction-based HPV testing is endorsed as a safe, effective strategy to increase participation, particularly among populations who are under-screened, with flexible access pathways recommended to address socioeconomic barriers. European Society of Gynecological Oncology/European Network of Gynecological Advocacy Groups formally endorse the Risk-Based Screening for Cervical Cancer recommendations and call for the reform of European cervical cancer screening programs through the adoption of risk-stratified, patient-centered strategies, supported by integrated population registries, standardized quality indicators, and continuous real-time monitoring of vaccination and screening outcomes.
Cilla S, Deodato F, Pezzulla D
… +18 more, Romano C, Campitelli M, Fodor A, Laliscia C, Trippa F, De Sanctis V, Ippolito E, Ferioli M, Titone F, Russo D, Balcet V, Vicenzi L, Di Cataldo V, Cossa S, Ferrandina G, Gambacorta MA, Morganti AG, Macchia G
Int J Gynecol Cancer
· 2026 Jun · PMID 42341404
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OBJECTIVE: To stratify the treatment outcomes of patients with oligometastatic gynecologic cancer receiving stereotactic body radiation therapy using an un-supervised clustering machine-learning method. METHODS: This mul...OBJECTIVE: To stratify the treatment outcomes of patients with oligometastatic gynecologic cancer receiving stereotactic body radiation therapy using an un-supervised clustering machine-learning method. METHODS: This multi-centric study was based on a cohort of 172 patients receiving curative-intent stereotactic body radiation therapy for oligometastatic uterine tumors, yielding a total of 268 lesions. The following clinical and dosimetric variables were collected: age, number of lesions per patient, type of lesion (lymph nodes vs parenchyma), lesion burden (number of treated lesions per patient), treatment site of lesion, number of fractions, total dose, biologically effective dose, and planning target volume. An un-supervised clustering method based on the K-means algorithm was used to identify clusters of lesions. The groups of lesions were compared in terms of local control, distant-metastases-free survival, and overall survival. RESULTS: The optimal number of clusters was found to be equal to 3. The analysis of variance indicated that the variables contributing the most to the separation of the clusters were the planning target volume, the biologically effective dose, and the type of lesion. Significant differences were found between the 3 groups of lesions in terms of local control (p =.002). At 2 years, local control was 84.6%, 74.7%, 47.5% for the 3 clusters that were "a posteriori" named as high-control, medium-control, and low-control, respectively. Distant-metastases-free survival was also found to be significantly different (p =.04) at 2 years, with values of 27.0%, 22.2%, 48.0% for the high-control, medium-control, and low-control, respectively. No differences were found for the overall survival (p =.22). CONCLUSIONS: In this study, un-supervised machine-learning partitioned oligometastatic lesions into 3 clusters associated with different treatment responses. A prospective validation is needed for prediction purposes.
Macdonald ER, Rose G, Simar D
… +5 more, McCarthy AL, Ford C, Warton K, Hayes S, Clifford BK
Int J Gynecol Cancer
· 2026 May · PMID 42330750
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OBJECTIVE: Elevated concentrations of circulating cell-free DNA and circulating tumor DNA (ctDNA) are often detectable in biofluid from individuals with cancer. Investigating cfDNA and ctDNA across the endometrial cancer...OBJECTIVE: Elevated concentrations of circulating cell-free DNA and circulating tumor DNA (ctDNA) are often detectable in biofluid from individuals with cancer. Investigating cfDNA and ctDNA across the endometrial cancer continuum provides insight into diagnostic and prognostic potential. This systematic scoping review provides an overview of studies evaluating the utility of cell-free DNA ± circulating tumor DNA in endometrial cancer. METHODS: Databases and clinical trials registries (Embase, PubMed, CINAHL, Scopus, Open Science Framework, ClinicalTrials.gov) were searched using terms related to "Endometrial cancer", "Cell-free DNA", and "Circulating tumour DNA". Primary articles and pre-registered protocols of observational or interventional studies reporting cell-free DNA ±ctDNA measurement using biofluid from individuals with endometrial cancer of any stage, grade, or sub-type, at any time point were included. RESULTS: Ninety-three records were identified. Studies evaluated cell-free DNA ± circulating tumor DNA in endometrial cancer for 1) diagnosis; 2) monitoring disease status; 3) molecular profiling; 4) determining prognostic risk. Cell-free DNA ± circulating tumor DNA was primarily isolated from blood and analyzed using PCR-based assays or Next Generation Sequencing. Circulating tumor DNA showed promising diagnostic performance with greater potential in endometrial cancer prognosis, profiling, and monitoring, compared to cell-free DNA. Study design, sample characteristics, and data collection, analysis, and reporting were heterogeneous, limiting the strength of evidence for any given relationship. CONCLUSIONS: Cell-free DNA ± circulating tumor DNA has promising potential as a clinically valuable marker in endometrial cancer diagnosis, tumor profiling, treatment, and surveillance. However, evidence supporting the clinical use of any given cell-free DNA ± circulating tumor DNA parameter in this cohort is immature and limited by the lack of standardized methods and reporting. Addressing study design limitations, standardizing analysis methods and outcome reporting, and improving understanding of cell-free DNA physiology represent opportunities to advance this field of clinical research.
Liu Q, Zhou H, Yu M
… +7 more, Cao D, Peng P, Wang T, Wang Y, Wang J, Cheng N, Yang J
Int J Gynecol Cancer
· 2026 Apr · PMID 42330749
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OBJECTIVE: To compare the efficacy and safety of gonadotropin-releasing hormone agonist combined with an aromatase inhibitor versus oral progestins as fertility-sparing treatment in patients with endometrial carcinoma or...OBJECTIVE: To compare the efficacy and safety of gonadotropin-releasing hormone agonist combined with an aromatase inhibitor versus oral progestins as fertility-sparing treatment in patients with endometrial carcinoma or atypical endometrial hyperplasia. METHODS: This prospective, open-label, randomized non-inferiority trial (March 2023-March 2025) allocated patients 1:1 to gonadotropin-releasing hormone agonist plus letrozole (Arm A) or oral progestins (Arm B). A pre-specified interim analysis was conducted with a data cutoff date of March 17, 2025. The primary endpoint was the 24-week complete response rate. RESULTS: At this interim analysis, a total of 131 patients who completed the 24-week assessment were analyzed (Arm A: n = 67; Arm B: n = 64). At 24 weeks, the per-protocol complete response rate was significantly higher in Arm A than in Arm B (98.5% vs 68.8%; odds ratio 30.00, 95% confidence interval 3.88 to 231.71, p <.001), with a shorter mean time to response (127.48 vs 185.30 days; mean difference = 57.8 days, 95% confidence interval 32.97 to 82.66, p <.001). Pregnancy (53.1% vs 35.7%, p =.14) and recurrence rates (6.1% vs 12.3%, p =.19) showed no significant differences between groups. Multi-variate analysis confirmed the gonadotropin-releasing hormone agonist-based regimen as an independent predictor of complete response (adjusted odds ratio 31.07, 95% confidence interval 4.00 to 241.26, p =.001), with no significant influence from histology or body mass index. Patients in Arm A experienced significantly less weight gain than those in Arm B (21.9% vs 43.9%, p =.012), although menopausal symptom scores were higher in Arm A. CONCLUSIONS: This pre-specified interim analysis demonstrates that the gonadotropin-releasing hormone agonist-based regimen met the criterion for non-inferiority compared with oral progestins and was associated with higher complete response rates and a more favorable metabolic profile (less weight gain). These exploratory findings support continued investigation, but final conclusions await trial completion.
Levin G, Agusti N, Beshar I
… +6 more, Ribeiro R, Wilke RN, Melamed A, Iniesta MD, Meyer R, Rauh-Hain JA
Int J Gynecol Cancer
· 2026 May · PMID 42302709
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Minimally invasive surgery for interval cytoreduction in advanced ovarian cancer has been associated with improved peri-operative outcomes without compromising survival; however, comparative data between robotic and lapa...Minimally invasive surgery for interval cytoreduction in advanced ovarian cancer has been associated with improved peri-operative outcomes without compromising survival; however, comparative data between robotic and laparoscopic approaches remain limited. We conducted a retrospective cohort study using the National Cancer Database, including patients with stage III high-grade serous ovarian cancer who underwent minimally invasive cytoreduction between 2010 and 2022. Patients were stratified by surgical platform (robotic vs laparoscopic). The primary outcome was overall survival, analyzed using Kaplan-Meier estimates and multivariable Cox regression adjusted for demographic, clinical, and facility-level factors. Among 2993 patients, 1718 (57.4%) underwent laparoscopy and 1275 (42.6%) robotic surgery; conversion to laparotomy occurred in 14.9% and 4.0%, respectively, p < .001. Median follow-up was 35 months (range; 3-166). Median overall survival was similar between robotic and laparoscopic groups (48.0 vs 45.0 months; p = .57), and surgical platform was not associated with overall survival on multivariable analysis (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.07). Robotic surgery was associated with shorter length of stay (2.2 vs 4.5 days, p = .001), this remained significant after adjusting for year of surgery, and lower conversion rates, with no differences in readmission or short-term mortality. These findings support both platforms as viable minimally invasive options in selected patients.