Iacobelli V, Camarda F, Anderson G
… +10 more, Buttarelli M, Mastrantoni L, Ferrara MG, Trozzi R, Duranti S, Salutari V, Sabetta G, Scambia G, Fagotti A, Nero C
Int J Gynecol Cancer
· 2026 May · PMID 42001859
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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...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.
Int J Gynecol Cancer
· 2026 May · PMID 42000305
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The combination of avutometinib (a rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase [RAF/MEK] inhibitor) and defactinib (a focal adhesion kinase [FAK] inhibitor) demonstrated meaningful efficacy a...The combination of avutometinib (a rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase [RAF/MEK] inhibitor) and defactinib (a focal adhesion kinase [FAK] inhibitor) demonstrated meaningful efficacy and tolerability in recurrent KRAS-mutated low-grade serous ovarian carcinoma, as evidenced by clinically meaningful response rates and manageable adverse events. Avutometinib plus defactinib is a new, individualized treatment option for recurrent KRAS-mutated low-grade serous ovarian carcinoma. The evidence supporting these agents highlights their potential to address the unique therapeutic needs of this patient population, offering an option tailored to molecular characteristics and disease recurrence. Avutometinib plus defactinib represents a significant advancement in the management of recurrent KRAS-mutated low-grade serous ovarian carcinoma, leading to US Food and Drug Administration accelerated approval and inclusion in the National Comprehensive Cancer Network guidelines as a Category 2A recommendation for this patient population. This literature review summarizes the pharmacology of avutometinib and defactinib and the clinical trial data supporting the combination's approval. The authors discuss adverse event management and the implications for integration into routine clinical practice. Clinicians caring for patients with low-grade serous ovarian carcinoma can use the drug knowledge and evidence outlined in this review to assist with implementing avutometinib and defactinib therapy.
Kildal W, Pradhan M, Kristensen GB
… +6 more, Vlatkovic L, Tobin KAR, Hveem TS, Lindemann K, Askautrud HA, Kleppe A
Int J Gynecol Cancer
· 2026 May · PMID 41990404
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OBJECTIVE: Endometrial carcinoma is molecularly classified into sub-types with distinct prognoses. The no specific molecular profile sub-group is prognostically heterogeneous. This study evaluates the prognostic signific...OBJECTIVE: Endometrial carcinoma is molecularly classified into sub-types with distinct prognoses. The no specific molecular profile sub-group is prognostically heterogeneous. This study evaluates the prognostic significance of ER (estrogen receptor) and L1CAM (L1 cell adhesion molecule) expression in no specific molecular profile tumors individually, in combination with tumor grade, and as a combined biomarker. METHODS: Immunohistochemistry was used to assess expression of ER and L1CAM in tumors from patients with endometrial carcinoma referred to Oslo University Hospital (2006-2017). ER and L1CAM expression were grouped as negative (<10%) or positive (≥10%). Survival analyses were performed using Cox regression with cancer-specific survival as the end point. RESULTS: In this study of 465 no specific molecular profile patients, ER negativity (78/446, 17.5%) and L1CAM positivity (76/454, 14.5%) were positively correlated with adverse clinicopathologic features, particularly non-endometrioid histology. Both markers, individually and in combination, were associated with shorter cancer-specific survival, especially in FIGO (International Federation of Gynecology and Obstetrics) stage I (2009) patients (n = 360). Combining ER and/or L1CAM with tumor grade (grade 1-2 vs grade 3/non-endometrioid) increased the hazard ratio in multi-variable analyses of cancer-specific survival, with hazard ratios of 10.3 (95% confidence interval [CI] 3.43 to 31.14) for ER-negative and/or high grade, 9.43 (95% CI 3.17 to 28.00) for L1CAM-positive and/or high grade, and 15.08 (95% CI 4.13 to 55.14) for ER-negative and/or L1CAM-positive and/or high grade, compared with their corresponding low-risk groups. Estimated 5-year cancer-specific survival rates among FIGO stage I patients were 98.5% for ER-positive/low grade, 98.6% for L1CAM-negative/low grade, and 99.2% for ER-positive/L1CAM-negative/low grade, and 80.5%, 79.5%, and 82.6% for the corresponding high-risk groups. CONCLUSIONS: ER and L1CAM appear to have comparable prognostic value in no specific molecular profile endometrial cancer, and their combination with tumor grade enhances risk stratification. A combined marker including ER, L1CAM, and grade may improve risk stratification beyond either pair of markers and may be used to tailor treatment.
Fischerova D, Facchetti E, Panizzolo E
… +8 more, Nanka O, Farsi E, Poonyakanok V, Meccariello ML, Rizzi A, Burgetova A, Querleu D, Cibula D
Int J Gynecol Cancer
· 2026 May · PMID 41980434
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OBJECTIVE: To propose and anatomically substantiate a 2-pathway model of lymphatic dissemination in gynecologic cancers by correlating patterns of lymphatic spread with reproducible vascular landmarks identifiable on ult...OBJECTIVE: To propose and anatomically substantiate a 2-pathway model of lymphatic dissemination in gynecologic cancers by correlating patterns of lymphatic spread with reproducible vascular landmarks identifiable on ultrasound and confirmed by cadaveric dissection. METHODS: A descriptive anatomical study was conducted integrating schematic anatomy, targeted cadaveric dissections, and high-resolution ultrasound correlation. Lymphatic dissemination pathways were identified using reproducible vascular landmarks, which were systematically assessed on ultrasound and anatomically verified on cadaveric specimens. Representative clinical imaging cases illustrating involvement of the posterior and anterior pathways were included. RESULTS: Two principal lymphatic pathways were consistently identified. The posterior pathway, organized along major retroperitoneal vessels and their tributaries, represented the predominant route of lymphatic dissemination across gynecologic cancers, reflecting its anatomical continuity and established caudo-cranial spread from pelvic to supradiaphragmatic nodal basins. In contrast, involvement of the anterior pathway was observed mainly in association with extensive peritoneal carcinomatosis affecting the anterior abdominal wall and diaphragm. Along both pathways, lymphatic dissemination followed consistent vascular landmarks that were reproducibly identifiable on ultrasound and anatomically confirmed on cadaveric specimens. CONCLUSIONS: This study anatomically substantiates a 2-pathway model of lymphatic dissemination in gynecologic cancers through integration of cadaveric dissection and ultrasound-based imaging correlation. A posterior (retroperitoneal) lymphatic pathway was identified as the predominant route of lymphatic spread, while an anterior (parietal) lymphatic pathway was observed in association with lymphatic drainage of the anterior abdominal and thoracic walls, particularly in advanced disease with carcinomatosis and ascites. This pathway-oriented framework provides an anatomical basis for structured interpretation of lymphatic dissemination patterns and supports imaging-based lymph node assessment using reproducible vascular landmarks.
Martin M, Sehouli J, Altmann J
… +6 more, Stark E, Karaman M, Busse A, von Selasinsky S, Blohmer JU, Dimitrova D
Int J Gynecol Cancer
· 2026 May · PMID 41974152
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OBJECTIVE: The objective of this pilot study was to identify the number of patients of reproductive age with gynecologic and hematologic cancer who received fertility preservation consultation and to analyze their requir...OBJECTIVE: The objective of this pilot study was to identify the number of patients of reproductive age with gynecologic and hematologic cancer who received fertility preservation consultation and to analyze their requirements and needs to improve the consultation. METHODS: This retrospective cross-sectional survey used a pseudonymized questionnaire to record demographics, cancer diagnosis and therapy, fertility preservation consultation and fertility preservation actions, as well as patients' requirements for an optimized fertility preservation consultation. Female patients aged between 18 and 45 with gynecologic, hematologic, and breast cancer who received fertility-sparing therapy were recruited at Charité hospital. The χ tests were used to compare frequencies. Multiple logistic regression was performed to analyze influencing variables. RESULTS: Between August 2022 and February 2024, 107 patients were recruited. Of all patients, 73% received fertility preservation consultation, and 56% were offered fertility preservation before starting therapy. Seventy-five percent were satisfied with their consultation. In multi-variate analysis, influencing factors such as age, origin, parity, partner status, completed family planning, cancer type, and therapy were examined. Women not born in Germany and women with completed family planning were less likely to receive fertility preservation consultation. Patients undergoing chemotherapy were more likely to be offered fertility preservation options. For an optimized consultation, most patients preferred an in-person consultation by their treating gynecologist at the hospital, together with their partners. Booklets, websites, and consultations with their general practitioner were suggested as additional sources of information. Most patients suggested a specialized fertility preservation consultation. CONCLUSIONS: Most women of reproductive age with cancer received fertility preservation consultation, but only half were offered fertility preservation before therapy. Fertility preservation consultation should be improved by considering diversity and individual needs to include all patients of reproductive age with cancer.
Bizzarri N, Lago V, Agusti N
… +16 more, Uccella S, Buda A, Torrent A, Perrone AM, Calderaro-Di Ruggiero F, Sadeghi R, Taskiran C, Lambrechts S, Cosentino F, Vizzielli G, Giannarelli D, Di Berardino S, Nero C, Domingo S, Díaz-Feijoo B, Fagotti A
Int J Gynecol Cancer
· 2026 Mar · PMID 41968027
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OBJECTIVE: Sentinel lymph node (SLN) biopsy is an emerging technique in apparent early-stage ovarian cancer, with the potential to detect low-volume lymph node metastases. However, the prognostic value of low-volume meta...OBJECTIVE: Sentinel lymph node (SLN) biopsy is an emerging technique in apparent early-stage ovarian cancer, with the potential to detect low-volume lymph node metastases. However, the prognostic value of low-volume metastases is still unknown. This study aimed to assess the incidence and the prognosis of low-volume metastases detected in patients with apparent early-stage ovarian cancer undergoing SLN biopsy as part of a clinical trial. METHODS: Retrospective, multi-center, international study. Inclusion criteria were apparent International Federation of Gynecology and Obstetrics 2014 stage I to II epithelial ovarian cancer, undergoing SLN biopsy with systematic bilateral pelvic and para-aortic lymphadenectomy, and complete peritoneal surgical staging, from October 2012 to December 2023. In the absence of lymph-node macro-metastasis, at least 4-level ultra-staging at the SLN was performed. Fertility-sparing surgery or no SLN detection were exclusion criteria. Low-volume metastases were defined as any tumor deposit ≤2 mm (isolated tumor cells as <0.2mm, micro-metastasis as 0.2-2 mm). Descriptive statistics and survival analyses, including multi-variable Cox regression, were performed. RESULTS: SLN mapping was attempted in 260 patients. At least 1 SLN was detected in 199 (76.5%) patients, and low-volume metastases were found in 14/199 (7.0%), including 7 (3.5%) isolated tumor cells and 7 (3.5%) micro-metastases. Macro-metastases were identified in 18/199 (9.0%) patients. Among patients with lymph node metastases, 29/32 (90.6%) received adjuvant chemotherapy, including 11/14 (78.6%) with low-volume metastases. Median follow-up was 37 months (95% confidence interval [CI] 34.5 to 39.5). Three-year disease-free survival was 89.9% in node-negative patients, 100.0% in patients with low-volume metastasis, and 64.2% in patients with macro-metastasis (p < .001). Three-year overall survival was 98.2%, 100.0%, and 87.8%, respectively (p < .001). Lymph node macro-metastasis was the only factor independently associated with worse disease-free survival (hazard ratio 1.532, 95% CI 1.111 to 2.112, p = .009) and overall survival (hazard ratio 1.894, 95% CI 1.091 to 3.286, p = .001). CONCLUSIONS: Lymph node low-volume metastases in apparent early-stage ovarian cancer were present in 7% of patients, and none of these patients experienced recurrence or death. Lymph node macro-metastasis independently impaired disease-free and overall survival.
Song M, Bandoni K, Rodriguez-Rodriguez L
… +1 more, Nelson RA
Int J Gynecol Cancer
· 2026 May · PMID 41967417
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OBJECTIVE: Cervical cancer is the fourth most common female cancer worldwide. As improved cancer survivorship rates continue, understanding any increased risk for subsequent cancers is vital for surveillance. This study...OBJECTIVE: Cervical cancer is the fourth most common female cancer worldwide. As improved cancer survivorship rates continue, understanding any increased risk for subsequent cancers is vital for surveillance. This study investigates the risk of developing second primary malignancies among women with cervical cancer, along with racial disparities in this risk between non-Hispanic Blacks (Blacks) and non-Hispanic Whites (Whites). METHODS: Using Surveillance, Epidemiology, and End Results data, we identified Black and White women diagnosed with stage I to IV cervical cancer from 2000 to 2021. Risk of second primary malignancy was calculated using standardized incidence ratios, which represent the observed number of cases divided by the expected number of cases after adjusting for age, race, and year of diagnosis. Likelihood ratio tests were used to determine statistical significance in standardized incidence ratios across race and by anatomic and exposure-related group sites. Multi-variate Cox regression and Kaplan-Meier methods were used to compare demographics and clinical factors across race and second primary malignancy status. RESULTS: Among 36,702 patients with cervical cancer, 2639 (7.2%) developed a second primary (524 Blacks and 2115 Whites). Both groups had elevated standardized incidence ratios, with Blacks showing significantly higher standardized incidence ratios than Whites (1.7 vs 1.3, p <.001). Anatomic- and exposure-related sites with the highest overall standardized incidence ratios were (human papillomavirus) HPV-related (6.4), respiratory (2.5), urinary (2.1), smoking-related (2.0), genital (1.9), and radiation-related (1.7) (all p <.05). HPV-related sites had the highest standardized incidence ratios and were significantly higher in Blacks than Whites (13.5 vs 5.3, p <.001). At 10 years, second primary malignancy-free survival (89% vs 91%), overall survival (52% vs 65%), and cancer-specific survival (63% vs 72%) were all lower in Blacks (all p <.001). CONCLUSIONS: Cervical cancer survivors face an elevated risk of second primary malignancies, disproportionately affecting Black patients and HPV-related sites, emphasizing the need for enhanced surveillance and targeted follow-up to address persistent disparities.
Vandecaveye V, Walgraeve MS, De Keyzer F
… +7 more, Vergote I, Han S, Van Nieuwenhuysen E, Van Gorp T, Vanmarcke C, Dresen RC, Baert T
Int J Gynecol Cancer
· 2026 May · PMID 41965229
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OBJECTIVE: To assess the value of delayed gadolinium-enhanced magnetic resonance imaging (MRI) in addition to standard T2- and diffusion-weighted (T2/diffusion-weighted) MRI for evaluating residual locoregional tumor in...OBJECTIVE: To assess the value of delayed gadolinium-enhanced magnetic resonance imaging (MRI) in addition to standard T2- and diffusion-weighted (T2/diffusion-weighted) MRI for evaluating residual locoregional tumor in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage-2009 IB2 to IIB cervical cancer treated with neoadjuvant chemotherapy. METHODS: This retrospective study included patients diagnosed with FIGO-2009 stage IB2 to IIB cervical cancer between 2016 and 2020, who were treated with neoadjuvant chemotherapy and radical hysterectomy with pelvic lymphadenectomy, and staged with pelvic T2-, diffusion-weighted, and delayed gadolinium-enhanced MRI after neoadjuvant chemotherapy. Diagnostic accuracies of T2/diffusion-weighted MRI and delayed gadolinium-enhanced MRI, assessed by a sub-specialty radiologist (reader 1) and a general radiologist (reader 2), were compared for identification of residual tumor, parametrial, vaginal invasion, and detection of lymph node metastases. Inter-observer agreement was calculated. Additionally, Bland-Altman plots were used to compare the residual tumor size measured by T2/diffusion-weighted MRI and delayed gadolinium-enhanced MRI. Histopathology after surgery was the standard reference. RESULTS: Forty-two patients were eligible for study analysis. Delayed gadolinium-enhanced (reader 1/reader2) enabled identification of all 4 complete responders, while T2/diffusion-weighted MRI identified only 2. Delayed gadolinium-enhanced MRI (reader 1/reader 2) significantly improved diagnostic accuracy for detecting lymph node metastases (84.5%/82.2% vs 72.6%/70.2%, p <.0001) compared to T2/diffusion-weighted MRI. The addition of delayed gadolinium-enhanced MRI improved accuracy for detecting parametrial invasion (97.6%/88.1% vs 85.7%/78.6%) and vaginal invasion (92.9%/88.1% vs 80.9%/76.2%, p =.063). Delayed gadolinium-enhanced MRI showed better inter-observer agreement than T2/diffusion-weighted MRI for assessment of vaginal invasion (κ, 0.86 vs 0.33), parametrial invasion (κ, 0.63 vs 0.44), and nodal status (κ, 0.90 vs 0.79). CONCLUSIONS: Addition of delayed gadolinium-enhanced MRI substantially improved pre-operative identification of extra-uterine primary tumor extent, significantly improved detection of metastatic lymph nodes, and allowed better assessment of residual tumor size compared with T2/diffusion-weighted MRI alone in patients with FIGO-2009 stage IB to IIB cervical cancer treated with neoadjuvant chemotherapy.
Lim H, Lee C, Back JW
… +6 more, Seol A, Kim SI, Kim HS, Chung HH, Kim JW, Lee M
Int J Gynecol Cancer
· 2026 May · PMID 41965228
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OBJECTIVE: Endocervical adenocarcinoma comprises biologically heterogeneous sub-types classified as human papillomavirus (HPV)-associated and HPV-independent, practically based on p16 immunohistochemistry according to th...OBJECTIVE: Endocervical adenocarcinoma comprises biologically heterogeneous sub-types classified as human papillomavirus (HPV)-associated and HPV-independent, practically based on p16 immunohistochemistry according to the 2020 World Health Organization (WHO) classification. This study explored the prognostic relevance of WHO-defined HPV-associated versus HPV-independent histologic classification and examined associations between primary treatment modality and clinical outcomes in locally advanced endocervical adenocarcinoma. METHODS: We conducted a single-center retrospective cohort study including patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3 to IVA endocervical adenocarcinoma treated between 2007 and 2024. All cases underwent expert slide review, and pre-treatment HPV testing was assessed when available. Patients were analyzed according to histologic sub-type and heterogeneous primary treatment approaches, including radical hysterectomy-based treatment with or without adjuvant therapy (n = 65) and definitive concurrent chemoradiation therapy-based treatment with or without completion hysterectomy (n = 37). Progression-free survival and overall survival were evaluated using Cox proportional hazards models. RESULTS: Among 102 patients, 53 had HPV-associated tumors and 49 had HPV-independent tumors, the latter predominantly gastric-type adenocarcinoma. HPV-independent tumors were associated with significantly worse progression-free survival and overall survival compared with HPV-associated tumors. Within the HPV-independent cohort, primary treatment modality was independently associated with both progression-free and overall survival, with radical hysterectomy-based treatment showing more favorable progression-free survival estimates compared with definitive chemoradiation therapy. A programmed death-ligand 1 combined positive score <1 was independently associated with overall survival. CONCLUSIONS: WHO-defined HPV-associated versus HPV-independent histologic classification was a strong prognostic marker in locally advanced endocervical adenocarcinoma. In exploratory analyses of HPV-independent tumors, associations between primary treatment modality and survival outcomes were observed; however, these findings should be interpreted with caution because of treatment selection bias and the retrospective study design. Further prospective studies are warranted to refine risk stratification and multi-disciplinary treatment strategies for this aggressive sub-group.
Zhang T, Zhang P, Zhu L
… +6 more, Wei L, Yang X, Liu Y, Deng X, Zhang J, Wang Y
Int J Gynecol Cancer
· 2026 May · PMID 41965227
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OBJECTIVE: Endometrial cancer is a common gynecological cancer with a rising incidence, yet effective non-invasive early diagnostic methods are lacking. Recent findings indicate that tumor-derived exosomal cargo, includi...OBJECTIVE: Endometrial cancer is a common gynecological cancer with a rising incidence, yet effective non-invasive early diagnostic methods are lacking. Recent findings indicate that tumor-derived exosomal cargo, including PIWI-interacting RNAs (piRNAs), may serve as promising cancer-specific biomarkers. Our study investigates the potential of serum-derived exosomal piRNAs for early detection of endometrial cancer. METHODS: Biomarker development involves 3 phases with independent patient cohorts. In the discovery phase, small RNA sequencing identified candidate exosomal piRNAs from serum samples of 5 healthy controls and 6 patients with endometrial cancer. In the training phase, a serum exosomal piRNA panel was created using receiver operating characteristic curve, logistic regression, a random forest algorithm, and the DeLong test. In the validation phase, we verified the diagnostic performance of the 3piRNA_panel using the receiver operating characteristic curve. RESULTS: In validation, the 3piRNA_panel (hsa_piR_009183, hsa_piR_014592, and hsa_piR_006767) showed high diagnostic accuracy for endometrial cancer, with an area under the curve of 0.942. It distinguished stage IA endometrial cancer from healthy controls with an area under the curve of 0.977 and was effective in patients with normal CA125 levels. It also potentially differentiated stage IA endometrial endometrioid carcinoma from atypical endometrial hyperplasia. A post-operative decrease in panel scores was observed in a limited subset of paired samples. The expression of hsa_piR_014592 was significantly associated with aggressive histopathological types, ≥50% myometrial invasion, substantial lymphovascular space invasion, lymph node metastasis, p53 mutation, and G3 endometrial endometrioid carcinoma. CONCLUSION: Our novel non-invasive serum exosomal piRNA panel demonstrated clinical potential for the early detection of endometrial cancer.