Frédéric Amant

European training requirements for gynecological oncology: the European Society of Gynaecological Oncology Curriculum

Cancer of the corpus uteri: A 2025 update

AbstractEndometrial cancer comprises a heterogeneous group of neoplasms. Its incidence is increasing, as is mortality from endometrial cancer. This article updates many aspects surrounding endometrial cancer, covering histopathology, staging, surgical and non‐surgical management, follow‐up, and management of recurrent disease.

Incorporating molecular profiling into endometrial cancer management requires prospective studies

Malignant germ cells tumor of the ovary

Malignant ovarian germ cell tumors are rare and diverse malignancies, accounting for approximately 5% of all ovarian cancers. Primarily affecting young women, these tumors present unique challenges, particularly in balancing effective treatment with fertility preservation. Early diagnosis is common due to the rapid tumor growth and symptoms such as abdominal pain and distension, leading to favorable prognoses when combined with the high chemosensitivity of platinum-based regimens. Fertility-sparing surgery is the cornerstone of treatment for stage I disease, often followed by close surveillance to minimize the long-term toxicities of chemotherapy. Pathology is pivotal for diagnosis, incorporating immunohistochemical markers to differentiate malignant ovarian germ cell tumors subtypes, including dysgerminomas, yolk sac tumors, and immature teratomas. Advanced imaging modalities like ultrasound, magnetic resonance imaging, and computed tomography are essential for staging, monitoring treatment response, and detecting recurrences. Despite high cure rates, long-term follow-up is crucial to manage late toxicities, such as gonadal dysfunction and secondary malignancies. Recurrent malignant ovarian germ cell tumors present significant therapeutic challenges. High-dose chemotherapy with stem-cell transplantation offers promise in select cases, while the role of secondary cytoreductive surgery and radiotherapy is limited to specific indications. Emerging targeted therapies and novel approaches, such as KIT inhibitors for dysgerminomas with KIT mutations, remain experimental, with limited success reported so far. The rarity and heterogeneity of malignant ovarian germ cell tumors impede large-scale research efforts, underscoring the need for greater understanding of their molecular and genetic landscape to develop more effective and personalized therapies.

How long is long enough? An international survey exploring practice variations on the recommended duration of maintenance therapy with PARP inhibitors in patients with platinum sensitive recurrent ovarian cancer and long-term outcomes

There are no data, and thus no consensus, on the optimal duration of poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy for exceptional responders (here defined as progression-free for 5 years or longer) with platinum sensitive recurrent ovarian cancer. The current licence is to continue PARP inhibitors until progression or toxicity; however, international practice varies considerably. The risks of late progression and late-onset myeloid malignancies, defined as occurring beyond 5 years of PARP inhibition, are unknown. This study aims to examine the practice patterns and opinions regarding the management and surveillance protocols of exceptional responders with platinum sensitive recurrent ovarian cancer. An online international survey of experts from June 2023 to June 2024 was carried out, disseminated at Gynaecologic Cancer Intergroup meetings and by Chairs of Cooperative Groups. 210 responses were received from 26 countries including Australia (27 respondents), Germany (24), the UK (21), the Netherlands (16), France (13), Spain (12), Canada (12), Italy (11), Japan (11), and other countries (63). Most respondents did not have institutional or trials group guidelines regarding duration of PARP inhibitors (154, 73.3%). For the minority with guidelines, recommendations varied: 1 year (2), 2 years (13), 3 years (4), and indefinite treatment (22). Individual practice varied considerably for those without guidelines: most (116, 76.3%) recommended ≥5 years of PARP inhibition, of which 73 (48.0%) recommended indefinite PARP inhibition. Sixty-six respondents (31.4%) reported having patients with late progression and 46 (22.0%) had cases with late-onset myeloid malignancies. Surveillance practices varied widely across all respondents. This international survey highlights the diverse practice variations and disparate views on the optimal duration of maintenance therapy with PARP inhibitors in platinum sensitive recurrent ovarian cancer. The responses suggest a notable risk of late progression and myelodysplastic syndrome/acute myeloid leukemia among exceptional responders which needs confirmation. Detailed individual patient data is required to draw more reliable conclusions; another study is underway addressing this.

An open-label, single-arm, prospective, multi-center, tandem two-stage designed phase II study to evaluate the efficacy of fulvestrant in women with recurrent/metastatic estrogen receptor-positive gynecological malignancies (FUCHSia study)

This study aimed to evaluate fulvestrant efficacy in women with estrogen receptor-positive low-grade gynecological cancers. The primary objective was to determine the response rate. Secondary objectives were progression-free survival, clinical benefit, duration of response, safety, tolerability, and quality of life. FUCHSia is an open-label, single-arm, prospective, multi-center phase II study. The study population included patients with recurrent/metastatic low-grade gynecological malignancies with estrogen receptor positivity who received a maximum of two lines of previous hormonal therapy. Patients received fulvestrant (FASLODEX, AstraZeneca) via two intramuscular injections (250 mg/5 mL each) in the gluteal muscle on day 1, day 15, day 29, and then every 28 days thereafter until disease progression, withdrawal from the trial due to any unacceptable adverse event, or withdrawal of patient consent. A total of 15 patients (uterine sarcoma n=4; sex cord-stromal ovarian tumors n=3; endometrial carcinoma n=4; serous ovarian cancer n=4) were enrolled. Median follow-up was 48 weeks (interquartile range (IQR) 26-122) in the uterine sarcoma cohort, 63 weeks (IQR 28-77) for sex cord-stromal tumors, 19 weeks (IQR 17-21) for endometrial carcinoma, and 60 weeks (IQR 40-119) for serous ovarian cancer. One partial response according to Response Evaluation Criteria in Solid Tumors v1.1 was observed in one uterine sarcoma patient. No responses were observed in the other cohorts. However, stable disease was observed in three uterine sarcomas (median duration 12 weeks), three sex cord-stromal tumors (median duration 32 weeks), and four low-grade serous ovarian cancer patients (median duration 20 weeks), leading to a disease control rate of 100% for these tumor types. All patients with endometrial carcinoma showed progressive disease. Fulvestrant may control tumor growth in recurrent/metastatic estrogen receptor-positive low-grade gynecological malignancies of specific histology. Further studies are needed to confirm these results.

Predicting resectable disease in relapsed epithelial ovarian cancer by using whole-body diffusion-weighted MRI

To determine the diagnostic value of whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to predict resectable disease at the time of secondary cytoreductive surgery for relapsed epithelial ovarian cancer with a platinum-free interval of at least 6 months. A retrospective cohort study between January 2012 and December 2021 in a tertiary referral hospital. Inclusion criteria were: (a) first recurrence of epithelial ovarian cancer; (b) platinum-free interval of ≥6 months; (c) intent to perform secondary cytoreductive surgery with complete macroscopic resection; and (d) WB-DWI/MRI was performed.Diagnostic tests of WB-DWI/MRI for predicting complete resection during secondary cytoreductive surgery are calculated as well as the progression-free and overall survival of the patients with a WB-DWI/MRI scan that showed resectable disease or not. In total, 238 patients could be identified, of whom 123 (51.7%) underwent secondary cytoreductive surgery. WB-DWI/MRI predicted resectable disease with a sensitivity of 93.6% (95% confidence interval [CI] 87.3% to 96.9%), specificity of 93.0% (95% CI 87.3% to 96.3%), and an accuracy of 93.3% (95% CI 89.3% to 96.1%). The positive predictive value was 91.9% (95% CI 85.3% to 95.7%).Prediction of resectable disease by WB-DWI/MRI correlated with improved progression-free survival (median 19 months vs 9 months; hazard ratio [HR] for progression 0.36; 95% CI 0.26 to 0.50) and overall survival (median 75 months vs 28 months; HR for death 0.33; 95% CI 0.23 to 0.47). WB-DWI/MRI accurately predicts resectable disease in patients with a platinum-free interval of ≥6 months at the time of secondary cytoreductive surgery and could be of complementary value to the currently used models.

PI3K/mTOR inhibition induces tumour microenvironment remodelling and sensitises pS6high uterine leiomyosarcoma to PD‐1 blockade

AbstractBackgroundUterine leiomyosarcomas (uLMS) are aggressive tumours with poor prognosis and limited treatment options. Although immune checkpoint blockade (ICB) has proven effective in some ‘challenging‐to‐treat’ cancers, clinical trials showed that uLMS do not respond to ICB. Emerging evidence suggests that aberrant PI3K/mTOR signalling can drive resistance to ICB. We therefore explored the relevance of the PI3K/mTOR pathway for ICB treatment in uLMS and explored pharmacological inhibition of this pathway to sensitise these tumours to ICB.MethodsWe performed an integrated multiomics analysis based on TCGA data to explore the correlation between PI3K/mTOR dysregulation and immune infiltration in 101 LMS. We assessed response to PI3K/mTOR inhibitors in immunodeficient and humanized uLMS patient‐derived xenografts (PDXs) by evaluating tumour microenvironment modulation using multiplex immunofluorescence. We explored response to single‐agent and a combination of PI3K/mTOR inhibitors with PD‐1 blockade in humanized uLMS PDXs. We mapped intratumoural dynamics using single‐cell RNA/TCR sequencing of serially collected biopsies.ResultsPI3K/mTOR over‐activation (pS6high) associated with lymphocyte depletion and wound healing immune landscapes in (u)LMS, suggesting it contributes to immune evasion. In contrast, PI3K/mTOR inhibition induced profound tumour microenvironment remodelling in an ICB‐resistant humanized uLMS PDX model, fostering adaptive anti‐tumour immune responses. Indeed, PI3K/mTOR inhibition induced macrophage repolarisation towards an anti‐tumourigenic phenotype and increased antigen presentation on dendritic and tumour cells, but also promoted infiltration of PD‐1+ T cells displaying an exhausted phenotype. When combined with anti‐PD‐1, PI3K/mTOR inhibition led to partial or complete tumour responses, whereas no response to single‐agent anti‐PD‐1 was observed. Combination therapy reinvigorated exhausted T cells and induced clonal hyper‐expansion of a cytotoxic CD8+ T‐cell population supported by a CD4+ Th1 niche.ConclusionsOur findings indicate that aberrant PI3K/mTOR pathway activation contributes to immune escape in uLMS and provides a rationale for combining PI3K/mTOR inhibition with ICB for the treatment of this patient population.

Vulvar and vaginal cancer during pregnancy: A pooled analysis of 15 cases from the International Network on Cancer, Infertility and Pregnancy and review of the literature

Abstract Introduction Vulvovaginal cancer in pregnancy is rare. Limited data complicate decision‐making and patient counseling. Our review, coupled with new case data, fills a current gap in the literature and provides practical insights. Material and Methods Oncological and obstetric data of these pregnancies were examined by a case collection from the International Network on Cancer, Infertility and Pregnancy (INCIP) registry (vulvar n  = 10, vaginal n  = 5) and a literature review (vulvar n  = 46, vaginal n  = 37). Results Although preoperative imaging of inguinofemoral lymph nodes is feasible, only 16.1% of vulvar cancer patients underwent ultrasound or MRI. Treatment was initiated during pregnancy for 69.1% of vulvar cancer and 28.4% of vaginal cancer patients. Surgical lymph node staging of vulvar cancer was postponed until after delivery in 10 cases, although uni‐ or bilateral lymphadenectomy during pregnancy was not associated with more complications. Delivery outcomes included a live birth rate of 96.4% for vulvar cancer and 50% for vaginal cancer due to the high rate of pregnancy terminations, with most births preterm. The overall 5‐year survival rates for vulvar (81.3%) and vaginal (66.4%) cancer during pregnancy are comparable to nonpregnant populations, indicating that pregnancy does not adversely impact maternal prognosis. Conclusions This study underscores the feasibility of adapting standard oncological care for pregnant patients, emphasizing multidisciplinary teams to optimize maternal and fetal outcomes.

Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2)

Current treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this vulnerable patient group. To compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery with definitive chemoradiation in patients with locally advanced vulvar cancer. Neoadjuvant chemotherapy followed by surgery is oncologically safe, potentially more effective than primary chemoradiation in establishing long lasting locoregional control, and associated with an improved quality of life. This study is a multicenter, prospective, phase II randomized controlled trial. Patients will be randomized 1:1 to the standard treatment arm (primary chemoradiation, consisting of a tumor dose of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for 6 weeks) or the experimental treatment arm (neoadjuvant chemotherapy, consisting of carboplatin and paclitaxel in a 3 weekly scheme, followed by surgery). Eligible patients must have a histologically confirmed primary or recurrent locally advanced squamous cell carcinoma of the vulva (International Federation of Gynecology and Obstetrics (FIGO) stages Ib-Iva; Lesions larger than 2 cm in size or stromal invasion larger than 1 mm (T1b or higher), any status of lymph node involvement (any N), no distant metastasis including pelvic lymph nodes (M0)) with the size or localization of the tumor requiring treatment through primary chemoradiation or extensive surgery. Patients with documented metastases of the pelvic lymph nodes will be excluded from participation in this study. Locoregional control at 24 months. 98 patients will be included in the study. Expected complete accrual in 2028 with presentation of results by 2030. ClinicalTrials.gov NCT05905315.

Successful cervical cancer treatment during a monochorionic diamniotic twin pregnancy in a patient with history of preterm delivery

Increased hospital case volume is associated with improved survival and quality of care for uterine corpus cancer in Belgium.

This study aimed to prospectively evaluate whether hospital case volume is positively associated with both the outcome and the quality of care of uterine corpus cancer in Belgium. This was a prospective, observational, registration-based, real-world database study. Hospital case volume was categorized according to the total number of patients treated on average per year: low (<10/y), medium (10-19/y), and high (≥20/y). Adjusting for patient case mix and intra-hospital correlations, logistic and Cox proportional hazards regression were used to test for associations between hospital case volume and a multi-disciplinary set of process and outcome indicators. Sub-group analyses by recurrence risk were performed for overall survival and disease-free survival. In total, 4178 patients diagnosed with a primary cancer of the uterine corpus between 2012 and 2016 in Belgium were included. Compared with patients treated in high-volume hospitals, patients treated in low-volume hospitals were more likely to die of any cause within 5 years after diagnosis (adjusted hazard ratio 1.37, p < .01), as were patients treated in medium-volume hospitals (adjusted hazard ratio 1.18, p < .05). Similar results were observed in the sub-group analyses, but only among patients with high-intermediate-risk and high-risk disease. In contrast, hazards for disease-free survival did not differ by hospital case volume, neither in the total study population nor in the sub-group analyses by recurrence risk. Furthermore, analysis of the process indicators showed that patients treated in low- and medium-volume hospitals were less likely to receive multiple guideline-recommended procedures compared with those treated in high-volume hospitals, including minimally invasive surgery, surgical lymph node staging, staging omentectomy, and adjuvant chemotherapy. On average, increased hospital case volume was positively associated with improved overall survival and quality of care, supporting centralization of uterine corpus cancer care into high-volume reference centers in Belgium.

GWAS meta-analysis identifies five susceptibility loci for endometrial cancer

Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined. Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan. GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells. Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer. This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.

ESGO/EURACAN/GCIG guidelines for the management of patients with uterine sarcomas

Primary Chemoradiation VS. Neoadjuvant Chemotherapy Followed By Surgery As Treatment Strategy For LAVC

A phase 2 randomised controlled trial will be performed in which the efficacy and safety of standard treatment (primary chemoradiation; consisting of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for six weeks) and experimental treatment (NACT; consisting of carboplatin and paclitaxel in a 3-weekly scheme) will be compared in 98 patients with LAVC, registered from eight national medical centres.