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Purpose: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. Experimental Design: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.

Around 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity in MMRd/MSI-H EC, especially response to first-line platinum-based treatment.We performed a multicentric retrospective analysis reporting the response to first line platinum CT in MMRd/MSI-H EC patients. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) with first line platinum-based CT.A total of 112 patients MMRd/MSI-H EC from 8 centers were identified. Median overall survival was 58.0 months (95% CI: 45.3-95.1). Among them, 78 patients received first line platinum CT in recurrent/metastatic setting. With a median follow up of 32.6 months (min: 0.03; max: 135.0), ORR and DCR (disease control rate) were 50% (95% CI: 38.5-61.5) and 68% (95% CI: 56.4-78.1), respectively. Median PFS and OS from first line platinum-based CT was 7.8 months (95% CI: 6.0-9.0) and 51.9 months (95% CI: 28.0-NE), respectively. Median PFS with ICI in second line (n = 48) was 10.7 months (95% CI: 3.4-NE) from ICI initiation.ORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.

Clinical data and outcomes of patients included

Purpose:Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance.Experimental Design:This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.Results:Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P < 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.Conclusions:Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction.

EWSR1/FUS-CREB-rearranged mesenchymal neoplasms are an emerging heterogeneous group of soft tissue tumors that encompasses low-grade lesions (angiomatoid fibrous histiocytoma/AFH) and a group of predominantly intra-abdominal aggressive sarcomas with epithelioid morphology and frequent keratin expression. Both entities occasionally harbor EWSR1::ATF1 fusions as alternate to the more frequent EWSR1/FUS::CREB1/CREM fusions. Although EWSR1/FUS-CREB-rearranged epithelioid malignant neoplasms have been described in diverse intra-abdominal sites, none involved the female adnexa. Herein, we describe three cases involving uterine adnexa in young females (41, 39, and 42-year-old); two associated with constitutional inflammatory symptoms. The tumors presented as a serosal surface mass of the ovary without parenchymal involvement (Case 1), as circumscribed nodule within ovarian parenchyma (Case 2), and as a periadnexal mass extending into the lateral uterine wall with lymph node metastasis (Case 3). They were composed of sheets and nests of large epithelioid cells with numerous stromal lymphocytes and plasma cells. The neoplastic cells expressed desmin and EMA, and variably WT1. One tumor expressed in addition AE1/AE3, MUC4, synaptophysin, chromogranin, and ALK. None expressed sex cord-associated markers. RNA sequencing identified EWSR1::ATF1 fusions in two cases and an EWSR1::CREM fusion in one. Exome-based RNA capture sequencing and clustering methods showed high transcriptomic proximity of tumor 1 with soft tissue AFH. This novel subset of female adnexal neoplasms should be included in the differential diagnosis of any epithelioid neoplasm involving female adnexa. Their aberrant immunophenotype can be misleading, underlining a wide spectrum of differential diagnosis.

Endometrioid borderline ovarian tumor (EBOT) is a rare subtype of borderline ovarian malignancies. This study was designed to determine the prognosis of a series of EBOT.This is a retrospective review of patients with EBOT treated in or referred to our institutions and a centralized, histological review by a reference pathologist. Data on the clinical characteristics, management (surgical and medical), and oncologic outcomes of patients were required for inclusion.Forty-eight patients were identified. Median age was 52 years (range 14-89). Fourteen patients underwent a conservative surgery and 32 a bilateral salpingo-oophorectomy (unknown in 2 cases). Two patients had bilateral tumors. Forty-three patients had stage I disease, and five patients had stage II disease (10%). Stromal microinvasion and intraepithelial carcinoma was observed in 6 (12%) and 13 (27%) patients respectively. Endometriosis was histologically associated in 12 patients (25%). Synchronous endometrial disease was found in 7 (24%) of 29 patients with endometrial histological evaluation. The median follow-up was 72 months (range 6-146). Two patients developed a recurrence after cystectomy in form of borderline disease (5%). No death related to EBOT occurred.Peritoneal restaging surgery should be performed if not realized initially, because 5% of EBOTS are diagnosed at stage II-III. Fertility-sparing surgery seems a safe option in selected patients. Because synchronous endometrial diseases, including endometrial carcinoma are frequent, systematic hysterectomy (or endometrial sampling in case of fertility-sparing surgery) is mandatory. Prognosis is generally excellent. Recurrence is a rare event (6%), but it can occur in the form of invasive disease.

Resume Le traitement des carcinomes endometriaux repose essentiellement sur les donnees histopathologiques de type histologique, de grade, de stade et d’emboles vasculaires. Nous revenons sur les modifications recentes de l’appreciation de ces parametres, en lien avec la derniere classification OMS 2020. Par ailleurs, le typage moleculaire des carcinomes endometriaux est devenu la regle car il est associe a des implications pronostiques et therapeutiques fortes. Les categories TP53-mutee/serous like et hypermute/dMMR sont facilement identifiables par le pathologiste a l’aide d’outils immunohistochimiques. La categorie ultramutee/POLE-mutee requiert quant a elle des techniques de sequencage. Nous detaillons ici comment apprehender de facon simple cette nouvelle classification histo-moleculaire, maintenant partie integrante des recommandations des societes savantes.

Resume Objectifs La strategie de preservation de fertilite (PF) dans le cancer du col de l’uterus est challengee depuis plusieurs annees et une desescalade therapeutique semble s’imposer. Dans ce contexte, nous avons evalue les resultats oncologiques, de fertilite et obstetricaux des techniques chirurgicales realisees dans notre centre en vue d’une PF. Methodes Cet essai uni centrique retrospectif a inclus 75 patientes, prises en charge a l’institut Gustave Roussy entre 1995 et 2020, pour un cancer de col (stade IB1 FIGO 2018) et ayant conduit un projet de preservation de la fertilite apres un bilan pre-therapeutique approfondi. L’objectif d’un tel recueil etait d’apprehender nos resultats sur la fertilite et les issues obstetricales et les correler aux donnees oncologiques et enfin d’evaluer l’evolution de nos pratiques chirurgicales. Resultats Cinquante quatre patientes ont beneficie d’une trachelectomie elargie, aucune atteinte ganglionnaire n’a ete constatee. 1 patiente a recu un traitement complementaire en post operatoire ne permettant pas de preserver sa fertilite. Le taux de recidive etait de 4,8 % (4/75) avec un deces decrit. 31 grossesses ont ete obtenues soit un taux de grossesse de 50 %. 74 % des grossesses ont ete obtenues spontanement et 60 % des grossesses ont ete conduites a terme. Conclusion Nos resultats sont similaires a ceux de la litterature. Malgre un projet de preservation de fertilite seulement la moitie des patientes a pu obtenir une grossesse.

Resume L’evolution des connaissances en oncologie gynecologique conduit progressivement vers une desescalade chirurgicale dans plusieurs domaines, notamment dans celui de la chirurgie ganglionnaire. L’indication du ganglion sentinelle (GS) dans le cancer de l’endometre, initialement reserve aux risques bas et intermediaire, est maintenant elargie a tous les stades FIGO (International Federation of Gynecology and Obstetrics) I et II. Le GS a aussi une place tres importante dans la stadification ganglionnaire des cancers du col a un stade precoce. Par ailleurs, une reflexion importante est menee sur la radicalite des hysterectomies chez les patientes operees de cancer du col a un stade precoce. De meme, la stadification ganglionnaire lombo-aortique dans les cancers du col localement avances ne serait benefique qu’a une minorite de patientes. Les cancers de l’ovaire n’echappent pas a la desescalade chirurgicale avec une diminution des indications de lymphadenectomie.

Resume De nombreuses etudes cliniques visent a integrer l’immunotherapie en oncologie radiotherapie, soit pour favoriser des reponses abscopales en association a la radiotherapie chez des patients atteints de cancer metastatique, soit dans le cadre du traitement d’une tumeur localement evoluee. La recherche de biomarqueurs de reponse au traitement est un axe majeur du developpement de ces associations therapeutiques, pour permettre l’identification precoce des patients qui tireront benefice du traitement, dans une approche personnalisee. Nous passons en revue certaines des strategies applicables pour la personnalisation aux traitements associant radiotherapie et immunotherapie.

Background Clear cell borderline ovarian tumor (CCBOT) is one of the rarest subtypes of borderline ovarian malignancies. The aim of this study was to determine the prognosis of a series of CCBOT. Patients and methods A retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion. Results Nineteen patients were identified. Median age was 62 (range 36-83) years. Four patients underwent a conservative surgery and 14 a bilateral salpingo-oophorectomy +/- hysterectomy (unknown in 1 case). One patient had bilateral tumor, and all cases were stage-I disease. All CCBOTs showed an adenofibromatous pattern. Stromal microinvasion was observed in seven cases and intraepithelial carcinoma in two cases. Endometriosis was histologically associated in one case. The median follow-up was 76 (range 6-231) months. No recurrence occurred. Two patients died of intercurrent disease. Conclusions Peritoneal staging procedures should always be associated, but restaging surgery could be omitted if there was no suspicious lesion in the peritoneum during initial surgery, since all patients reported had stage-I disease. Fertility-sparing surgery appears to be a safe alternative in young patients. Synchronous endometrial disorders with atypia are infrequent. Prognosis is generally excellent, and long-term risk of recurrence is low. The two recurrences described in literature occurred in stage-IC diseases, highlighting the importance of avoiding perioperative rupture.

Our aim was to assess the opinion of a panel of experts and obtain a consensus on the management of endometrial cancer in France and French Switzerland. A Delphi survey was carried out among a panel of French and French-speaking Swiss experts. The first questionnaire included 65 questions divided into eight categories: characterization of experts, histo-molecular characteristics and radiological data of endometrial cancer, and management of low-risk, intermediate-risk, intermediate–high-risk, high-risk, and metastatic cancers. The experts were asked to reply on a 9-point scale, both on the validity and the clarity of each question. After the answers were analyzed, a second questionnaire was sent to the same experts. The study took place between December 2021 and March 2022. Further, 58 (57.4%) of the 101 experts responded in the first round, and 39 recommendations were obtained (60%). Six questions were voted redundant and 20 discordant. These questions were reformulated, and, at the end of the second round, 17 recommendations were validated (85%). In total, the study presents an analysis of 56 questions and related responses. Expert advice helps to clarify non-consensual issues, standardize the management of endometrial cancer, and optimize clinical practices.

The latest European recommendations of the European Societies of Gynecological Oncology (ESGO), Radiotherapy and Oncology (ESTRO) and Anatomopathology (ESP) concerning the management of patients with endometrial cancer were published in 2021. On behalf of the French Society of Gynecologic Oncology (SFOG) and the SFOG campus, we wish to summarize for the French-speaking readership the main measures with a more specific application for France. We also incorporate data from a Delphi survey conducted with a panel of French and French-speaking Swiss experts. The data presented in this article relate to histo-molecular characteristics, radiological data of endometrial cancer, and management of low-risk, intermediate-risk, intermediate-high-risk, and metastatic cancers. The aim of this review article is to show the application of the latest international recommendations to clinicians and pathologists for the implementation of these recommendations.

BACKGROUNDThe efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors has been demonstrated in several phase III trials. However its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test.PATIENTS AND METHODSA novel biomarker to identify HRD was developed using TCGA data and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 phase 3 trial using the OncoScan™ CNV Assay. Results were compared to the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the Olaparib+Bevacizumab and placebo+Bevacizumab arms.RESULTSAnalysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions (nLST) by the number of whole genome doubling events allows a better separation and classification of HRD samples than the GIS. The Oncoscan+nLST test yielded a lower failure rate on the 469 PAOLA-1 samples (10/469 vs 59/469 inconclusive results) and positive and negative agreement values of 96% (204/213) and, 81% (159/197) respectively. In nLST-positive samples, the hazard ratio (HR) was 0.40 (95% CI: 0.28-0.57) compared with 0.35 for Myriad GIS. In tumors that were BRCA wild-type and nLST-positive, the HR was 0.53 (Myriad: 0.41). In this subpopulation the nLST test and the Myriad myChoice test yielded a similar 1-year PFS (87% and 88%) but a different 2-year PFS (52% vs 60%) upon Olaparib+ Bevacizumab treatment.CONCLUSIONThe proposed test is a viable alternative to the Myriad myChoice HRD test and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the commercial test but its lower failure rate allows a 10% increase in the number of patients who will receive a conclusive laboratory result.Highlights-A novel laboratory-developed test that increased HRD scoring accessibility for ovarian cancer patients-Clinically validated on 469 samples from the PAOLA-1 trial within the ENGOT HRD European Initiative-A similar performance as the Myriad myChoice Dx HRD test but at a lower failure rate

Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).

Most frequent borderline ovarian tumors are serous and mucinous subtypes. Less frequent borderline diseases are endometrioid, clear-cell, and Brenner tumors (BBOT). Very little is known about the latter subtype, and most studies include very short series or case reports. The aim of this study is to determine the prognosis of a continuous series of BBOT and analyze data published in the literature on this rare entity. A retrospective review of patients with BBOT treated or referred to our institutions was conducted. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion. Overall, 17 patients were identified. Median age was 62 (range 42–85) years. Six patients underwent unilateral salpingo-oophorectomy, and 11 bilateral salpingo-oophorectomy +/− hysterectomy and/or staging surgery. In total, 16 patients had unilateral tumor, and all patients had stage I disease. Stromal microinvasion was observed in three cases. Median follow-up was 60 months (range 7–118 months). One patient developed a recurrence in contralateral ovary after unilateral salpingo-oophorectomy. One patient had previous history of urothelial tumor. Peritoneal staging surgery is not required because all patients reported had stage I disease. One recurrence occurred. When reviewing all the 82 cases reported in the literature (including ours), 9% had previous history or synchronous urothelial tumor, suggesting the need to carefully check for urological disease in patients with BBOT.

Background The disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome. Method We identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%. Results In our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival. Conclusion TIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.

The landscape of uterine sarcomas is becoming increasingly complex with the description of new entities associated with recurrent molecular alterations. Uterine sarcomas, as well as soft tissue sarcomas, can be distinguished into complex genomic sarcomas and simple genomic sarcomas. Leiomyosarcoma and pleomorphic type undifferentiated uterine sarcoma belong to the first group. Low-grade and high-grade endometrial stromal sarcomas, NTRK, COL1A1::PDGFB, ALK, RET, ROS1 associated sarcomas, and SMARCA4 deficient uterine sarcoma belong to the second group. Leiomyosarcoma is the most common uterine sarcoma followed by endometrial stromal sarcomas. Three different histologic subtypes of leiomyosarcomas are recognized with distinct diagnostic criteria and different clinical outcomes, the myxoid and epithelioid leiomyosarcomas being even more aggressive than the fusiform type. The distinction between low-grade and high-grade endometrial stromal sarcoma is based first on morphology and immunohistochemistry. The detection of fusion transcripts helps in the diagnosis. Definitely recognized as a separate entity, uterine PEComa is a rare tumor whose diagnostic criteria are being recently defined. Uterine PEComa has a specific algorithm stratifying the tumors into uncertain malignant potential and malignant tumors. Embryonal rhabdomyosarcomas of the uterine cervix are not restricted to children but can also be observed in adult women and are almost always DICER1 mutated, unlike embryonal rhabdomyosarcoma of the vagina which are DICER1wild-type, and adenosarcoma which can be DICER1 mutated but with less frequency. As sarcomas associated with fusion transcripts involving the NTRK, ALK, COL1A1::PDGFB genes can benefit from targeted therapy, systematic detection are now relevant especially for patients with high risk of relapse or in recurrent setting. The integration of molecular data with dedicated expert pathology review for histology and clinical data allows better identification of uterine sarcomas in order to better treat them.