Spatial profiling of ovarian carcinoma and tumor microenvironment evolution under neoadjuvant chemotherapy.

PURPOSE: Immune tumor microenvironment (iTME) determines ovarian cancer development. This study investigates changes in HLA-I expression, CD8+/Foxp3 ratio, CD8+ cells and coregulators density at diagnosis and upon neoadjuvant chemotherapy (NACT), correlating changes with clinical outcomes. EXPERIMENTAL DESIGN: Multiplexed immune profiling and cell clustering analysis was performed on paired matched OC samples to characterize the iTME at diagnosis and under NACT from patients enrolled in the CHIVA trial (NCT01583322). RESULTS: Several immune cells (IC) subsets and immune coregulators were quantified pre-/post-NACT. At diagnosis, patients with higher CD8+ T cells and HLA-1+ enriched tumors were associated with -better outcome. The CD8+/Foxp3+ ratio increased significantly post-NACT in favor of increased immune surveillance and the influx of CD8+ T cells predicted better outcomes. Clustering analysis stratified pre-NACT tumors into 4 subsets: high Binf, enriched in B clusters; high Tinf, low Tinf, according to their CD8+ density; and desert clusters. At baseline, these clusters were not correlated with patient outcomes. Under NACT, tumors segregated into 3 clusters: high BinfTinf, low Tinf and desert. The high BinfTinf, more diverse in IC composition encompassing T, B and NK cell, correlated with improved survival. PD-L1 was rarely expressed, while TIM-3, LAG- and IDO-1 were more prevalent. CONCLUSIONS: Several iTMEs exist during tumor evolution and NACT impact on iTME is heterogeneous. Clustering analysis of patients, unravels several IC subsets within OC and can guide future personalized approaches. Targeting different checkpoints such as TIM-3, LAG-3 and IDO-1, more prevalent than PD-L1, could more effectively harness anti-tumor immunity in this anti-PD-L1 resistant malignancy.

Uterine adenosarcoma: Clinical significance of histological classification and SNP array analysis.

Mullerian adenosarcoma is a rare malignant biphasic tumor. The mesenchymal component may be low or high grade, with or without sarcomatous overgrowth (SO). Little is known about the molecular heterogeneity of these tumors. In this study, we aim to reclassify a large retrospective monocentric cohort of uterine adenosarcomas according to tumor grade and SO, to evaluate the clinical significance of pathological classification and to correlate with copy-number variations inferred from single nucleotide polymorphism array. Of the 67 uterine adenosarcomas, 18 (26.9%) were low grade without SO, 7 (10.4%) low grade with SO, 8 (11.9%) high grade without SO and 34 (50.7%) high grade with SO. SO, necrosis and RMS were more frequent in high grade than low grade adenosarcomas (p < 0.001). Low-rank test showed that recurrence-free survival was significantly shortened in high grade than low grade adenosarcomas (p = 0.035) and SO was associated with shortened overall and recurrence-free survival (p = 0.038 and p = 0.009, respectively). High-grade tumors displayed complex genomic profiles with multiple segmental losses including TP53, ATM and PTEN genes. The median genomic index was significantly higher in high grade than low grade tumors (27 [3-60] vs 5,3 [0-16], p < 0.0001) and was significantly higher in presence of SO in low grade tumors (12,8 [10-16] vs 2,6 [0-10], p = 0.0006). We propose to report sarcomatous overgrowth with the tumor grade for prognostication in adenosarcoma and representative sampling is crucial for evaluation of these histological criteria.

Correlation between peritoneal cancer index and survival in advanced epithelial ovarian cancer with complete resection.

OBJECTIVE: The aim of this study was to investigate the relation between the peritoneal cancer index, overall survival, and recurrence free survival, in patients with epithelial ovarian cancer. METHODS: Patients treated at the Gustave-Roussy Institute between December 2004 and November 2017 for advanced epithelial ovarian cancer in complete resection were included. The correlation between the peritoneal cancer index and survival was studied using statistical modeling. Multivariate analysis was performed with a logistic regression model. RESULTS: Of the 351 patients included, 94 (27%) had initial surgery and 257 (73%) had interval surgery. Median follow-up was 52.7 months (range 47.6-63.9). Median peritoneal cancer index was 10 (range 0-32). The linear model best represented the relationship between peritoneal cancer index and overall survival. Patients with neoadjuvant chemotherapy had a greater instantaneous risk of baseline death than those with initial surgery, as well as a more rapid increase in this risk as the peritoneal cancer index increased. Overall survival and recurrence free survival were better in the initial surgery group (103.4 months (79.1-not reached (NR)) vs 66.5 months (59.1-95.3) and 31.8 months (23.7-48.7) vs 25.9 months (23.2-29), respectively). Risk factors for death were body mass index, peritoneal cancer index, and need for neoadjuvant chemotherapy. CONCLUSION: The peritoneal cancer index is a prognostic indicator, but its linear relationship with survival precluded setting a unique peritoneal cancer index cut-off. Moreover, the prognostic impact of peritoneal cancer index was stronger in the setting of neoadjuvant chemotherapy.

[Current post-surgical treatment strategies in first-line ovarian cancer]. / Stratégies thérapeutiques post-chirurgicales actuelles dans les cancers de l'ovaire en première ligne de traitement.

Although the management of epithelial ovarian cancer has evolved significantly over the past few years, it remains a public health issue, as most patients are diagnosed at an advanced stage and relapse after first line treatment. Chemotherapy remains the standard adjuvant treatment for International Federation of Gynecology and Obstetrics (FIGO) stage I and II tumors, with some exceptions. For FIGO stage III/IV tumors, carboplatin- and paclitaxel-based chemotherapy are the standard of care, in combination with targeted therapies, especially bevacizumab and/or poly-(ADP-ribose) polymerase inhibitors, that have become a key milestone of first-line treatment. Our decision making for the maintenance therapy is based on the FIGO stage, tumor histology, timing of surgery (i.e. primary or interval debulking surgery), residual tumor, response to chemotherapy, BRCA mutation and homologous recombination (HR) status.

[Diagnosis of uterine sarcomas and rare uterine mesenchymal tumours with malignant potential. Guidelines of the French Sarcoma Group and Rare Gynaecological Tumours]. / Diagnostic des sarcomes utérins et tumeurs mésenchymateuses utérines rares à potentiel de malignité. Référentiels du Groupe Sarcome Français et des Tumeurs Rares Gynécologiques.

The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.

Immune checkpoints are predominantly co-expressed by clonally expanded CD4+FoxP3+ intratumoral T-cells in primary human cancers.

BACKGROUND: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. METHODS: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. RESULTS: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. CONCLUSIONS: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

European multidisciplinary tumor boards support cross-border networking and increase treatment options for patients with rare gynecological tumors.

OBJECTIVE: To evaluate outcomes of European cross-border multidisciplinary tumor boards in terms of participation, adherence to treatment recommendations, and access to novel treatment strategies. METHODS: The European reference network for rare gynecological tumors (EURACAN G2 domain) aims to improve the diagnosis, management, and treatment of patients with these cancers. Cross-border multidisciplinary tumor boards were initiated to facilitate intercollegiate clinical discussions across Europe and increase patients' access to specialist treatment recommendations and clinical trials. All G2 healthcare providers were invited to participate in monthly multidisciplinary meetings. Patient data were collected using a standardized form and case summaries were distributed before each meeting. After each tumor board, a meeting summary with treatment recommendations was sent to all participants and the project manager at the coordinating center. The multidisciplinary tumor board format and outcomes were regularly discussed at G2 domain meetings. Anonymized clinical data and treatment recommendations were registered in a prospective database. For this report, clinical data were collected between November 2017 and December 2020 and follow-up data retrieved until May 2021. RESULTS: During the 3-year period, 31 multidisciplinary tumor boards were held with participants from 10 countries and 20 centers. 91 individual patients were discussed between one and six times for a total of 109 case discussions. Follow-up data were retrieved from 64 patients and 80 case discussions. Adherence to treatment recommendations was 99%. Multidisciplinary tumor board recommendations resulted in 11 patients getting access to off-label treatment and one patient being enrolled in a clinical trial in another European country. 14/91 patients were recommended for surveillance only when additional treatment had been considered locally. CONCLUSION: Cross-border multidisciplinary tumor boards enable networking and clinical collaboration between healthcare professionals in different countries. Surveillance strategies, off-label drug use, and increased participation in clinical trials are possible benefits to patients with rare gynecological tumors.

Circulating Tumor DNA from Ascites as an alternative to tumor sampling for genomic profiling in ovarian cancer patients.

Genomic testing is crucial for the management of ovarian cancer. DNA from biopsies at diagnostic laparoscopies or interval debulking surgery after neoadjuvant chemotherapy, has a high failure rate. At relapse, biopsies may not be feasible. The aim of our study was to evaluate the feasibility and usefulness of measuring genomic instability score (GIS) on cell-free DNA (cfDNA) from ascites.Patients enrolled in a prospective study (NCT03010124) consented to analysis of biological samples. CfDNA was extracted from 1 to 4 ml of double-centrifuged fresh ascites. Targeted Next-generation sequencing (NGS) including TP53 mutation (TP53m) was performed on cfDNA to confirm the presence of tumor cfDNA. Single Nucleotide Polymorphism Array estimating somatic copy number alterations (SCNA) was performed to calculate GIS for Homologous-Recombination deficiency (HRD).Twenty nine ascites were collected from 20 patients with suspected or confirmed OC. 93% (27/29) samples had detectable cfDNA (median 1120 ng [24-5732]) even when obtained during chemotherapy. A deleterious mutation was identified in 100%, with high allelic frequencies (median 60% [3.3-87%]), confirming that cfDNA was tumoral. SCNA analyses on 17 patients showed 11 high GIS, and 6 low GIS. 4 patients with confirmed BRCA mutation had a high GIS on ascites. When available from the same patient, SCNA profiles on ascites and tumor were superimposable.Ascites is frequent at diagnosis and relapse and yields large amounts of tumoral cfDNA. SCNA analysis on ascitic cfDNA is feasible and can detect the same HRD scar as tumor testing. Ascites could provide an alternative to tumor sampling for HRD and BRCA testing.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022­2023 : Prise en charge du cancer du col de l'utérus avancé.

French recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of advanced cervical cancer The prognosis of cervical cancer remained pejorative until recently, first-line treatment consisting of platinum-based chemotherapy, associated with bevacizumab whenever possible, without any other therapeutic innovation for several years. However in 2022, immunotherapy appeared in the therapeutic landscape. Pembrolizumab can now be prescribed, thanks to the early access status granted by the HAS in September 2022, in patients with PD-L1 positive tumors. In parallel, bevacizumab generic is now reimbursed, allowing its association with chemotherapy on top of pembrolizumab, if indicated. For patient relapsing after platinium salts, and who never received immunotherapy, cemiplimab could be delivered and reimboursed since spring 2023, whatever could be PD-L1 status. Pretherapeutic work-up includes imaging combining MRI and PET/CT or CT of the chest, abdomen and pelvis, as well as evaluation of PD-L1 status on tumor and immune cells to define the CPS score that will determine eligibility to pembrolizumab treatment (CPS > 1). Possibilities of locoregional treatment depend on individual situations and are discussed on a case-by-case basis in multidisciplinary meetings. Early supportive care is always recommended and inclusion in clinical trials must be systematically considered.

Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial.

PURPOSE: Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS: ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1-positive populations (alpha .025 for each population). RESULTS: Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1-positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1-positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION: ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.

Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.

Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.

[Uterin adenosarcoma: French Guidelines of the French Sarcoma Group and the Rare Gynecologic Tumor Group]. / Adénosarcomes mullériens de l'utérus ­ référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine adenosarcoma is a very rare malignancy defined as a biphasic tumor composed of both benign epithelial component and a malignant sarcoma component. The stage of the disease is determined by the presence of myometrial invasion and the extent of extra-uterine disease. The most important histopronostic factors are the existence of a sarcomatous overgrowth defined by a sarcomatous contingent occupying more than 25 % of the volume of the tumor (directly correlated to the grade of the disease), the presence of a heterologous and/or a high-grade component. Stage I adenosarcomas without sarcomatous overgrowth have a good prognosis, with an overall 5-year survival of up to 80 %. In localized disease, complete surgical removal is recommended. The role of hormone therapy, chemotherapy and adjuvant radiotherapy is not established. If possible, relapses should be re-treated surgically, with the aim of achieving complete resection. In the advanced inoperable or metastatic setting, hormone therapy is an option for low-grade adenosarcomas with estrogen receptor (ER) and progesterone receptor (PR) overexpression. For high-grade tumors, the standard chemotherapies are doxorubicin-based combinations, although an integrated approach of surgery and medical treatment should also be considered in this setting.

Impact of surgery and chemotherapy in ovarian sex cord-stromal tumors from the multicentric Salomé study including 469 patients. A TMRG and GINECO group study.

OBJECTIVE: Identifying prognostic factors and evaluating the impact of adjuvant chemotherapy in patients with sex cord stromal tumors (SCST) is crucial. In this study, we aimed to address these challenges. METHODS: We conducted a retrospective analysis of data from 13 centers of the French Rare malignant gynecological tumors (TMRG) network. We enrolled 469 adult patients with malignant SCST who received upfront surgery since 2011 to July 2015. RESULTS: 75% were diagnosed with adult Granulosa cell tumors, and 23% had another subtype. With a median follow-up of 6.4 years, 154 patients (33%) developed a first recurrence, 82 (17%) two recurrences, and 49 (10%) three recurrences. Adjuvant chemotherapy was administered in 14.7% of patients at initial diagnosis. In relapse, perioperative chemotherapy was administered in 58.5%, 28.2%, and 23.8% of patients, respectively, in the first, second, and third relapse. In the first-line therapy, age under 70 years, FIGO stage, and complete surgery were associated with longer progression-free survival (PFS). Chemotherapy had no impact on PFS in early-stage disease (FIGO I-II). The PFS was similar using BEP or other chemotherapy regimens (HR 0.88 [0.43; 1.81]) in the first-line therapy. In case of recurrence, PFS was statistically prolonged by complete surgery, but perioperative chemotherapy use did not impact PFS. CONCLUSION: Chemotherapy use did not impact survival in the first-line or relapse setting in SCST. Only surgery and its quality demonstrated benefit for PFS in ovarian SCST in any lines of treatment.

Clinical Relevance of BRCA1 Promoter Methylation Testing in Patients with Ovarian Cancer.

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. See related commentary by Garg and Oza, p. 2957.

[Uterin sarcoma, high-grade stroma, indifferenciated, referential]. / Sarcomes utérins du stroma de haut grade et sarcomes indifférenciés ­ Référentiels de prise en charge du Groupe Sarcome Français et du Groupe des Tumeurs Rares Gynécologiques.

High-grade endometrial stromal sarcoma (HGESS) and uterine undifferentiated sarcoma (UUS) are rare uterine malignancies arising from mesenchymal endometrial cells. They are characterized by aggressive behavior and poor prognosis. Median age of diagnostic is 55years. The most common symptoms are vaginal bleeding, abdominal pain, and pelvic mass. Approximately 65 % are diagnosed witch advance disease stage III or IV according to the International Federation of Gynecology and Obstetrics classification. Median overall survival is around 20months. The management of the disease must be discussed in multidisciplinary staff meetings. The standard management of HGESS and UUS is total hysterectomy with bilateral oophorectomy. Systematic lymphadenectomy is not recommended. Adjuvant therapies, such as chemotherapy and radiotherapy must be discussed. In case of oligo-metastasic disease, surgery of the primary tumor and metastasis must be discussed and if not operable the standard management is doxorubine-based chemotherapy.

[Uterine leiomyosarcoma - French guidelines from the GSF/NETSARC and TMRG groups]. / Léiomyosarcomes utérins ­ Référentiel de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine leiomyosarcomas represent the most common uterine sarcomas. The prognosis is poor with metastatic recurrence in more than half of the cases. The purpose of this review is to make French recommendations for the management of uterine leiomyosarcomas within the framework of the French Sarcoma Group - Bone Tumor Study Group (GSF-GETO)/NETSARC+ and Malignant Rare Gynecological Tumors (TMRG) networks in order to optimize their therapeutic management. The initial assessment includes a MRI with diffusion perfusion sequence. The diagnosis is histological with a review in an expert center (Reference Network in Sarcoma Pathology (RRePS)). Total hysterectomy with bilateral salpingectomy, en bloc without morcellation, is performed when complete resection is possible, whatever the stage. There is no indication of systematic lymph node dissection. Bilateral oophorectomy is indicated in peri-menopausal or menopausal women. Adjuvant external radiotherapy is not a standard. Adjuvant chemotherapy is not a standard. It can be an option and consists in doxorobucin based protocols. In the event of local recurrence, the therapeutic options are based on revision surgery and/or radiotherapy. Systemic treatment with chemotherapy is most often indicated. In case of metastatic disease, surgical treatment remains indicated when resecable. In cases of oligo-metastatic disease, focal treatment of metastases should be considered. In the case of stage IV, chemotherapy is indicated, and is based on first-line doxorubicin-based protocols. In the event of excessive deterioration in general condition, management by exclusive supportive care is recommended. External palliative radiotherapy can be proposed for symptomatic purposes.

[Endometrial stromal sarcoma: French Guidelines from the French Sarcoma Group and the Rare Malignant Gynecologic Tumors Group]. / Sarcomes du stroma endométrial de bas grade : référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Low-grade endometrial stromal sarcoma (LG-ESS) accounts for approximately 15% of all uterine sarcomas. Median age of patients is around 50 years and half of the patients are premenopausal. In all, 60% of cases present with FIGO stage I disease. Preoperatively radiologic findings of ESS are not specific. Pathological diagnosis remains essential. This review aimed to present the French guidelines for low grade ESS treatment within the Groupe sarcome français - Groupe d'étude des tumeurs osseuse (GSF-GETO)/NETSARC+ and tumeur maligne rare gynécologique (TMRG) networks. Treatments should be validated in multidisciplinary team involved in sarcomas or rare gynecologic tumors. Hysterectomy is the cornerstone of treatment for localized ESS, and morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome and is not recommended. Leaving the ovaries in situ in stage I tumors could be discussed for young women. Adjuvant hormonal treatment could be considered, for two years for stage I with morcellation or stage II and livelong for stages III or IV. Nevertheless, several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Tamoxifen is contraindicated. Secondary cytoreductive surgery if feasible for recurrent disease, appears to be an acceptable approach. Systemic treatment for recurrent or metastatic disease is mainly hormonal, with or without surgery.

Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse.

OBJECTIVE: Chemotherapy for high-grade serous ovarian cancers in platinum-sensitive relapse includes carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin. According to in vitro data, BRCA mutated patients are sensitive to replicative stress agents but BRCA status is not yet used for the choice of chemotherapy at relapse. Our aim was to assess these doublets according to BRCA status in first platinum-sensitive relapse. METHODS: The ESME ovarian cancer database comprises a multicenter retrospective cohort of patients with ovarian cancer treated in French cancer centers between January 2011 and December 2017. Patients with high-grade serous ovarian cancers at first platinum-sensitive relapse who received one of these doublets were included. The objective was to compare progression-free survival of each chemotherapy doublet according to BRCA status. RESULTS: Among the 10 263 patients in the database, 1539 patients had a first platinum-sensitive relapse: 825 BRCA wild type patients (53.6%) and 304 BRCA mutated patients (19.8%) (7 patients had a homologous recombination mutation and BRCA status was unkown for 403 patients). Median progression-free survival was longer in BRCA mutated patients than in BRCA wild type patients when receiving carboplatin/pegylated liposomal doxorubicin without maintenance treatment (15.8 vs 11.8 months; p<0.001). In contrast, we observed no difference in patients treated with carboplatin/paclitaxel (14.6 vs 14.3 months, respectively; p=0.70) or in those treated with carboplatin/gemcitabine (12.0 vs 9.8 months, respectively; p=0.18). In BRCA wild type patients without maintenance, better progression-free survival occurred with carboplatin/paclitaxel (median progression-free survival 14.3 months) than with carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin (9.8 and 11.8 months, respectively; p=0.017). In BRCA mutated patients without maintenance, there was no difference between the three doublets (median progression-free survival of 14.6, 12.0, and 15.8 months with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin, respectively; p=0.40). CONCLUSION: While treatment with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin shows comparable efficacy in BRCA mutated patients, treatment with carboplatin/paclitaxel appears to be more effective than carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin in BRCA wild type patients with high-grade serous ovarian cancers at first platinum-sensitive relapse.

Response to first line platinum-based chemotherapy in mismatch repair deficient (MMRd)/ microsatellite instability high (MSI-high) endometrial carcinoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: ORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.