PURPOSE OF REVIEW:Desmoplastic small round cell tumor (DSRCT) is an ultra-rare, fusion-driven sarcoma with a dismal prognosis despite multimodal therapy. Most patients present with advanced intra-abdominal and/or metastatic disease at diagnosis, and long-term survival remains uncommon. This review summarizes recent advances in the molecular and biological understanding of DSRCT. It highlights current diagnostic and therapeutic standards, and discusses emerging targeted and immunotherapeutic strategies with translational relevance. RECENT FINDINGS:DSRCT is defined by the pathognomonic EWSR1::WT1 fusion, which acts as an aberrant transcription factor driving oncogenesis. Although there is no consensus standard of care, multimodal strategies combining dose-intense chemotherapy, complete cytoreductive surgery, and whole abdominopelvic radiotherapy remain the cornerstone of management when feasible. However, outcomes remain poor, particularly in patients with extra-peritoneal disease. Recent genomic studies have identified actionable vulnerabilities, including dysregulation of the angiogenic pathways, and IGF axis. In parallel, innovative immunotherapeutic approaches - particularly antibody-drug conjugates targeting HER2 and B7-H3 - have shown encouraging early signals of activity. SUMMARY:Despite multimodal treatment, DSRCT remains a highly lethal malignancy. Advances in molecular characterization are reshaping the therapeutic landscape and supporting the development of targeted strategies, especially antibody-drug conjugates. Enrollment in prospective clinical trials and international collaborative efforts are essential to improve outcomes in this orphan disease.

INTRODUCTION:Synovial sarcoma (SyS) and myxoid round-cell liposarcoma (MRCL) are rare, aggressive soft tissue sarcomas with poor outcomes at the advanced and metastatic stage. Novel therapeutic strategies are urgently needed. Afamitresgene autoleucel (afami-cel) is the first Food and Drug Administration (FDA)-approved, affinity-enhanced T-cell receptor (TCR) therapy targeting the cancer-testis antigen MAGE-A4 in HLA-A*02-positive patients. AREAS COVERED:This review summarizes clinical evidence from one early-phase study and the pivotal phase 2 SPEARHEAD-1 trial. Afami-cel achieved objective response rates of 39% in SyS and 25% in MRCL, with durable responses exceeding 11 months in SyS. The safety profile is manageable, with hematological toxicities from lymphodepletion and predominantly low-grade cytokine release syndrome; no treatment-related deaths occurred in SPEARHEAD-1. EXPERT OPINION:Afami-cel represents a milestone in sarcoma therapy, establishing proof of concept for engineered TCR T-cell therapies in solid tumors. However, challenges remain regarding HLA restriction, tumor microenvironment resistance, manufacturing delays and cost. Future efforts should focus on broadening applicability, optimizing combinations, and ensuring equitable access.

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

UTROSCT are a rare entity that can sometimes present as metastatic disease. Hormonal therapy may address this issue.

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.

Background: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. Patients and methods: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. Results: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III–IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3–20.6) and 14.8 months (95% CI 13.1–17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2–49.2) and 30.6 months (95% CI 24.1–40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0–NR) and 18.9 months (95% CI 14.0–45.6) for UCS stages I–II and stages III–IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2–NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9–72.9) (HR 0.44 (0.20–0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5–5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1–8.5) and 2.2 months (95% CI 1.9–2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). Conclusions: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Background: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. Methods: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. Results: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). Conclusions: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

Cervical cancer (CC) still has a high incidence despite screening programmes and access to human papillomavirus (HPV) vaccination, with a poor prognosis in the advanced setting. Most cases of cervical carcinoma are related to HPV infection. The pathogen-induced nature of the disease, the involvement of genes regulating the immune response and the high grade of immune infiltration provide the rationale to evaluate anti-programmed death-(ligand)1 (PD-[L]1) immune checkpoint inhibitors in CC. This article reviews the promising outcomes of the KEYNOTE-826 phase III trial, which evaluates the addition of pembrolizumab to chemotherapy in patients with PD-L1-positive disease and recurrent, persistent or metastatic cancer of the cervix, leading to an improvement of progression-free survival and overall survival. We also aim to address some outstanding questions and discuss the next steps in immunotherapy for CC.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Rare ovarian cancers occur frequently. Almost half of ovarian malignancies relate to several different ‘rare’ histotypes, according to the World Health Organization. The most common tumors are epithelial tumors, including high grade serous carcinomas, the presumed ‘frequent ovarian cancers’, together with low grade serous, mucinous, endometrioid, clear cell, and carcinosarcomas. Sex cord stromal tumors and germ cell carcinomas define two other groups of different subtypes, and small cell carcinomas are an independent high grade subtype closely related to the family of rhabdoid tumors. All of these cancers are primary ovarian cancers, classified by the International Federation of Gynecology and Obstetrics. However, the tumor subtypes display various epidemiologic, clinical, pathological, prognostic, and therapeutic characteristics. Because of the scarcity of data, current understanding of each subtype is limited and treatment has generally been derived from the more common tumor types. The aim of this article is to review the current literature on rare ovarian malignancies.

Rare ovarian cancers occur frequently. Almost half of ovarian malignancies relate to several different 'rare' histotypes, according to the World Health Organization. The most common tumors are epithelial tumors, including high grade serous carcinomas, the presumed 'frequent ovarian cancers', together with low grade serous, mucinous, endometrioid, clear cell, and carcinosarcomas. Sex cord stromal tumors and germ cell carcinomas define two other groups of different subtypes, and small cell carcinomas are an independent high grade subtype closely related to the family of rhabdoid tumors. All of these cancers are primary ovarian cancers, classified by the International Federation of Gynecology and Obstetrics. However, the tumor subtypes display various epidemiologic, clinical, pathological, prognostic, and therapeutic characteristics. Because of the scarcity of data, current understanding of each subtype is limited and treatment has generally been derived from the more common tumor types. The aim of this article is to review the current literature on rare ovarian malignancies.

Purpose of review In the past few years, the advent of PARP inhibitors has been a revolution in the management of ovarian cancer. Patients harboring somatic or germ line BRCA1/2 mutations exhibit different clinical and treatment response behavior. The BRCA gene is involved in repairing DNA repair via homologous recombination, and mutation of this gene leads to homologous recombination deficiency (HRD). Recent findings HRD constitutes a therapeutic opportunity for these patients, thanks to the development of poly(ADP-ribose) polymerase inhibitors (PARPi) in the late 2000s. Indeed, using PARPi in patients with HRD simultaneously compromises two mechanisms of DNA repair, resulting in synthetic lethality. Summary This breakthrough in clinical practice has raised remaining questions: which population will most benefit from PARPi? Are all ovarian cancers susceptible to synthetic lethal strategy? At which stage of ovarian cancer should PARPi be used? Is earlier always better? Are PARPi all equivalent? Which strategies are reasonable to overcome PARPi resistance? Which combination strategies should be efficient?

Introduction/Background In SOLO1 trial, maintenance therapy with olaparib considerably improved progression-free survival (PFS) among women with newly-diagnosed, advanced BRCA-mutated HGEOC. Based on the large real-life ESME ovarian cancer (OC) cohort, we aimed to describe the patient‘s characteristics and survival outcomes of a selected cohort of BRCA-mutated patients before the era of PARP inhibitors maintenance in first line. Methodology ESME OC is a national cohort including all patients (pts) with EOC managed in the 18 French Comprehensive Cancer Centres (NCT03275298). ESME Research program collected retrospective data from patient‘s medical records. BRCA1, BRCA2, or both mutated patients with de novo diagnosed advanced (FIGO stage III or IV) high-grade serous or endometrioid EOC were eligible. Primary objective was to describe patient‘s characteristics, clinical features and treatment patterns. Results Of the 4777 patients with OC treated in first line by platinum-based chemotherapy between 2011 and 2016, 266 were included. Median age was 57.0 (33–81). 187 pts (70.3%) harbored a BRCA1 mutation, and 75 (28.2%) a BRCA2 mutation. 66.9% of patients had FIGO stage III disease. Almost all patients (95.5%) underwent surgical resection, after neoadjuvant chemotherapy (48%), or primary debulking surgery (44.9%). 119 pts (44.7%) received maintenance therapy and majority with bevacizumab alone (78.9%). After a median follow-up of 51.7months, the median PFS (mPFS) was 28.6months [95 CI: 26.2–32.4]. Patients exhibited higher mPFS in case of FIGO stage III than stage IV (32.4 months and 25.4 months, respectively), or BRCA2 mutation than BRCA1 (33.3 months and 27.7 months, respectively). Although populations were non comparable, mPFS was close between patients treated with or without maintenance (28.3 and 29.5 months, respectively). Median PFS2 were 51.4 months and 50.4 months, respectively. Estimated 5-year OS for the whole population was 69.2% [95 CI: 65.3–73.0]. Conclusion This large ESME OC cohort described clinical features and real-life survival outcomes among pts with newly diagnosed advanced BRCA-mutated HGEOC treated in specialized centres. Disclosure This work was supported by UNICANCER. The ESME OC database is supported by an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analyses and publications are totally managed by R&D UNICANCER independently of the industrial consortium. All the authors declare that there is no conflict of interest regarding the publication of this article.

Background. Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. Methods. MYCA was a multicenter 2-step phase lb-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m(2) during phase lb step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. Results. From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6-11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. Conclusion. Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments. (C) 2018 Elsevier Inc. All rights reserved.