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BACKGROUND: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. METHODS: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. RESULTS: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. CONCLUSIONS: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
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Anilidas/farmacologia , Leiomiossarcoma/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Proteínas Sanguíneas/genética , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/genética , Crizotinibe , Intervalo Livre de Doença , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Expressão Gênica , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Leiomiossarcoma/genética , Leiomiossarcoma/secundário , Masculino , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Proteína S , Ensaio Tumoral de Célula-Tronco , Adulto Jovem , Receptor Tirosina Quinase AxlRESUMO
Therapeutic options for synovial sarcoma (SyS) have not evolved for several decades and the efficacy of second-line treatments is very limited. The expression of a large family of proteins known as cancer testis antigens (CTAs) in SyS has spurred the development of targeted T-cell therapies currently in clinical trials, such as those aimed at melanoma-associated antigen (MAGE)-A4 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1), which have shown promising clinical efficacy. Extensive knowledge of the prevalence of expression and coexpression of CTAs is critical to design T-cell therapies with optimal coverage of the patient population. We analyzed the expression of CTAs of the MAGE-A family as well as NY-ESO-1 and preferentially expressed antigen in melanoma (PRAME) by RNA sequencing in a large cohort of 133 SyS samples from patients registered in the French sarcoma database (NETSARC+). Among MAGE-As, MAGE-A4 had the highest prevalence (65%), followed by MAGE-A10 (15%) and MAGE-A9 (13%). Almost all samples (92%) expressing any of the MAGE-As also expressed MAGE-A4. NY-ESO-1 was expressed in 65% of samples, with a large but incomplete overlap with MAGE-A4, whereas PRAME was present in 121 (91%) samples. Complementary immunohistochemical analyses were used to establish the positive correlation between RNA and protein expression for MAGE-A4 and NY-ESO-1. These data inform the strategy for optimal coverage of the SyS patient population with T-cell therapies, offering patients with SyS new options for single or combined second lines of treatment.
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BACKGROUND AND AIMS: Alveolar soft part sarcoma (ASPS) is an ultra-rare chemo-resistant sarcoma in children, occurring preferentially in young adults. We aimed to describe and compare its clinical presentation and behaviour in children and young adults to determine whether the same therapeutic strategy should be addressed for both populations. METHODS: National retrospective multicentre study of children (0-18 years) vs. young adults (19-30 years) included in the "ConticaBase" sarcoma database, treated for ASPS between 2010 and 2019 with pathology reviewed via the NETSARC + network. RESULTS: Overall, 45 patients were identified, 19 children (42%) and 26 young adults (58%). All ASPS diagnoses were confirmed with TFE3 rearrangement by immunohistochemistry or FISH. All clinical characteristics were balanced between both populations with frequent metastases at diagnosis (8/19 vs. 10/26). The therapeutic strategy was based on surgery (17/19 vs. 21/26), radiotherapy (8/19 vs. 12/26) ± systemic treatment (8/19 vs. 9/26). In patients with initially localized disease, metastatic relapse occurred only in adults (8/16), whereas metastatic progression was present in both metastatic groups (5/8 vs. 8/10). After a median follow-up of 5.2 years (range, 0.2-12.2), 5-year EFS was 74% [95%CI, 56-96] vs. 47% [30-74] (p = 0.071) respectively, and 5-year OS was 95% [85-100] vs. 85% [70-100] (p = 0.84). For localized tumours, 5-year MFS was 100% [100-100] vs. 60% [39-91] (p = 0.005). The 5-year OS of all patients with metastasis at diagnosis was 80.2% (62.2%-100%). CONCLUSIONS: ASPS appears to have the overall same clinical characteristics, but a more aggressive behaviour in young adults than in children. However, despite frequent metastases at diagnosis, long-term survival is high in both groups. Overall, the same therapeutic strategies may be considered for both populations.
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Sarcoma Alveolar de Partes Moles , Humanos , Sarcoma Alveolar de Partes Moles/terapia , Sarcoma Alveolar de Partes Moles/patologia , Adolescente , Masculino , Feminino , Adulto , Criança , Adulto Jovem , Estudos Retrospectivos , Pré-Escolar , França/epidemiologia , Lactente , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Recém-NascidoRESUMO
Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors characterized by KIT or PDGFRA mutations. Over three decades, significant changes in drug discovery and loco-regional (LR) procedures have impacted treatment strategies. We assessed the evolution of treatment strategies for metastatic GIST patients treated in the three national coordinating centers of NetSarc, the French network of sarcoma referral centers endorsed by the National Institute of Cancers, from 1990 to 2018. The primary objective was to describe the clinical and biological profiles as well as the treatment modalities of patients with metastatic GIST in a real-life setting, including access to clinical trials and LR procedures in the metastatic setting. Secondary objectives were to assess (1) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment, (2) patients' overall survival (OS), (3) evolution of patients' treatment modalities and OS according to treatment access: <2002 (pre-imatinib approval), 2002-2006 (pre-sunitinib approval), 2006-2014 (pre-regorafenib approval), post 2014, and (4) the impact of clinical trials and LR procedures on TNT and OS in the metastatic setting. 1038 patients with a diagnosis of GIST made in one of the three participating centers between 1990 and 2018 were included in the national prospective database. Among them, 492 patients presented metastasis, either synchronous or metachronous. The median number of therapy lines in the metastatic setting was 3 (range 0-15). More than half of the patients (55%) participated in a clinical trial during the course of their metastatic disease and half (51%) underwent additional LR procedures on metastatic sites. The median OS in the metastatic setting was 83.4 months (95%CI [72.7; 97.9]). The median TNT was 26.7 months (95%CI [23.4; 32.3]) in first-line, 10.2 months (95%CI [8.6; 11.8]) in second line, 6.7 months (95%CI [5.3; 8.5]) in third line, and 5.5 months (95%CI [4.3; 6.7]) in fourth line, respectively. There was no statistical difference in OS in the metastatic setting between the four therapeutic periods (log rank, p = 0.18). In multivariate analysis, age, AFIP Miettinen classification, mutational status, surgery of the primary tumor, participation in a clinical trial in the first line and LR procedure to metastatic sites were associated with longer TNT in the first line, whereas age, mitotic index, mutational status, surgery of the primary tumor and LR procedure to metastatic sites were associated with longer OS. This real-life study advocates for early reference of metastatic GIST patients to expert centers to orchestrate the best access to future innovative clinical trials together with LR strategies and further improve GIST patients' survival.
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BACKGROUND: CIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like" undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database. METHODS: Pediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival. RESULTS: Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission. CONCLUSION: FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.
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Neoplasias Ósseas , Sarcoma de Ewing , Sarcoma de Células Pequenas , Sarcoma , Neoplasias Cutâneas , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Feminino , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Sarcoma de Ewing/diagnóstico , Estudos Retrospectivos , Sarcoma de Células Pequenas/diagnóstico , Sarcoma de Células Pequenas/patologia , Sarcoma/epidemiologia , Sarcoma/genética , Sarcoma/terapia , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/terapia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/terapia , Neoplasias de Tecidos Moles/diagnóstico , Morte , Proteínas de Fusão Oncogênica , Biomarcadores TumoraisRESUMO
Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.
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BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
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Sarcoma/epidemiologia , Sarcoma/patologia , Adolescente , Adulto , Idoso , Feminino , França/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Sarcoma/classificação , Sarcoma/diagnóstico , Organização Mundial da Saúde , Adulto JovemRESUMO
Rare cancer patients face lower survival and experience delays in diagnosis and therapeutic mismanagement. Considering the specificities of rare cancers, referral networks have been implemented in France to improve the management and survival of patients. The IGéAS research program aims to assess the networks' ability to reduce inequalities. Data analysis of the IGéAS cohort (n = 20,590, sarcoma diagnosed between 2011 and 2014) by gathering medical data and geographical index will identify risk factors associated with the belated access to expertise or with no access to expertise. Intermediate results show that referral networks give sarcoma patients access to sarcoma expertise despite the remoteness of some of them. Regional expert centers mostly receive requests from within their area while national referral centers receive requests from the whole country. Delays in the access to expertise may be reduced by making outside practitioners more sensitive to the issues of rare cancers. The perception and involvement of outside practitioners in this device will be assessed using a qualitative survey. All the results are discussed and will contribute to design guidelines to improve early access to expertise and reduce inequalities. Results of the IGéAS research program may contribute to the assessment of referral sarcoma networks and provide some useful lessons to improve cancer care management.