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The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS).This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/mBetween 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin.Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.

Background BRAF mutations occurring in 1%–5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSe vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. Patients and methods Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). Results Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%–54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8–6.8), and OS was 10 months (95% CI 6.8–15.7). The vemurafenib safety profile was consistent with previous publications. Conclusion Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. Trial registration ClinicalTrials.gov identifier: NCT02304809.

Background Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. Patients and methods This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3weeks, as monotherapy or in combination with paclitaxel 80mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. Results No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000mg administered every 2weeks. Conclusions Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688)

Guidelines recommend that retroperitoneal sarcoma (RPS) be managed in a reference sarcoma center (RSC), but the benefit remains to be demonstrated. This study investigated the impact of initial surgery performed within the NetSarc network on overall survival (OS). NetSarc is a network of 26 RSCs with specialized multidisciplinary tumor boards (MDTs) that is funded by the French NCI. Since 2010, presentation to an MDT and second pathological review are mandatory for sarcoma patients, and data have been collected in a nationwide database. We extracted data for all patients who received surgery in or outside the network and who presented at a NetSarc center (NSC) for primary nonmetastatic RPS between 2010 and 2017. A total of 2945 patients were included: 1078 (36.6%) underwent the first surgery in an NSC, and 1867 (63.4%) in an out-of-network center. The median number of operations at an NSC during the study period was 23 (range: 3–209), and the corresponding median was 1 (range: 1–2) at out-of-network centers. The diagnostic procedures followed significantly more clinical practice guidelines within NetSarc, where there were significantly more first R0 resections [452 (41.9%) vs. 230 (12.3%)]. The OS was significantly superior for patients treated within NetSarc, with a 2-year OS of 87% vs. 70% (p

Background In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. Patients and methods This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. Results Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR) = 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P = 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR = 0.71, 95% CI (0.57; 0.89), P = 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR = 0.88, 95% CI (0.65; 1.21), P = 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. Conclusions With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

Leiomyosarcoma (LMS) is an aggressive smooth muscle cancer with few therapeutic options. LMSs show a high level of genomic instability (GI) and the mechanisms underlying their oncogenic processes are poorly understood. While the level of GI influences treatment efficacy and resistance, an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP “hotspotness” magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (Transcription-Associated Chromosomal instability index (iTRAC) and iRACIN (Replication-Associated Chromosomal INstability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in LMS and that they may be combined to form a new classifier called MAGIC (Mixed transcription-and replication-Associated Genomic Instability Classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers.

© 2020 The Author(s)., Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions., GDD was supported in part by the Ludwig Center at Harvard; the Dr Miriam and Sheldon G. Adelson Medical Research Foundation; and the Pan Mass Challenge (no grant numbers). IMS is supported by the National Institutes of Health/National Cancer Institute (grant number K08 CA241085). JYB was supported by NetSARC (INCA & DGOS) and RREPS (INCA & DGOS), RESOS (INCA & DGOS), EURACAN (EC 739521), LYRICAN (INCA-DGOS-INSERM 12563), LabEx DEvweCAN (ANR-10-LABX-0061), Institut Convergence PLASCAN (17-CONV-0002), RHU4 DEPGYN (ANR-18-RHUS-0009).

Background While the anti-PDGFRA antibody olaratumab failed to confirm an impact on survival in unselected advanced soft tissue sarcoma (STS) patients, the level of expression and the prognosis of platelet-derived growth factor (PDGF) receptors and ligands in STS remain unclear. Patients and methods We analyzed PDGF ligands and receptors' expression levels in a series of 255 patients with different histologies of STS [gastrointestinal stromal tumor (GIST), myxoid liposarcoma (MLPS), sarcoma with complex genomics, synovial sarcoma (SyS)] with Agilent single-color micro-arrays. We explored expression levels as prognostic values in univariate and multivariate analysis using R software (version 3.4.2). Results Complex patterns of correlation of expression between ligands and receptors were observed for each histotype. PDGFA levels were highest in SyS and lowest in MLPS (P < 4 × 10−9), PDGFB and C levels were lower in GIST (P < 2 × 10−15 and P < 3 × 10−9) while PDGFD expression was similar across histological subtypes. PDGF receptor (PDGFR) A expression was lowest in MLPS (P < 0.002), whereas PDGFRB and L expressions were lowest in GIST and SyS (P < 0.0004). Interestingly, high PDGFA expression levels were associated with higher risk of metastasis (P = 0.006), whereas PDGFD levels above average were associated with a reduced risk of metastasis (P = 0.01) in univariate and multivariate analysis. Conclusions The expression of PDGF ligands and receptors varies across sarcoma histological subtypes. PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse., Highlights • The expression of PDGF ligands and receptors substantially varies across sarcoma histological subtypes. • PDGFA and D expression levels independently and inversely correlate with the risk of metastatic relapse. • The differential expression of ligands might be used as biomarker of efficacy for PDGFRα antibodies in STS.

ObjectiveHigh grade endometrial stromal sarcoma and undifferentiated uterine sarcomas are associated with a very poor prognosis. Although large surgical resection is the standard of care, the optimal adjuvant strategy remains unclear.MethodsA retrospective analysis of patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas (stages I–III) treated in 10 French Sarcoma Group centers was conducted.Results39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas treated from 2008 to 2016 were included. 24/39 patients (61.5%) were stage I at diagnosis. 38/39 patients underwent surgical resection, with total hysterectomy and bilateral oophorectomy completed in 26/38 (68%). Surgeries were mostly resection complete (R0, 23/38, 60%) and microscopically incomplete resection (R1, 6/38, 16%). 22 patients (58%) underwent postoperative radiotherapy (including brachytherapy in 11 cases), and 11 (29%) underwent adjuvant chemotherapy. After a median follow-up of 33 months (range 2.6–112), 17/39 patients were alive and 21/39 (54%) had relapsed (9 local relapses and 16 metastases). The 3 year and 5 year overall survival rates were 49.8% and 31.1%, respectively, and 3 year and 5 year disease free survival rates were 42.7% and 16.0%, respectively. Median overall survival and disease free survival were 32.7 (95% CI 16.3–49.1) and 23 (4.4–41.6) months, respectively. Medians were, respectively, 46.7 months and 39.0 months among those who underwent adjuvant radiotherapy and 41.0 months and 10.3 months for those who underwent adjuvant chemotherapy. In multivariate analysis, adjuvant radiotherapy was an independent prognostic factor for overall survival (P=0.012) and disease free survival (P=0.036). Chemotherapy, International Federation of Gynecology and Obstetrics I–II stages, and Eastern Cooperative Oncology Group-performance status 0 correlated with improved overall survival (P=0.034, P=0.002, P=0.006), and absence of vascular invasion (P=0.014) was associated with better disease free survival.ConclusionsThe standard treatment of primary localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas is total hysterectomy and bilateral oophorectomy. The current study shows that adjuvant radiotherapy and adjuvant chemotherapy appear to improve overall survival. A prospective large study is warranted to validate this therapeutic management.

International audience; Both authors contributed equally as senior authors. Background: Soft-tissue sarcomas (STSs) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. We hypothesized that the Genomic Grade Index (GGI), a 108-gene signature previously developed in early-stage breast cancer, might improve the prognostic assessment of patients with early-stage STS. Patients and methods: We collected gene expression and clinicopathological data of 678 operated STS, and searched for correlations between the GGI-based classification and clinicopathological variables, including the metastasis-free survival (MFS). Results: Based on GGI, 275 samples (41%) were classified as 'GGI-low' and 403 (59%) as 'GGI-high'. The 'GGI-high' class was more associated with poor-prognosis features than the 'GGI-low' class: pathological grade 3 (P ¼ 9.50E–11), undifferentiated sarcomas and leiomyosarcomas (P < 1.00E–06), location in extremities (P < 1.00E–06), and complex genetic profile (P ¼ 2.1E–20). The 5-year MFS was 53% (95%CI 47–59) in the 'GGI-high' class versus 78% (95%CI 72–85) in the 'GGI-low' class (P ¼ 3.02E–11), with a corresponding hazard ratio for metastatic relapse equal to 2.92 (95%CI 2.10–4.07; P ¼ 2.23E–10). In multivariate analysis, the GGI-based classification remained significant, whereas the pathological grade did not. In fact, the GGI-based classification stratified the patients with pathological grades 1 and 2 and those with pathological grade 3 in two classes with different 5-year MFS. Comparison of the GGI and CINSARC multigene signatures revealed similar correlations with clinicopathological variables, which were, however, stronger with GGI than with CINSARC, a strong concordance (71%) in terms of low-risk or high-risk classifications, and independent prognostic value for MFS in multivariate analysis, suggesting complementary prognostic information. Conclusion: GGI refines the prediction of MFS in operated STS and might improve the tailoring of adjuvant chemotherapy. Further clinical validation is warranted in larger retrospective, then prospective series, as well as the functional validation of relevant genes that could provide new therapeutic targets.

Item does not contain fulltext AIMS: Epithelioid sarcoma is a soft tissue sarcoma associated with a high rate of local recurrence after wide resection and high incidence of distant metastasis. Little is known about the clinical course and response to systemic treatments in epithelioid sarcoma patients. We carried out a retrospective analysis of clinical data from epithelioid sarcoma patients to provide a reference for the design of future epithelioid sarcoma-specific studies. PATIENTS AND METHODS: Data from patients with epithelioid sarcoma entered in prospective multi-sarcoma phase II/III trials were pooled: EORTC trial 62012 (doxorubicin versus doxorubicin/ifosfamide), 62043 (pazopanib), 62072 (pazopanib versus placebo) and 62091 (doxorubicin versus trabectedin). Patients had either a local or a centrally confirmed diagnosis of epithelioid sarcoma, had inoperable/metastatic disease at study entry and were eligible for the according trial. Response was assessed according to RECIST 1.1. Progression-free survival (PFS) and overall survival were calculated from date of entry. RESULTS: Among 976 patients with advanced sarcomas, 27 epithelioid sarcoma patients (2.8%) were eligible for the analysis (17 men, median age at diagnosis 50 years, range 19-72). Eighteen (66.7%) received chemotherapy as first-line treatment (five doxorubicin, eight doxorubicin/ifosfamide, two pazopanib, three trabectedin) and nine (33.3%) received pazopanib as second line or later. The primary tumour was located in the lower extremity (n = 8; 29.6%), upper extremity (n = 5; 18.5%), retro/intra-abdominal (n = 4; 14.8%) and in other locations (n = 10; 37.0%). At entry, metastases were mainly found in lung (n = 17; 63%), lymph nodes (n = 9; 33.3%), bone (n = 8; 29.6%) and soft tissue (n = 7; 25.9%). The best response for first-line patients was four partial responses (22.2%), 10 stable disease (55.6%) and four progressive disease (22.2%). In subsequent lines, pazopanib achieved one partial response (11.1%), four stable disease (44.4%) and four progressive disease (44.4%). All patients but one progressed on treatment. The median PFS and overall survival were 3.8 (95% confidence interval 2.2-4.8) and 10.8 months (95% confidence interval 8.1-21.3), respectively. Five patients were still alive at the time of the according trial analysis. CONCLUSION: With all limitations of such a rare disease and small data set, objective response and survival outcomes are similar in epithelioid sarcoma to non-selected sarcoma populations. The clinical testing of novel systemic treatments for epithelioid sarcoma remains an unmet medical need and a high priority.

Background: Around 15% of adult GIST are wild type for KIT/PDGFRA mutations (KPWT), usually have SDH deficiencies, and are resistant to imatinib (IM). The underlying mechanisms include overexpression of HIF1α in SDH deficient-GIST, high IGFR signaling through MAPK, BRAF mutation or STAT3 activation. Regorafenib (RE), targeting these pathways, could be more active as upfront therapy in KPWT GIST. Methods: Patients (pts) >18, with advanced non pretreated KPWT GIST were eligible after central confirmation by next-generation sequencing (NGS). Eligible pts received RE at 160mg/d for 21/28d cycles. Primary end-point was disease control rate (DCR) at 12 weeks (RECIST 1.1 ) by central radiological assessment (CRA). Secondary objectives were PFS, OS, ORR (RECIST,Choi), safety and QoL. An amendment allowed previous IM (adjuvant). Statistical assumptions [H0 73% and H1 90% (α 0.1 and β 0.2)], defined a sample size of 20 pts. Results: From May 2016 to October 2020, 30pts with KPWT GIST (by Sanger) underwent central molecular screening. Among the 15 non-eligible pts, 8 harbored KIT exon 11 mutations, 3 exon 9 and 3 PDGFRA exon 18 by NGS. The remaining 16 (53.3%) molecularly eligible pts were enrolled and started RE except one pt due to COVID-19 pandemic. The trial was prematurely closed due to low recruitment, especially after COVID outbreak. Demographics and treatment details in the table. Based on CRA, 12w-DCR was 86.7%. With a median (m) FU of 26 (5-44) months (mo), 10/15 pts progressed, with a mPFS of 10.8 mo (95% CI 6.9-14.8). 6 mo, 9 mo and 12 mo PFS rates were 65%, 48% and 29% respectively. 2 pts were PD-free at 25 and 43 mo from start of RE. 6/15 pts died, with a mOS of 33.5 mo (95% CI NR). [Formula presented] Conclusions: The study results approach the prespecified activity threshold. The low recruitment rate could have affected this attainment. Other analysis of secondary endpoints are ongoing. The high percentage of overlooked mutant GIST by Sanger raises the need of NGS in presumed KPWT GIST. Clinical trial identification: NCT02638766. Legal entity responsible for the study: Spanish Group for Research on Sarcoma (GEIS). Funding: Bayer. Disclosure: J. Martin Broto: Financial Interests, Personal, Expert Testimony, Honoraria: Lilly;Financial Interests, Personal, Expert Testimony, Honoraria: PharmaMar;Financial Interests, Personal, Expert Testimony, Honoraria: Eisai;Financial Interests, Personal, Expert Testimony, Honoraria: Bayer;Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Institutional, Invited Speaker: PharmaMar;Financial Interests, Institutional, Invited Speaker: Eisai;Financial Interests, Institutional, Invited Speaker: Novartis;Financial Interests, Institutional, Invited Speaker: IMMIX Biopharma;Financial Interests, Institutional, Invited Speaker: Lixte;Financial Interests, Institutional, Invited Speaker: Karyopharm;Financial Interests, Institutional, Invited Speaker: Bayer;Financial Interests, Institutional, Invited Speaker: Celgene;Financial Interests, Institutional, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker: BMS;Financial Interests, Institutional, Invited Speaker: Blueprint;Financial Interests, Institutional, Invited Speaker: Deciphera;Financial Interests, Institutional, Invited Speaker: Nektar;Financial Interests, Institutional, Invited Speaker: FORMA;Financial Interests, Institutional, Invited Speaker: Amgen;Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo;Financial Interests, Institutional, Invited Speaker: Lilly;Financial Interests, Institutional, Invited Speaker: AROG;Financial Interests, Institutional, Invited Speaker: Adaptimmune;Financial Interests, Institutional, Invited Speaker: GSK. N. Hindi: Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Personal, Advisory Board: PharmaMar;Financial Interests, Institutional, Research Grant: PharmaMar;Financial Interests, Institutional, Sponsor/Funding: PharmaMar;Financial Interests, Institutional, Research Grant: Nova tis;Financial Interests, Institutional, Research Grant: Eisai;Financial Interests, Institutional, Research Grant: Immix Bio;Financial Interests, Institutional, Sponsor/Funding: Bayer;Financial Interests, Institutional, Sponsor/Funding: Deciphera;Financial Interests, Institutional, Sponsor/Funding: Daychii;Financial Interests, Institutional, Sponsor/Funding: Blueprint;Financial Interests, Institutional, Sponsor/Funding: Adaptimmune;Financial Interests, Institutional, Sponsor/Funding: GSK;Financial Interests, Institutional, Sponsor/Funding: Karyopharm;Financial Interests, Institutional, Sponsor/Funding: Celgene;Financial Interests, Institutional, Sponsor/Funding: AROG. J. Lavernia: Financial Interests, Personal, Invited Speaker: PharmaMar;Financial Interests, Personal, Invited Speaker: BMS. C. Serrano: Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Institutional, Research Grant: Bayer. D. Moura: Financial Interests, Institutional, Research Grant: Novartis;Financial Interests, Institutional, Research Grant: Eisai;Financial Interests, Institutional, Research Grant: PharmaMar;Financial Interests, Institutional, Research Grant: Immix Bio. J. Blay: Financial Interests, Institutional, Research Grant: Bayer;Financial Interests, Personal, Invited Speaker: Bayer;Financial Interests, Institutional, Research Grant: Novartis;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Institutional, Research Grant: Deciphera;Financial Interests, Personal, Research Grant: Deciphera. E.R. Fumagalli: Financial Interests, Institutional, Research Grant: Bayer. All other authors have declared no conflicts of interest.

International audience; Soft tissue sarcomas are a group of rare and aggressive connective tissue neoplasms for which curative therapeutic opportunities are limited in advanced phase. Clinical trials assessing immunotherapy in these tumors have so far reported limited efficacy. The objective of this study is to provide a description of the immunologic landscape of sarcomas to guide the next clinical trials of immunotherapy in these diseases. The gene expression profile of 93 immune checkpoint (ICP) and membrane markers (MM) of immune cells was analyzed in a series of 253 soft tissue sarcoma (synovial sarcoma, myxoid liposarcoma, sarcoma with complex genomic and GIST) using Agilent Whole Human Genome Microarrays. The unsupervised hierarchical clustering of gene expression level was found able to properly group patients according to the histological subgroup of sarcoma, indicating that each sarcoma subgroup is associated with a specific immune signature defined by its gene expression pattern. Using the prognostic impact of CIBERSORT signature on metastatic-free survival in each subgroup, specific target could be proposed for each of the four groups: Treg through ICOS and GITR in GIST, M0 macrophages in all four sarcoma subtypes, OX40 in SS, CD40 in GIST and SS. The immune landscape of sarcoma was found to be as heterogeneous as the histotypes and molecular subtypes, but strongly correlated to the histotype. Histotype adapted immunotherapeutic approaches in each sarcoma subtypes must be considered in view of these results, consistently with the already reported specific response of histotypes of ICPs.

Survival of adolescents and young adults (AYA) with sarcoma is lower than in younger patients. The objective of this study was to describe the regional healthcare circuits, the differences in the management between adult, paediatric and mixed units and to assess the prognostic impact of compliance with clinical practice guidelines (CPGs) on overall survival (OS) and on relapse free survival (RFS).Retrospective analysis of the management and long term follow-up of all 13-25 year old patients with a sarcoma diagnosed in the Rhône-Alpes area between 2000 and 2005.140 patients satisfied inclusion criteria and were selected. The majority of 13-25 year old patients were treated in paediatric units. Joint management resulted in a higher rate of discussion in multidisciplinary tumour board, inclusion in clinical trials, and fertility preservation. Non-compliance with guidelines was observed in 65% of cases. Overall compliance was not reported to correlate to survival. Compliance of radiotherapy with CPG's seemed associated with a better prognosis for OS (HR = 0.20, 95% CI = [0.10-0.40]; p 0.0001) and RFS (HR = 0.18, 95% CI = [0.09-0.37; p 0.0001) as well as compliance of surgery for OS (HR = 0.43, 95% CI = [0.23-0.81]; p = 0.01). Multivariate Cox regression analysis revealed other independent predictors of OS like age at diagnosis, stage and histological subtype.Management of AYA in joint units seems to improve the quality of care. Compliance of surgery and radiotherapy with CGP's seems to improve survival.

Purpose There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. Patients and methods This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. Results Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7–40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1–negative tumour. Conclusion Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. Trial registration This study is registered with ClinicalTrials.gov, number NCT02406781 .

Despite being associated with a very poor prognosis, long-term survivors across all series of Desmoplastic Small Round Cell Tumor (DSRCT) have been reported.To analyze patients 'characteristics associated with a prolonged survival after DSRCT diagnosis.All consecutive patients treated for DSRCT in nine French expert centers between 1991 and 2018 were retrospectively analyzed. Patients with a follow-up of less than 2 years were excluded and cure defined as being disease-free at least 5 years.100 pts were identified (median age 25 years, 89% male). 27 had distant metastases at diagnosis and 80 pts underwent upfront chemotherapy (CT). 71 pts were operated, 20 pts without prior CT). Surgery was macroscopically complete (CC0/1) in 50 pts. Hyperthermic intraperitoneal Chemotherapy (HIPEC) was administered during surgery in 15 pts 54 pts had postoperative CT and 26 pts had postoperative whole abdomino-pelvic RT (WAP-RT). After a median follow-up of 103 months (range 23-311), the median overall survival (OS) was 25 months. The 1- year, 3-year and 5-year OS rates were 90%, 35% and 4% respectively. 5 patients were considered cured after a median disease-free interval of 100 months (range 22-139). Predictive factors of cure were female sex (HR = 0.49, p = 0.014), median PCI12 (HR = 0.32, p = 0.0004), MD Anderson stage I (HR = 0.25, p 0.0001), CC0/1 (HR = 0.34, p 0.0001), and WAP-RT (HR = 0.36, p = 0.00013). HIPEC did not statistically improve survival.Cure in DSRCT is possible in 5% of patients and is best achieved combining systemic chemotherapy, complete cytoreductive surgery and WAP-RT. Despite aggressive treatment, recurrence is common and targeted therapies are urgently needed.

Item does not contain fulltext Background: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. Patients and methods: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. Results: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. Conclusion: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Item does not contain fulltext BACKGROUND: Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas. PATIENTS AND METHODS: Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared. RESULTS: Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having >/=2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352). CONCLUSIONS: Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Background The EDIFICE surveys have been conducted since 2005 to provide a better understanding of the participation of the French population in cancer screening programs. The breast cancer (BC) screening program is nowadays widely implemented throughout the target female population: women aged 50-74 years are invited for a mammogram once every two years. We analyzed the behavior of women over time (between 2005 and 2016) regarding BC screening according to age-group, socioprofessional categories (SPC) and social vulnerability. Methods The fifth nationwide observational survey, EDIFICE 5, was conducted by phone interviews using the quota method. A representative sample of 1299 subjects aged 50-74 years with no history of cancer was interviewed between November 22 and December 7, 2016. Interviewees (women aged 50-74 yrs; N=657) were asked about their uptake of BC screening, and the date of the last examination to determine the follow-up rate. Demographic data on social characteristics and SPC were also collected to determine the level of social vulnerability (validated EPICES score). Results Compliance with BC screening (a mammogram within the past 2 years) decreased significantly from 81% in 2014 to 75% in 2016 (P=0.02). From 2014, a significant impact of age was observed (P=0.02 in 2014 and 2016). In 2016, and for the first time, a significant and disturbing decrease in follow-up rate was recorded among younger women (age 50-54 yrs: 88% in 2014 vs 74% in 2016, P=0.01). SPC had no effect on compliance with screening. However, since 2008, fluctuations have been observed among unemployed individuals (U), with a significant decline in compliance in 2016 (U: 81% in 2014 vs 73% in 2016, P=0.03). In 2016, social vulnerability was seen as a factor that negatively impacts on compliance with BC screening (P≤0.01), but not in 2011 or 2014. We also observed a significant overall decrease in 2016 among both vulnerable (76% in 2014 vs 65% in 2016; P=0.04) and non-vulnerable populations (85% in 2014 vs 79% in 2016, P=0.04), highlighting a general loss of confidence. Conclusion For the first time since 2005, compliance with BC screening dropped significantly in France in 2016. A significant overall decline was observed regardless of social vulnerability status. Disturbing significant decreases were observed among the younger age-group (women aged 50-54 yrs) of the target population of the organized program, and among unemployed women. Although organized programs have been shown to ensure equitable access to cancer screening, this achievement remains precarious and requires regular monitoring. Citation Format: Morère JF, Eisinger F, Blay J-Y, Greillier L, Brignoli-Guibaudet L, Lhomel C, Cortot AB, Couraud S, Viguier J. Decline in compliance to breast cancer screening in France: Results of the 5th EDIFICE survey [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-08-07.

Tenosynovial giant cell tumors (TGCT), are rare colony stimulating factor-1(CSF-1)-driven proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks the CSF-1 receptor. This study investigated the long term effects of IM in TGCT. We conducted an international multi-institutional retrospective study to assess the activity of IM: data was collected anonymously from individual patients with locally advanced, recurrent or metastatic TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States were identified. Four patients with metastatic TGCT progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable patients achieved complete response (CR) or partial response (PR). One- and five-year progression-free survival rates were 71% and 48%, respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1–80) months. Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%), mostly grade 1–2 (89%). Five patients experienced grade 3–4 toxicities. This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high rates of treatment interruption and additional treatments.