ABSTRACT Metastatic Ewing sarcoma (MES) has a poor prognosis. This multicenter observational study provides real‐world data on treatment patterns of patients with MES in France. Treatment characteristics, outcomes such as time to next treatment (TTNT) and overall survival (OS), and prognostic factors of patients aged ≥ 12 years treated for a MES in 11 French reference network centers were retrieved from our national database. From 2008 to 2018, 156 patients with MES were included: 82 were metastatic at diagnosis (upfront metastatic cohort), 74 had developed secondary metastases after treatment of a localized disease (metastatic relapse cohort). 94% of patients received systemic treatment, with a median of three lines (1–11), 61% had at least one loco‐regional procedure and 42% of patients participated in a clinical trial in the metastatic setting. Median OS from metastatic diagnosis was 20.3 months [95% CI 14.0; 27.7] in the metastatic relapse cohort and 31.4 months [95% CI 26.5; 42.5] in the upfront metastatic cohort (p = 0.02). Median TTNT in first metastatic line was 16.8 months [95% CI 12.9; 21.3] in the upfront metastatic cohort and 7.4 months [95% CI 5.0; 11.1] in the metastatic relapse cohort, 5.8 months [95% CI 3.6; 7.3] in 2nd line and 3.8 months [95% CI 2.8; 5.7] in 3rd line, without significant difference between cohorts and treatment regimens. Patients with upfront MES have a longer OS than patients with relapsing disease, mainly due to first metastatic line dose‐dense polychemotherapy and loco‐regional procedures in selected patients. Main regimens used at relapse are associated with the same range of benefit and survival, while TKIs such as regorafenib or cabozantinib have modest activity. Inclusion in clinical trials should be prioritized.

OBJECTIVE:The efficacy of adjuvant chemotherapy (AC) in improving survival for patients with sarcoma is debated. We performed a cost-effectiveness analysis (CEA) comparing AC vs. no AC for non-metastatic sarcoma based on the nationwide retrospective study DEEPSARC. METHODS:The CEA was carried out over a 1-, 3-, and five-year horizon, using data from the French NETSARC+ database linked to the French national health data system (SNDS).There was no age limit and no specific histological type selection in the reference case analysis. Costs (expressed in 2021 EUR) were provided by the SNDS from the French national health insurance perspective. Incremental cost effectiveness ratios (ICER) were expressed in cost per life-year gained (LYG). Propensity score analysis with 1:1 matching was undertaken. Sensitivity and subgroup analyses were performed. RESULTS:Of the 33,548 patients from the French NETSARC+ database, 24,539 were linked to the SNDS. A total of 14,808 patients diagnosed between 2012 and 2017 were included in the reference case analysis with 2,784 patients after propensity score matching. Mean costs (SD) [95% CI] differences per patient between AC and no AC were €12,826 (36,758) [10,883-14,719], €15,706 (49,849) [13,330-18,383], and €16,841 (56,060) [13,590-19,657] at 1, 3, and 5 years, respectively. Mean overall survival differences per patient (in years) were 0.0066 (0.1685) [-0.0021 to 0.0157], -0.0728 (0.9336) [-0.1237 to -0.0229], and -0.1204 (1.3595) [-0.1926 to -0.0475] at 1, 3, and 5 years, respectively. ICER was €1,934,511 [-11,767,351-15,829,959] per LYG at 1 year. AC lagged behind at 3 and 5 years. CONCLUSIONS:In the reference case analysis, AC outperformed its use in terms of outcomes at 1 year, but a high level of willingness to pay would be required for AC to be cost-effective. At 3 and 5 years, AC was deemed to be not cost-effective for patients with non-metastatic sarcoma.

The DeFi trial revealed a significant improvement in progression-free survival (PFS) with nirogacestat in patients with desmoid tumors. The DeNi study reports outcomes of patients treated with nirogacestat through the French compassionate use program. DeNi is a retrospective, real-world study. Outcomes included objective response, pain improvement, 1-year PFS, and toxicity. Between February and June 2024, 55 patients with desmoid tumors were included (37 women). Data were updated until November 2025. The median age was 38.6 years (range: 18.0-66.7). The median number of previous therapies was 2, including local therapies. The median follow-up was 21.4 months [95% CI: 19.5; 25.6]. The estimated median duration of nirogacestat treatment was 16 months. Partial response and stable disease were observed in 33 (60%) and 17 patients (31%), respectively. The 1-year PFS rate was 76.2%, and 77.0% of patients remained without treatment change at 1 year, including patients with dose reductions. Of the 49 patients with baseline pain, 38 (78%) experienced pain improvement under nirogacestat; 35 (71%) reduced or discontinued analgesics. The most frequent side effects (all grades) were diarrhea (53%), fatigue (47%), and rash (29%). Thirteen patients (24%) required dose reduction: 11 for digestive adverse events (85%), 1 for mucositis, and 1 for fatigue with hypertension. The DeNi study confirms the clinical benefits of nirogacestat in patients with desmoid tumors, with improvements in pain and tumor shrinkage observed in 60% of patients and PFS consistent with that reported in the phase III DeFi trial.

BACKGROUND:Alveolar soft part sarcoma (ASPS) is an ultra-rare sarcoma with limited chemotherapy sensitivity affecting mostly young patients. Tyrosine kinase inhibitors (TKIs) and immunotherapy are therapeutic advances with promising results in this disease. The aim of this study was to describe the characteristics, management and survival of patients with ASPS in France. PATIENTS AND METHODS:The French NETSARC+ database was screened for all adult patients with ASPS managed in French sarcoma centers between 2010 and 2023. RESULTS:Sixty-four patients from 18 centers were analyzed. The 5-year overall survival (OS) of the entire cohort was 87.3 % (95 % CI, 75.0-93.8 %). Fifty-six percent of patients had localized tumors at diagnosis; all were treated surgically, and 47 % received perioperative radiotherapy. With a median follow-up of 91 months, their 5-year OS was 96.3 % (95 % CI, 76.5-99.5 %). Half of the patients experienced metastatic recurrence with a median metastasis-free survival of 87.9 months (95 % CI, 29.6-NE). In patients with metastases, the first-line systemic treatment yielded an overall response rate of 7 %, 26 %, and 40 % for chemotherapy, TKIs, and immunotherapy, respectively. The 5-year OS after metastasis diagnosis was 67.7 % (95 % CI: 50.5-80.0 %). CONCLUSION:Our cohort reinforces existing data on clinical characteristics and demonstrated prolonged survival in both localized and metastatic stages. Among systemic treatments, immunotherapy achieved the highest response rates. We confirmed that ASPS may follow an indolent course in some cases and highlighted recent advances in its management, driven by standardized local treatments in reference centers and innovative systemic therapies.

Perivascular epithelioid cell neoplasms (PEComas) are ultra-rare mesenchymal tumors lacking a molecular classification to guide therapy. Here we perform comprehensive multi-omic profiling of an unselected PEComa cohort. We identify frequent MITF rearrangements involving actin gene partners (ACTA2, ACTG1 and ACTB). Anatomical stratification reveals cyclin-dependent kinase module mutations in gynecologic tumors, whereas soft tissue, gastrointestinal, and pelvic tumors lacked mTOR pathway alterations but are enriched for TFE3/MITF rearrangements. Transcriptomic analysis defines four subtypes with distinct lineage programs-melanocytic, mesenchymal, or adipogenic-as well as unique mutational patterns and clinical behaviors. Notably, an aggressive stem-like subtype enriched for TP53/RB1 mutations exhibits high proliferation, activation of embryonic and Hedgehog signaling, immune infiltration, and resistance to mTOR inhibitors, but potential responsiveness to immunotherapy. Single-nucleus RNA sequencing reveals intra-tumoral heterogeneity within this subtype, including divergent inflammatory states. Together, these findings establish a molecular classification framework and identify actionable vulnerabilities in PEComa.

Background:Whether adjuvant chemotherapy (AC) improves overall survival (OS) after complete resection in localized soft tissue sarcoma (STS) remains unproven and optional in guidelines. We measured OS in patients with operated non-metastatic STS treated with or without AC in the nationwide exhaustive NETSARC+ registry. Methods:The DEEPSARC project linked the NETSARC+ registry and the French nationwide health data system (SNDS) into a retrospective cohort. Adults with non-metastatic, undergoing primary surgical resection between 2012 and 2017 were included, excluding those with incomplete linkage data or prior neoadjuvant chemotherapy. We analysed the entire series of 8331 patients with successful linkage and a complete-case subset of 4296 patients. Survival with or without AC were compared using crude and multivariate Cox proportional hazards regression models, including adjustment for confounders and inverse probability of treatment weighting (IPTW). Sensitivity analyses and subgroups analysis in high-risk patients were performed. Findings:In the complete-case series, the commonest histotypes were liposarcoma (30%), undifferentiated pleomorphic sarcoma (23%) and leiomyosarcoma (17%). Overall, 389 (9.1%) patients received AC and, compared with those not receiving AC, had fewer comorbidities and presented more high-risk tumour features. With 5.8 years median follow-up, 5-yr OS was 61% (95%CI: 60-63) in the entire series, and 64% (95%CI: 63-66) in the complete-case analysis. 5-yr OS was inferior in patients receiving AC, both in the entire series (50% [47%-54%] vs. 63% [61%-64%]) and in the complete-case analysis (53% [48-59%] vs. 65% [64-67%]). After adjustment (HR = 1.46 [1.12-1.93]) or IPTW (HR = 1.56 [1.17-2.08]), AC remained associated with inferior OS. Findings were consistent across sensitivity and subgroup analyses. Interpretation:In this real-world nationwide study, AC was not associated with superior OS, but rather with an inferior OS in patients operated of a localized STS and did not compensate for the adverse prognostic profile of treated patients. Future research should therefore focus on identifying predictive biomarkers in order to better identify patients who are likely to derive real benefit from systemic treatment. Funding:This work was supported by the Health Data Hub; the Institut National Du Cancer and the French Ministry of Health (Direction Générale de l'Offre de Soins, DGOS) for the NETSARC, RRePS and RESOS networks; the INTERSARC+ program; the Agence Nationale de la Recherche; the LYriCAN+ program; the Ligue Nationale contre le Cancer; the Ligue contre le Cancer (Comité de l'Ain); the Fondation ARC; and the European Reference Network for Rare Adult Solid Cancers.

AIM:Chordoma is an ultra-rare malignancy with no approved therapies. In this study, we analyzed individual patient-level data (IPD) for patients with chordoma reconstructed from previously completed clinical trials. Our primary objectives were to synthesize the historical objective response rate (ORR) and to generate a pooled Kaplan-Meier progression-free survival (PFS) curve. Our overarching goal is that these data will inform future trial design and interpretation of results. METHODS:A literature review was conducted to identify prospective chordoma systemic therapy clinical trials. Eligible studies were required to be prospective; to include locally advanced/metastatic conventional chordoma; to report a PFS Kaplan-Meier curve; and to assess PFS/ORR by RECIST (1.0/1.1). IPD were reconstructed from the PFS curves and data were synthesized to estimate the pooled PFS and ORR. RESULTS:Twelve studies met eligibility, contributing 328 patients (320 response evaluable). The combined ORR was 4.7% and median PFS was 10.8 months (95% CI 9, 12). Sensitivity analyses revealed no significant differences in PFS between studies partitioned by study-level variables. In "leave-one-out" analyses of each study alone versus pooled data, only everolimus/imatinib showed a significantly longer PFS (p = 0.0014), with a median PFS of 14.0 months (95% CI 11.5, NA) compared to 10.0 months (95% CI 8.3,11.2) for the remaining pooled cohort (estimated hazard ratio: 0.50 [95% CI 0.33, 0.77]). CONCLUSION:IPD from 12 trials were reconstructed and analyzed, consolidating outcomes for 328 trial-eligible patients with chordoma. The estimated overall response rate (ORR) is 4.7% and median PFS 10.8 months, providing a historical benchmark useful for future trial design. Notably, everolimus/imatinib was the only study treatment associated with a statistically significant improvement in PFS, which may warrant further investigation.

11533 Background: Real-life data on the impact of adjuvant treatment in GIST pts are limited. Methods: We conducted a retrospective study (Deepsarc) merging data from the NETSARC+ dataset of the French Sarcoma Group with the exhaustive health data from the national social security system (SNDS). Eligible pts were treated between January 1, 2012, and December 31, 2017 with localized GIST. The relation between overall survival (OS) and adjuvant therapy was studied univariate and multivariate, using different methods to address confounding factors. Results: A total of 2166 GIST pts were included, with a median age of 68.0 years (interquartile range (IQR): 58.0, 76.0), a sex ratio of 1.01. The two most common primary sites were gastric (1301, 60%) and small intestine (527, 24%). Median tumor size at diagnosis was 5.3 cm (IQR 3.6-8.1). Median mitotic count was 3.0 (IQR 1.0-5.0). According to Miettinen/AFIP classification, 331/1026 (32%) were high-risk, 192/1026 (19%) intermediate risk, and 503/1026 (49%) very low or low risk vs 490/912 (53%) high-risk, 193/912 (21%) intermediate risk, and 229/912 (25%) very low or low risk with Joensuu classification. From 2012 to 2017, the proportion of pts receiving adjuvant therapy remained remarkably stable at around one third of all GIST, with higher use in high-risk (70%; 231/331) than intermediate-risk (43%; 83/192) and low-risk pts (6%; 32/503). Pts receiving adjuvant therapy were younger (p<.001), with less comorbidities (p<.001), larger tumor (p<.001), higher mitotic count (p<.001), higher risk according to Miettinen/AFIP (p<0.001), or Joensuu (p<.001), higher rate of R1 resection (p=.019) and higher rate of tumor rupture (p=.001). Median follow-up was 5.0 years (4.8-5.2). Overall, the 5y OS rate was 81% [79-83%]. Regardless of risk, for the entire population, 5y OS rate of those receiving adjuvant therapy was 82% [79%-85%] and for those not receiving adjuvant therapy was 81% [78%-83%]. For both prognostic classifications, in univariate analysis, adjuvant therapy was associated with improved survival only for high-risk pts. Multivariate analysis propensity-score adjusted analyses for age, sex, social deprivation index, morbidity index, and tumor size (3 categories: ≤5/ 5-10/ >10 cm) highlights a benefit of adjuvant therapy for high-risk pts, according to both AFIP/Miettinen or Joensuu classifications (Table). No clear benefit was observed in intermediate-risk pts. Conclusion: This study confirms the benefit of adjuvant therapy for high-risk pts (according to AFIP/Miettinen or Joensuu), but not for other risk groups. Overall survival (risk of death) in high-risk GIST patients according to adjuvant therapy (reference = No adjuvant treatment), Deepsarc study (2012-2017), France. Risk classification N 1y HR* 95% CI** P -value Miettinen/AFIP 214 0.23 0.06 ; 0.92 0.017 Joensuu 312 0.49 0.24 ; 0.98 0.029 *HR = Hazard Ratio, **CI = Confidence Interval.

11514 Background: There is a growing rationale for combining immunotherapy and VEGF inhibitors in sarcoma. We report results of an open-label multicentre phase 2 study assessing the anti-PD-1 antibody pembrolizumab (pembro) in combination with cabozantinib (cabo) in patients (pts) with advanced undifferenciated pleomorphic sarcoma (UPS). Methods: Pts aged > 18 years old, with advanced or metastatic UPS who received no more than three previous lines and no previous history of exposure to anti PD1/L1 or cabozantinib were included to receive cabo 40 mg daily and pembro 200 mg IV q21 days. The primary endpoint was 6-month non-progression (NP) per RECIST v1.1. This trial used a 2-stage optimal Simon’s design needing 8 NP at 6 months observed among 29 evaluable pts to be considered positive. Results: 33 pts were enrolled from December 27th, 2022 to September 25th, 2024, 32 were assessable for safety and 31 for efficacy. Overall, 13 (40.6%) pts had at least one dose reduction of cabo and 5 (15.6%) stopped treatment for a drug-related adverse event (3 related to cabo, 1 to pembro and 1 to both drugs). The most frequent adverse events related to treatment were asthenia, diarrhea, palmo-plantar syndrom and aminotransferase increase. There was no new emerging toxicity with the combination. One grade 5 pneumothorax was considered possibly related to cabozantinib by the investigator. At a median follow up of 13.8 months [95% CI: 12 – 17.2], 8 pts out of the first 29 evaluable pts were NP at 6 months (27.6% [95% CI: 12.7%-47.2%]). Among the efficacy population, 14 pts experienced tumor shrinkage resulting in a partial response (PR) in 8 (25.8%). Responses were long-lasting. The median overall survival was not reached. Conclusions: Combining VEGF and PD-1 inhibition showed favorable activity in unselected UPS compared to available evidence for each treatment in monotherapy. Correlative studies of immune biomarkers on paired tumor biopsies and plasma samples done at baseline and on-treatment are on-going to decipher biomarkers of response and resistance to treatment. Clinical trial information: NCT05182164 . Number of patients with at least one Grade 3 to 5 adverse event related to treatment. Adverse Event Grade 3 Grade 5 Diarrhea 2 (6.2%) 0 Palmo-plantar syndrom 2 (6.2%) 0 Aminotransferase increase 2 (6.2%) 0 Hypertension 1 (3.1%) 0 Headache 1 (3.1%) 0 Dysgeusia 1 (3.1%) 0 Skin rash 1 (3.1%) 0 Pyoderma 1 (3.1%) 0 Left ventricular dysfunction 1 (3.1%) 0 Pneumothorax 1 (3.1%) 1 (3.1%)

BACKGROUND:Youth patient organizations have taken action to address the specific needs of adolescents and young adults (AYAs), and the third National Cancer Control Plan has made this a requirement. This study presents the center's rehabilitation program. PATIENTS AND METHODS:Following initial treatment, patients aged 18-25 were seen annually for 5 years by a multidisciplinary team. Quality of life using the World health organization quality of life (WHOQOL)-BREF and anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) were assessed. The sexologist developed his own scale. The Patients' Global Impression of Change scale (P-GIC) was used to evaluate patients' feedback about the program. RESULTS:Forty-five patients were included. The main reason for being unable to work effectively was cancer and/or its treatment for 20 patients out of 23 in activity (87%). Ten patients (22.2%) reported financial difficulties, and 14 patients (31.1%) received support from a social worker. Regarding sexological accompaniment, only 17 patients could be evaluated; most of these patients (N = 11, 65%) required a sexologist appointment more than a year after the end of their treatment. Regarding psychological support, 44 patients completed the WHOQOL-BREF questionnaire. No particular trend was observed over time. A total of 45 patients completed the HADS. Symptoms of depression may decrease over time, from the end of the treatment to up to 5 years later, whereas anxiety symptoms may not. Of the 48 responses received for the P-GIC satisfaction survey, 43 (89%) indicated satisfaction. CONCLUSION:The AYA team conducts systematic needs assessment and works to address these needs.

(Abstracted from N Engl J Med 2024;391(9):789–799) The incidence of leiomyosarcomas in France is 9.7 per 1 million people, and they make up approximately a quarter of soft-tissue sarcomas, which often occur in the uterus. Prognosis is typically not good, although cases have large variation between individuals.

Background:Liposarcomas (LPS) are among the most common sarcomas, but gather a diversity of rare to ultrarare molecular subtypes whose presentations and natural histories are partially characterized. The aim of the work was to describe the presentation and outcome of the different LPS histotypes from the NETSARC+ registry. Methods:NETSARC+ (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB), funded by the French INCA since 2010 aiming to improve the quality of care of sarcoma patients. Patients' characteristics, treatment and outcomes are collected in a nationwide database. This work describes the outcome of all LPS confirmed by central review pathology review and integrated between 2010 and 2023 in the NETSARC+ database. Findings:11,132 liposarcomas are included in the database for an estimated incidence of 11.5/106/y. Median age was 65 (Q1-Q3: 53-74, range 0-97 y), with 6529 males (58.7%), with 4220 (37.9%) dedifferentiated (DDLPS), 1838 (16.5%) well differentiated LPS (WDLPS) & 2424 (21.8%) atypical lipomatous tumours (ALT), 1371 (12.3%) myxoid LPS (MyxLPS), 450 (4.0%) pleomorphic LPS (PLPS), 177 (1.6%) high grade myxoid LPS (HGMLPS), 24 (0.2%) mixed type liposarcomas (MTLPS), 14 (0.1%) myxoid pleomorphic LPS (MPLPS) and 614 (5.5%) non classified LPS (NCLPS). Age, sex and sites differed across histotypes, but overall, all histotypes were represent in all age groups and sites. We report first on a difference in the sex ratio of liposarcoma in different age groups. Women were less frequently affected with liposarcomas after 50, in DDLPS, MyxLPS and HGMLPS. The median overall survival of DDLPS was 144 months, significantly worse than that of MyxLPS (HR: 0.26 [95% CI 0.21-0.33]), PLPS (HR: 0.76 [95% CI 0.59-0.98]), HGMLPS (HR: 0.30 [95% CI 0.18-0.50]), WDLPS (HR: 0.30 [95% CI 0.24-0.37]), unclassified LPS (HR: 0.53 [95% CI 0.37-0.75]). In addition to a lower incidence, women aged >50 had a better relapse free and overall survival than male, while this was not observed in the group aged 50 or under. In multivariate analyses, size and age were independent prognostic factors for the most common subgroups, but specific prognostic parameters were observed in each molecular subgroup. Female >50 was an independent favorable prognostic factor for the largest groups of DDLPS. Interpretation:In this nationwide series of pathology-confirmed LPS, the clinical presentation, management and survival of histotypes are very different with age-related sex differences favoring women >50. DDLPS is the subtype with the worse prognosis. Funding:This work was supported by the following grants: NetSARC+ (INCA), RREPS (INCA), RESOS (INCA), INTERSARC+ (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), LYriCAN+ (INCa-DGOS-INSERM-ITMO cancer_18,003), Ligue Nationale contre le Cancer, Ligue Contre le Cancer (Comité de l'Ain), Fondation ARC, and EURACAN (EU project 739521).

Background Liposarcomas (LPS) are among the most common sarcomas, but gather a diversity of rare to ultrarare molecular subtypes whose presentations and natural histories are partially characterized. The aim of the work was to describe the presentation and outcome of the different LPS histotypes from the NETSARC+ registry. Methods NETSARC+ (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB), funded by the French INCA since 2010 aiming to improve the quality of care of sarcoma patients. Patients’ characteristics, treatment and outcomes are collected in a nationwide database. This work describes the outcome of all LPS confirmed by central review pathology review and integrated between 2010 and 2023 in the NETSARC+ database. Findings 11,132 liposarcomas are included in the database for an estimated incidence of 11.5/106/y. Median age was 65 (Q1–Q3: 53–74, range 0–97 y), with 6529 males (58.7%), with 4220 (37.9%) dedifferentiated (DDLPS), 1838 (16.5%) well differentiated LPS (WDLPS) & 2424 (21.8%) atypical lipomatous tumours (ALT), 1371 (12.3%) myxoid LPS (MyxLPS), 450 (4.0%) pleomorphic LPS (PLPS), 177 (1.6%) high grade myxoid LPS (HGMLPS), 24 (0.2%) mixed type liposarcomas (MTLPS), 14 (0.1%) myxoid pleomorphic LPS (MPLPS) and 614 (5.5%) non classified LPS (NCLPS). Age, sex and sites differed across histotypes, but overall, all histotypes were represent in all age groups and sites. We report first on a difference in the sex ratio of liposarcoma in different age groups. Women were less frequently affected with liposarcomas after 50, in DDLPS, MyxLPS and HGMLPS. The median overall survival of DDLPS was 144 months, significantly worse than that of MyxLPS (HR: 0.26 [95% CI 0.21–0.33]), PLPS (HR: 0.76 [95% CI 0.59–0.98]), HGMLPS (HR: 0.30 [95% CI 0.18–0.50]), WDLPS (HR: 0.30 [95% CI 0.24–0.37]), unclassified LPS (HR: 0.53 [95% CI 0.37–0.75]). In addition to a lower incidence, women aged >50 had a better relapse free and overall survival than male, while this was not observed in the group aged 50 or under. In multivariate analyses, size and age were independent prognostic factors for the most common subgroups, but specific prognostic parameters were observed in each molecular subgroup. Female >50 was an independent favorable prognostic factor for the largest groups of DDLPS. Interpretation In this nationwide series of pathology-confirmed LPS, the clinical presentation, management and survival of histotypes are very different with age-related sex differences favoring women >50. DDLPS is the subtype with the worse prognosis. Funding This work was supported by the following grants: NetSARC+ (INCA), RREPS (INCA), RESOS (INCA), INTERSARC+ (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), LYriCAN+ (INCa-DGOS-INSERM-ITMO cancer_18,003), Ligue Nationale contre le Cancer, Ligue Contre le Cancer (Comité de l’Ain), Fondation ARC, and EURACAN (EU project 739521).

OBJECTIVES:Primary ovarian leiomyosarcomas are exceptionally rare, constituting less than 1% of ovarian tumors, and they typically have a poor prognosis. The available data on the management of these tumors are sparse, with limited publications mainly comprising small retrospective series that include multiple histologic types. The aim is to evaluate the clinical, surgical, pathologic characteristics and clinical outcome of patient affected by primary ovarian leiomyosarcomas. METHODS:Using the national database (NetSarc), we conducted a retrospective study of the outcomes of primary ovarian leiomyosarcomas at 18 French Sarcoma Group centers. Patients with any International Federation of Gynecology and Obstetrics stage of primary ovarian leiomyosarcoma at first diagnosis and available follow-up were included. RESULTS:A total of 39 patients with primary ovarian leiomyosarcomas were included: 35 had localized disease and 4 had metastatic disease. The median tumor size was 134 mm. Radical and wide surgery was performed on 21 (62%) and 13 patients (38%), respectively. Tumor grade 3, presence of necrosis, mitoses ≥20 high-power field, and high Ki-67 expression >30% were reported in 17 of 34 (50%), 29 of 34 (85%), 17 of 34 (50%), and 17 of 27 patients (63%), respectively. Positive estrogen receptor expression was reported in 14 of 27 patients (52%), whereas progesterone receptor expression was observed in 10 of 27 patients (37%). Adjuvant chemotherapy was administered in 12 of 34 patients (35%), whereas pelvic adjuvant radiotherapy in 8 of 34 (23%). Of the early-stage primary ovarian leiomyosarcomas, 9 had isolated pelvic recurrence, whereas 18 had parenchymal distant metastases. A total of 15 patients (44%) died of disease. In early-stage primary ovarian leiomyosarcomas, high mitotic counts and progesterone receptor negativity were variables associated with worse survival. CONCLUSIONS:Surgery is the cornerstone of treatment for early-stage primary ovarian leiomyosarcoma, whereas the role of adjuvant treatment remains unclear. Some pathologic features were associated with poorer survival. Owing to the rarity of ovarian leiomyosarcomas, referring patients to expert sarcoma centers is highly recommended.

e23542 Background: Angiosarcoma is a rare, aggressive vascular malignancy with limited treatment options. Preclinical data suggest beta-adrenergic blockers like propranolol may have anti-tumor effects. Only one window-of-opportunity trial (Embaby et al., 2024) has prospectively evaluated the activity of propranolol in angiosarcoma. Propranolol's efficacy is believed to fluctuate dose-dependently. We used an innovative phase I-II dose-finding method integrating toxicity, efficacy, and a time-to-event parameter (Rivière et al., 2018), tailored to small samples and optimizing recruitment. The PROPAN trial aimed to determine the optimal dose of propranolol combined with metronomic cyclophosphamide in patients with LAMA, using a sequential dose-finding design based on a bivariate continual reassessment method. Methods: Patients were enrolled in cohorts of 2, with sequential dose adaptations made for the next cohort among three dose levels (80, 120, or 160 mg/d) based on toxicity (grade ≥3 at 1 month per NCI-CTCAE v4.0) and efficacy (non-progression rate at 3 months per RECIST 1.1). The safe most successful dose (sMSD) was determined using a Bayesian model (dfmta package), balancing an non progression efficacy of 15, 30 and 50 % for respectively 80, 120 and 160 mg/j and ≤25% toxicity). This approach determined the next adapted dose based only on toxicity assessed early compared to efficacy, reducing waiting time between cohorts. The trial ended early if all doses failed efficacy or exceeded toxicity targets, with a maximum of 24 patients. Results: Fifteen patients were enrolled, with 12 used for dose optimization. 2 patients were treated in the second line, and the others in the third lines Efficacy data were unavailable for 3 in the final model. One grade 3 toxicity (dyspnea at 120 mg/d) was reported, and 4 patients met the non-progression endpoint at 3 months (3 at 80 mg/d, 1 at 120 mg/d). The final model identifies 80 mg/day as the optimal dose minimizing toxicity, with no efficacy gain at higher doses. Median progression-free survival was 3 months (0.7-6). Conclusions: This trial confirms a favorable safety profile but limited efficacy. This innovative method demonstrates feasibility for rare diseases. However, dose adjustment based on early toxicity assessment optimizes patient recruitment but risks over-reliance on toxicity data for dose optimization. Clinical trial information: NCT02732678 .

5034 Background: Since 2014, adaptation of chemotherapy based on tumor marker decline after the cycle of BEP (Bleomycin, Etoposide, Cisplatin) is a standard for patients with IGCCCG poor-risk NSGCT based on data from the GETUG-13 phase 3 trial (Fizazi et al, Lancet Oncol 2014; J Clin Oncol 2024). The aim of this multicenter study was to evaluate the GETUG-13 algorithm when used in routine practice. Methods: We collected data from all poor-risk NSGCT patients treated consecutively in 13 expert centers from 2013 to 2019. After one cycle of BEP, tumor marker levels were assessed at day 18-21. Pts with a favorable decline continued with BEP for 3 additional cycles (Fav group), whereas those with an unfavorable decline received up to 4 cycles of dose-dense chemotherapy (Unfav group). Data was analysed descriptively, and the Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Results: Data from 146 patients were collected (46 with PS ≥ 2, 35 with mediastinal NSGCT): 111 (76%) had an Unfav decline and 35 (24%) had a Fav decline. More pts with hCG > 50 000 UI/L and AFP > 10 000 were in the Unfav group (44.9% vs 17.6%, p=0.0045, and 26.9% vs 8.8%, p=0.0282). Surgery of residual masses was performed in 85.7% and 74.3% in the Fav and Unfav groups, and the procedure was complete in 83.3% and 59%, respectively. With a median follow-up of 5.8 years (95% CI,63.2-77.2), 5-year PFS rates were 68.6% (95% CI, 50.5-81.2) and 61.1% (95% CI, 51.2-69.6) in the Fav and Unfav groups, respectively. Five-year OS rates were 73.8% (95% CI, 55.6-85.4) and 64.6% (95% CI, 54.6; 73.0), respectively. In the short term, neuropathy, anemia and thrombopenia were more frequent in the Unfav group. Treatment-related deaths were reported in 2 (5.7%) and 5 (4.5%) (including 2 post-surgery deaths) pts in the Fav and Unfav groups, respectively. Peripheral neuropathy evolved favorably, with 4 (5.9%), 2 (3.8%) and no pts in the Unfav group reporting grade 3 toxicity at 6 months, 1 year and at last follow-up, respectively. Long-term side effects were infrequent with only one pt with grade 3 cardiovascular toxicity in the Unfav group. Late grade 2 toxicities included cardiovascular toxicity (1.4%), hypoacousia (1.4%), peripheral neuropathy (4.2%), chronic renal failure (CRF) (9.9%) in the Unfav group, and grade 2 CRF (8.3%) in the Fav group. In both groups, almost 80% pts had returned to work. Among pts with progression or relapse, salvage high-dose chemotherapy with stem-cell transplant was used in 4/11 (36.4%) and 13/33 (43.3%) in the Fav and Unfav groups, respectively. Conclusions: The GETUG-13 algorithm can be safely used in routine practice by expert centers, with a high cure rate similar to that reported in the original phase 3 trial and rare long-term toxicity. This data confirms that this algorithm is standard for poor-risk NSGCT.

BACKGROUND:Clinical practice guidelines for managing superficial non-dermatofibrosarcoma soft tissue sarcomas (NDSTS) vary depending on surgical margins. This study assessed NDSTS outcomes by margin status and re-excision (RE) in the nationwide NETSARC+ database. METHODS:This retrospective study (MR004-346) of 1773 patients used clinical data from the NETSARC database between 01/01/2010 and 12/30/2017. Analyses focused on local relapse-free survival (LRFS) and overall survival (OS). RESULTS:Pre-surgery, 31 % of patients underwent local staging with imaging, 46 % biopsy, and 17.8 % a reference center multidisciplinary tumor board (MDTB). Initial margin quality was R0, R1, R2, and unknown for 37 %, 36 %, 13 %, and 12.8 % of patients respectively. Univariate analysis positively correlated R0 surgery with preoperative biopsy (p < 0.001), adequate local imaging for tumors ≥ 5 cm (p < 0.009), case discussion within a NETSARC+ MDTB (p < 0.001), and tumor size< 5 cm (p < 0.001). Reference network surgery resulted in higher proportions of R0 margins (p < 0.001). Re-excision (RE) was performed in 9.7 %, 63 %,79 %, and 34 % of patients following initial surgery with R0, R1, R2, and unknown margins, respectively. Multivariate analysis identified several poor LRFS prognostic factors: size ≥ 5 cm (HR=1.47, p = 0.002), angiosarcoma (HR=2.95, p < 0.001), surgery outside a NETSARC network (HR=1.61, p = 0.003), old age (p < 0.001), and no final R0 margin (HR=2.60, p < 0.001). Multivariate analysis identified several poor OS prognostic factors: angiosarcoma (HR=2.03, p = 0.065), trunk/head and neck site (HR=1.57, p = 0.004), grades 2 and 3 (respectively HR=2.21, p = 0.039 and HR=4.35, p < 0.001), age (p < 0.001), and no final R0 margins (HR=2.02, p < 0.001). CONCLUSION:Sarcoma clinical practice guideline compliance was associated with better surgery quality, reduced local relapse rates, and improved survival.

Metastatic osteosarcoma (MOS) has a poor prognosis, and few treatment options. This multicentre observational study provides real-world data on treatment patterns of patients with MOS in France. The primary objective was to describe treatment modalities of patients with MOS aged ≥12 years treated in 11 reference network centers. Secondary objectives were to assess time to next treatment (TTNT), overall survival (OS) and prognostic factors for TTNT and OS. From 2008 to 2018, 262 patients with MOS were included; 88 patients were metastatic at diagnosis, and 174 patients had a metastatic relapse. Median age at diagnosis was 26 (12-86). A total of 227 (86.6%) patients received systemic treatment in the metastatic setting, and 75 (28.6%) patients received more than two lines. Overall, 153 (58.4%) patients underwent at least a loco-regional procedure, and 50 patients (19.1%) participated in a clinical trial in the metastatic setting. Median OS from metastasis diagnosis was 21.5 months [95% CI 18.9-27.0], 23.0 months [95% CI 15.0-31.1] in the synchronous cohort, and 21.4 months [95% CI 18.7-29.7] in the metachronous cohort. Median TTNT was 8.2 months [95% CI 6.7-9.9], 5.7 months [95% CI 4.2-7.2], 3.7 months [95% CI 3.0-4.3], and 2.9 months [95% CI 1.8-3.9] in first, second, third, and fourth line. It was 7.6 months [95% CI 5.1-12.5], 6 months [95% CI 3.6-8.7], and 4.8 months [95% CI 2.9-7.5] for tyrosine kinase inhibitors such as regorafenib or cabozantinib in first, second, and third line. In MOS, the benefit of chemotherapy after first line is limited. TKIs show encouraging activity from first line. Inclusion in clinical trials should be prioritized.

BACKGROUND:Trabectedin, which is approved for advanced soft tissue sarcoma management, has a complex mechanism of action, but can be classified as an alkylating agent. The need to maintain a high relative dose intensity (RDI) is not clearly established in this clinical setting. METHODS:We conducted a retrospective study in five expert centers to compare the progression-free survival (PFS) and overall survival (OS) of patients with advanced L-Sarcomas (liposarcomas or leiomyosarcoma) according to the RDI calculated over the first three cycles (RDI < 80% and RDI ≥ 80%). Comparisons of patients' characteristics were done using Chi-2, Fisher exact, and Wilcoxon tests. Associations between PFS/OS and RDI were estimated and tested in Cox models. RESULTS:Out of 332 patients treated with trabectedin between 09/1999 and 12/2021, 244 have received at least 3 cycles before progression. Among these 244 patients, the median RDI during the first 3 cycles was 83% (range, 48%-106%), the mean RDI was 81% (±14%) and 106 patients had RDI < 80%. An RDI < 80% was more frequently observed in patients treated in a center with a high volume of activity (82/169, 49%, vs. 24/75, 32%, p = 0.02), in patients who had previously received pazopanib (12/18, 67%, vs. 94/225, 42%, p = 0.04), and in patients who experienced grade 3 neutropenia during the first cycle (56/77, 73% vs. 35/127, 28%, p < 0.001). PFS did not significantly differ according to RDI (p = 0.08): HR(< 80%/≥ 80%) = 0.79 (95% CI, 0.61-1.03), median PFS = 8.4 months (7.0-9.3) when RDI < 80% vs. 5.9 months (4.4-6.8) when RDI ≥ 80%. We observed no significant difference in terms of OS (p = 0.53): HR(< 80%/≥ 80%) = 0.92 (95% CI, 0.70-1.20), median OS = 18.2 months (15.6-23.4) when RDI < 80% vs. 15.8 months (13.2-19.7) when RDI ≥ 80%. CONCLUSION:This retrospective study does not support a link between high trabectedin RDI and PFS or OS for advanced L-sarcoma patients.