Diffuse intrinsic pontine glioma (DIPG) is the pediatric tumor with the worst prognosis. BIOMEDE was a randomized phase 2 trial comparing the efficacy in terms of overall survival (OS) (primary endpoint) of epidermal growth factor receptor (EGFR) inhibitor erlotinib, mTOR inhibitor everolimus and multitargeted tyrosine kinase inhibitor dasatinib in combination with radiotherapy in patients with a biopsy-proven DIPG. Tumors were assessed centrally for immunohistochemical biomarkers (EGFR overexpression or PTEN loss) together with whole-exome and RNA sequencing. A cohort of 66 children with the same inclusion criteria and treated previously with temozolomide-based regimen was used to compare outcome. Treatment allocation was performed by randomization in 233 patients, designed so that a drug could not be allocated if the corresponding biomarker was absent: 36 received erlotinib, 102 received dasatinib and 95 received everolimus. The trial was ended for futility of the primary endpoint following the recommendations of the independent data monitoring committee: OS from biopsy was not different from the control cohort (median OS = 10.8 months (95% confidence interval (CI): 9.5-13.0)) in any of the three arms (median OS = 9.7 months (95% CI: 7.8-14.6) for erlotinib; 9.9 months (95% CI: 8.8-11.2) for dasatinib; and 11.9 months (95% CI: 10.7-14.2) for everolimus). Everolimus showed significantly less ocular, renal, skin and gastrointestinal side effects and treatment discontinuation for toxicity (secondary endpoint). TP53 mutations, frequently linked to multiple structural chromosomal aberrations, were the strongest predictor for poor survival in multivariate analysis (hazard ratio = 2.8 (95% CI: 1.9-4.2), P < 0.0001). Both mutations in and activation of the mTOR pathway were associated with a better response to everolimus. Four long-term survivors treated with an mTOR inhibitor were alive free of treatment over 6 years from diagnosis. With comprehensive tumor profiling, BIOMEDE validated prognostic biomarkers as well as informative theranostic biomarkers for future trials. ClinicalTrials.gov: NCT02233049 .

INTRODUCTION:Data about intra-abdominal desmoid-type fibromatosis (IA-DTFs) are limited. METHODS:We examined patients with IA-DTFs enrolled in the ALTITUDES study (NCT02867033). We compared their characteristics with those of other locations using chi-square and Wilcoxon tests, as appropriate, and assessed their outcomes using event-free survival (EFS). Association between primary location and EFS was determined using a Cox univariate model. Subgroup analysis was performed for patients initially managed with active surveillance (AS). RESULTS:95/610 tumors (15.5%) enrolled in ALTITUDES were intra-abdominal. Compared with other locations, patients with IA-DTFs were older (p < 0.001), more often men (p < 0.001), had more frequently a history of polyposis (p = 0.001), larger tumors (p = 0.003), different CTNNB1 mutation profiles (p = 0.004), and a diagnosis established more frequently on surgical specimens (p < 0.001). These patients reported less pain (p = 0.01) and fewer emotional difficulties (p = 0.001), but more constipation (p = 0.004). Surgery was the most common first-line approach (51.6%); AS accounted for the management of only 29.5%. Overall, we observed no significant difference between IA-DTFs and other locations in terms of EFS (hazard ratio, HR = 0.84; 95%CI, 0.56-1.26) and overall survival (HR = 1.84; 0.50-6.80). Among patients managed by AS, EFS was similar between both groups (HR = 1.05; 0.55-2.00). CONCLUSION:One third of IA-DTFs patients were managed using AS, and their outcome was similar to those of patients with other locations. These observational data may help to discuss SA as a first-line approach in the management of IA-DTFs patients.

Introduction Symptoms associated with vulvovaginal atrophy affect up to 73% of patients with breast cancer, whether menopausal or non-menopausal, because certain breast cancer treatments are responsible for oestrogen deprivation on the genital tract. These symptoms are currently underdiagnosed and undertreated but can significantly impair the quality of life and can be a cause of premature discontinuation of adjuvant hormone therapy. Treatment of vulvovaginal atrophy in patients managed for breast cancer should be the first-line treatment with non-hormonal local moisturising therapy. However, this treatment is often insufficient. Systemic menopause hormone treatment is not indicated and local oestrogen treatment is not a first-line treatment in this neoplastic context. Therapeutic alternatives, such as vaginal radiofrequency (RF) treatment, could be considered. Vaginal RF increases collagen synthesis by stimulating fibroblasts. However, the vaginal RF has not been sufficiently evaluated in the literature. We hypothesised that vaginal RF can improve a patient’s experience of vaginal dryness after breast cancer treatment when first-line local moisturising treatment is insufficient.Methods and analysis The RF-Vaginale trial will be a multicentre randomised phase III trial in two parallel groups until the 6-month assessment comparing a reference treatment with local moisturising (hyaluronic acid-based treatment, three times a week) versus the experimental treatment combining reference treatment+vaginal RF treatment. The vaginal RF treatment will consist of three sessions spaced 4–6 weeks apart (MATMATECH, GynWave 360). The primary outcome will be vaginal dryness, assessed at 6 months using a patient-rated 0–10 numerical scale. The secondary outcomes will be dyspareunia and Vaginal Health Index Score (VHIS). Dyspareunia will be assessed by the patient using a patient-rated 0–10 numerical scale, in patients reporting a sexual life with a male partner engaged in vaginal intercourse. The VHIS will be assessed by a physician blinded to the treatment group. All outcomes will also be evaluated at 3 and 12 months.This trial will be proposed to a population receiving an adjuvant treatment for breast cancer with an aromatase inhibitor ±luteinising hormone-releasing hormone (LHRH) agonist.The primary analysis will focus on the evaluation of the mean difference in vaginal dryness score at 6 months between arms, adjusted for baseline value, patient age (<50 vs 50–54 vs 55–64 vs ≥65) and type of hormone therapy (anti-aromatase with vs without LHRH agonist), estimated using an analysis of covariance model. Assuming a SD of 4.5 for the score at 6 months, 71 patients need to be analysed to ensure an 80% power if the difference between the groups is 3, the test being performed at the two-sided alpha threshold of 0.05. Assuming a 5% rate of non-evaluable patients at 6 months, we plan to recruit a total of 75 patients.Ethics and dissemination The study protocol has been approved by the ethics committee (CPP Sud Est I, 12 November 2024), complied with the Declaration of Helsinki and French laws and regulations, and followed the International Conference on Harmonisation E6 Guideline for Good Clinical Practice (reference number EMA/CHMP/ICH/135/1995). The trial results, even if inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals.Trial registration number NCT06900374.

PURPOSE:Euro-EWING99 study was a large, international, prospective study recruiting patients with Ewing sarcoma (EWS) between 1999 and 2015. It assessed three different clinical questions through randomized trials. We report here the characteristics and outcomes of all patients. METHODS:Patients younger than 50 years with EWS were included in the study. They received induction chemotherapy (six courses of vincristine [day 1], ifosfamide [day 1-3], doxorubicin [day 1-3], and etoposide [day 1-3; VIDE], administered every 3 weeks), local therapy (surgery/radiotherapy), and different consolidation treatments according to clinical risk group and trial.The objectives of the study were to describe the entire cohort according to the initial staging group, to describe the survival outcomes (overall survival [OS]; progression-free survival [PFS]; and local control), and to evaluate prognostic factors associated with OS and PFS. RESULTS:Three thousand three hundred ninety-five patients were included in the study, including 2,267 with a localized disease, 614 with pleuropulmonary metastases, and 514 with extrapulmonary metastases. Ninety-eight percent of patients received ≥4 neoadjuvant VIDE courses. The modalities of local treatment and consolidation therapy differed among the three staging groups. With a median follow-up of 7.2 years, PFS of the entire cohort was 60.2% and 55.4% at 3 and 5 years, respectively. OS was 72.6% and 64.6% at 3 and 5 years, respectively. In addition to metastatic status at diagnosis, main prognostic factors included patient age, tumor volume, and histologic response both for PFS and OS, independent of metastatic status. CONCLUSION:To our knowledge, this study is the largest published series of patients with EWS and may serve as a landmark paper for EWS. It confirms the major prognostic value of the complete histologic response after neoadjuvant therapy.

INTRODUCTION:Immune checkpoint inhibitors (ICIs) are widely prescribed as the first-line treatment for metastatic renal clear-cell carcinoma because of their overall survival (OS) benefits. However, ICIs are associated with unreliable efficacy and sometimes severe and unpredictable toxicities. There is a lack of biomarkers for efficacy or toxicity beyond the IMDC score. Body composition (fat and muscle mass) may also be a biomarker of interest. The aim of this retrospective study was to analyze the association between body composition, OS, and toxicities in patients with RCC treated with ICI as a first-line metastatic treatment. METHODS:Body composition parameters - subcutaneous fat index (SFI), visceral fat index (VFI), total fat index (TFI), and skeletal muscle index (SMI) - were measured on computed tomography scans using semiautomated software. RESULTS:In 71 patients, no significant association was found between TFI and OS (adjusted HR, 0.71 [0.35; 1.45]) or toxicities. The TFI was strongly correlated with BMI (r = 0.81), whereas the SFI and VFI were weakly correlated. CONCLUSION:Larger studies would be valuable to better define the thresholds of different parameters (SFI, VFI, TFI, and SMI) and their association with the efficacy and toxicity of ICI.

BACKGROUND:Bilateral salpingo-oophorectomy is the gold-standard risk-reducing surgery for women at high risk of tubo-ovarian or primary peritoneal cancer. Fimbriectomy with delayed oophorectomy has emerged as a promising alternative, potentially reducing tubo-ovarian cancer risk while minimizing the adverse effects of premature menopause. Larger cohorts and longer follow-up are required to confirm these findings. PRIMARY OBJECTIVES:To evaluate the effectiveness of the chosen care pathway in controlling the risk of advanced-stage tubo-ovarian carcinoma, and more specifically to determine whether prophylactic fimbriectomy with delayed oophorectomy is non-inferior to standard bilateral salpingo-oophorectomy in women at high risk and with germline mutations. STUDY HYPOTHESIS:Fimbriectomy with delayed oophorectomy is non-inferior to bilateral salpingo-oophorectomy in preventing oncological risk and reduces menopause-related health disorders. TRIAL DESIGN:This multi-center, non-randomized, pragmatic, preference-based controlled trial allows participants to choose their preventive surgical strategy between standard bilateral salpingo-oophorectomy (according to national guidelines) and fimbriectomy (considered from the age of 35, once childbearing is completed), followed by delayed oophorectomy at age 50 or at clinical menopause. Participants will undergo annual long-term follow-up until age 70. The association between the chosen care pathway and outcomes will be estimated using an inverse probability-weighted, cause-specific Cox model, with age as the time scale. MAJOR INCLUSION/EXCLUSION CRITERIA:This study will be proposed during oncogenetic counseling to pre-menopausal women aged 30 to 50 years with a documented pathogenic germline mutation (BRCA1, BRCA2, RAD51C, RAD51D, or PALB2). Exclusion criteria include prior bilateral oophorectomy or salpingectomy and a personal history of tubo-ovarian cancer. PRIMARY ENDPOINT:Advanced-stage tubo-ovarian or primary peritoneal carcinoma. SAMPLE SIZE:A total of 1100 patients is planned. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS:Recruitment will last 5 years (2026-2031). The first interim analysis is planned 6 to 8 years after study initiation (2032-2034). Final analysis is planned when all patients reach age 70 (around 2071). TRIAL REGISTRATION NUMBER:NCT06726330.

11556 Background: Regorafenib has been evaluated in several sarcoma clinical trials and the common primary endpoint of these studies was Progression-Free Survival (PFS) according to RECIST, with OS as secondary endpoint. We aimed to assess the impact of regorafenib on OS using pooled analysis of REGOSARC (NCT01900743, five cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, other soft tissue sarcoma and non-adipocytic sarcoma post-pazopanib) and (NCT02389244, four cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma and chordoma). Both trials were placebo-controlled trials with potential switch to regorafenib in placebo-arm at progression. Methods: The primary endpoint was OS in months (mo.) from randomisation estimated by Kaplan-Meier method. The Hazard Ratio (HR) of death in a Cox model was stratified by histological . We used 2 methods for controlling regorafenib switch on OS: Rank-Preserving Structural Failure Time Model (RPSFTM; White et al. 1997) and Modified Iterative Parametric Estimation (MIPE: Zhang et al. 2016), with bootstrap-based 95%CI for both methods. Two populations were considered: in the primary analysis included all patients in both trials (n=355), and in secondary analysis excluded chordoma and liposarcoma patients (n=289), since regorafenib failed to demonstrate activity in these subtypes. Results: In primary analysis, the median age was 56.0 years (range, 16.0; 85.0); 325 patients (91.5%) had metastatic disease. 218 (61.4%) patients had soft tissue sarcoma and 137 (38.6%) patients had bone sarcoma. Median follow-up was 70.9 mo (IQR: 54.0-87.5). The median OS was 9.5 mo. (95%CI, 7.7-12.4) in Placebo arm versus 12.8 mo. (95%CI, 11.0-15.8) in regorafenib arm (HR: 0.85 (95%CI, 0.67-1.06); p=0.148). When correcting regorafenib switch effect, the estimated HR was 0.59 (0.31-1.25) and 0.62 (0.27-1.46) using RPSFTM and MIPE methods, respectively. Conclusions: In this pooled analysis, we observe a marked difference in OS, but which does not reach the , even after exclusion of chordomas and liposarcomas patients (20%-risk reduction, with p=0.083). After controlling for the switch effect, the corrected effect of regorafenib increased dramatically from 20% risk-reduction of death to a 45%-50% reduction in the population excluding chordomas and liposarcomas.

The outcome of patients with osteosarcoma after relapse is very poor, with a 5-year overall survival (OS) below 30

Single nucleotide polymorphisms (SNPs) of cancer-immunity relevant genes may decide the extent of tumor immunosurveillance and have clinical significance. The Immuno ALCL trial was designed to investigate whether genetic variability in 13 cancer-immunity relevant genes correlated with clinical features and outcome of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients. One hundred eighty patients were enrolled and genotyped for 14 SNPs. Age at diagnosis, progression-free survival, histological subtype and anti-ALK antibody titer data were collected. IL10 rs1800872, IL10 rs1800896 and TLR3 rs3775291 variants significantly correlated with age at diagnosis. TLR3 rs3775291 was associated with progression-free survival in a recessive model. Combination of multiple genetic variations showed a trend to associate with post-therapeutic relapse. None of the SNP analyzed associated with histological or clinical parameters. Despite the low number of patients, our work uncovered potential associations between certain cancer-immunity relevant genes and clinical features of ALK-positive ALCL patients. Associations do not imply causations. However, our work highlighted a possible contribution of the IL10 and TLR3 pathways to ALK-positive ALCL pathogenesis and suggested that several genetic variants in concert may modulate the risk of post-therapeutic relapse. clinicaltrial.gov NCT02902874. Registered 07 September 2016 https//clinicaltrials.gov/study/NCT02902874.

BACKGROUND:Ovarian carcinoma is a leading cause of cancer-related mortality in women. Approximately 20 % of cases are hereditary, mainly BRCA mutations. Current clinical guidelines recommend bilateral salpingo-oophorectomy between ages 35-45 for high-risk individuals, leading to premature menopause. Given evidence supporting the tubal origin of most ovarian cancers, radical fimbriectomy followed by delayed oophorectomy may offer a menopause-sparing alternative for women refusing early ovariectomy. OBJECTIVE:To evaluate the oncologic safety and clinical outcomes of this two-step risk-reducing strategy. METHODS:This retrospective single-center study included all high-risk premenopausal women who had completed childbearing, declined BSO and underwent radical fimbriectomy between 2014 and 2022. The primary outcome was the incidence of ovarian or pelvic cancer following radical fimbriectomy, estimated using the Kalbfleisch-Prentice method. Secondary outcomes included surgical complications, tubal lesions, menopause onset, breast cancer incidence and delayed oophorectomy rate. RESULTS:A total of 132 women were included; 62.9 % had BRCA1, 25.8 % BRCA2, and 11.3 % other high-risk mutations (RAD51C, PALB2). No tubal lesions were found in 121 cases (91.7 %), while 11 (8.3 %) had abnormalities: one high-grade serous carcinoma, six serous tubal intraepithelial carcinoma, and four minor lesions. After a median 30.4-month follow-up, no high-grade serous carcinoma was reported. Delayed bilateral oophorectomy was performed in 24 women (18.5 %), and menopause occurred in 27 at a median age of 45. One pregnancy occurred post-fimbriectomy via assisted reproductive technology. CONCLUSION:Radical fimbriectomy with delayed oophorectomy may be a safe and feasible option for high-risk women seeking to avoid early menopause. Longer-term prospective studies are needed.

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.

PURPOSE:Limited data exist on the role of fractionated stereotactic radiotherapy in the therapeutic strategy for neurinomas, particularly for extracranial locations. The objective of this study was to describe intra- and extracranial schwannomas using stereotactic body radiotherapy. MATERIALS AND METHODS:A multicentric, non-interventional study was conducted using retrospectively collected data between January 2007 and September 2021. Patients who received fractionated stereotactic radiotherapy were included. Patient characteristics, data on localization, acute and chronic toxicity, local control, as well as progressive-free survival were collected. RESULTS:A total of 72 patients were included with 17 being treated with surgery beforehand. Intracranial localizations concerned nerve VIII (36 lesions), but also nerve IV, V, X and mixed nerves (XII). Extracranial localizations could be cervical, thoracic or lumbar. Treatment regimens were mainly delivering 36Gy in nine fractions of 4Gy (23.6 %) and 21Gy in three fractions of 7Gy (48.6 %). The median follow-up was 49.2 months. Local control was 84.8 % at 3 and 81.8 % at 5 years. Localization and dose schedule did not affect local control (P=0.67 and P=0.46 respectively). Besides surgery, no other factors were associated with local control (P=0.01). Two patients (5.0 %) experienced improvement in their hearing symptoms, while 35 (87.5 %) remained stable. CONCLUSION:Our large multicentre study results add to evidence that fractionated stereotactic radiotherapy is a safe and effective treatment option for managing intracranial schwannomas but also extracranial localizations, including those of larger sizes.

DIPG is the most aggressive brain cancer. Radiotherapy offers transient palliation but survival could not be improved significantly since 50 years. 233 patients with biopsy-confirmed DIPG harboring H3K27me3 loss were randomized to one of the three drugs (erlotinib, everolimus or dasatinib) in addition to radiotherapy. Immunohistochemical biomarkers were assessed centrally together with whole exome and RNA sequencing. Treatment allocation was designed so that a drug could not be randomized if the corresponding biomarker was absent in the tumor. Toxicity was manageable, everolimus showing significantly less adverse events. With a median follow-up of 5.3 years, median OS from the date of treatment start was 9.0, 11.3 and 9.4 months for erlotinib, everolimus and dasatinib, respectively (p=NS). The presence of TP53 mutations frequently associated with numerous structural chromosomal aberrations was the strongest predictor for poor survival (HR of 2.552; 95% CI = 1.476-3.345; p=0.0002). Mutations in the mTOR pathway or its pathway activation on gene expression analysis were associated with a better response to everolimus. Four long-term survivors all treated with everolimus were alive more than six years from diagnosis.

514 Background: Locoregional management of early stage breast cancer (BC) has evolved from maximal tolerable to minimal effective therapies. Significant advancements in radiation therapy (RT), such as limited target volumes and hypofractionation, have led to accelerated partial breast irradiation (APBI). This study reports on toxicity and cosmetic outcomes of APBI in post-menopausal women with unifocal pT1-N0-M0 invasive BC. Methods: The SHARE trial (NCT01247233) is a non-inferiority, multicenter, randomized trial comparing local control of APBI versus Whole Breast Irradiation (WBI). Eligible patients were postmenopausal women over 50 years who had lumpectomy with surgical margins > 2mm. Only patients who had at least 4-5 clips placed in the tumor bed during surgery were eligible. Patients were randomized to receive either WBI (50Gy in 25 fractions (fr) with optional 16Gy-boost or 40Gy in 15 fr, or 42.5Gy in 16fr) or APBI (38.5Gy or 40Gy in 10fr twice daily). Primary endpoint was local recurrence. Secondary endpoints included grade >2 toxicity (NCI-CTCAE-v4) and cosmetic outcomes (good/excellent versus intermediate/poor) evaluated by both patients and doctors, over the follow-up time. We estimated the cumulative incidences (CI) using the Kalbfleisch-Prentice method due to competing events, and cause-specific Hazard Ratios (cs-HR APBI/WBI ) from Cox models adjusted on stratification factors. Results: Among 1006 patients (503 per arm) enrolled between December-2010 and July-2015, with a median follow-up of 5.8 years, 28 deaths and 11 local recurrences were reported. The risk of severe toxicity appeared significantly reduced in the APBI-arm when considering all type of toxicity (cs-HR APBI/WBI =0.74, [95%-CI: 0.61-0.89], p=0.001; 3-year CI=45% [41-49] in WBI vs 36% [32-40] in APBI), or only breast skin toxicity (cs-HR=0.55 [0.44-0.70], p<0.001; 3-year CI=36% [32-40] vs 21% [18-25], respectively). Conversely, for non skin breast toxicities, WBI was less toxic: cs-HR APBI/WBI =2.06 (1.49-2.86), p<0.001). We observed no significant difference of patient-reported cosmetic results: cs-HR APBI/WBI =1.08 (0.85-1.37), p=0.54. Findings were similar for doctor-evaluated results. Rib fractures incidence was nearly double in APBI compared to WBI. Conclusions: The SHARE trial showed that APBI is associated with reduced severe and skin-related toxicities compared to WBI, with no significant difference in cosmetic outcomes. Conversely, WBI was less toxic concerning non-skin breast toxicity, mainly breast fibrosis. The question that currently remains open on a practical level is how to consider APBI in the context of the widespread adoption of the “Fast Forward” regimen for patients at low risk of recurrence. Clinical trial information: 2010-A00243-36 .