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Abstract Background Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. Methods This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). Discussion Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. Trial registration ClinicalTrials.gov: NCT06059014.

Background and purpose: In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric personalized medicine trials MOST, MOST Plus and MEGAMOST. Patients/material and methods: MOST, MOST Plus and MEGAMOST comprise 14 cohorts with different targeted agents and immunotherapies. Results and interpretation: PROFILER has recruited 5,991 patients in 10 years, MOST and MOST Plus 875 patients since 2014 and MEGAMOST 172 patients since 2020, and are still ongoing. We provide a description of the local, national and international implications of these initiatives, and we review the results of the sorafenib and olaparib cohorts.

RATIONALE:CSF1R tyrosine kinase inhibitors (TKI) and antibodies yield response rates and tumor control in patients with diffuse type tenosynovial giant cell tumors (dTGCT). The long term management of patients with dTGCT treated with TKI is however not known. PATIENTS AND METHODS:We conducted a retrospective single center study on the 39 patients with advanced and/or inoperable dTGCT referred to the Centre Leon Berard for a medical treatment. The clinical characteristics and treatments of patients who had received at least one line of CSF1R TKI or Ab was collected from the electronic patient records and analyzed, after this study was approved by the Institutional Review Board of the Centre Leon Berard. Statistics were conducted using SPSS 23.0. RESULTS:Thirty-nine patients received at least one line of TKI among the 101 patients with histologically confirmed dTGCT refered to this center. Imatinib, nilotinib, pexidartinib, emactuzumab were the most frequently used agents. First line treatment was given for a median duration of 7 months. With a median follow-up from the initiation of TKI of 30 months, the progression-free rate at 30 months is 56% for the 39 patients. 15 patients had recurrent disease after first line CSF1R inhibitor: 12 (80%) received a 2nd line treatment for a median duration of 6 months and a median time to progression (TTP) of 12 months. Six patients had afterwards a recurrent disease and 5 (83%) received a 3rd line treatment for a median duration of 5 months and a median TTP of 9 months. Progression-free rate at 30 months was observed in 3 of 12 (25%) after line 2 and 1 of 5 (20%) after line 3. None of the patients refered died with a median follow-up of 67 months. CONCLUSIONS:CSF1R TKI or Ab provide prolonged tumor control and symptom relief for a majority of patients with inoperable or relapsing dTGCT, in first and subsequent lines. Multiple lines are required for close to 50% of patients with relapsing dTGCT.

Abstract Introduction The objective was to determine the added value of comprehensive molecular profile by whole‐exome and RNA sequencing (WES/RNA‐Seq) in advanced and refractory cancer patients who had no molecular‐based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array‐based comparative genomic hybridization (aCGH). Materials and Methods In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90‐gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA‐Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA‐Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). Results After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1–10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA‐Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA‐Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA‐Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA‐Seq. Conclusions In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA‐Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

Abstract Background Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). Methods We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan–Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman’s correlation coefficient. Analyses were conducted by tumor subtype. Results 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8–6.2) for HR-/HER2 − subtype to 13.3 months (36% CI 12.7–14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR − /HER2 − mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. Conclusions Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.

Resistance of advanced hormone‐dependent endometrial carcinoma to endocrine therapy remains a worldwide clinical issue. We recently reported that the combination of Vistusertib (V, mTOR inhibitor) and Anastrozole (A, aromatase inhibitor) improves the progression‐free rate compared to Anastrozole alone. However, a better patient selection based on biomarkers would improve patient outcome. We evaluate for the first time the usage of ribosome biogenesis (RiBi) factors as a source of innovative markers. Using 47 FFPE tumours (A n = 18; V + A n = 29), 32 blood samples (A n = 13; V + A n = 19) and 30 samples of total RNAs (A n = 12; V + A n = 18) from the VICTORIA clinical trial, we observed an association between RiBi‐associated markers and drug activity or prediction of treatment response. NOP10 and NHP2 mRNA levels were significantly higher in non‐responders compared to responders in the Vistusertib + Anastrozole arm (P = 0.0194 and P = 0.0002 respectively; i.e. 8 weeks progression‐free survival as endpoint). This study provides RiBi‐based markers relevant for a better selection of patients with advanced endometrial carcinoma by predicting the response of endocrine therapy combined with mTOR inhibitor.

Background and purpose: To prevent the occurrence of grade ≥ 2 radiodermatitis after post-operative breast irradiation in patients with non metastatic breast cancer. Methods: This prospective randomised open-label multicenter study allocated patients from 3 French institutions, ≥18 years, requiring postoperative radiotherapy for histologically proven, early-stage (non-metastatic) unilateral breast adenocarcinoma or in situ breast cancer, with R0 or R1 post-operative status, to receive hygiene rules, associated with either Cicaderma® (Arm A), or preventive treatment according to the investigator preference (mainly hyaluronic acid (ialuset®), essential oils, or water spray, or no medication (Arm B). The primary outcome was to compare the efficacy of Cicaderma® versus local standard management in preventing the occurrence of grade ≥ 2 radiodermatitis. Main secondary objectives include Cicaderma® impact on radiotherapy discontinuation and on skin toxicity (pruritus), pain, quality of life, satisfaction. Results: The CICA-RT study enrolled from June 2020 to April 2021, 258 women with a median age of 61 (22–91) years in 3 institutions. Patients received either Cicaderma® (A: N = 130) or standard practice (B: N = 128). In the 123 patients who initiated radiotherapy in each arm, 95 (77%, 95%CI 68.8%–84.3%) patients did not develop grade ≥ 2 dermatitis. Sensitivity and per-protocol analyses confirmed the absence of differences between arms. Conclusion: This prospective study did not meet its primary endpoint of superiority of Cicaderma® over routine practice skin care in terms of prevention of acute radioinduced dermatitis of grade 2 or higher. However, Cicaderma® showed a significant decrease in the occurrence of pruritus with less patients reporting at least once grade ≥ 2 pruritus (A: N = 38, 31%; B: N = 58, 47%; p = 0.009).ClinicalTrials.gov identifier NCT04300829.

Abstract Background A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. Methods Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours. Results We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct. Conclusion Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.

Background:The clinical management of ependymoma in childhood and adolescence is complex and the clinicobiopathological correlates of outcome remain poorly understood. This international SIOP Ependymoma II (SIOP EPII) trial aims to improve the outcome of patients with ependymoma.MethodsSIOP EPII includes any patient

Abstract Background Patients with a metastatic breast cancer suffer from a deteriorated health-related quality of life and numerous symptoms such as pain, severe fatigue and a decrease of their physical fitness. As the feasibility of a physical activity program has been demonstrated in this population, ABLE02 aims to assess the efficacy of a 6 month-physical activity program using connected devices to improve health-related quality of life and to reduce fatigue in women with metastatic breast cancer. Methods ABLE02 is a prospective, national, multicenter, randomized, controlled and open-label study. A total of 244 patients with a metastatic breast cancer, with at least one positive hormone receptor and a first-line chemotherapy planned, will be randomly assigned (1:1 ratio) to: (i) the intervention arm to receive physical activity recommendations, an activity tracker to wear 24 h a day during the whole intervention (6 months) with at least three weekly walking sessions and quizzes each week on physical activity and nutrition (ii) the control arm to receive physical activity recommendations only. Health-related quality of life will be assessed every 6 weeks and main assessments will be conducted at baseline, M3, M6, M12 and M18 to evaluate the clinical, physical, biological and psychological parameters and survival of participants. All questionnaires will be completed on a dedicated application. Discussion An activity program based on a smartphone application linked to an activity tracker may help to improve quality of life and reduce fatigue of patients with a metastatic breast cancer. The growth of e-health offers the opportunity to get real-time data as well as improving patient empowerment in order to change long-term behaviors. Trial registration NCT number: NCT04354233 .

Background: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents. Methods: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program. Results: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1–3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without. Conclusion: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease.

ObjectiveThis article describes the Personalized Reimbursement Model (PRM) program methodology, limitations, achievement and perspectives in using real-world data of cancer drugs use to improve and personalize drug pricing and reimbursement in France.Materials and methodsPRM platform aggregates Electronic Pharmacy Records (EPR) data from French medical centers (PRM centers) to build retrospective cohorts of patients treated with injectable cancer drugs in a hospital setting. Data extracted on January 1st, 2020, from breast cancer (BC) patients who received trastuzumab, trastuzumab emtansin or pertuzumab since January 1st, 2011, and from lung cancer (LC) patients who received bevacizumab or atezolizumab since January 1st, 2015, enabled recovering their injectable cancer drugs history from diagnosis date until December 30th, 2019, and served as dataset for assessment.Results123 PRM centers provided data from 30,730 patients (25,660 BC and 5,070 LC patients respectively). Overall, 20,942 (82%) of BC and 4,716 (93%) of LC patients were analyzed. Completion rate was above 98% for patients characteristics, diagnostic and treatment related data. PRM centers cover 48% and 33% of BC and LC patients in-hospital therapeutic management in France, respectively. Distribution of BC and LC patients therapeutic management, by medical center category and geographic location, was similar in PRM centers to all French medical centers, ensuring the representativeness of the PRM platform.ConclusionPRM Platform enabled building a national database generating on demand Real-World Evidence based on EPR. This enabled the first performance-based risk-sharing arrangements based on PRM data, between the CEPS and Roche, for atezolizumab cancer immunotherapy in metastatic non-small cell lung cancer indication.

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.

Introduction Despite safety and benefits of physical activity during treatment of localised breast cancer, successful exercise strategies remain to be determined. The primary objective of the ‘dispositif connecté’, that is, connected device in English trial is to evaluate the efficacy of two 6-month exercise interventions, either single or combined, concomitant to adjuvant treatments, on the physical activity level of patients with breast cancer, compared with usual care: an exercise programme using a connected device (activity tracker, smartphone application, website) and a therapeutic patient education intervention. Secondary objectives are to evaluate adherence to interventions, their impact at 6 and 12 months, representations and acceptability of interventions, and to assess the cost-effectiveness of the interventions using quality-adjusted life-years.Methods and analysis This is a 2×2 factorial, multicentre, phase III randomised controlled trial. The study population (with written informed consent) will consist of 432 women diagnosed with primary localised invasive breast carcinoma and eligible for adjuvant chemotherapy, hormonotherapy and/or radiotherapy. They will be randomly allocated between one of four arms: (1) web-based connected device (evolving target number of daily steps and an individualised, semisupervised, adaptive programme of two walking and one muscle strengthening sessions per week in autonomy), (2) therapeutic patient education (one educational diagnosis, two collective educational sessions, one evaluation), (3) combination of both interventions and (4) control. All participants will receive the international physical activity recommendations. Assessments (baseline, 6 and 12 months) will include physical fitness tests, anthropometrics measures, body composition (CT scan, bioelectrical impedance), self-administered questionnaires (physical activity profile (Recent Physical Activity Questionnaire), quality of life (European Organization for Research and Treatment of Cancer Quality-Of-Life Questionnaire-30, EQ-5D-5L), fatigue (Piper Fatigue Scale-12), social deprivation (Evaluation of Deprivation and Inequalities in Health Examination Centres), lifestyle, physical activity barriers, occupational status) and biological parameters (blood draw).Ethics and dissemination This study was reviewed and approved by the French Ethics Committee. The findings will be disseminated to the scientific and medical community via publications in peer-reviewed journals and conference presentations.Trial registration number NCT03529383; Pre-results.

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment's efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT's ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial's statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

PurposeObservational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsCausal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative.ResultsIn the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model.ConclusionUnmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p

Background: Advanced sarcoma is a group of heterogeneous disease with poor prognosis and poor efficacy of medical treatment. They represent a promising group of tumors to assess molecular-based therapy (MBT) strategy. Patients and methods: Genomic profiles of patients with advanced sarcoma included in the ProfiLER program were established by NGS using a 69 genes panel and CGH array. A weekly molecular board reviewed genomic reports to select relevant genomic alterations and propose recommendations for MBT. Results: A genomic profile was available for 158 of 164 patients. At least 1 relevant genomic alteration was reported for 106 patients (67%), with frequent multiple alterations (68%). In total, 289 relevant genomic alterations were identified in 143 different genes; 139 homozygous deletions, 86 gene amplifications and 64 somatic mutations. The most frequently impacted genes were TP53, Rb1, CDKN2A, CDK4, MDM2, and PTEN. MBT was recommended for 47 patients and initiated for 13 patients.One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization. Conclusion: Genomic profiling for advanced sarcoma is feasible, even for bone sarcoma. A small proportion of patients are eventually treated with MBT, similar to other tumor types. We could not demonstrate this strategy to be beneficial to patients. Our data suggest that molecular profiling should not be used in routine practice but warrants further exploration in clinical trials, focusing on sarcoma with complex genomic, and adding transcriptomic analysis to the copy number and mutational analyses.

Abstract Background Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. Methods Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90Y-OTSA-101 for radionuclide therapy. Results From January 2012 to June 2015, 20 pts. (median age 43 years [21–67]) with advanced SS were enrolled. Even though 111In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. Conclusions Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. Trial registration The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Abstract Purpose  The optimal therapy of oligodendrogliomas remains uncertain. Although chemosensitive, these tumors are not chemocurable. We investigated whether chemotherapy delays the need for radiation therapy (RT) without decreasing length and quality of survival. Methods and materials  Among 89 patients treated for oligodendrogliomas at the Centre L�on B�rard of Lyon from 1982 to 1999, 59 patients fitted inclusion criteria, having had centrally reviewed pure oligodendroglioma requiring treatment. According to the WHO’s classification 35 patients had Grade III and 24, Grade II oligodendrogliomas. Results  According to the intent to treat, patients were retrospectively classified in three groups as exclusive RT (Group 1), radio-chemotherapy (Group 2), or exclusive chemotherapy (Group 3). Median progression-free survival (PFS): was 47 months [95% confidence interval (CI) 39–56], and median overall survival (OS) was 109 months (95% CI 83–134). In univariate analysis, PFS was correlated with frontal location and WHO classification; OS was correlated with frontal location and Post-operative Karnosky performans status both appearing as independent prognostic factors for OS in multivariate analysis. There was no significant difference between the treatment groups with regard to PFS (P = 0.82) and OS (P = 0.64). In the group of patients treated with exclusive chemotherapy the 5-year PFS and OS rates were 44 and 71%, respectively. Conclusion  Front-line exclusive chemotherapy results in prolonged OS in patients with confirmed pure oligodendroglioma. Whether this strategy improves quality of life remains debatable. [ABSTRACT FROM AUTHOR]

Abstract Background Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors. Methods In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics. Results Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139–427) and 494 (227–761) μg.h/mL at Day 1, and 738 (487–989) and 1071 (678–1464) μg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion. Conclusions The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination. Trial registration The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th.

Surgery is the only curative treatment in patients with colorectal liver metastases (CLM), but only 10-20% of patients are eligible. High Intensity Focused Ultrasound (HIFU) technology is of proven value in several indications, notably prostate cancer. Its intra-operative use in patients with CLM has not previously been studied. Preclinical work suggested the safety and feasibility of a new HIFU device capable of ablating volumes of up to 2cm x 2cm in a few seconds.We conducted a prospective, single-centre phase I-IIa trial. HIFU was delivered immediately before scheduled hepatectomy. To demonstrate the safety and efficacy of rapidly ablating liver parenchyma, ablations were performed on healthy tissue within the areas scheduled for resection.In total, 30 ablations were carried out in 15 patients. These ablations were all generated within 40 seconds and on average measured 27.5mm x 21.0mm. The phase I study (n = 6) showed that use of the HIFU device was feasible and safe and did not damage neighbouring tissue. The phase IIa study (n = 9) showed both that the area of ablation could be precisely targeted on a previously implanted metallic mark (used to represent a major anatomical structure) and that ablations could be undertaken deliberately to avoid such a mark. Ablations were achieved with a precision of 1-2 mm.HIFU was feasible, safe and effective in ablating areas of liver scheduled for resection. The next stage is a phase IIb study which will attempt ablation of small metastases with a 5 mm margin, again prior to planned resection.ClinicalTrials.govNCT01489787.