Search

PURPOSE Rogaratinib, an oral pan-fibroblast growth factor receptor (FGFR1-4) inhibitor, showed promising phase I efficacy and safety in patients with advanced urothelial carcinoma (UC) with FGFR1-3 mRNA overexpression. We assessed rogaratinib efficacy and safety versus chemotherapy in patients with FGFR mRNA-positive advanced/metastatic UC previously treated with platinum chemotherapy. METHODS FORT-1 (ClinicalTrials.gov identifier: NCT03410693 ) was a phase II/III, randomized, open-label trial. Patients with FGFR1/ 3 mRNA-positive locally advanced or metastatic UC with ≥ 1 prior platinum-containing regimen were randomly assigned (1:1) to rogaratinib (800 mg orally twice daily, 3-week cycles; n = 87) or chemotherapy (docetaxel 75 mg/m2, paclitaxel 175 mg/m2, or vinflunine 320 mg/m2 intravenously once every 3 weeks; n = 88). The primary end point was overall survival, with objective response rate (ORR) analysis planned following phase II accrual. Because of comparable efficacy between treatments, enrollment was stopped before progression to phase III; a full interim analysis of phase II was completed. RESULTS ORRs were 20.7% (rogaratinib, 18/87; 95% CI, 12.7 to 30.7) and 19.3% (chemotherapy, 17/88; 95% CI, 11.7 to 29.1). Median overall survival was 8.3 months (95% CI, 6.5 to not estimable) and 9.8 months (95% CI, 6.8 to not estimable; hazard ratio, 1.11; 95% CI, 0.71 to 1.72; P = .67). Grade 3/4 events occurred in 37 (43.0%)/4 (4.7%) patients and 32 (39.0%)/15 (18.3%), respectively. No rogaratinib-related deaths occurred. Exploratory analysis of patients with FGFR3 DNA alterations showed ORRs of 52.4% (11/21; 95% CI, 29.8 to 74.3) for rogaratinib and 26.7% (4/15; 95% CI, 7.8 to 55.1) for chemotherapy. CONCLUSION To our knowledge, these are the first data to compare FGFR-directed therapy with chemotherapy in patients with FGFR-altered UC, showing comparable efficacy and manageable safety. Exploratory testing suggested FGFR3 DNA alterations in association with FGFR1/ 3 mRNA overexpression may be better predictors of rogaratinib response.

In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K).Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score.At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94]).Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.

Sarcomas are rare, heterogeneous, ubiquitously localized malignancies with many histologic subtypes and genomic patterns. The survival of patients with sarcoma has rarely been described based on this heterogeneity; therefore, the authors' objective was to estimate survival outcomes in patients who had sarcomas using the 2020 version of the World Health Organization classification of soft tissue and bone tumors.Patients older than 15 years who had incident sarcoma diagnosed between 2005 and 2010 were extracted from 14 French population-based cancer registries covering 18% of the French metropolitan population. Vital status for each patient was actively followed up to June 30, 2013. Net survival (NS) was estimated using the unbiased Pohar-Perme method.Overall, 4202 patients were included. NS declined with increasing age at diagnosis. According to topographic groups, large 5-year NS disparities were observed, ranging from 47% among women with gynecologic sarcomas to 89% among patients with skin sarcomas. Patients with soft tissue, bone, and gastrointestinal sarcomas had 5-year NS rates of 53%, 61%, and 70%, respectively. Similar heterogeneity was observed according to histologic subtypes, with 5-year NS ranging from 19% for patients with angiosarcomas to 96% for patients with dermatofibrosarcomas. Patients with sarcoma who displayed missense mutations had a better 5-year NS (74%); those with MDM2-amplified sarcomas had the worst NS (45%).NS rates in patients with sarcoma are presented here for the first time based on the 2020 World Health Organization classification applied to population-based registry data. Large prognostic heterogeneity was observed based on age, topographic and histologic groups, and genomic alteration profiles, constituting a benchmark for future studies and clinical trials.

Objectives Cancer patients with pre-existing autoimmune disease, such as systemic sclerosis (SSc), are excluded from clinical trials, so the data on tolerability and efficacy of immune checkpoint inhibitors in these patients are limited. This study investigated the tolerability and efficacy of anti–programmed death ligand 1 (PD (L)1) immunotherapies in patients with pre-existing SSc. Methods Scleronco-01 was a multicentre, nationwide, open-label, phase IV observational study, from 2019 to 2021. Results Seventeen SSc patients receiving treatment for lung carcinoma (n = 13, 77%), head and neck cancer (n = 2, 12%), melanoma (n = 1, 6%), and colorectal carcinoma (n = 1, 6%) were included. The median (interquartile range) patient age was 60 (34–82) years. Fifteen (88%) patients received anti-PD1 (nivolumab and pembrolizumab) and two (12%) anti-PD-L1 (durvalumab). The median follow-up duration was 12 (range, 2–38) months. Four patients (24%) experienced flare-up of SSc symptoms. Ten patients (59%) developed an immune-related adverse event (grade I–II in 11 patients [65%], grade III–IV in one [6%]) without grade V. The overall response rate was 41% (7/17 patients). The median overall survival was 15.8 (95% confidence interval: 7.3 to not reached) months. Conclusion Anti-PD1 or PD-L1 immunotherapies are suitable options for cancer patients with pre-existing SSc. Longer follow-up periods are required for long-term safety analyses.

International audience; Background: Intracranial solitary fibrous tumour (iSFT) is an exceptional mesenchymal tumour with high recurrence rates. We aimed to analyse the clinical outcomes of newly diagnosed and recurrent iSFTs.Methods: We carried out a French retrospective multicentre (n = 16) study of histologically proven iSFT cases. Univariate and multivariate Cox models were used to estimate the prognosis value of the age, location, size, WHO grade, and surgical extent on overall survival (OS), progression-free survival (PFS), and local recurrence-free survival (LRFS).Results: Eighty-eight patients were included with a median age of 54.5 years. New iSFT cases were treated with gross tumour resection (GTR) (n = 75) or subtotal resection (STR) (n = 9) and postoperative radiotherapy (PORT) (n = 32, 57%). The median follow-up time was 7 years. The median OS, PFS, and LRFS were 13 years, 7 years, and 7 years, respectively. Forty-two patients experienced recurrence. Extracranial metastasis occurred in 16 patients. Median OS and PFS after the first recurrence were 6 years and 15.4 months, respectively. A higher histological grade was a prognosis factor for PFS (p = 0.04) and LRFS (p = 0.03). GTR influenced LRFS (p = 0.03).Conclusion: GTR provided benefits as a first treatment for iSFTs. However, approximately 40% of patients experienced relapse, which remains a challenging state.

Background The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15–30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. Results Among 3,227 patients aged 15–30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p Conclusions This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

International audience; The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P =.18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P =.013) and tumor site (P

BackgroundWe report the clinical activity, safety, and identification of a predictive biomarker for bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGFβRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1, in patients with advanced triple-negative breast cancer (TNBC).MethodsIn this expansion cohort of a global phase 1 study, patients with pretreated, advanced TNBC received bintrafusp alfa 1200 mg every 2 weeks intravenously until disease progression, unacceptable toxicity, or withdrawal. The primary objective was confirmed best overall response by RECIST 1.1 assessed per independent review committee (IRC).ResultsAs of May 15, 2020, a total of 33 patients had received bintrafusp alfa, for a median of 6.0 (range, 2.0-48.1) weeks. The objective response rate was 9.1% (95% CI, 1.9%-24.3%) by IRC and investigator assessment. The median progression-free survival per IRC was 1.3 (95% CI, 1.2-1.4) months, and median overall survival was 7.7 (95% CI, 2.1-10.9) months. Twenty-five patients (75.8%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 patients (15.2%); no patients had a grade 4 TRAE. There was 1 treatment-related death (dyspnea, hemolysis, and thrombocytopenia in a patient with extensive disease at trial entry). Responses occurred independently of PD-L1 expression, and tumor RNAseq data identified HMGA2 as a potential biomarker of response.ConclusionsBintrafusp alfa showed clinical activity and manageable safety in patients with heavily pretreated advanced TNBC. HMGA2 was identified as a potential predictive biomarker of response.ClinicalTrials.gov identifierNCT02517398

ObjectiveIdentifying new modifiable prognostic markers is important for ovarian cancer (OC). Low parasympathic activity is associated with inflammation, oxidative stress and sympathetic nervous system activation. Previous studies reported that low vagal nerve activity, measured by low heart rate variability (HRV), may predict poor cancer prognosis. We aimed to examine the prognostic value of HRV in OC.MethodsThis bicentric retrospective study included patients diagnosed with serous OC FIGO stage ≥IIB, between January 2015 and August 2019, with electrocardiograms (ECG) available around diagnosis. HRV was measured from ECG using the time domain parameter of standard deviation of all normal-to-normal heartbeat intervals (SDNN). Optimal SDNN cut-off was determined using the Youden index criteria of time-dependent ROC curves. We used multivariate cox proportional hazard models to investigate the association between HRV and overall survival (OS), while adjusting for well-known OC prognostic factors.ResultsThe 202 patients included were 65.7 years-old on average, 93% had stage FIGO IIIC/IV, 56% had complete surgical resection. Median OS was 38.6 months [95%CI:34.4-47.4]. The median SDNN was 11.1ms, with an optimal cut-off of 10ms to predict OS. OS was shorter for patients with low HRV compared to high HRV (26.4 vs 45.1 months; pConclusionLow HRV, was associated with worse OS in OC patients, supporting previous studies on the prognostic role of HRV in cancer. If replicated in prospective studies, vagal nerve activity may be a new therapeutic target in OC.

Purpose: This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations. Experimental Design: ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy. Results: Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71). Conclusions: We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS. See related commentary by Greene and Van Tine, p. 3911

Background This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy. Patients and methods Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%). Results From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib. Conclusion Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy. Clinical trial registration The trial is registered at ClinicalTrials.gov ( NCT02389244 ).

Human epidermal growth factor 2 (HER2) alterations (protein overexpression, gene amplification and mutation) play a key role in oncogenesis and are more likely correlated to poorer outcome in solid tumors. We reviewed recently published studies in the last 18 months on novel treatment approaches for HER2 positive solid tumors (excluding breast cancer).Results of clinical studies assessing anti-HER2 therapies have been recently issued.One of the most promising drugs is transtuzumab deruxtecan, an antibody-drug conjugate which demonstrated clinically meaningful activity in gastric or gastroesophageal junction cancer and colorectal cancers.Small molecules such as poziotinib, pyrotinib, neratinib, which target both epidermal growth factor receptor (EGFR) and HER2 also showed promising activity, especially in heavily pretreated ERRB2-mutated non-small cell lung cancer (NSCLC) cancer patients. Yet, these findings need to be confirmed in confirmatory randomized trials with larger cohorts.Trastuzumab-based combinations with chemotherapy or immune checkpoint inhibitors are under development with promising results, but not in all HER2 tumors. Emerging adverse events with anti-HER2 are interstitial pneumopathy and diarrhea.Tyrosine kinase inhibitors, antibody drug conjugate in monotherapy and combinations are emerging strategies in many HER2-positive cancers; HER2 therapies are now part of standard of care of HER2-amplified gastric or gastroesophageal junction cancer. Data are pending on several unmet medical needs.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Resume La prise en charge de patients oncologiques, notamment hospitalises, peut amener a discuter, quasi quotidiennement les « Limitation et/ou Arret des Therapeutiques » (LAT). Nous proposons ici l’historique et la synthese des textes encadrant la notion de limitation des therapeutiques actives en oncologie en France. Cette decision est encadree par la Loi Claeys-Leonetti du 2 fevrier 2016 qui recommande une reflexion collegiale et la tracabilite de l’information dans le dossier medical. La decision de LAT est l’objet d’une discussion avec le patient, ses medecins et ses proches qui peut avoir lieu a tout moment de sa prise en charge. Les travaux de nos collegues reanimateurs fournissent de nombreuses recommandations, utiles, dans des situations aigues observees en milieu oncologique. Cependant il y a peu d’articles specifiques a la pratique oncologique . Il s’agit d’une thematique dont doivent s’emparer les oncologues.

Resume La reforme du troisieme cycle des etudes de medecine mise en place en 2017 a cree le statut de « Docteur Junior » pour la derniere phase, appelee phase de consolidation. Elle a pour principe la mise en autonomie croissante et supervisee de l’etudiant de troisieme cycle, afin de mieux l’accompagner vers son statut de praticien senior. Des recommandations pour definir les missions specifiques a l’oncologie medicale paraissent indispensables a la bonne mise en place de la reforme. Ce document, realise conjointement par l’association pour l’enseignement et la recherche des internes en oncologie (AERIO) et le College national des enseignants en cancerologie (CNEC) est une reference nationale qui vise a orienter les pratiques locales, sans s’imposer a elles, en vue de l’arrivee des premiers Docteurs Juniors en oncologie medicale en novembre 2021. Les principaux roles du Docteur Junior y sont explicites : activite de reunion de concertation pluridisciplinaire, de consultation, d’hopital de jour, d’hospitalisation complete, d’enseignement, de recherche notamment clinique et de demarche qualite. L’option oncologie-radiotherapie n’est pas abordee dans ce document.

Background: IMMUcan (SPECTA NCT02834884) is a European public-private effort to generate molecular and cellular profiling data of the human tumor microenvironment (TME) from up to 3,000 patients, to better understand how the immune system and tumors interact. Triple-negative breast cancer (TNBC) is a heterogenous disease with distinct molecular subtypes characterized by different gene expression, genomic profiles, and clinical outcomes. Here, we explored the association between molecular subtypes and response to neoadjuvant chemotherapy as well as levels of immune cell infiltration in the prospective IMMUcan TNBC cohort. Methods: At the cut-off date on June 29th, 2022, we identified a first cohort of 132 patients to perform preliminary analyses, of which 109 had pre-treatment RNAseq data available. Among those, pathological Complete Response (pCR) information was available for a total of 86 patients. Preliminary data included the density of CD3+, CD20+ and CD8+ immune cells from the stroma and tumor compartments from multiplex-immunofluorescence (mIF) for 69 patients. TNBC subtypes were computed as described by Bareche et al. Association of continuous variables with pCR was evaluated with logistic regression (univariate analysis). Results: The pCR rates differed across TNBC subtypes (Fisher’s test, P = 0.02). In detail, pCR was achieved in 88% (8/9) of basal like (BL), 63% (17/27) of immunomodulatory (IM) and 45% (16/35) of mesenchymal (M) tumors, while lower pCR rates were observed for the mesenchymal stem-like (MSL) and luminal androgen receptor (LAR) subtypes with 37% (3/8) and 14% (1/7), respectively, suggesting differences in the sensitivity to neoadjuvant chemotherapy in line with previous reports. When considered as continuous signature scores, pCR was positively associated to BL levels (OR = 2.7, 95% CI, 1.5-4.8; False Discovery Rate [FDR] = 0.0031), and negatively associated to MSL and LAR signature levels (OR = 0.53, 95% CI, 0.32-0.87; FDR = 0.019; OR = 0.30, 95% CI, 0.12-0.74; FDR= 0.019). In addition, CD3+ cell densities in the tumor and stroma were significantly higher in IM tumors (P = 0.002 and P < 0.001), while lower levels were found in M tumors (P = 0.005, P = 0.002). Similarly, stromal CD20+ levels were higher in IM tumors (P = 0.008) and lower in M tumors (P = 0.006), suggesting a more immunosuppressive TME in the M subtype. CD8+ cells levels were not significantly different between subtypes. Conclusions: These preliminary results show relevant differences in the pCR rates among TNBC subtypes, to be confirmed on a larger series of patients and further suggesting a substantial TNBC heterogeneity regarding treatment response. Of note, preliminary mIF results suggest a differential role of the immune response across molecular subtypes. Additional analyses integrating mIF and genomic data are currently ongoing. Funding: IMI2 JU grant agreement 821558, supported by EU’s Horizon 2020 and EFPIA. Citation Format: Andrea Joaquin Garcia, Mattia Rediti, Abdelkader Benyagoub, Stéphanie Tissot, Sylvie Rusakiewicz, Robin Liechti, Flavia Marzetta, Nicolas Penel, Julio Oliveira, Jean-Charles Goeminne, Pierre Fournel, Andreia Capela, Xiaoxiao Wang, Delphine Vincent, Françoise Rothe, Marie Morfouace, Henoch Hong, Donald Jackson, Christos Sotiriou, Laurence Buisseret. Pathologic complete response rate across triple negative breast cancer subtypes in the IMMUcan study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4522.

Purpose: The role of resection of the primary tumour in management of patients with OMBC is controversial. Loco-regional treatment (LRT) with curative intent could be discussed considered for OMBC patients, who experience good response to systemic therapy. We retrospectively studied the impact of resection of the primary tumour on overall survival (OS) for de novo OMBC treated at Oscar Lambret Center in Lille.Patients and methods: Between 2005 and 2017, all consecutive patients were selected. De novo OMBC was defined by 1 to 5 metastases in 1 or 2 organs, diagnosed within three months after primary tumor. Clinical data, tumor characteristics, metastatic sites, locoregional treatment, systemic first line treatment were recorded retrospectively. We set up 2 groups according to therapeutic strategy. Group 1 patients were managed with a prior planned curative intent surgery and systemic treatments and group 2 included patients with systemic therapy alone, without plan of surgery.Results: 116 patients were included in our analysis; 78 patients in group 1 and 38 patients in group 2. Median age was 54,9 years (25,2-86,2) with no difference between both groups (p=0,08). TNM stage, cancer histologies were comparable in both groups, excluding that there were more HER2+ tumour in Group 2 (p=0.003). 81 patients underwent LRT, 69 patients in group 1 and 12 patients in group 2. 59% of them had radical mastectomy and 89% had axillary surgery. For 29% of them, surgery was performed before knowledge of metastatic disease. The other main indications of breast surgery included stable disease (50%), local progression (9%), palliation (5%), single metastasis (5%) and complete metastatic response after chemotherapy (2%). 59 of 81 patients had adjuvant radiotherapy. Regarding systemic first line treatment, patients in group 1 received more chemotherapy (63% vs 86%, p=0.01), anti-HER2 treatment was appropriate except for 6 patients because of heart disease and 69% of patients had hormone therapy with no difference in both groups. Regarding metastases at diagnosis, the mean number of metastases was 2,1 (SD=1,2), 103 patients (89%) had one metastatic site, and 13 patients (11%) had two metastatic sites, with no difference between both groups. Secondary bone involvement was most prevalent site (69%). There was no difference between both groups in metastasis distribution. Median OS was 70,2 months in our cohort. LRT did not improve OS (HR 1,23; 95% CI [0,75-2,00] p=0,41), even after adjustment on age and HER2 status. Median progression free survival (PFS) was 30,2 months in our cohort. LRT did not improve PFS in comparison with systemic treatment alone (HR 1,38; 95% CI [0,91- 2,11] p=0,13).Conclusion: We found that LRT did not improve outcome (PFS or OS) in OMBC patients. This is in line with recently issued large randomized phase III trial. LRT is not a standard of care in OMBC, nevertheless, further clinical studies are needed to better identify the subgroup of OMBC patients that could benefit from LRT, at least in term of quality of life. Citation Format: Charlotte Debuquoy, Claudia Regis, Jennifer Wallet, David Pasquier, Nicolas Penel, Marie-Cecile Le Deley, Marie-Pierre Chauvet, Emilie Kaczmarek. The role of resection of the primary tumour in patients with de novo oligometastatic breast cancer (OMBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-58.

The incidence of different soft tissue sarcoma (STS) histotypes among ethnic and geographic populations has not been comprehensively investigated.Data from 2013 to 2016 were obtained from national cancer registry databases in France and Taiwan. Liposarcoma (LPS), leiomyosarcoma (LMS), angiosarcoma (AS), synovial sarcoma (SS), and malignant peripheral nerve sheath tumor (MPNST) were selected as index STSs to estimate the age-standardized incidence rates (ASRs) and other clinical features between patients.In total, 9398 patients (7148 from France and 2250 from Taiwan) were included. The ASRs of AS (5.4 vs. 2.8) and MPNST (2.0 vs. 1.0) were significantly higher in Taiwan; France had significantly higher ASRs for LPS (12.0 vs. 10.0), LMS (9.7 vs. 7.6), and SS (1.7 vs. 1.2). Patients in Taiwan with LMS or LPS were younger than their French counterparts. With regard to the distribution according to primary anatomic site, French patients had higher odds for extremity and truncal LMS (odds ratio [OR], 2.84; p .001), AS (OR, 2.67; p .001), MPNST (OR, 1.55; p = .027), and LPS (OR, 1.38; p .001) and for breast AS (OR, 10.58; p .001). Taiwanese patients had higher odds for liver AS (OR, 10.72; p .001) and uterine LMS (OR, 3.21; p .001). SS age and distribution according to primary anatomic site did not differ significantly between the French and Taiwanese populations.Significant differences in the incidence and clinical characteristics of index STS suggested that geographic (environmental) and ethnicity factors likely play a vital role in the pathogenesis of STS.

International audience

MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI.Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients.Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease forgt;12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p lt; 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e).In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.

Background: Approximately 10%-20% of breast cancers (BCs) are classified as triple-negative breast cancer (TNBC). TNBC lacks targeted treatment options and has a poor prognosis. Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. We report interim results in patients with advanced TNBC treated with bintrafusp alfa in an expansion cohort of an ongoing, open-label, phase 1 trial (NCT02517398). Methods: Eligible patients had confirmed TNBC (ER: IHC Results: As of August 24, 2018, 33 patients with heavily pretreated TNBC (54.5% of patients had ≥4 prior regimens) were enrolled in this study of bintrafusp alfa. Patients received a median of 3 doses of bintrafusp alfa (range, 1-24). Confirmed responses as assessed by IRC and investigator occurred in 3 patients (1 complete response and 2 partial responses as assessed by IRC; ORR, 9.1% [95% CI, 1.9%-24.3%]); disease control was achieved in a total of 5 patients (15.2% [95% CI, 5.1%-31.9%]) by both IRC and investigator read. The median progression-free survival per IRC was 1.3 months (95% CI, 1.2-1.4 months), and the median overall survival was 7.8 months (95% CI, 2.1-12.8 months). Importantly, a biomarker related to TGF-β biology was identified via RNAseq analysis of tumor samples with 32.0-fold higher expression in patients who experienced disease control (response or stable disease) compared with those who had progressive disease (biomarker results for this expansion cohort are presented in a separate abstract). PD-L1 expression was not associated with response to treatment. In the entire cohort, 6 patients (18.2%) experienced ≥1 grade 3 treatment-related adverse event (TRAE), including anemia (n=3), asthenia, decreased appetite, generalized rash, hypophysitis, and increased transaminases (all n=1). No grade 4 TRAEs were reported. Three patients discontinued treatment due to TRAEs, including 1 death that was assessed by the investigator as related to treatment. Dyspnea, hemolysis, and thrombocytopenia were reported as grade 5 TRAEs in this patient, who had extensive disease at trial entry and was noted to have multiple pulmonary emboli, progressive disease, and expanding pleural effusion after 3 doses. No autoantibodies mediating hemolysis or thrombocytopenia were identified on workup. Conclusions: In summary, bintrafusp alfa was well tolerated, with a safety profile consistent with expectations in this heavily pretreated, advanced TNBC cohort. We identified high expression of a potential predictive biomarker of response in patients with advanced TNBC treated with bintrafusp alfa. Detailed biomarker data are presented in the separate abstract and warrant further investigation of bintrafusp alfa in TNBC. Citation Format: Alexander Spira, Ahmad Awada, Nicolas Isambert, David Lorente Estellés, John Nemunaitis, Nicolas Penel, Laureen S Ojalvo, Christoph Helwig, Christian Borel. Bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1, in advanced triple-negative breast cancer: Preliminary results from a phase 1 cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-06.

Background Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. Patients and methods This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours–based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 ( ClinicalTrials.gov , NCT01900743 ). Results From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4–not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15–0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23–1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). Conclusion The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

International audience

BackgroundRecurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004).MethodsEligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety.ResultsBetween April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0–6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths.ConclusionAvelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.

The benefit of chemotherapy (CT) in rare bone sarcomas is not documented in prospective studies. This retrospective study from the French sarcoma network for bone tumors ResOs was performed in adult patients (pts) from 1976 to 2014, with histologically verified diagnosis of leiomyosarcomas (LMS), undifferentiated pleomorphic (UPS), or radiation-associated sarcomas of bone. The median follow-up was 4.7 years (95% CI 3.7-6.5). Clinical features, treatment modalities and outcomes were recorded and analyzed from 145 pts (median age 53 years [range 20-87]). Site of disease was extremities (66%) or axial skeleton (34%), 111 (77%) presented with localized and potentially resectable disease. The most common histological subtypes were UPS (58%) and LMS (33%); 58% were high-grade tumors. Surgery was performed in 127 pts. In the 111 localized pts, 28 pts (25%) underwent upfront surgery or exclusive radiotherapy (RT; > 50 Grays) without CT, whereas 83 pts (75%) received either neo-adjuvant (n = 26) or adjuvant CT (n = 13) or both (n = 44). Neo-adjuvant and adjuvant CT was mostly doxorubicin- (95%/86%) and cisplatin- (67%/63%) based. R0 resection was achieved in 59 pts, and a good histological response in 15 patients (25%). Adjuvant RT was performed in 24 (22%) pts. For the whole cohort (n=145), the 5-year overall survival (OS) rate was 53% [42; 62]. In univariate analysis, age ≤60 was associated with a longer disease-free survival (DFS)(p = 0.0436). Neo-adjuvant and adjuvant CT tended to be associated with better DFS (p=0.056) with no significant impact on OS in this retrospective series. This article is protected by copyright. All rights reserved.

Introduction: Admission of metastatic cancer patients to the intensive care unit (ICU) poses medical and ethical challenges in the absence of reliable prognostic tools to guide decision-making. Material and Methods: We retrospectively analyzed the medical charts of 129 consecutive patients with metastatic solid tumors admitted to the ICU between January and September 2014 and identified prognostic factors (PFs) using Cox models. Results: The mean patient age at ICU admission was 58.9 years (range, 25–81 years; males, 51%). Performance status (PS) was 0–1 and 2–3 in 61% and 39% of the patients, respectively. The most prevalent cancers were lung cancer (20%), sarcoma (17%), and breast cancer (16%). ICU admission was attributable to the cancer itself (53%), cancer treatment toxicity (43%), and comorbidities (37%). The median overall survival (OS) after ICU admission was 2.6 months; 15% of the patients died during the ICU stay. Poor PFs for OS were PS >1 before ICU admission (p = 0.007) and ICU admission for the cancer itself (p < 10−3). After ICU discharge, 58% and 42% of the patients received systemic treatment within 12 months and showed good PS recovery, respectively. Multiple organ failure and a multidisciplinary decision to limit therapeutic efforts were poor PFs for reinitiation of systemic treatment (p = 0.2 and 0.006, respectively), and the latter was also a poor PF for PS recovery (p = 0.004). Discussion: In the ICU, the OS of adult patients with solid tumors was similar to that of the noncancer population. For ICU admissions related to the cancer itself, the prognosis is poor.

Background Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). Patients and methods Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). Conclusions These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending., Highlights • Long-term results on PFS and OS of doxorubicin and trabectedin in first-line treatment for advanced leiomyosarcoma. • The update confirms the impressive efficiency of the doxo+trab in terms of PFS and OS. • Results of a randomized phase-III study comparing dox+trab combination versus doxo alone in first-line therapy in metastatic LMS are pending.

Purpose of review Desmoid-type fibromatosis, a rare locally aggressive fibroblastic proliferation, is a treatment challenge. This review aimed to explore recent data about the management of desmoid-type fibromatosis. Recent findings New data underline the role of kinases and [Latin Small Letter Gamma]-secretase in stimulating cell proliferation and invasiveness in desmoid-type fibromatosis. This explains the proven activity of multikinase inhibitors (sorafenib or pazopanib) in the management of desmoid-type fibromatosis or the emerging role of a [Latin Small Letter Gamma]-secretase inhibitor. An international guideline for management was recently published, and this guideline take into account patient point of view. Lastly, recent studies highlight the multidimensional burden of desmoid-type fibromatosis, particularly health-related quality of life (HRQoL). Summary Active surveillance with planned MRI is the first-line management in desmoid-type fibromatosis. A site-specific and stepwise approach should be considered for progressive desmoid-type fibromatosis. Further, a risk-benefit analysis that considers the side effects and long-term sequelae should be conducted before deciding to start any treatment. A less aggressive approach should be considered. Multikinase inhibitors are effective, but their tolerability and side effects should be discussed with the patients. The symptoms and HRQoL should be integrated in decision-making. Desmoid-type fibromatosis patients should be offered support to address their needs supportive care.

We review the role of hormonal therapy in the management of different conjunctive tumors. Progestin and aromatase inhibitors seem active in low-grade endometrial stromal sarcoma, but larger case-series are needed. There is no evidence to support the use of hormonal therapy as an adjuvant treatment for low-grade endometrial stromal sarcoma. We did not find relevant data on the use of hormonal therapy for other uterine sarcomas (e.g., high-grade endometrial sarcoma, undifferentiated uterine sarcoma, and adenosarcoma). Gonadotropin-releasing hormone agonist, anti-estrogens and aromatase inhibitor seem active in advanced aggressive angiomyxoma, but larger studies are warranted. The use of aromatase inhibitor in estrogen-receptor-positive uterine leiomyosarcoma requires further clinical investigation. There is no evidence supporting the use of hormonal therapy in desmoid-type fibromatosis. International collaboration efforts are warranted to better explore the role of hormonal therapies in management of estrogen-receptor-positive uterine leiomyosarcoma, low-grade endometrial stromal sarcoma, and aggressive angiomyxoma.

Screening (secondary prevention) is a public health action aimed at identifying diseases at their earliest stages, before the onset of signs and symptoms and, thus, avoiding or mitigating their negative consequences. The abnormality can be a genetic defect, an infection or the preclinical phase of a chronic disease such as cancer. We discuss elements common to the cancer screening debate: vocabulary about screening, overdiagnosis, and program indication criteria. Finally, we present some significant evolutions on the programs since their implementation in France.

The editorial board of Bulletin du Cancer presents some hot topics published or presented in major oncology meetings in 2018. This selection is related to pediatric oncology and to solid and hemato-malignancies in adults, with immunotherapy approaches (checkpoints or CAR-T) as one of the major breakthroughs. Putative impacts on daily practices are discussed, in order to detail what will really change our practice.

Introduction: Rare cancers are defined as having an incidence lower than 6 per 100,000 new cases per year. Despite advances in treatments and personalised medicine for cancer, rare cancers are often left behind due to limited knowledge regarding molecular characterization, heterogeneity of the population and poor access to screening platform or interventional trials.To bridge this gap, EORTC, in collaboration with EURACAN, has developed a project within the EORTC-SPECTA platform to assess the molecular landscape of rare cancers in Europe and the actionability of the different findings. Material and Methods: The pan-European Arcagen project is prospectively analyzing tumor material or blood of patient with rare cancers, using Foundation Medicine NGS panels, while collecting baseline and follow-up clinical data. Results: At the cut-off date of 10/10/2021, 629 patients were evaluable (baseline clinical data and successful molecular profiling performed by a Foundation Medicine test), molecular alterations were found in 620 patients, theoretically actionable ones in 421 patients. Importantly, approved treatment in the right tumor type was proposed in 58 patients (9.2%). Longer follow-up is needed to assess treatment adaptation and response. Most analyses were performed based on FFPE material (451 out of 629), but in case of low sample quality, low content of tumor cells, or old sample, rescue analysis was performed on liquid biopsy (177 out of 629). The main reason for switching to liquid biopsy was due to low FFPE tissue quality (90 out of 178). This rescue pathway was used on average in 28.1% of cases, ranging from 14.7% in salivary gland cancers to 48% for Cancer of Unknown Primary. Comparing per tumor type the molecular profile obtained either with FFPE or blood analysis, we noticed that SNVs are nicely detected in both compartments. However, copy number loss and amplifications are mainly detected when FFPE material is used. This is especially true for copy number loss of CDKN2A/B (cholangiocarcinoma, mesothelioma and salivary gland), or MTAP (mesothelioma), and MYC amplification (brain and rare skin cancer).As expected according to other datasets, some clonal hematopoiesis of indeterminate potential (CHIP) was observed on liquid biopsy, with DNMT3A being in the top ten mutations detected in the blood of patients with salivary gland tumors, endocrine tumors, Merkel cell carcinoma and uveal melanoma. Conclusion: This project highlights the clear need for more collaboration, research and clinical trials on rare cancers, to improve the treatment accessibility for targeted therapy for these patients. The use of liquid biopsy, despite its limitations, is an ideal candidate to gain understanding of a patient tumor molecular profile, while being non-invasive and easily performed longitudinally. Citation Format: Marie Morfouace, Aleksandra Stevovic, Julio Oliveira, Nicolas Penel, Julien Péron, Paolo G. Casali, Michael J. SECKL, Jourik A. GIETEMA, Wouter de HERDER, Lucjan WYRWICZ, Christelle de la FOUCHARDIERE, Lisa LICITRA, Nicolas GIRARD, Sophie PIPERNO-NEUMANN, Ellen KAPITEIJN, Ahmed IDBAIH, Jean-Yves Blay. Screening somatic genomic alteration for rare adult cancers: the SPECTA-ARCAGEN project of the EORTC/EURACAN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 45.

5572 Background: AcSé Pembrolizumab is a Phase 2, non-randomized parallel arms, multicentric basket trial investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the results in the rare ovarian tumors cohort. Methods: Selected histotypes were all rare ovarian cancers (incidence < 6/100,000/year). Main inclusion criteria were age > 18, ECOG PS≤1, resistant disease to platinum based chemotherapy, and systematic histological central review by expert pathologist from TMRG network. Patients (pts) received pembrolizumab 200 mg IV on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1 at 12 weeks. Secondary endpoints included best response rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. The 7 subgroups of pts analyzed were carcinosarcoma (CS), clear cell carcinoma (CCC), low grade serous carcinoma (LGSC), mucinous carcinoma (MEOC), sex cord tumors (SCT), germ cell tumor (GCT), and smarcA4 deficient hypercalcemic ovarian tumor (SCHOCCT). Results: 62 pts from 22 centers, were included from 08/2017 to 12/2020. Median Age was 53.5 years old [36-64]. Median number of previous lines of chemotherapy was 2 (range 1-4). The median number of cycles was 8 (range, 1-35) with 44 pts (70.9%) who discontinued the trial after a mean number of 6.8 cycles. There were 2 pts (3.2%) with partial response (PR) at 12 weeks. The best response in ITT was complete response (CR) in 1 patient (1%), PR in 3 (14.3%), and stable disease (SD) in 21 (33.8%). The occurrence of best response depended on the histotype with 1 CR (33%) in GCT (cancerized teratoma), 2 PR (20%) in CCC, and 1 PR (4%) in LGSC. 4/4 pts (100%) reported PD as best response in SCOOHT (Table 1). Median duration of response or stabilized disease was 7.8 months [IQR, 4.1 to 9.0]. At the data cut off, 6-month PFS was 29% [19.7-42.8] and 6-month OS was 77.8% [67.7-89.3] on the overall population. Outcomes differed according to subgroups and will be presented. There were a total of 62 adverse events (AEs) reported in 28 pts. For 5 pts (8%) AEs lead to drug discontinuation. AEs were of grade 1 (n = 9), grade 2 (n = 8), or grade ≥ 3 (n = 45: 42 grade 3, 2 grade 4, and 1 grade 5). Conclusions: Pembrolizumab is safe and well tolerate in this population of rare ovarian cancer pts. AcSé study reports prolonged responses in very selected subtypes of rare ovarian tumor (CCC, cancerized teratoma, and LGCS). Acknowledgements: TMRG (national cancer network dedicated to rare gynecological tumors), GINECO group for partnership, La Ligue Nationale contre le Cancer, INCa and MSD. Clinical trial information: NCT03012620. [Table: see text]

3130 Background: PROFILER-02 is a multicenter randomized prospective study comparing the proportion of metastatic cancer patients (pts) with Targeted Agent (TA) recommendation provided by large NGS panel (FOne panel, 324 genes) vs home 87-gene NGS panel (CTRL) (PMID 30865223). Methods: Adult pts with advanced/metastatic cancer during 1st or 2nd line of therapy without known targetable gene alteration were eligible and randomized (1:1) to FOne vs CTRL panel. Both panels were performed for each patient. The randomization arm defined the first panel reviewed by dedicated Molecular Tumor Board (MTB) at disease progression while the 2nd panel remained blinded. The primary objective was the pts rate with at least one TA recommendation by the MTB using either FOne or CTRL panel. The study was designed in order to detect difference in proportions of 10% between the two panels. A sample size of 289 pts with both panels were requested to show this difference with an expected proportion of discordant pairs of 20% using a McNemar's test with 98% power and 5% two-sided significance level. Secondary endpoints included number of pts receiving at least one TA, progression free survival (PFS) and overall survival (OS). Results: From June 2017 to June 2019, among the 339 included pts 171 and 168 pts were randomized in FOne or CTRL panels’ first use, respectively. Median age was 57 years [19.0 - 85.0]; 54.9% were female. The median time from randomization to first MTB was 7.62 months [range 0.80 - 48.1]. Among the 339 pts, 147 pts (43.4%) had no TA recommendation, 108 pts (31.9%) had at least one TA recommendation according to both panels, 67 pts (19.8%) had one or more TA recommendation according to FOne panel only and 17 pts (5%) according to CTRL panel only (McNemar p < 0.001). At the time of the analysis, 51/339 (15%) pts started recommended treatment: 27 pts (8%) with TA recommendation from both panels, 21 pts (6.2%) from FOne only and 3 pts (0.3%) from CTRL only. Main initiated TA were PARP inh. (FOne n = 12; CTRL n = 9), PI3K/AKT/mTOR inh. (FOne n = 10; CTRL n = 9) and immunotherapy (ICI) (FOne n = 7; CTRL n = 0). Median PFS following first MTB were 3.2 months (95% CI 2.5-3.8) and 2.6 months (95% CI 2.0-3.8), median OS were 8.7 months (95% CI 6.6-10.8) and 8.4 months (95% CI 6.4-9.7), in the FOne and CTRL arm, respectively. Conclusions: Larger NGS panel including Tumor Mutational Burden increased the number of recommended options (TA and ICI), as well as the number of treatment initiation. Clinical trial information: NCT03163732.

TPS11585 Background: Primary metastatic osteosarcoma (OS) patients are treated with a curative intent following the same principles of non-metastatic OS, while the treatment of recurrent OS is primarily surgical in the case of isolated lung metastases. When complete removal of all metastases cannot be achieved, the prognosis remains poor, with a median Progression-Free Survival (PFS) between 3 to 8 months, and therefore there is a clinical need to reduce the risk of progression after the initial treatment sequence. The REGOBONE study reported a significant PFS benefit of regorafenib (REG) compared to placebo (in osteosarcomas: median PFS: 16.4 versus 4.1 weeks) and a manageable safety profile in patients with histologically confirmed HGBS (i.e., osteosarcoma or other bone sarcomas with the exception of Ewing sarcomas, chondrosarcoma and chordoma). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REG in pts > = 16 years old with HGBS, without complete remission but with no progressive disease after standard treatment, either at diagnosis or at relapse. Sixty pts will be randomly allocated in a 1:1 ratio to receive either oral REG at a daily dose of 120mg or its matching placebo, continuously for a maximum of 12 months. Randomization is stratified according to the setting of the disease: initial diagnosis versus relapse. The primary objective is to compare the efficacy (PFS) between the 2 arms. The expected 4-month PFS rates are 30% in the control arm and 60% in the REGO arm (HR = 0.42). Fifty-two events will provide 87% power to show significant improvement in PFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Overall Response Rate (ORR), Disease Control Rate (DCR), Time to Treatment Failure (TTF), Overall Survival (OS), Quality of Life (QoL), and safety profile. Radiological endpoints will be evaluated using the RECIST 1.1 with tumor assessments every 2 months (first 6 months) and then every 3 months. Translational objectives will identify predictive biomarkers for efficacy of REG as maintenance therapy. Pts of the control arm who experience disease progression may switch to receive open label REG. As of Feb 1st, 2022, 3 patients have been randomized. 14 sites of the French Sarcoma Group will participate. An amendment is being implemented to lower the age limit (12 years old) and to expand tumor types to other HGBS (Ewing sarcomas, chondrosarcomas, Undifferentiated Pleomorphic Sarcomas, Leiomyosarcomas and angiosarcomas). Clinical trial information: NCT04698785.

e21601 Background: MBD4 encodes a glycosylase implicated in repair of lesions induced by DNA deamination and its inactivation in tumors is associated with a hypermutated phenotype. Uveal melanoma (UM) is a rare but aggressive form of melanoma carrying an extremely low mutation burden. Although metastatic UM (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI. Since then, other MBD4-inactivated UMs, acute myeloid leukemias, colorectal adenocarcinomas, gliomas and spiradenocarcinoma cases have been reported. Methods: Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients. Results: Three hundred mUM patients were analyzed. Median follow-up was 17.3 months. Ten objective responses and 20 stable disease for > 12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (CB; i.e. responder patients and stable disease) rate of 10%. Median progression-free survivals (PFS) in patients without and with CB were 3.1 and 16.3 months, respectively (p < 0.0001). Of the 134 tumors sequenced for MBD4, five (3.7%) were mutated. MBD4 inactivation was associated with higher mutation burden (179 to 643 variants versus a median of 16 in MBD4 wild-type), better objective response rate as 60% of MBD4m versus 4% of MBD4-wild type patients responded (Fisher’s exact p-test = 0.0009). Median PFS was 4.0 months in MBD4-wild type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median overall survival was 16.6 months in MBD4-wild type and unreached in MBD4m patients (HR = 0.11; p = 0.004). Conclusions: In mUM patients, MBD4 mutation is highly predictive for response to ICI, PFS and overall survival benefit. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM and other tumor types where MBD4 mutations are reported.

11555 Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p < 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p < 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.

We propose herein a short synthesis of evidence leading to deny organized screening of prostate cancer using PSA plus or minus rectal digital examination. Nevertheless, many scientific societies support opportunistic screening on basis of shared decision. Today, numerous proposals had been made to reduce the overdiagnosis and overtreatreatment.

BackgroundSpatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients.MethodsUsing the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery.ResultsSome clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities.ConclusionsIn the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks’ organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.

Retrospective analyses suggest that patients with advanced KIT exon 9-mutated gastrointestinal stromal tumors (GISTs) receiving imatinib 800 mg (rather than 400 mg) daily have better outcomes. In the adjuvant setting, the question of the optimal dose of imatinib remains unsettled. We aimed to retrospectively assess the activity of imatinib 400 mg in both the adjuvant and the advanced settings. We performed a multicenter study of patients with KIT exon 9-mutated GIST starting imatinib at 400 mg daily. We examined the relapse-free survival (RFS) among high-risk patients either receiving or not receiving adjuvant imatinib. In patients with advanced disease, progression-free survival (PFS, progression under imatinib 400 mg), time to imatinib failure (TIF, progression under imatinib 400, then 800 mg upon first progression), and overall survival (OS) were analyzed. In the post-operative setting (n = 37), 20 patients received adjuvant imatinib. Median RFS in high-risk patients receiving adjuvant imatinib (n = 14) was not reached (95% CI 17.5–46.6) versus 13.6 months (95% CI 4.7–13.6) for those who did not (p = 0.37), after a median follow-up of 58 months. RFS at 36 months was 63% (30.3–96.6) versus 40% (95% CI 0–82.9), p = 0.2. In advanced disease (n = 28), median PFS, TIF and OS were 12.7 months (95% CI 6.1–18.2), 21.0 months (95% CI 17.4–28.1) and 47.0 months (95% CI 33.5–69.2), respectively. Despite the limitations of a retrospective analysis and the small number of patients, the benefit of adjuvant imatinib 400 mg daily in high-risk patients appeared relevant. Patients with advanced disease receiving imatinib 400 mg with subsequent dose escalation had a TIF similar to that observed with an initial dose of 800 mg. Intra-patient dose escalation in this setting might be an option.

[Background] This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions., [Methods] Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method., [Results] Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported., [Conclusion] Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

International audience; Tradition oblige, les membres du comité de rédaction du Bulletin du Cancer vous font partager leur analyse des points marquants en cancérologie pour l’année passée : qu’a révélé l’an 2020 ? Que le lecteur nous en excuse par avance : nous ne parlerons pas de la COVID-19 ni de ses répercussions sur nos patients, sur leur prise en charge, sur les retards diagnostiques, sur les réorganisations hospitalières, etc. Par ailleurs, peut-être que certains points manquent ou, qu’à l’inverse, nous insistons un peu trop sur des thèmes que vous pourriez trouver anodins ou sans intérêt, mais l’exercice de synthèse n’est pas si simple. Même réalisé avec un peu de recul, il peut toujours être influencé par nos enthousiasmes immédiats. L’objectif reste d’assurer une lecture réfléchie, didactique et pratique

Meningeal fibrous solitary tumors/hemangiopericytoma are rare and aggressive mesenchymal neoplasms considered as sarcomas. They represent less than 1% of intracranial tumors and derive from the pericytes of Zimmerman which permit capillary contraction. They tend to occur more often in males in the fifth decade. They are often revealed by intracranial hypertension. Some scannographic and MRI characteristics permit to distinguish meningeal fibrous solitary tumor/hemangiopericytoma from other meningeal tumors. Meningeal hemangiopericytoma and fibrous solitary tumors were considered as different entities until 2016. Following the discovery of an identical genetic event, the locus 12q13 chromosome inversion leading to a NAB2-STAT6 fusion with nuclear immunoreactivity for STAT6 protein, the 2016 WHO classification defines these tumors as a single entity. Meningeal fibrous solitary tumors/hemangiopericytoma have a high recurrence rate. Long-term recurrences may occur. Local relapses are more frequent than extracranial metastasis. A multimodal management is recommended to treat a localized disease. It involves a complete resection followed by adjuvant radiotherapy. When local recurrences occur, surgery or stereotactic radiosurgery permit sometimes a local control. Metastatic disease has a poor prognostic and a weak chimiosensitivity. Targeted therapies, like pazopanib, are a hopeful option.