3 research outputs found
Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial
International audienceAbstract Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 âcandidate cancerâ genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a âmatched therapyâ and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68â75%). Only 94/550 patients (17%, 95%CI 14â21) received an âAGA-matched therapyâ on progression. The most frequent AGAs leading to âmatched therapyâ included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such âmatched therapyâ improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of âmatched therapyâ was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with âmatched therapy,â and 6-month overall survival (OS) was 62% (95%CI 52â73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a âmatched therapyâ in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158
Caractérisation phénotypique et génomique des patients Becker avec délétion des exons 45-55
International audienceLa dystrophie musculaire de Becker (BMD) est une pathologie liĂ©e Ă lâX qui se caractĂ©rise par une dĂ©gĂ©nĂ©rescence des muscles squelettiques et/ou associĂ©e Ă une cardiomyopathie. Les patients Becker BMDdel45-55 prĂ©sentent une dĂ©lĂ©tion âen phaseâ des exons 45 Ă 55 dans le gĂšne DMD. Les introns 44 et 55 qui bordent cette dĂ©lĂ©tion contiennent des sĂ©quences rĂ©gulatrices comme des long-non-coding ARN (lncRNA). Chaque patient BMDdel45-55 prĂ©sente un point de cassure diffĂ©rent et donc un neo-intron unique avec potentiellement des modifications dans les sĂ©quences de lncRNA.Lâobjectif du projet est dâĂ©tablir une caractĂ©risation gĂ©nomique dâune cohorte unique de patients BMDdel45-55 et dâĂ©tudier des facteurs impliquĂ©s dans leur variabilitĂ© phĂ©notypique.Nous avons rĂ©alisĂ© (i)une caractĂ©risation phĂ©notypique chez 49 patients, (ii)un sĂ©quençage du gĂ©nome entier chez 19/49 patients et (iii)une Ă©tude des lncRNA chez 38/49 patients. Nous avons Ă©tabli le profil des lncRNA dans des myoblastes immortalisĂ©s des sujets sains et DMD avec une dĂ©lĂ©tion des exons 45-52 (Myo-45-52).LâĂ©tude phĂ©notypique de notre population identifie une cardiomyopathie dilatĂ©e (22%), des difficultĂ©s Ă la marche/course (46%), la fatigabilitĂ© (34%). Dans 51% lâĂąge dâapparition des premiers signes est <18 ans (inconnu 22%). LâĂ©tude de la prĂ©sence de lncRNA au niveau gĂ©nomique met en Ă©vidence plusieurs clusters. Lâabsence gĂ©nomique de certains lncRNA sâassocie avec un phĂ©notype clinique modĂ©rĂ©. LâĂ©tude des mĂȘmes lncRNA dans les myoblastes immortalisĂ©s a permis dâidentifier deux lncRNA non-exprimĂ©s dans les Myo-45-52.Notre travail prĂ©sente une caractĂ©risation phĂ©notypique et gĂ©nomique de la plus grande cohorte de patients BMDdel45-55. Nous avons identifiĂ© des clusters avec un phĂ©notype clinique modĂ©rĂ© en fonction du nombre gĂ©nomique de lncRNA. La caractĂ©risation gĂ©nomique des candidats pour la thĂ©rapie par saut dâexons 45-55 serait favorable dans le design des futures essais cliniques thĂ©rapeutiques
Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors
International audienceThe association between pancreatic ductal adenocarcinoma (PDAC) location (head vs. Body/Tail (B/T)) and clinical outcome remains controversial. We collected clinicopathological and gene expression data from 249 resected PDAC samples from public data sets, and we compared data between 208 head and 41 B/T samples. The 2-year overall survival (OS) was better for the head than for the B/T PDACs (44 vs. 27%, p = 0.043), especially when comparing tumors with similar TNM classification (T3/4N0M0: 67% vs. 17%, p = 0.002) or from the same molecular class (squamous subtype: 31% vs. 0%, p < 0.0001). Baileyâs molecular subtypes were differentially distributed within the two groups, with the immunogenic subtype being underrepresented in the âB/Tâ group (p = 0.005). Uni- and multivariate analyses indicated that PDAC anatomic location was an independent prognostic factor. Finally, the supervised analysis identified 334 genes differentially expressed. Genes upregulated in the âheadâ group suggested lymphocyte activation and pancreas exocrine functions. Genes upregulated in the âB/Tâ group were related to keratinocyte differentiation, in line with the enrichment for squamous phenotype. We identified a robust gene expression signature (GES) associated with B/T PDAC location, suggesting that head and B/T PDAC are different. This GES could serve as an indicator for differential therapeutic management based on PDAC location