Basal Breast Cancer: A Complex and Deadly Molecular Subtype

During the last decade, gene expression profiling of breast cancer has revealed the existence of five molecular subtypes and allowed the establishment of a new classification. The basal subtype, which represents 15-25% of cases, is characterized by an expression profile similar to that of myoepithelial normal mammary cells. Basal tumors are frequently assimilated to triple-negative (TN) breast cancers. They display epidemiological and clinico-pathological features distinct from other subtypes. Their pattern of relapse is characterized by frequent and early relapses and visceral locations. Despite a relative sensitivity to chemotherapy, the prognosis is poor. Recent characterization of their molecular features, such as the dysfunction of the BRCA1 pathway or the frequent expression of EGFR, provides opportunities for optimizing the systemic treatment. Several clinical trials dedicated to basal or TN tumors are testing cytotoxic agents and/or molecularly targeted therapies. This review summarizes the current state of knowledge of this aggressive and hard-to-treat subtype of breast cancer

Down-Regulation of ECRG4, a Candidate Tumor Suppressor Gene, in Human Breast Cancer

INTRODUCTION: ECRG4/C2ORF40 is a potential tumor suppressor gene (TSG) recently identified in esophageal carcinoma. Its expression, gene copy number and prognostic value have never been explored in breast cancer. METHODS: Using DNA microarray and array-based comparative genomic hybridization (aCGH), we examined ECRG4 mRNA expression and copy number alterations in 353 invasive breast cancer samples and normal breast (NB) samples. A meta-analysis was done on a large public retrospective gene expression dataset (n = 1,387) in search of correlations between ECRG4 expression and histo-clinical features including survival. RESULTS: ECRG4 was underexpressed in 94.3% of cancers when compared to NB. aCGH data revealed ECRG4 loss in 18% of tumors, suggesting that DNA loss is not the main mechanism of underexpression. Meta-analysis showed that ECRG4 expression was significantly higher in tumors displaying earlier stage, smaller size, negative axillary lymph node status, lower grade, and normal-like subtype. Higher expression was also associated with disease-free survival (DFS; HR = 0.84 [0.76-0.92], p = 0.0002) and overall survival (OS; HR = 0.72 [0.63-0.83], p = 5.0E-06). In multivariate analysis including the other histo-clinical prognostic features, ECRG4 expression remained the only prognostic factor for DFS and OS. CONCLUSIONS: Our data suggest that ECRG4 is a candidate TSG in breast cancer, the expression of which may help improve the prognostication. If functional analyses confirm this TSG role, restoring ECRG4 expression in the tumor may represent a promising therapeutic approach

Whole-genome/exome analysis of circulating tumor DNA and comparison to tumor genomics from patients with heavily pre-treated ovarian cancer: subset analysis of the PERMED-01 trial

IntroductionThe poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.MethodsWe performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.ResultsTumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.ConclusionsCombination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158

Signaling pathway switch in breast cancer.

International audienceNext generation sequencing studies have drawn the general landscape of breast cancers and identified hundreds of new, actual therapeutic targets. Two major signaling pathways seem to be altered in a vast proportion of breast cancers. The PI3 kinase/AKT pathway is activated and the JUN/MAPK pathway is repressed. Via the regulation of the cell cycle this metabolic switch impacts on the balance between self-renewal, proliferation and differentiation of the tumor-initiating cells

Exemple de dispositif de formation à l'utilisation des jeux à l'école pour les apprentissages mathématiques

International audienceGames are often used by primary school teachers in their professional practice of the mathematics. However, without a formation in the use of these supports, they risk not to result in learnings. In this contribution, the authors present a device of formation of primary school teachers underlain by two questions: 1) How can a game become a support of mathematics studies ? 2) How to implement it in a relevant way in a class?Les jeux sont souvent utilisés par les professeurs des écoles dans leur pratique professionnelle des mathématiques. Cependant, sans une formation à l'utilisation de ces supports, ils risquent de ne pas déboucher sur de réels apprentissages. Les auteurs présentent dans cette contribution un dispositif de formation de professeurs des écoles sous-tendu par deux questions : 1) En quoi un jeu peut devenir un support d'apprentissage pour les mathématiques ? 2) Comment le mettre en oeuvre de façon pertinente dans une classe

Exemple de dispositif de formation à l'utilisation des jeux à l'école pour les apprentissages mathématiques

International audienceGames are often used by primary school teachers in their professional practice of the mathematics. However, without a formation in the use of these supports, they risk not to result in learnings. In this contribution, the authors present a device of formation of primary school teachers underlain by two questions: 1) How can a game become a support of mathematics studies ? 2) How to implement it in a relevant way in a class?Les jeux sont souvent utilisés par les professeurs des écoles dans leur pratique professionnelle des mathématiques. Cependant, sans une formation à l'utilisation de ces supports, ils risquent de ne pas déboucher sur de réels apprentissages. Les auteurs présentent dans cette contribution un dispositif de formation de professeurs des écoles sous-tendu par deux questions : 1) En quoi un jeu peut devenir un support d'apprentissage pour les mathématiques ? 2) Comment le mettre en oeuvre de façon pertinente dans une classe

Exemple de dispositif de formation à l'utilisation des jeux à l'école pour les apprentissages mathématiques

International audienceGames are often used by primary school teachers in their professional practice of the mathematics. However, without a formation in the use of these supports, they risk not to result in learnings. In this contribution, the authors present a device of formation of primary school teachers underlain by two questions: 1) How can a game become a support of mathematics studies ? 2) How to implement it in a relevant way in a class?Les jeux sont souvent utilisés par les professeurs des écoles dans leur pratique professionnelle des mathématiques. Cependant, sans une formation à l'utilisation de ces supports, ils risquent de ne pas déboucher sur de réels apprentissages. Les auteurs présentent dans cette contribution un dispositif de formation de professeurs des écoles sous-tendu par deux questions : 1) En quoi un jeu peut devenir un support d'apprentissage pour les mathématiques ? 2) Comment le mettre en oeuvre de façon pertinente dans une classe

IDENTIFICATION DES POTENTIALITES D’UN JEU DE RȎLES DANS LE CADRE D’UNE FORMATION DE PROFESSEURS DES ECOLES

International audienceIn this article, we try to identify the mathematical, didactical and pedagogical knowledge potentially at stake in role-play (Lajoie et Pallascio, 2001 ; Lajoie, 2010), training situations of primary schoolteachers, that are unusual in French training practices. We use an analysis framework (Guille-Biel Winder et al., 2015 ; Mangiante-Orsola et al., forthcoming) which characterises training activities according to their type, to the posture of the prospective teachers expected by the teacher educator and to the knowledge at stake.Dans cet article nous cherchons à identifier les potentialités d’un type de situations de formation peu usuel dans la pratique des formateurs d’enseignants en France, le Jeu de Rôles (Lajoie et Pallascio, 2001 ; Lajoie, 2010), en termes de connaissances mathématiques, didactiques et pédagogiques à transmettre à des professeurs des écoles. Nous utilisons pour cela un cadre d’analyse de situations de formation (Guille-Biel Winder et al., 2015 ; Mangiante-Orsola et al., à paraître) permettant de caractériser les activités de formation en fonction de leur nature, du positionnement du formé et des connaissances convoquées

Quel programme de formation des professeurs des écoles pour enseigner les mathématiques ? Contenus, enjeux et repères.

International audienceLe référentiel de compétences professionnelles en vigueur depuis 2013 constitue un point d’appui pour l’élaboration des maquettes de formation de professeurs des écoles. Or celui-ci est transversal et n’évoque pas les savoirs spécifiques à l’enseignement de chaque discipline qui sont convoqués dans l’exercice de ces compétences. Pour combler ce manque, nous mettons au jour les enjeux essentiels de la formation des futurs professeurs des écoles à l’enseignement des mathématiques et proposons des contenus et repères. L’atelier a initié un échange sur les savoirs « incontournables » et leur articulation dans la formation des professeurs des écoles en mathématiques en vue de l’élaboration et de la diffusion d’un document-cadre recensant les savoirs qu’il serait pertinent d’aborder en formation