A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients

International audienceTo assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m)–cyclophosphamide (750 mg/m) for four cycles followed by docetaxel (100 mg/m) for four cycles]. HER2-negative patients ( = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5–8 or no additional treatment, while HER2-positive patients confirmed by FISH ( = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier's classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming's design used in this trial

Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen

BACKGROUND: In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown. METHODS AND FINDINGS: In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m(2) epirubicin and 1,200 mg/m(2) cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status. CONCLUSIONS: This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin–cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features

Presentation of Dogmatis, An Inter and Multidisciplinary Programme for the Assessment of the Impacts of Genetically Modified Fish, and Results About Risk of fortuitous Import on French Market

DOGMATIS is a research project funded by the French Research Agency (ANR, programme ANR-OGM 2007-2010). The transgenic technologies have been applied to fish since more than 20 years now and some strains are at the premarket or market stage in countries outside Europe. In Europe the main risk is a fortuitous import. Any rumour of uncontrolled arrival of GM fish on the European market may have strong impacts on the market chain, the research and innovation system and the trust in public regulation. The aim of DOGMATIS is to anticipate the answers. It associates specialists of fish transgenesis, GMO detection and regulation, fish market chain economy, consumer sociology and contemporary science philosophy and epistemology. To tackle this multifactorial subject, we developed original methodologies including assumptions based on the quantitative and qualitative knowledge from the different experts of DOGMATIS. We propose to present the programme and the results of our investigation concerning an assessments of the risk of fortuitous presence of GM Fish on the French market, which has been done by crossing the data from scientific literature gathered in a data bank and an expert analysis of filtered statistics of international trade, for the two farmed species concerned by transgenesis techniques and imported on the French market, salmon and tilapia.Keywords: Posters, Markets and Trade, Fisheries Economic

Стратегічне планування як основний інструмент ефективності підприємства

Наук. кер.: А.Ю. Жулавськи

A PCR-microarray method for the screening of genetically modified organisms

A new method to screen and to identify genetically modified organisms (GMO) is presented in this paper. It is based on the detection of multiple genetic elements common to GMO by their amplification via PCR followed by direct hybridisation of the amplicons on microarray. The pattern of the elements is then compared to a database of the composition of EU-approved GMO and an identification of the GMO is then proposed. The limit of detection of the method was ≤0.1% GMO content (w/w) expressed as the amount of target DNA present in the template for single unprocessed material. The DNA targets were detected both in reference materials and in mixtures with the same detection limit. The specificity for the detection of the different elements was found to be very good with no cross-reaction even in samples with two GMO present at different concentrations. The paper presents examples of GMO identification and discusses the potential and limitation of such approaches and how they can facilitate the work of private and enforcement detection laboratories.This study was supported by the European Commission through the FP5 program “GMOchips” (contract G6RD-CT2000-00419 2000-2003), the Belgian SSCT program and the Integrated Project “Co-Extra”, contract no. 007158 2005-2009, under the 6th Framework Programme, priority 5, food quality and safety.Peer reviewe

"Nouvelles techniques" de modification des génomes et épigénomes (NTMGE)

Controverse enregistrée sur les techniques NBT / NGT (New Breeding Techniques) de type Crispr-ca

Nourrir le monde : quelle position pour les biotechnologies ?

Ce texte est le résumé d’un chapitre intitulé « Feeding the world : are biotechnologies the solution ? » paru en 2016 dans le livre « Advances in biotechnology » édité par Ravishankar Rai V et paru chez Wiley. Il ne peut représenter totalement, par certains raccourcis employés, la complexité de ce chapitre dont il ne reprend qu’une partie de sa bibliographie