Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy.

Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.

Enrollment in early-phase clinical trials in pediatric oncology: The experience at Institut Curie.

BACKGROUND: The European Paediatric Regulation was introduced in 2007 to facilitate access to new medicines for children. Our study explored accessibility of early-phase trials in pediatric oncology, in line with the European Paediatric Regulation, to identify the reasons for not inviting patients to participate, parents' refusal, or inclusion failure. PROCEDURE: We conducted a retrospective chart review at Institut Curie, Paris, for all pediatric patients whose cancer progressed despite known effective treatments between July 2010 and December 2013. RESULTS: Out of 100 patients in the palliative phase, 52 received one or more invitations to participate in early-phase trials. Twenty parents declined the invitation, mainly prioritizing quality of life or fearing constraints. Fourteen inclusions failed despite parental approval, mostly due to rapid clinical deterioration. Five patients received no invitations because no early-phase trials were available. Major reasons for noninclusion in the 43 remaining patients were presence of exclusion criteria or other physical factors, preference for conventional treatment, constraints, psychological factors, and follow-up in another hospital after moving. CONCLUSIONS: The Paediatric Regulation has led to increased availability of early-phase trials. Better timing of the proposal, designing less constraining early-phase trials, reducing waiting lists, and improving information for parents and children would facilitate pediatric access to new medicines.

The qLabs® FIB system, a novel point-of-care technology for a rapid and accurate quantification of functional fibrinogen concentration from a single drop of citrated whole blood.

Hypofibrinogenemia is often associated with excessive bleeding and requires immediate treatment. The qLabs FIB® is a handheld and easy-to-use point-of-care (POC) device designed for the rapid measurement of functional fibrinogen concentration from a single drop of citrated whole blood. The aim of this study was to evaluate the analytical performances of the qLabs FIB system. Fibrinogen concentrations from 110 citrated whole blood specimen were measured by both the qLabs FIB and the Clauss laboratory reference methods (STA®-Liquid Fib assay on STA-R® Max from Stago). A three-laboratories comparison study was conducted to assess reproducibility and repeatability of the qLabs FIB using plasma quality control material. In addition, single-site assays were conducted to assess the repeatability from citrated whole blood specimen covering the qLabs FIB reportable range. A very strong correlation between the qLabs FIB and the Clauss laboratory reference method was observed (r = 0.95). Using a clinical cut-off value of 2.0 g/L, the area under the receiver operating characteristic curve (ROC) of citrated whole blood was 0.99 and sensibility and specificity were 100 % and 93.5 %, respectively. Percent CVs for reproducibility and repeatability assessed from quality control material, were both <5 %. Repeatability assessed from citrated whole blood specimen showed a CV of 2.6 to 6.5 %. In conclusion, the qLabs FIB system enables a rapid and reliable measurement of functional fibrinogen levels from citrated whole blood and exhibits a strong prediction power at the 2 g/L clinical cut-off when compared to the Clauss laboratory reference. Further clinical studies should demonstrate its ability to quickly confirm the diagnosis of acquired hypofibrinogenemia and help identify patients who may benefit from targeted hemostatic treatment.

First-line Bevacizumab and Paclitaxel for HER2-negative Metastatic Breast Cancer: A French Retrospective Observational Study.

AIM: To assess outcomes in patients treated with first-line bevacizumab-containing therapy for human epidermal growth factor receptor (HER)2-negative metastatic breast cancer (mBC) at a single centre with a homogenous standard-of-care. PATIENTS AND METHODS: Information on patient and disease characteristics, efficacy, and safety was extracted from computer-based records of all patients receiving first-line bevacizumab-paclitaxel at the Curie Institute, Paris, France, between 2008 and 2011. RESULTS: Median progression-free survival in the 116 treated patients was 13.2 months; median overall survival was 38.4 months. Corresponding values were 9.0 and 18.8 months, respectively, in patients with triple-negative mBC, and 19.4 and 58.8 months, respectively, in patients receiving maintenance endocrine therapy. No new safety signals were seen. CONCLUSION: Outcomes in patients treated with bevacizumab-paclitaxel at our center were consistent with efficacy in prospective clinical trials, with notable activity in poor-prognosis disease. Maintenance endocrine or oral therapy with bevacizumab after paclitaxel discontinuation was associated with long-term disease control.

[First outpatient satisfaction questionnaire with day-surgery in a French comprehensive cancer center]. / Première enquête de satisfaction dans une unité de chirurgie ambulatoire dédiée à la cancérologie.

INTRODUCTION: To assess the patient's satisfaction in a day-surgery unit in oncology for a surgical diagnosis or therapeutic act. METHODS: Between October 2013 and February 2014, we conducted a satisfaction survey from the validated questionnaire COPS-D. This questionnaire analyse the patient's stages in the care system, from the preoperative consultation to the return home: 9 stages with 23 items rated 1 (bad) to 5 (excellent). It was sent by postmail 3 weeks after their hospitalization. RESULTS: Four hundred and sixty-seven questionnaires were mailed, with a response's rate to 38% (172/467). Participant's characteristics: 88% are women, 45% are full time workers, 54% of senology. Two-third of the assessments were rated 4 or 5. Five percent were rated 1 or 2. The patient's exit is the least preferred step. The operating room's assessment is the most preferred by patients. Sixty-one percent of participants have written a free comment, 31% are positives, 36% are negatives, and 32% are mixed. The wait was the negative recurrent comment (21%). DISCUSSION: Most participants are very satisfied. Improving the wait before the operation and output is already underway. Studies are now needed to assess the care's safety and the economic aspect of day-surgery.