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Purpose The Time to First Metastatic Recurrence (TFMR) could be considered as an indirect reflection of the tumour growth kinetics which plays an important role in cancer. Molecular subtypes such as expression of estrogen receptor are known predictive factors of TFMR. The CinéBreast study aimed to identify predictive factors of the time to TFMR. Methods The French Epidemiological Strategy and Medical Economics (ESME) Metastatic Breast Cancer (MBC) Database (NCT03275311) was used, which contains data from a cohort of metastatic breast cancer patients from 2008 to 2016 using retrospective data collection. It is a national multi-centre database. The impact of TFMR on overall survival (OS) since first metastasis was also evaluated. Results Among 16 702 patients recorded in the ESME MBC database, 10 595 had an initially localised breast cancer with hormone receptor (HR) and HER2 status available, with a metastatic recurrence. Median follow up was 56 months. Median TFMR was 59 months (120: 24%). HER2+ and TNBC were respectively 4 times and 12 times (p, Highlights • ESME is a large-scale real-life database of 16 702 metastatic breast cancer patients. • A short time to first metastatic recurrence is associated with poor overall survival. • Triple-negative tumours were more likely to recur early than HR+ and HER2+ tumours.

Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

PurposeThe currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme.ParticipantsAll consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually.Finding to dateWith a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort.Future plansThese real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings.Trial registration numberNCT03275311; Pre-results.

Resume Les personnes qui participent a une recherche biomedicale doivent recevoir une information lisible et intelligible afin de pouvoir donner un consentement libre et eclaire. A ce jour, on note que les promoteurs ont tendance a apporter de nombreuses informations de differentes natures n’ayant pas toujours un rapport direct et reellement informatif pour les personnes qui se pretent a cette recherche. Ce constat a conduit a l’organisation d’une table ronde lors des rencontres de Pharmacologie Clinique et a une reflexion sur l’etablissement d’une charte relative a la redaction d’un document d’information des personnes participant a une Recherche Biomedicale ainsi que des bonnes pratiques de redaction. Les recommandations qui ont ete faites, sont basees sur les travaux des differents groupes de travail tels que ceux de la Conference Nationale des Comites de Protection des Personnes (CNCP), des representants des usagers, des associations de patients, ceux des promoteurs industriels et institutionnels (CPI), et issus de la litterature. La restitution de cette table ronde est structuree en 3 categories et 14 points. 1) Le format : la conception ; les regles de la redaction ; la mise en forme ; le sommaire et le lexique. 2) Le contenu : la page d’introduction ; la description de l’etude ; les risques et les benefices. 3) Les aspects reglementaires : les aspects Juridiques ; les mentions CNIL (Commission Nationale Informatique et Liberte) ; les aspects financiers ; les conflits d’interets et les signatures multiples et variees. Ce document doit contribuer a l’attractivite de la Recherche en France et il a ete convenu de presenter la charte et ses documents apres les rencontres de Pharmacologie Clinique et de les faire avaliser par l’ensemble des acteurs : DGS (Direction Generale de la Sante), Afssaps (Agence francaise de securite sanitaire des produits de sante), CNCP, CPI et Leem (Les entreprises du medicament). Une fois, cette charte validee, elle pourra etre mise a disposition des Promoteurs et des CPP (Comites de Protection des Personnes) afin de rendre l’information donnee aux patients uniforme et lisible.

e12592 Background: During last decade, therapeutic arsenal has expanded for metastatic breast cancer (mBC), but few data are available about mTNBC, a poor prognosis subtype. In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data. This base represents a great opportunity to update the outcomes and the treatment practice patterns of this population. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All pts who initiated treatment for mBC between 01-Jan-2008 and 31-Dec-2014 were selected. The primary objective of this study was to assess overall survival (OS) of mTNBC pts. TNBC status was defined as ER and PR < 10% in both primary and metastatic disease, as well as the absence of overexpression or amplification of HER2. The secondary objectives were to describe the characteristics of this population, clinical management (duration and sequence of treatments) and to evaluate the prognostic value of several clinical factors (age, distant disease free interval, location and number of metastatic sites) Results: Among 16703 pts in the ESME-mBC database, 2368 (14%) had mTNBC. Median OS over this time period was 14.8 months (95% CI 14-15.6). Median age at diagnosis of mBC was 57 years. For the pts who relapsed, median metastasis free interval was 24 months, while 25.5% of the pts were de novo metastatic. 61% of the pts presented visceral metastasis and 12% had cerebral metastasis as first metastatic site. The pattern of metastatic involvement (visceral and cerebral) and a short metastasis free interval ( < 24 months) were the most important prognostic factors in multivariate analysis. The description of treatment sequences (duration, prognostic value) will be presented. Conclusions: In this real-life setting database, mTNBC remain of poor prognosis despite a trend for a better OS than the historical data available (12-13 ms). This TNBC ESME cohort is one of the largest available and offers an updated assessment of the outcomes of this population.

1078 Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p

Hemkens and colleagues investigated the effects of treatment on mortality in routinely collected data and subsequent randomised trials.1 They found that observational studies with routinely collected data substantially overestimated the effects of treatment, despite the use of propensity scores to address confounding bias. This overestimation might, however, be partially due to the selection of studies. In randomised controlled trials, a pitfall is choosing a control that reflects the realities of medical care, and a major …

1013Background: In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data in oncology. Metastatic breast cancer (mBC) was first selected to address the value of bevacizumab (B) added to paclitaxel (P) as first-line chemotherapy (CT) for HER2-negative tumours, while randomized trials have led to mixed results on outcome. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All patients who started a first-line anti-cancer treatment for mBC between 01-Jan-2008 and 31-Dec-2013 were selected. The primary objective of the present study was to assess overall survival (OS) in patients with HER2-mBC treated with a first-line P-based CT ± B. Cox regression with adjustment for the main prognostic covariates was used to estimate the hazard ratio (HR) for OS and progression-free survival (PFS). To ad...

Subjects taking part in biomedical research must be provided with legible and intelligible information enabling them to freely give their informed consent. At present, sponsors tend to provide many different types of information, not all of which is directly connected with or indeed really informative about studies for those taking part. As a result of this observation, a round table was convened during the Clinical Pharmacology meetings to deliberate on the creation of a charter concerning the drafting of information documents for biomedical research participants as well as a code of good practice for the preparation of such documents. Recommendations were made based on the efforts of the various working groups concerned, such as the French National Conference of Ethics Committees (CNCP), users' representatives, patients associations and the French industrial and insti- tutional sponsors association (CPI), together with proposals contained in the literature. The deliberations of the round table may be subsumed under the following 3 categories and 14 points: 1) Format: design, drafting rules, layout, table of contents, glossary 2) Content: introductory page, description of the study, risks, benefits 3) Regulatory aspects: legal aspects, CNIL message (data protection), financial aspects, conflict of interests, model and varied signatures. This document should help make research in France more attractive and it was decided after the Clinical Pharmacology meeting to submit the charter and related documents for approval by the various actors involved: DGS (Direction Generale de la Sante), Afssaps (Agence Francaise de Securite Sanitaire des Produits de Sante), CNCP, CPI and LEEM (Les entreprises du medicament). Once the charter has been validated, it will be made available to Sponsors and Ethics Committees in order to ensure greater uniformity and legibility regarding information given to study subjects.

BACKGROUND: Herein are reported the results obtained in all multiple myeloma patients transplanted with peripheral blood hematopoietic progenitor cells submitted to ex vivo expansion. STUDY DESIGN AND METHODS: Patients had blood progenitor cell mobilization with cyclophosphamide and filgrastim. CD34+ cells were expanded for 10 days in a medium containing granulocyte–colony-stimulating factor (G-CSF), stem cell factor, and megakaryocyte growth and development factor (MGDF). Twenty-seven patients underwent transplantation with expanded and nonexpanded cells and 7 patients underwent transplantation with expanded cells only. RESULTS: The median fold cell expansion was 29.1. The number of colony-forming unit–granulocyte-macrophage (CFU-GM) and CD34+ cells, and the long-term culture-initiating cell (LTC-IC) activity increased with median fold values of 14.7, 2.75, and 2.25, respectively. Postmyeloablative neutropenia was abrogated in 24 of 27 patients transplanted with expanded cells plus nonexpanded cells. The median duration of severe neutropenia was 0 days and correlated with the number of cells and CFU-GM infused. Survival was similar to that of a historical control group. Our LTC-IC and NOD-SCID mice studies showed that the expanded cells are able of sustaining long-term hematopoiesis. Seven other patients received transplantation with expanded cells alone. Absolute neutropenia was abrogated in 6 patients. The median duration of neutropenia was 0 days. Two patients who received the lower number of total cells or CFU-GM had brief secondary neutropenia, which resolved after G-CSF injections. CONCLUSION: CD34+ cells expanded ex vivo can abrogate absolute and severe neutropenia after high-dose therapy. The results of the amplification process are strongly related to the delay of hematopoietic recovery.

Although previous findings have suggested that some adult stem cells are pluripotent and could differentiate in an appropriate microenvironment, the fate conversion of adult stem cells is currently being debated. Here, we studied the ability of mobilized stem cells to repair cardiac tissue injury in a nonhuman primate model of acute myocardial infarction. Mobilization was carried out with stem cell factor, 25 mcg/Kg/d (D), and granulocyte-colony-stimulating factor, 100 mcg/Kg/D administered 5 days before (D - 5 group; n = 3) or 4 hours after (H + 4 group; n = 4) circumflex coronary artery ligation; no growth factor was administered to 3 baboons of the control group. No adverse effect relating to growth factor administration was observed. Flk-1 and transcription factors of cardiac lineages could be detected in peripheral blood only by reverse transcriptase-polymerase chain reaction. When comparing positron emission tomography (PET) with [11C]-acetate between examinations from D2 and D30, a relative increase (perfusion ratio between infarct and noninfarct regions) of 26% ( P = .01) in myocardial blood flow was found in the H + 4 group; the relative rate of oxidative metabolism remained unaltered in the 3 groups. No change was observed in the echographic indices of the left ventricular enlargement or systolic function in the 3 animal groups during the 2-month follow-up. The PET findings concurred with the immunohistochemistry analysis of left ventricular myocardial sections with evidence of endothelial cells but no myocyte differentiation; few cycling cells were observed at this time. Thus, the present data suggest that, in nonhuman primates submitted to coronary artery ligation, mobilization by hematopoietic growth factors could promote angiogenesis in the infarcted myocardium, without detectable myocardial repair. (Blood. 2003;102:4361-4368).

Abstract 502 Autologous stem cell transplantation with PBSC after high-dose chemotherapy remains standard therapy for patients with symptomatic Multiple Myeloma (MM). Strategies to minimize complications could significantly reduce the morbidity of that procedure. One possibility could be to shorten the duration of induced neutropenia through the injection of an ex-vivo expanded graft. Nineteen patients (pts) received EVEC after high-dose Melphalan (HDM) (200 mg/m2) as the only graft. The ex-vivo expanded procedure has been described elsewhere (Boiron et al. Transfusion 2006 and Ivanovic et al. Transfusion 2006). Briefly, thawed peripheral blood CD 34+ cells collected after G-CSF mobilisation and selected with immunomagnetic devices were incubated for 10 days in a serum free medium (Maco Biotech HP01) with Stem Cell Factor (Amgen), G-CSF (Amgen) and TPO (Amgen: 7 pts; Cellgenix:12 pts). The expanded cells were then thoroughly washed and injected 48h after the HDM injection. The ex-vivo expansion lead to a median fold of 5,4 for CD34+ cells (1,3-11,8); 118 for CD33+ (1-703880); 3386 for CD14+ (4-101075); 28,5 for CD13+ (10-703880) and 13 for CFUs (6-21). The median N° of CD34+ cells injected was 14×10e6/kg (5,3-48). The results of these transplants were compared to those achieved in 38 pts who received unmanipulated PBSC after HDM. Pts and controls were matched for age, sex, stage of the disease, first line chemotherapy ( VAD or VD) status of the disease at time of transplant, year of transplant, time between diagnosis and transplant, CD34+ mobilisation technique (HD cytoxan + G-CSF or G-CSF alone) and the median N° of total nucleated cells and of CD34+ collected. The results are summarized on the table: There was no secondary neutropenia in the patients who received EVEC. With a median FU of the entire cohort of 30 m, the median OS for pts who received their first transplant with EVEC and with PBSC is 69 m and not reached respectively (p=NS), the median PFS is 18 m and 27 m (p = NS) and the median time to progression is 14 m and 15 m (p=NS). Conclusion: EVEC is feasible, safe and reduce significantly the morbidity of autologous stem cell transplantation after HDM for multiple myeloma. Disclosures: Milpied: Amgen France: Honoraria.

We show that absolute and severe neutropenia after high-dose therapy with melphalan with or without total body irradiation can be abrogated by cells generated ex vivo. This may change the clinical practice of haematopoietic cell transplantation and high-dose chemotherapy because the morbidity and hospitalisation associated with neutropenia could be avoided or reduced.

Background: Ancestim (r-met human stem cell factor; Amgen Inc, CA, USA) is available in France for compassionate use in patients who have failed prior mobilization or an insufficient number of CD34+ cells for autograft. We retrospectively reviewed data from these patients to evaluate the efficacy of ancestim combined with filgrastim in achieving an adequate stem cell yield. Patients and methods: Between January 1998 and July 2007, permission for ancestim use was granted by the French health authority and Amgen to 550 patients (pts) at 82 sites (median age 55 yrs (range, 18–74); 50% male). Non-Hodgkin’s lymphoma (NHL) accounted for 50% of pts, multiple myeloma (MM) 28%, chronic lymphocytic leukaemia 6%, Ewing’s sarcoma 4%, neuroblastomas 3%, ovarian carcinoma 1%, osteosarcomas 1%, and other tumours 7%. Of the 508 pts for whom data were available and analysed, 378 had undergone prior mobilization and 117 were considered to have insufficient harvests; mobilization history was unknown for 13 pts. Fifty-eight percent of the pts were treated with ancestim (20 microg/kg/day s.c.) and filgrastim (10 microg/kg/day s.c.) alone for a median of 6 days (range, 2–21), while the other pts received chemotherapy followed by ancestim (20 microg/kg/day s.c.) and filgrastim (5 microg/kg/day s.c.) for a median of 11 days (range, 1–33). Results: The target threshold of 2x106 CD34+ cells/kg was reached in 198/508 pts (39%) (including 51% of the 144 MM pts and 31% of the 254 NHL pts) after a median of 2 leukaphereses (range, 1–6). 35% of pts with prior mobilization failure and 52% of pts with prior insufficient harvests reached the target of 2 x106 CD34+ cells/kg, with a median number of CD34+ cells harvested of 3.4 x106/kg (range, 0.5–39.5). Of these, 150 pts (76%) proceeded to autologous transplantation. Data on engraftment are available for 137 pts: the median times to reach 0.5 x 109/L neutrophils and 20 x 109/L platelets were 12 days (range, 6–40) and 13 days (range, 0–31), respectively. All pts receiving ancestim were premedicated and treatment was generally well tolerated. Four pts were reported to have experienced severe mast cell-mediated reactions, none of which were life-threatening. Conclusion: Ancestim plus filgrastim, alone or with chemotherapy, successfully rescued adequate CD34+ cell mobilization and collection in preparation for autologous transplantation in approximately 40% of pts.

Ex-vivo expansion of mature hematopoietic cells and progenitors is a major cell therapy technology aiming to shorten chemotherapy-induced cytopenias. The goal of amplifying the most primitive hematopoietic stem cell populations in clinically acceptable conditions is currently difficult, due to the absence of clinical grade early acting-cytokines and lack of adequate stem cell assays. Stem cell factor (SCF) and granulocyte colony stimulating factor (G-CSF) are both clinically applicable and they have been shown to induce a dose-response effect with regard to the expansion of mature cell populations when used in combination with early- acting cytokines. The combined effects of high concentrations of G-CSF and SCF on hematopoietic cells and progenitors and the effects of this procedure on the more primitive stem cell subsets have not been studied. We have developed a preclinical protocol to evaluate the feasibility of expansion of granulomonocytic cells using SCF and G-CSF with the goal of translating this protocol to the clinical application. In preliminary assays, the effects of low and high concentrations of both cytokines on total nucleated cell numbers and progenitors from purifed CD34+ cells (50 104cells/ml) have been tested. As compared to low concentrations (G-CSF 10 ng/ml and SCF 50 ng/ml) high concentrations of G-CSF and SCF (100 ng/ml and 300 ng/ml respectively) induced a two-fold increase of the nucleated cells and progenitors after 9 days of culture (n=7 experiments). High concentrations were therefore chosen for further experiments. CD34+ cells purified from mobilized peripheral blood grafts (purity 99%) have been cultured in a clinically acceptable medium containing clinical grade fetal calf serum ( 10 %), G-CSF (100 ng/ml) and SCF (300 ng/ml) for 9 days. Cells were analyzed using apoptosis tests, immunophenotyping and clonogenic assays at day 0 and day+9. In several experiments ( n= 9) a mean 21-fold expansion of total viable cell numbers was obtained, with a mean 4-fold expansion of clonogenic progenitors. Expanded cells had consistently CD11b+, CD13+, CD15+ phenotype and 2–4% of them remained CD34+. In a scale-up experiment started with 23.106 CD34+ cells, the total cell numbers expanded 16-fold at day+9, with generation of high numbers of CD11b + (18%), CD13+(98%) and CD15+ cells (91%) demonstrating the feasibility of the protocol in clinical scale. To determine if ex-vivo expansion would lead to a significant exhaustion of more primitive stem cells, we have evaluated the NOD/SCID-repopulating cell (RC) contents of the cultures before (day 0) and after ex-vivo expansion (day 9), in mice transplanted with day 0 and day+9 cells. In two experiments, the numbers of NOD/SCID mice engrafted with CD45+ human cells have been found increase from 30% ( 3/10) at day 0 to 100 % ( 10/10 ) at day 9 (Exp1 ) and from 50 % (3/6) at day 0 to 90 % ( 7/8 ) at day9 (Exp 2), demonstrating the persistence of NOD/SCID-RC potential after ex-vivo expansion. Overall the large-scale granulomonocytic cell production protocol that we developed could be of major interest in order to maintain the dose-intensity in high dose chemotherapy regimens and to shorten neutropenia after autologous PBSC transplantation while maintaing the stem cell potential of the graft.