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Resume Maintenir, voire renforcer, la medicalisation des metiers dans le champ des produits de sante au sein des structures publiques et privees est aujourd’hui un enjeu majeur. Force est de constater en France le manque de medecins a meme d’exercer dans ces domaines, les structures publiques ou privees ayant en effet d’importantes difficultes a pourvoir les postes disponibles. A la difference de ce qui existe ailleurs en Europe et en dehors des parcours complexes imposes aux hospitalo-universitaires, les cursus francais de formation ne permettent pas de former des medecins veritablement specialistes des produits de sante. Pourtant, des carrieres a la fois nombreuses et variees sont possibles. Les metiers restent, cependant, insuffisamment visibles tant des futurs medecins que du grand public. Pour repondre aux nombreux besoins des structures publiques et des entreprises privees, il est necessaire de proposer un cursus dedie plus specialise. Il convient, cependant, que ce cursus s’appuie sur une formation initiale clinique solide, socle indispensable quel que soit le metier reellement exerce dans le futur. Pour une meilleure visibilite, la creation d’une specialite en pharmacologie medicale et en therapeutique doit etre accompagnee et soutenue par les differentes instances nationales. Dans le contexte d’activites largement mondialisees, disposer en France de specialistes des produits de sante est determinant pour conserver sur le territoire national la maitrise d’activites a forts impacts economiques et de sante publique.

It has become a major challenge not only to retain but also to attract medical professionals to a career in the healthcare products field whether in the public or private sector. There is no denying that France has a shortage of doctors qualified to work in these fields and that public or private organisations alike are experiencing great difficulty in filling vacancies. Unlike elsewhere in Europe, and with the exception of complex pathways imposed on university hospital professors, French training courses do not really provide doctors with specialised training in healthcare products. Many and varied careers nevertheless do exist. However, these careers are not sufficiently visible to future doctors or to the general public. A more dedicated specialist curriculum is called for to meet the many needs of public institutions and private companies. Any such curriculum should be underpinned by solid initial clinical training as an indispensable foundation regardless of future career path. To improve visibility, specialty training in Clinical Pharmacology and Therapeutics must be set up with the support and assistance of the various national bodies. Against a backdrop of activities with a largely globalised reach, the availability in France of healthcare product specialists is key to maintaining national control of activities that exert a significant impact on the economy and on public health.

Background The genomic grade index (GGI) completes the prognostic value of histological grade (HG). Other proliferation markers include the mitotic activity index (MAI) and the Ki67 immunohistochemistry (IHC) status. We compared the prognostic value of GGI, HG, MAI, Ki67 IHC and messenger RNA (mRNA) status in node-positive breast cancer (BC) patients treated with adjuvant anthracycline-based chemotherapy in the prospective PACS01 trial. Patients and methods The five proliferation-related parameters (GGI, Ki67 mRNA expression and centrally determined HG, MAI, and Ki67 IHC status) of tumours were available for 204 cases and analysed as continuous values. We compared the correlations of each one with the other proliferation-related parameters and with histoclinical variables including the disease-free survival (DFS). Results Expected correlations were observed between the five parameters and for each parameter with biological features (hormone-receptor and HER2 status, molecular subtypes), but the GGI displayed the strongest correlations. The GGI outperformed the prognostic performance of the four other proliferation-related parameters for the DFS in all 204 patients and in the 95 HG2 patients. In multivariate analysis including the classical prognostic factors, only GGI remained significant. Finally, the GGI outperformed the prognostic performance of MKI67 mRNA expression in a series of 1599 samples and 656 HG2 cases. Conclusions In this small pilot biomarker study ancillary to the PACS01 trial, the GGI outperforms the prognostic performance of centrally determined HG, MAI, Ki67 IHC status and mRNA expression. Further validation is warranted in larger series.

Background: Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast cancer (IBC) (Sotiriou JNCI 2006). It is particularly useful in stratifying HG2 tumors into GG-1 (low grade) and GG-3 (high grade) tumors. In order to extend the applicability of GG on routinely-used formalin-fixed-paraffin-embedded (FFPE) samples, the original microarray MapQuant Dx® signature was converted into a RQ-PCR assay (PCR-GG). The study aimed at validating the grading classification performance of the newly developed PCR-GG test. Methods: Subsets of genes derived from the original GG were selected by testing their grading classification and prognostic performances using different classifiers on 15 independent public microarray data sets. 25 most-performing genes were quantified by RQ-PCR using a TaqMan assay on a training set consisting of 91 early IBC cases graded acc. to the Elston-Ellis recommendations, and classification performance of various combinations assessed. Analytical performance of the final reduced signature was assessed on 4 samples (5 RNA extractions and 3 RQ-PCR per sample) and used to define a 95% CI around the GG-1/GG-3 cut-off. Cases with a PCR-GG score falling into the 95% CI were considered “Equivocal” (Eq). Concordance with the MapQuant Dx® GG was assessed on 44 paired FFPE/frozen samples of the training set. Grade classification performance of the PCR-GG test was evaluated on an independent validation set of 396 FFPE samples retrieved from the Department of Pathology (2004 to 2010) of Institut Jules Bordet (Brussels, Be). FFPE samples from early invasive, N0, ER+, HER2−, ductal or lobular BC containing ≥30% inv. tumor cells were selected. Classification performance was evaluated on the whole cohort and by histological subtype. Results: The PCR-GG signature is based on the expression of 6 reporter and 3 reference genes. Most of the genes are overexpressed in grade 3 tumors and are associated with proliferation. The 9-gene PCR-GG showed a high concordance with the original GG microarray test (95%). 388 eligible cases were available for validation. 336 samples contained ≥30% inv. tumor cells and 322 were successfully amplified, corresponding to a 96% technical success rate. The HG1, HG2 and HG3 distribution in the validation cohort were 27%, 55% and 18% resp. PCR-GG reclassified 84% of all tumors (Table 1) with an overall concordance of 90% (92% HG1/GG-1 concordance and 88% HG3/GG-3). 82% of HG2 tumors were reclassified into 74% GG-1 and 26% GG-3. Overall concordance was 91% in the Ductal subset (comprising 84% of all cases) and 89% in the Lobular subset. Conclusion: The newly developed PCR-GG test composed of 9 genes can be performed on FFPE samples. It is highly concordant with HG and recapitulates the classification performance of the original 97-gene microarray GG test with 84% reclassified tumors. Further validation is planned on the BIG 1–98 cohort. Applicability of GGI on FFPE samples will open its use in routine clinical practice. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-08.

Background: The Nottingham Prognostic Index (NPI) is a clinically validated prognostic model which predicts survival for patients with early primary breast cancer. The NPI combines information on tumor size, lymph node stage and tumor grade and stratifies patients into risk groups useful for treatment decisions. Classically, NPI defines 5 risk categories: Excellent, Good, Moderate I, Moderate II and Poor Prognostic Group (EPG, GPG, MPGI, MPGII and PPG). However, the value of NPI to identify EPG patients has recently being challenged. The Genomic Grade Index (GGI) is a 97-gene test which has been shown to improve tumor grading by resolving the intermediate Histological Grade (HG) 2 tumors into high or low Genomic Grades. In this study, we investigated the potential of GGI to refine the NPI classification, and especially to discriminate patients with the lowest risk. Material and methods:Breast cancer microarray profiles from node negative, untreated patients with the required clinical and pathological information were retrieved from 3 public databases. GGI was calculated using the Ipsogen MapQuant Dx® protocol which defines two classes, GG1 and GG3 (results falling in the CI are reported as Undetermined, “UD”). Standard NPI was calculated based on HG according to the usual formula: [0.2 x tumor size (cm) + HG(1-3) + LN stage (I-III)]. NPI scores were also calculated using GGI (“G-NPI”): the HG was replaced by the GG in the equation, and UD patients were given a value of 2 for tumor grade. Patients were classified into prognostic groups (cut-offs 2.4, 3.4 and 5.4) for both NPI (EPG, GPG, MPG and PPG) and G-NPI (G-EPG, G-GPG, G-MPG and G-PPG). NPI and G-NPI risk classifications were compared and prognostic performances were analyzed using Kaplan Meier survival curves (10-yr MFS). Results:Unique microarray expression profiles with adequate MapQuant Dx® quality criteria and relevant clinical information were identified for 472 patients. HG was distributed as follows: 18 % HG1, 52 % HG2 and 30% HG3 with size ranging from 0.1 to 6 cm (mean = 2.1 cm). HG2 cases (n=246) were reclassified into 47% GG1 and 28% GG3, with 25% remaining UD. There were no patients classified in the PPG, using the standard NPI or the G-NPI. Comparison of risk group classification showed that G-NPI globally shifted patients from low to better prognostic groups: 28% of patients were classified in the G-EPG as opposed to only 12% in the EPG [Table 1]. Within the HG2 subgroup, none of the patients were classified in the EPG by standard NPI, while 75 patients were classified in this group by G-NPI. In the entire cohort, EPG and G-EPG 10-yrs MFS were comparable (82 and 88% resp.). In the HG2 subgroup, 10-yrs MFS was 92% for the G-EPG, 87 % for the G-GPG and 57% for the G-MPG. Conclusion: Using GGI to calculate NPI scores provides additional information compared to standard NPI. This is particularly true in the HG2 group where G-NPI is able to identify patients matching the EPG definition with a 92% 10-yr MFS. Combining genomic information with NPI may facilitate adjuvant therapy decision making. This approach deserves further validation. Prognostic Group Classification according to classic NPI and G-NPI Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-08.

Background: Elston-Ellis grading (EE) is one of the key criteria for adjuvant therapy decision in ER+/HER2-/pN0/pT1 -2 tumors. The genomic grade index (GGI) is a 97-gene micro-array assay able to identify tumors of high or low genomic grade. GGI has been developed in order to improve the prognosis determination, especially in EE2 tumors which represent a significant proportion of breast carcinomas and where the inter-assessor variability is the highest. The aim of the present study was to model the influence of the GGI on adjuvant treatment decision in EE2 patients, using a cohort of ER+/HER2-/pN0/pT1-2 tumors. Methods: A randomly selected series of pT1-2, pN0 breast cancers from the Institut Curie 1995-1996 cohort was profiled using Affymetrix HGU133 Plus 2.0 gene chips. The GGI was calculated using Ipsogen Mapßuant Dx®. Treatment decisions were made for EE2 cases based on the Institut Curie adjuvant treatment guidelines (www.curie.fr). The treatment decision algorithm was firstly run using the grade as defined by Elston Ellis, and secondly using the GGI (undetermined cases were classified as grade2). Results: Out of 72 EE2 tumors, 35 were classified as GGI-1 (49%) and 13 (18%) as GGI-3. Based on EE, 7% of patients would have received adjuvant chemotherapy (ACT) alone (all were ER-/PR-), 50% adjuvant hormonal therapy (AHT) alone, and 43% both. Using the GGI, 7% (n=5) of patients would have been spared AHT and 10% (n=7) ACT. In the ER+/HER2- subgroup of 62 pts, 58% of patients would have received AHT alone and 42% AHT+ACT based on EE; GGI would have lead to a 14% reduction in AHT prescription and to a 26% reduction in ACT prescription. Conclusion: Applying the Genomic Grade Index instead of the Elston Ellis Grade to determine the adjuvant treatment strategy in a series of EE2/ER+/HER2-/pN0/pT1-2 breast carcinomas would lead to a 14% and 27% reduction in the administration of, respectively, adjuvant hormone-therapy and chemotherapy. Adjuvant treatment decision: models based on Elston-Ellis or Genomic Grading Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-11.

Introduction Mutations in isocitrate dehydrogenase genes IDH1 or IDH2 are frequent in glioma, and IDH mutation status is a strong diagnostic and prognostic marker. Current IDH mutation screening is performed with an immunohistochemistry (IHC) assay specific for IDH1 R132H, the most common mutation. Sequencing is recommended as a second-step test for IHC-negative or -equivocal cases. We developed and validated a new real-time quantitative polymerase chain reaction (PCR) assay for single-step detection of IDH1 R132H and 11 rare IDH1/2 mutations in formalin-fixed paraffin-embedded (FFPE) glioma samples. Performance of the IDH1/2 PCR assay was compared to IHC and Sanger sequencing. Results The IDH1/2 PCR assay combines PCR clamping for detection of 7 IDH1 and 5 IDH2 mutations, and Amplification Refractory Mutation System technology for specific identification of the 3 most common mutations (IDH1 R132H, IDH1 R132C, IDH2 R172K). Analytical sensitivity of the PCR assay for mutation detection was

1. 1. The motor effect of the α2 adrenoreceptor antagonist, idazoxan, was compared to that of L-dopa in MPTP-treated monkeys. 2. 2. Idazoxan 2.0 mg/kg improved parkinsonian motor abnormalities which was comparable to the effects of a minimal effective dose of L-dopa. 3. 3. At 2.0 and 5.0 mg/kg, the parkinsonian rigidity was the item most frequently alleviated by idazoxan (respectively 63.6% and 68.2%). 4. 4. These findings provide support for the therapeutic utility of α2 antagonists in the treatment of Parkinson's disease.

We have tested, in a prospective randomized, double-blind, placebo-controlled, crossover, 12-week study, the effects of 2 mg efaroxan, a potent alpha-2 antagonist, given three times per day to 14 patients with progressive supranuclear palsy. Efaroxan did not induce any significant change on any motor assessment criteria. The present data do not confirm the assumption that the blockade of alpha-2 receptors might be a useful pharmacologic strategy to improve patients with progressive supranuclear palsy.

Postmortem studies have shown that noradrenergic neurotransmission is impaired in Parkinson’s disease. This abnormality may have functional importance because (α2-adrenoceptor antagonists, which increase central noradrenergic transmission, improve motor behaviour in various animal models of this disease. Pilot clinical data suggest that (α2-antagonists may indeed have several potential indications in the treatment of Parkinson’s disease: (i) 3 recent placebocontrolled studies reported an improvement in motor scores following short term intravenous or long term oral administration of two different (α2-antagonists (idazoxan and efaroxan), suggesting that both drugs provide symptomatic benefit with regard to motor symptoms, especially rigidity and akinesia; (ii) an acute oral challenge with idazoxan reduced the severity of ‘peak-dose’ levodopa-induced dyskinesia, one of the most disabling complications of long term therapy with that drug, in a placebo-controlled study; (iii) biochemical and pharmacological experiments have suggested that levodopa-resistant parkinsonian symptoms, such as frozen gait, cognitive dysfunction, depressive state and dysautonomia, could be improved by enhancing central noradrenergic function; however, controlled clinical studies are necessary to evaluate the usefulness of (α2-adrenoceptor antagonists in these indications; and (iv) some preliminary experimental data support the hypothesis that noradrenergic mechanisms could be involved in the progression of Parkinson’s disease; thus, there is a rationale for testing the putative neuroprotective effects of (α2-adrenoceptor antagonists in this disorder. It has yet to be determined whether the antiparkisonian effects of (α2-antagonists are due to a direct effect of noradrenaline (norepinephrine) on motor systems or to an indirect effect, by means of noradrenergic interactions with dopamine or other neurotransmitters controlling motor behaviour or via other mechanisms. A careful evaluation of (α2-antagonists in the treatment of Parkinson’s disease must also consider their potential adverse effects, because these drugs possess cardiovascular and psychiatric properties which might compromise their risk-benefit ratio.

Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. Methods: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS). Results: A total of 166 patients were classified by GG. HG classified 33 (20%) tumors as HG1, 120 (73%) as HG2 and 12 (7%) as HG3. GG classified 106 (64%) tumors as GG low (GG1), 29 (17%) as GG high (GG3) and 31 (19%) as equivocal (cases not classified as GG1 or GG3). The median follow-up time was 6.5 years. In multivariate analyses, GG was associated with IDFS [HRGG3 vs GG1 5.6 (2.1-15.3); P < 0.001] and OS [HRGG3 vs GG1 7.2, 95% CI (1.6-32.2); P = 0.01]. Conclusions: GG outperformed HG in ILC and added prognostic value to classic clinicopathologic variables, including nodal status

BackgroundGenomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score.MethodsA series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R).ResultsGG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02).ConclusionsIn a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma.

The benefit of adjuvant chemotherapy (CT) added to hormonal therapy (HT) compared with HT alone remains debated for women >70 with ER+ HER2- breast cancer (BC). Selection of valid indications might be improved by the use of better prognosticator. This trial compares the impact of both strategies on overall survival (OS) according to Genomic Grade (GG). Following surgery, ∼2,000 patients (Pts) will have a GG performed centrally on FFPE specimens by RT-PCR. Those with a high risk (high or equivocal GG) will be randomized to HT alone vs CT+HT. Pts with a low GG will be followed as an observational cohort. OS (all deaths) is the primary endpoint. Secondary objectives include competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimension, willingness and health-related quality of life including specific ELD15. Translational research will focus on prognostic biomarkers and pharmacogenetics. Statistical design: sample size based on 4-year OS benefit favouring CT (87.5 vs 80%; HR 0.60); bilateral test α=0.05, β=0.20; 129 events expected in 700 randomized Pts enrolled over 4 years. From 04/12-05/14, 67 centres in France and Belgium have included 990 Pts aged 70-92. Only 31 GG evaluations were not performed (tumour blocks not available, 14; consent withdrawal or central pathology review discordance, 7 each; treatment choice, 3). In the main recruiting site, the study was not proposed to 20% of pre-screened Pts mostly because of team choice (50%) and inclusion criteria (25%). Amongst those informed, 66% accepted to participate. Median time to get GG information was 17 days (11-25) from sending tumour sample to providing the information to patient. Of 932 cases with GG report, 374 (40%), 187 (20%) and 362 (39%) were low, equivocal and high GG respectively; 9 tests (1%) failed for technical reasons. The proportion of high-risk tumours (high/equivocal GG 59%) is similar to that observed in general BC populations (40% to 60%) and only 21 of high-risk cases were not randomized (consent withdrawal, 6; treatment choice, 5; laboratory values, 4; tumour phenotype not confirmed or distant metastasis, 3 each). With 75% of target recruitment in < 2 years, we confirm the feasibility of such innovative multicentre program in an usually underserved population. This might help to better select adjuvant strategy in the elderly BC population and to avoid jeopardising any benefit if stymied by uncontrolled side effects. Citation Format: Coraline Dubot, Emmanuelle Bourbouloux, Olivier Mir, Sylvie Kirscher, Olivier Rigal, Jean-Marc Ferrero, Herve Cure, Emmanuel Blot, Djelila Allouache, Paul Cottu, Gilles Romieu, Claudia Lefeuvre, Emmanuelle Malaurie, Nicole Tubiana-Mathieu, Magali Lacroix-Triki, Florence Rollot, Hélène Peyro-Saint-Paul, Christine Orsini, Franck Bonnetain, Etienne Brain. ASTER 70s UNICANCER phase III trial: Can a genomic prognosticator help tailoring adjuvant systemic treatment for luminal breast carcinoma in elderly women? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-3-02.

To the editor: We have analyzed with great interest the recent correspondence by Warshawsky et al describing 2 cases of myeloproliferative neoplasms (MPNs) where the Ipsogen MutaScreen kit failed to identify JAK2 V617F mutations when another variant was present.[1][1] These variants were, however

606 Background: Genomic grade index (GGI) is a 97-gene signature which improves accuracy and prognostic value of histological grading (HG) in invasive breast carcinoma (IBC). GGI is particularly useful in segregating HG2 tumors into low or high Genomic Grade (GG1 and GG3). We aimed at prospectively evaluating the feasibility to implement GGI in routine practice with the primary objective of obtaining GGI in at least 80% of fresh tumor samples collected at surgery. Secondary objectives include GGI classification performance and impact on treatment recommendations. Methods: Eligible patients were pT1pT2 or operable pT3, N0-3 IBC. Fresh surgical samples with a H&E slide representative of the tumor specimen were sent at room temperature in the MapQuantKit for centralized analysis. Genomic profiles (Affymetrix U133 Plus 2.0) were determined for samples containing ≥ 30% invasive tumor cells and GGI calculated using the Ipsogen MapQuantDx protocol, which defines tumors as GG1 or GG3. Results: Between Jan and Dec...

535 Background: The utility of histological grade (HG) in invasive lobular carcinoma (ILC) remains controversial as one of the 3 Elston-Ellis components (tubule formation) is not present. Pleomorphic ILC (PILC) is a subtype of ILC characterized by an aggressive clinical behaviour. Genomic grade index (GGI) is a 97-gene signature which improves the accuracy and prognostic value of HG in invasive ductal carcinoma. It is particularly useful in segregating HG2 tumors into low and high genomic grade (GG1 and GG3). In the current study we evaluated the ability of GGI to grade ILC, and hypothesized that GGI would have prognostic value in ILC. Methods: A consecutive series of tumors diagnosed at Institut Jules Bordet, Brussels between 1995 and 2005 as early stage ILC was selected. Gene expression data were generated from frozen tumor samples using Affymetrix U133 Plus 2.0 arrays. GGI was calculated using the Ipsogen MapQuant Dx protocol, which defines tumors as GG1 or GG3; non classified cases are reported as UD ...