Joseph Gligorov

First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity

BackgroundIMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8+ T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4.MethodsMBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m2 at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses.ResultsThirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group.ConclusionsThe absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens.Trial registrationClinicalTrials.gov NCT00349934

MMP2 and MMP9 serum levels are associated with favorable outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study

Purpose Addition of bevacizumab to trastuzumab-based neoadjuvant chemotherapy in HER2-positive inflammatory breast cancer (IBC) was associated with favorable outcome in the BEVERLY-2 phase II trial. Circulating levels of matrix metalloproteinases (MMP) 2 and 9 were correlated to high response rate and prolonged survival in high-grade glioma treated with bevacizumab. We examined the prognostic impact of MMP2 and MMP9 serum levels in BEVERLY-2 patients. Experimental design MMP2 and MMP9 serum levels were assessed using ELISA at baseline and before surgery in 45/52 available samples. Correlations were tested with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Results Baseline (b) MMP2 and MMP9 serum levels were independent from patient characteristics and circulating tumor or endothelial cells, and were not correlated to pCR. High bMMP2 was correlated to better DFS (p=0.001) and OS (p=0.032), while low bMMP9 was correlated to better OS (p=0.022) and tended to be associated with longer DFS (p=0.071). In multivariate analyses, bMMP2 (p=0.003, Hazard Ratio [HR]: 0.115) and bMMP9 (p=0.041, HR: 3.511) remained correlated to DFS. As continuous variables, bMMP2 was associated with relapse (p=0.002) and death (p=0.049), while bMMP9 was associated with death (p=0.035). During treatment, significant increase in MMP2 and decrease in MMP9 levels (p<0.001 for both) were observed in 100% and 87% of patients respectively. Conclusions High bMMP2 and low bMMP9 serum levels were associated with better survival in HER2-positive IBC patients treated with bevacizumab- and trastuzumab-based neoadjuvant chemotherapy. Their predictive value of bevacizumab benefit should be evaluated in a randomized trial.

[Node negative breast cancer. Beyond international consensus: a pragmatic approach].

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.

Renovascular safety of sunitinib in renal cell carcinoma: The prognostic value of hypertension and proteinuria

Background The potential prognostic value of hypertension and proteinuria of anti- vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in metastatic renal cell carcinoma (mRCC). The objectives were to (i) assess the prevalence of proteinuria and hypertension at baseline; (ii) their incidence under anti-VEGF drug treatment; and (iii) evaluate a possible link with overall survival. Methods Patients from 8 centers were included between 2009 and 2011 with a follow-up of 1 year. They were naïve of any previous anti-VEGF drug treatment and planned to be started on one. The results of the group of patients with mRCC receiving sunitinib are presented. Results A total of 1,124 patients were included, among whom 137 had mRCC and 112 received sunitinib. At inclusion, hypertension prevalence was 44%, proteinuria 16%, hematuria 8%, mean modification of diet in renal disease (MDRD) formula 69 mL/min/1.73m2. The incidence of de novo proteinuria and hypertension during follow-up was 75% and 21%, respectively. Among patients with de novo proteinuria, 76% afterwards improved/normalized. Mean MDRD was 72 at the end of follow-up. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria or hypertension were not associated with OS in mRCC patients treated with sunitinib. Conclusions These results showed that (i) hypertension and proteinuria were frequent at baseline in mRCC patients; (ii) de novo hypertension and proteinuria frequently occur under sunitinib treatment; and (iii) neither hypertension nor proteinuria, either at baseline or de novo, were associated with overall survival in our cohort of “real-life” patients.

Innovations en oncologie : la tomosynthèse mammaire

L’imagerie par tomosynthese mammaire est une innovation technologique recente en imagerie permettant une analyse volumique du sein en utilisant une imagerie par rayons X. De nombreuses etudes ont montre son interet, non seulement pour ameliorer la detection des cancers, mais egalement pour optimiser la caracterisation lesionnelle permettant d’ameliorer significativement la sensibilite et la specificite de la mammographie. Technique irradiante, elle est actuellement utilisee en France en complement de la mammographie, ce qui pose un probleme important de surcroit d’irradiation. Le developpement d’une nouvelle technique de mammographie reconstruite a partir des donnees de tomosynthese (ou mammographie 3D) est tres prometteur et pourrait dans l’avenir remplacer la mammographie classique bidimensionnelle (mammographie 2D).

Résistance aux traitements antihormonaux : théorie et pratique

Le cancer du sein est un cancer dit hormonodependant dans la majorite des cas. Historiquement, la demonstration de l’interet therapeutique d’une manipulation hormonale ayant un impact therapeutique antitumoral et l’emergence, de ce fait, d’une strategie de traitement cible, expliquent les progres realises depuis pres d’un siecle sur la comprehension des voies de signalisation impliquees dans la sensibilite et la resistance a ces traitements. Les progres scientifiques ont permis non seulement le developpement de nouvelles classes therapeutiques ciblant soit le recepteur des œstrogenes, soit la synthese de ces œstrogenes, mais egalement une serie de medicaments visant des proteines impliquees dans les mecanismes de resistance a ces traitements. Toutefois, l’impact de ces traitements et leur mise en perspective strategique demeurent compliques et necessitent une meilleure comprehension non seulement des mecanismes de resistance, mais egalement des populations etudiees dans les essais explorant ces strategies, afin de definir au mieux leur interet et leur positionnement en clinique.

Étude prospective de l’impact de l’utilisation du test de 21 gènes, le Recurrence Score, sur les décisions thérapeutiques prises chez les femmes ayant un cancer du sein à un stade précoce HER2 négatif et avec des récepteurs aux œstrogènes positifs

Le test de 21 genes, OncotypeDX® — Recurrence Score® (RS), est un test valide qui aide a choisir le meilleur traitement chez des femmes ayant un cancer du sein a un stade precoce Her2-negatif et avec des recepteurs aux oestrogenes positifs en situation adjuvante. Les attitudes therapeutiques varient considerablement entre les pays. Cette etude multicentrique est la premiere a evaluer l’impact de l’utilisation du tests OncotypeDX® dans le contexte francais.

Catégorisation des décisions hors «référentiel de pratiques cliniques»: Une application à la prise en charge des cancers du sein avec le système OncoDoc2

Despite multidisciplinary staff meetings (MSMs) and the publication of clinical practice guidelines (CPGs), actual cancer management may still vary from guideline-based recommendations. Motivations that support non-compliance with guidelines are not well characterized. From the model of evidence-based medicine practice elaborated by Haynes et al. (2002), we propose a categorization of the reasons that lead to non-CPG-compliant decisions. Theses reasons are classified as particular case, patient choice, MSM choice, and evolution of practices. OncoDoc2 is a clinical decision support system developed to deliver the “CancerEst” local guideline recommendations on breast cancer management used at the Tenon hospital, Paris, France. After a before/after intervention study in 2005– 2006, OncoDoc2 has been routinely used at Tenon, during weekly MSMs in the sake of quality management. After nearly 3 years, a high CPG adherence rate has been maintained over 90%. An evaluation of non-compliant decisions has been performed according to the proposed categorization illustrating that a 100% adherence rate would be neither reachable, nor desirable.

Les traitements oncologiques actuels permettent-ils une meilleure préservation de la fertilité ? Les progrès en chimiothérapie et radiothérapie

Le cancer du sein est le cancer de la femme le plus frequent dans nos pays industrialises. Les progres realises ces dernieres annees ont permis une amelioration notable des guerisons. On estime en gain absolu le benefice de la chimiotherapie comme permettant la guerison d’au moins 15 % de patientes en plus par rapport aux traitements locoregionaux seuls. Le tamoxifene et le trastuzumab ciblant respectivement les recepteurs estrogeniques (2/3 des cancers du sein) et le recepteur HER2 (1/5 des cancers du sein) reduisent encore de moitie le risque de survenue d’une recidive. L’ensemble de ces progres permettent aujourd’hui d’ecrire que le cancer du sein est probablement, en depit de sa frequence, l’un des cancers ou l’espoir de guerison est le plus important. Ces progres s’accompagnent toutefois d’un risque accru d’infertilite ce qui constitue un probleme capital dans une population jeune comme celle des femmes non menopausees.