Brain metastasis and renal cell carcinoma : prognostic scores assessment in the era of targeted therapies

Aim: This study aimed at exploring several brain metastatic prognostic scores in patients with renal cell carcinoma. Patients and Methods: We retrospectively analyzed data of 93 metastatic renal cell carcinoma patients who were diagnosed with brain metastases between October 2005 and July 2016 who received targeted therapy. Potential prognostic factors (RTOG RPA, BS-BM, and a newly developed score CERENAL) were analyzed. Results: A total of 75 patients received targeted therapy. All scores showed prognostic value in progression-free survival after first-line treatment with CERENAL being the sole independent prognostic factor associated with improved duration of first-line treatment. Both RTOG RPA and CERENAL were potential prognosticators for overall survival, whereas only the CERENAL score was associated with prolonged disease-specific survival. Conclusion: Several prognostic scores can be useful to predict survival of patients with brain metastases from renal cancer, especially the newly developed CERENAL score

Evaluation des Single Nucleotide Polymorphisms comme facteurs prédictifs de réponse histologique complète à la chimiothérapie néoadjuvante dans le cancer du sein

Contexte : La chimiothérapie néoadjuvante (NCT) à base d anthracyclines et de taxanes est le traitement standard dans le cancer du sein localement avancé ou inflammatoire. Son efficacité est évaluée par la réponse histologique complète (pCR), élément pronostique majeur. Les variations interindividuelles de réponse au traitement peuvent être expliquées par les single nucleotide polymorphisms (SNP). L objectif de notre étude était d identifier les SNP prédictifs de pCR à la NCT dans le cancer du sein. Méthode : Entre novembre 2007 et janvier 2012, 191 patientes (pts) suivies au Centre Oscar Lambret (COL) de Lille pour un adénocarcinome mammaire en situation néoadjuvante ont été incluses : 118 traitées par une chimiothérapie séquentielle associant FEC100 et Docétaxel (TXT), et 46 par FEC100, TXT et Trastuzumab. Les 46 SNP décrits dans la littérature comme facteurs prédictifs potentiels de réponse ont été testés. Le génotypage a été réalisé sur un prélèvement de sang total, en utilisant une discrimination allélique avec SNPType assays (Fluidigm) et TaqMan assays (Life Technologies) sur la plateforme BioMark (Fluidigm). Les caractéristiques cliniques et histologiques ont été comparées par le test du Chi2. L association entre la pCR selon Sataloff et les 3 génotypes de chaque SNP, isolés puis combinés, a été étudiée par régression logistique. Résultats : Dans la population traitée par FEC100 - TXT, 25 pts sur 118 (21.2%) présentent une pCR. Ce taux est plus élevé parmi les tumeurs de grade III (p=0.009), récepteurs hormonaux négatifs (p=0.005) et triple négatives (p=0.006). 4 SNP sont associés à la pCR dans ce groupe : BRCA1 rs799917 (au moins un allèle T : OR=3.15, IC95(1.04-9.6)), CYP1B1 rs1056836 (pts homozygotes CC ou GG, p=0.02), ERCC1 rs11615 (au moins un allèle C : OR=3.63 ; IC95(1.15-11.5)), SLCO1B3 rs11045585(au moins un allèle G, OR=2.77, IC95 (1.10-6.7)). L analyse multivariée retrouve un taux de pCR doublé pour les patients porteurs des génotypes ERCC1-CT et CYP1B1-CC (OR=8.5 (1.6-46)), résultat restant significatif après ajustement au statut RE (p=0.05). La pCR est liée à 4 SNP chez les pts surexprimant Her2 traités par chimiothérapie et trastuzumab. Conclusion : Plusieurs SNP sont significativement liés à la pCR après NCT par anthracyclines et taxanes dans le cancer du sein. ERCC1 est lié à la pCR dans les tumeurs ER+, ER- et Her2 positives, même si les génotypes associés diffèrent dans chaque groupe. Enfin, la combinaison ERCC1-CT/CYP1B1-CC semble intéressante pour prédire la réponse à la NCT dans la population sans surexpression Her2.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

High expression levels of egfl7 correlate with low endothelial cell activation in peritumoral vessels of human breast cancer

International audienceTumor blood vessels participate in the immune response against cancer cells and we previously used pre-clinical models to demonstrate that egfl7 (VE-statin) promotes tumor cell evasion from the immune system by repressing endothelial cell activation, preventing immune cells from entering the tumor mass. In the present study, the expression levels of egfl7 and that of ICAM-1 as a marker of endothelium activation, were evaluated in peritumoral vessels of human breast cancer samples. Breast cancer samples (174 invasive and 30 in situ) from 204 patients treated in 2005 were immunostained for CD31, ICAM-1 and stained for egfl7 using in situ hybridization. The expression levels of ICAM-1 and egfl7 were assessed in peritumoral areas using semi-quantitative scales. There was a strong and significant inverse correlation between the expression of ICAM-1 and that of egfl7 in CD31 + blood vessels. When the ICAM-1 score increased, the egfl7 score reduced significantly (P=0.004), and vice-versa (Cuzick's test for trend across ordered groups). In order to determine which gene influenced the other gene between egfl7 and ICAM-1, the expression levels of either gene were modulated in endothelial cells. Egfl7 regulated ICAM-1 expression while ICAM-1 had no effects on egfl7 expression in the same conditions. Altogether, these results provide further results that egfl7 serves a regulatory role in endothelial cell activation in relation to immune infiltration and that it is a potential therapeutic target to consider for improving anticancer immunotherapies

Impact of early palliative care on overall survival of patients with metastatic upper gastrointestinal cancers treated with first-line chemotherapy: a randomised phase III trial

International audienceINTRODUCTION : Palliative care (PC) has usually been offered at the end-of-life stage, although the WHO recommends providing PC as early as possible in the course of the disease. A recent study has shown that early PC (EPC) provides a more meaningful effect on quality of life and, surprisingly, on overall survival (OS) than standard treatment for patients with metastatic lung cancer. Whether EPC benefits also apply to patients with metastatic upper gastrointestinal (GI) cancers is unknown.METHODS AND ANALYSIS : EPIC is a randomised phase III trial comparing EPC plus standard oncologic care versus standard oncologic care in patients with metastatic upper GI cancers. Its primary objective is to evaluate the efficacy of EPC in terms of OS. Its secondary objectives are to assess the effects of EPC on patient-reported outcomes (quality of life, depression and anxiety) and the effect of EPC on the number of patients receiving chemotherapy in their last 30 days of life. Assuming an exponential distribution of survival time, 381 deaths are required to ensure an 80% power for an absolute difference of 10% in 1 year OS rates (40% vs 50.3%, HR=0.75; log rank test two-sided alpha=5%), leading to a planned sample size of 480 patients enrolled over 3 years and a final analysis at 4 years. The main analysis will be performed on the intent-to-treat dataset.ETHICS AND DISSEMINATION : This study was approved by the 'Comité de Protection des Personnes Nord-Ouest I' (4 April 2016), complies with the Helsinki declaration and French laws and regulations and follows the International Conference on Harmonisation E6 (R1) Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals.TRIAL REGISTRATION NUMBERS : EudraCT: 2015-A01943-46; Pre-results. NCT02853474

Once weekly paclitaxel associated with a fixed dose of oral metronomic cyclophosphamide: a dose-finding phase 1 trial

International audienceBACKGROUND:The primary aim of this trial was to determine the recommended phase II dose (RP2D) of weekly paclitaxel (wP) administered in combination with oral metronomic cyclophosphamide (OMC).METHODS:Patients ≥ 18 years of age with refractory metastatic cancers were eligible if no standard curative measures existed. Paclitaxel was administered IV weekly (D1, D8, D15; D1 = D28) in combination with a fixed dose of OMC (50 mg twice a day). A 3 + 3 design was used for dose escalation of wP (40 to 75 mg/m2) followed by an expansion cohort at RP2D. Dose-limiting toxicity (DLT) was defined over the first 28-day cycle as grade ≥ 3 non-hematological or grade 4 hematological toxicity (NCI-CTCAE v4.0) or any toxicity leading to a dose reduction.RESULTS:In total, 28 pts. (18 in dose-escalation phase and 10 in expansion cohort) were included, and 16/18 pts. enrolled in the dose-escalation phase were evaluable for DLT. DLT occurred in 0/3, 1/6 (neuropathy), 0/3 and 2/4 pts. (hematological toxicity) at doses of 40, 60, 70 and 75 mg/m2 of wP, respectively. The RP2D of wP was 70 mg/m2; 1/10 patients in the expansion phase had a hematological DLT. At RP2D (n = 14), the maximal grade of drug-related adverse event was Gr1 in three patients, Gr2 in six patients, Gr3 in one patient and Gr4 in one patient (no AE in three patients). At RP2D, a partial response was observed in one patient with lung adenocarcinoma.CONCLUSION:The combination of OMC and wP resulted in an acceptable safety profile, warranting further clinical evaluation.TRIAL REGISTRATION:TRN: NCT01374620 ; date of registration: 16 June 2011

Additional file 1 of Once weekly paclitaxel associated with a fixed dose of oral metronomic cyclophosphamide: a dose-finding phase 1 trial

Table S1. Adverse events (treatment related or not) reported over the entire treatment duration (all patients, N = 28). Table S2. Characteristics and outcome of patient with lung cancer. (DOCX 31 kb