Downregulating the leukocyte adhesion molecules expressed by endothelial cells that line tumor blood vessels can limit the entry of immune effector cells into the tumor mass, thereby contributing to tumoral immune escape. Egfl7 (also known as VE-statin) is a secreted protein specifically expressed by endothelial cells in normal tissues and by cancer cells in various human tumors. High levels of Egfl7 correlate with higher tumor grade and poorer prognosis. Here we show that expression of Egfl7 in breast and lung carcinoma cells accelerates tumor growth and metastasis in immunocompetent mice but not in immunodeficient mice. Tumors expressing Egfl7 were infiltrated relatively poorly by immune cells and were characterized by reduced levels of immunostimulatory cytokines ] and fewer endothelial adhesion molecules [intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)]. In vitro studies revealed that Egfl7 inhibited the expression of leukocyte adhesion molecules by endothelial cells, preventing lymphocyte adhesion. In contrast, Egfl7 did not exert any effects on immune cell activation. Human breast cancer lesions expressing high levels of Egfl7 also expressed less ICAM-1 and VCAM-1 in their blood vessels, also indicating an inverse correlation between expression levels of Egfl7 and IFN-g. Thus, Egfl7 expression in tumors promotes tumor progression by reducing the expression of endothelial molecules that mediate immune cell infiltration. Our findings highlight a novel mechanism through which tumors escape immune control. Cancer Res; 71(23); 7176-86. Ó2011 AACR.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

Purpose: Leptin and obesity are clearly related, and obesity is associated with an increased risk of breast cancer. We therefore measured the expression of leptin and its two main receptor isoforms, OBR-L and OBR-S, in 322 breast cancers. We analyzed their relations with the classical prognostic factors and with survival to establish their links with breast cancer. Experimental Design: The expression of leptin and its receptors was quantified by real-time reverse transcription-PCR, usingTaqMan fluorogenic probes and an ABI PRISM 7700 sequence detector system (Applied Biosystems, Courtaboeuf, France). TATA box binding protein was used to normalize expression.The human breast cancer cell, SK-BR-3, expressing the three targets, was chosen as the calibrator sample (i.e., target expression = 1). Results: All the tumors expressed both receptors, and 318 of 322 expressed leptin. These three variables correlated positively with each other and with estradiol and progesterone receptors, whereas they correlated negatively with histoprognostic grading and tumor diameter. OBR-L/ OBR-S expression was inversely correlated with progesterone receptors. Patients with elevated OBR-S expression had longer relapse-free survival (P = 0.008), whereas high OBR-L/OBR-S was associated with a shorter relapse-free survival (P = 0.05). In Cox multivariate analyses, OBR-S maintained its prognostic value (P = 0.02; relative risk, 0.51).Conclusions: This study shows that (a) almost all of the breast cancers coexpress leptin and its two main isoforms of receptors, suggesting that the human epithelial breast cancer cells respond to leptin acting via an autocrine pathway; (b) high expression levels of leptin and leptin receptors are biological markers of a more differentiated phenotype; and that (c) OBR-S is an independent prognostic factor.

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The aim of this study was to prospectively evaluate the predictive value of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to detect the absence of pathological response to preoperative chemotherapy in patients (pts) with breast cancer. 63 consecutive pts with non-metastatic, non-inflammatory breast cancer, eligible for neoadjuvant chemotherapy (3 FEC 100 followed by 3 Docetaxel) were enrolled. FDG-PET was performed just before the first as well as before the second course. Metabolic activity (tumour FDG uptake) was measured by standardised uptake value (SUV(max)). Pts were classified as non-responders (NR) when the decrease of SUV(max) in the primary tumour was less than 15% at the time of the second PET (EORTC 1999 criteria). The metabolic response in FDG-PET was correlated with WHO criteria (clinical evaluation and ultrasound and/or mammography) evaluated after three cycles, pathological complete response (pCR) after surgery (according to Sataloff classification) and 4-year relapse-free survival (RFS). The mean SUV(max) decrease according to histological response was -52 ± 21% in case of pCR (Sataloff A) and 25 ± 34% in other cases (Sataloff B + C + D). Out of the 16 pts with no PET response (SUV decrease less than 15%), only one had a clinical response after the third cycle, and no pCR was observed. The 4-year RFS rate was significantly longer for metabolic responders than for NR (respectively, 85 vs. 44%; P = 0.01). This prospective study shows that a decrease in the SUV of less than 15% after the first chemotherapy course is a very potent predictor for failure of neoadjuvant chemotherapy, especially of pCR. It is interesting to note that this was shown despite the fact that the chemotherapy regimen was changed after the third course.

Abstract. Egfl7 (VE-statin) is specifically expressed by endothelial cells of normal tissues but its expression is deregulated in human cancers. Analysis of expression of Egfl7 protein and transcripts in 211 human breast cancer samples shows that Egfl7 is strongly expressed by breast tumor cells. Egfl7 expression is significantly higher in invasive ductal than in invasive lobular carcinoma. Expression of Egfl7 transcripts is also higher in lower SBR grade lesions and in lesions which are not associated with lymph node invasion. Within the invasive ductal carcinoma sub-population, expression of Egfl7 transcripts is correlated with the SBR score and with the ER + status. High transcript and Egfl7 protein levels significantly correlate with the absence of axillary lymph node invasion. In lymph nodes, the levels of Egfl7 are correlated with the histological type of the primary lesions; they are higher in ductal than in lobular carcinoma. Egfl7 expression is thus associated with better prognosis factors and with the absence of lymph node invasion in human breast cancer lesions.

Tumor 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.

Forty-two evaluable pediatric patients with a variety of recurrent primary brain tumors participated in a phase II ifosfamide trial. Their mean age was 10 years. All patients were treated with ifosfamide, 3 g/m2/day for 2 days every 2 weeks. Response was assessed on clinical and radiological criteria after at least 2 courses of therapy. The overall response rate was 12% (5/42). One complete and 2 partial responses were documented in 21 patients with medulloblastoma. A partial response was demonstrated in 1 patient with primitive neurectodermal tumor (PNET) and in 1 patient with ependymoma. No activity was observed in astrocytic tumors. Toxicity was primarily neurologic (16 out of 54 patients, 30%). Hematological toxicity, without severe morbidity, was encountered in 9% of courses (16/179). Ifosfamide, administered at this dose regimen has modest efficacy in the treatment of recurrent childhood medulloblastoma and ependymoma and appears inactive for gliomas. Further trials with other dose schedules are necessary to assess the activity of this drug. However, according to the neurotoxicity observed in our trial, we would not recommend building a protocol using ifosfamide for highly progressive brain tumors.