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Hurvitz S.A.,University of California at Los Angeles | Andre F.,University Paris - Sud | Jiang Z.,Beijing 307 Hospital of PLA | Shao Z.,Fudan University | And 16 more authors.
The Lancet Oncology | Year: 2015

Background: mTOR inhibition reverses trastuzumab resistance via the hyperactivated PIK/AKT/mTOR pathway due to PTEN loss, by sensitising PTEN-deficient tumours to trastuzumab. The BOLERO-1 study assessed the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer. Methods: In this phase 3, randomised, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were aged 18 years or older, with locally assessed HER2-positive advanced breast cancer, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, who had not received previous trastuzumab or chemotherapy for advanced breast cancer within 12 months of randomisation, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) or bone lesions in the absence of measurable disease, without previous systemic treatment for advanced disease except endocrine therapy. Patients were randomly assigned (2:1) with an interactive voice and web response system to receive either 10 mg everolimus once a day orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on day 1 with subsequent weekly doses of 2 mg/kg of each 4 week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4 week cycle. Randomisation was stratified according to previous use of trastuzumab and visceral metastasis. Patients and investigators were masked to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival in the full study population and in the subset of patients with hormone receptor-negative breast cancer at baseline; the latter was added during the course of the study, before unmasking based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final progression-free survival analyses are presented here. This trial is registered with ClinicalTrials.gov, number NCT00876395. Findings: Between Sept 10, 2009, and Dec 16, 2012, 719 patients were randomly assigned to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41·3 months (IQR 35·4-46·6). In the full population, median progression-free survival was 14·95 months (95% CI 14·55-17·91) with everolimus versus 14·49 months (12·29-17·08) with placebo (hazard ratio 0·89, 95% CI 0·73-1·08; p=0·1166). In the HR-negative subpopulation (n=311), median progression-free survival with everolimus was 20·27 months (95% CI 14·95-24·08) versus 13·08 months (10·05-16·56) with placebo (hazard ratio 0·66, 95% CI 0·48-0·91; p=0·0049); however, the protocol-specified significance threshold (p=0·0044) was not crossed. The most common adverse events with everolimus were stomatitis (314 [67%] of 472 patients in the everolimus group vs 77 [32%] of 238 patients in the placebo group), diarrhoea (267 [57%] vs 111 [47%] patients), and alopecia (221 [47%] vs 125 [53%]). The most frequently reported grade 3 or 4 adverse events in the everolimus group versus the placebo group were neutropenia (117 [25%] vs 35 [15%]), stomatitis (59 [13%] vs three [1%]), anaemia (46 [10%] vs six [3%]) and diarrhoea (43 [9%] vs 10 [4%]) On-treatment adverse event-related deaths were reported in 17 (4%) patients in the everolimus group and none in the placebo group. Interpretation: Although progression-free survival was not significantly different between groups in the full analysis population, the 7·2 months prolongation we noted with the addition of everolimus in the HR-negative, HER2-positive population warrants further investigation, even if it did not meet prespecified criteria for significance. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of adverse events in patients given everolimus and chemotherapy is crucial. Funding: Novartis Pharmaceuticals. © 2015 Elsevier Ltd.


Kaklamani V.G.,Northwestern University | Xu B.H.,Peking Union Medical College | Gomez H.L.,Instituto Nacional Of Enfermedades Neoplasicas
Expert Review of Anticancer Therapy | Year: 2011

Ixabepilone approval in a number of countries across the world as monotherapy and in combination with capecitabine has led to widespread uptake in the later-line breast cancer setting. However, individualized data for ixabepilone in different ethnic groups are limited. Overall, data from small numbers of ethnic subgroups including Hispanic, Japanese and Chinese patients have revealed no clinically significant variation in the disposition, efficacy or tolerability of ixabepilone from that established in pivotal trials. Global use of ixabepilone, while usually along the lines of standard practice, may vary because of local regulatory decisions, clinical practice guidelines and cost considerations. Further information on the global patterns of use of ixabepilone will assist in optimizing the use of this novel therapy. © 2011 Expert Reviews Ltd.


Balko J.M.,Vanderbilt University | Cook R.S.,Vanderbilt University | Vaught D.B.,Vanderbilt University | Kuba M.G.,Vanderbilt University | And 14 more authors.
Nature Medicine | Year: 2012

Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ∼30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy. © 2012 Nature America, Inc. All rights reserved.


Pow-Sang M.R.,Instituto Nacional Of Enfermedades Neoplasicas | Ferreira U.,University of Sao Paulo | Pow-Sang J.M.,H. Lee Moffitt Cancer Center and Research Institute | Nardi A.C.,Clinica Integra Urologia | Destefano V.,Instituto Nacional Of Enfermedades Neoplasicas
Urology | Year: 2010

An extensive literature search was performed using the key words squamous cell carcinoma of the penis, phimosis, circumcision, chronic balanitis, cigarette smoking, genital warts and human papillomavirus (HPV) infection. All selected studies were classified according to the level of evidence (LE). The final grades of recommendation were assigned after discussion by the full panel of the International Consultation on Penile Cancer in November 2008. The factors positively associated with invasive penile cancers include the presence of phimosis (LE 3a), tobacco smoking (LE 3a-4), chewing tobacco (LE 3a), injury to the penis (LE 3a), balanitis (LE 3a), genital warts (LE 3a), and high-risk HPV infection (LE 3a-4). © 2010 Elsevier Inc.


Rivera E.,Cornell University | Gomez H.,Instituto Nacional Of Enfermedades Neoplasicas
Breast Cancer Research | Year: 2010

Resistance to chemotherapy is a major obstacle to the eff ective treatment of many tumor types. Although many anticancer therapies can alter tumor growth, in most cases the eff ect is not long lasting. Consequently, there is a signifi cant need for new agents with low susceptibility to common drug resistance mechanisms in order to improve response rates and potentially extend survival. Approximately 30% of the women diagnosed with early-stage disease in turn progress to metastatic breast cancer, for which therapeutic options are limited. Current recommendations for fi rst-line chemotherapy include anthracycline-based regimens and taxanes (paclitaxel and docetaxel). They typically give response rates of 30 to 70% but the responses are often not durable, with a time to progression of 6 to 10 months. Patients with progression or resistance may be administered capecitabine, gemcitabine, vinorelbine, albumin-bound paclitaxel, or ixabepilone, while other drugs are being evaluated. Response rates in this setting tend to be low (20 to 30%); the median duration of responses is <6 months and the results do not always translate into improved longterm outcomes. The present article reviews treatment options in taxane-resistant metastatic breast cancer and the role of ixabepilone in this setting. © 2010 Rivera and Gomez; licensee BioMed Central Ltd.


Montes-Moreno S.,Hospital Universitario Marques Of Valdecilla | Ramos-Medina R.,Monoclonal Antibody Unit | Martinez-Lopez A.,Hospital Universitario Marques Of Valdecilla | Cornejo C.B.,Instituto Nacional Of Enfermedades Neoplasicas | And 8 more authors.
Blood | Year: 2013

SPIB is an Ets transcription factor that is expressed exclusively in mature B cells, T-cell progenitors, and plasmacytoid dendritic cells. In the present study, we developed a novel mAb against the SPIB protein and characterized its expression in major hematolymphoid neoplasms, including a series of 45 cases of blastic plasmacytoid dendritic cell (BPDC) neoplasms and their potential cutaneous mimics.We found that SPIB is expressed heterogeneously among B- and T-cell lymphoma types. Interestingly, SPIB is expressed in a large proportion of nongerminal center type DLBCLs. In cutaneous neoplasms, SPIB is overexpressed in all BPDC neoplasms, but none of its cutaneous mimics. SPIB remains overexpressed in all cases that lack 1 or 2 of the markers used for BPDC neoplasms (ie, CD4, CD56, TCL1, and CD123). We conclude that SPIB expression can be used as a tool for diagnosing BPDCneoplasms, but it needs to be tested in conjunction with the growing arsenal of markers for human plasmacytoid dendritic cells. © 2013 by The American Society of Hematology.


Piris M.A.,Hospital Universitario Marques Of Valdecilla | Cornejo C.B.,Instituto Nacional Of Enfermedades Neoplasicas
Blood | Year: 2013

In this issue of Blood, Quintanilla-Martinez and colleagues describe a series of Hydroa vacciniforme-like lymphoma (HVLL) and find that this is an Epstein-Barr virus (EBV)-associated lymphoproliferative disorder with a diverse (αβ-, γδ-, or NK-cell) phenotype and a broad clinical spectrum, in most cases showing a prolonged clinical course, but with a distinct risk for progression to systemic disease. © 2013 by The American Society of Hematology.


Dennison J.B.,University of Houston | Molina J.R.,University of Houston | Mitra S.,University of Houston | Gonzalez-Angulo A.M.,University of Houston | And 8 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. Experimental Design: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes - those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basallike subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006). Conclusions: Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy. ©2013 AACR.


Ruiz R.,Instituto Nacional Of Enfermedades Neoplasicas | Hunis B.,Florida International University | Raez L.E.,Florida International University
Current Oncology Reports | Year: 2014

Non-small-cell lung cancer usually carries a dismal prognosis. Novel treatment approaches are clearly warranted. Immunotherapy has emerged as a promising area of research developing agents that manipulate the immune system to induce antitumor responses while avoiding major toxicity. New vaccines and checkpoint inhibitors are currently undergoing investigation in phase II and phase III clinical trials. In advanced non-small-cell lung cancer (NSCLC), belagenpumatucel-L, an allogeneic cell vaccine directed against transforming growth factor β in the tumor microenvironment, knocks down the immune suppression caused by the tumor and has demonstrated a dose-and time-dependent efficacy in some subgroups of patients. LBLP25 and TG4010 are both antigenic vaccines that target mucin 1, whose encoding proto-oncogene is commonly mutated in solid tumors. The L-BLP25 vaccine achieved a significant improvement in overall survival in the subgroup of patients with stage IIIB NSCLC treated with chemoradiotherapy. TG4010 vaccination resulted in better progression-free survival when added to cisplatin-gemcitabine chemotherapy. These results are being addressed in the currently ongoing phase III TIME trial. In the adjuvant setting, MAGE-A3, an antigen-based vaccine, showed promising results in melanoma-associated antigen A3 positive lung cancer patients who underwent resection in the phase II study; however, no improvement in progression-free survival was observed in the phase III MAGRIT study. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. It has improved overall survival in patients with advanced NSCLC who achieve seroconversion. Ipilimumab, an immune checkpoint inhibitor that targets cytotoxic T-lymphocyte antigen 4, demonstrated improved progression-free survival in advanced NSCLC patients who received the drug after chemotherapy in a phased regimen. Finally, anti-programmed death receptor 1 agents have achieved durable response rates in phase I studies. This review gives an overview of the current data and the most promissory immunotherapeutic agents for NSCLC. © Springer Science+Business Media 2014.


All around the world, lung cancer is the most common cancer among men and women, followed by breast, colon and rectum, stomach, and liver cancer. It affects most frequently people in their 50s and 60s, and tobacco consumption is the risk factor most strongly associated to the development of this type of cancer. It is most common among men; however, the prevalence among women has increased over the last ten years. Imaging tests for diagnosis include positron emission tomography (PET) with computed-tomography fusion, and transesophageal and bronchoscopic ultrasound, as the most relevant. Among the early detection techniques, the low-dose helical tomography stands out. However, it has not been able to prove to be useful as a screening tool. Conventional methods for diagnostic confirmation of lung cancer are bronchoscopy and percutaneous needle aspiration biopsy. The most common histologic type is the adenocarcinoma, being clinical stages III and IV being the most frequently found. At early clinical stages, surgical treatment has proven to be effective, and there is a good 5-year survival rate. In late stages, chemotherapy and radiotherapy are the most useful treatment methods to control the disease and palliate cancer signs and symptoms. Research in genomic analysis may provide a better understanding of cancer genetics, and therefore, new therapeutic strategies in the future.

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