Menée sur une cohorte espagnole incluant 741 patients atteints d'un cancer de la prostate traité par radiothérapie externe puis sur deux cohortes de réplication incluant au total 1 001 autres patients, cette étude d'association sur le génome entier identifie sur le chromosome 2q24.1 un locus de susceptibilité associé à la toxicité à long terme de la radiothérapie

A three-stage genome-wide association study identifies a susceptibility locus for late radiotherapy toxicity at 2q24.1

Fachal, Laura ; Gomez-Caamano, Antonio ; Barnett, Gillian C. ; Peleteiro, Paula ; Carballo, Ana M. ; Calvo-Crespo, Patricia ; Kerns, Sarah L. ; Sanchez-Garcia, Manuel ; Lobato-Busto, Ramon ; Dorling, Leila ; Elliott, Rebecca M. ; Dearnaley, David P. ; Sydes, Matthew R. ; Hall, Emma ; Burnet, Neil G. ; Carracedo, Angel ; Rosenstein, Barry S. ; West, Catharine M. L. ; Dunning, Alison M. ; Vega, Ana

There is increasing evidence supporting the role of genetic variants in the development of radiation-induced toxicity. However, previous candidate gene association studies failed to elucidate the common genetic variation underlying this phenotype, which could emerge years after the completion of treatment. We performed a genome-wide association study on a Spanish cohort of 741 individuals with prostate cancer treated with external beam radiotherapy (EBRT). The replication cohorts consisted of [...]

Menée sur 201 patients atteints d'un cancer primitif du poumon ou présentant des métastases pulmonaires (durée médiane de suivi : 41,9 mois), cette étude japonaise évalue, du point de vue du contrôle local de la maladie et des taux de survie globale à 3 et 5 ans, l'efficacité d'une radiothérapie corporelle stéréotaxique, puis identifie les facteurs pronostiques associés

Outcomes after stereotactic body radiotherapy for lung tumors, with emphasis on comparison of primary lung cancer and metastatic lung tumors

Yamamoto, Takaya ; Jingu, Keiichi ; Shirata, Yuko ; Koto, Masashi ; Matsushita, Haruo ; Sugawara, Toshiyuki ; Kubozono, Masaki ; Umezawa, Rei ; Abe, Keiko ; Kadoya, Noriyuki ; Ishikawa, Youjirou ; Kozumi, Maiko ; Takahashi, Noriyoshi ; Takeda, Ken ; Takai, Yoshihiro

Background : The goal of this study was to determine the prognostic factors associated with an improved overall outcome after stereotactic body radiotherapy (SBRT) for primary lung cancer and metastatic lung tumors. Methods : A total of 229 lung tumors in 201 patients were included in the study. SBRT of 45 Gy in 3 fractions, 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions was typically used to treat 172 primary lungs cancer in 164 patients and 57 metastatic lung tumors in 37 [...]

Menée sur 110 patients atteints d'un cancer localisé de la prostate à haut risque de récidive (durée médiane de survie : 56,5 mois), cette étude évalue, du point de vue de l'absence d'échec biochimique ou local et de la survie sans métastases distantes à 3 et 5 ans, l'efficacité d'un traitement combinant de manière concomitante une radiothérapie avec modulation d'intensité de la région pelvienne et une radiothérapie de type boost de la région de la prostate

Intensity-modulated pelvic radiation therapy and simultaneous integrated boost to the prostate area in patients with high-risk prostate cancer: a preliminary report of disease control

Saracino, Biancamaria ; Petrongari, Maria Grazia ; Marzi, Simona ; Bruzzaniti, Vicente ; Sara, Gomellini ; Arcangeli, Stefano ; Arcangeli, Giorgio ; Pinnarò, Paola ; Giordano, Carolina ; Ferraro, Anna Maria ; Strigari, Lidia

The aim of the study was to report the clinical results in patients with high-risk prostate cancer treated with pelvic intensity-modulated radiation therapy (IMRT) and simultaneous integrated boost (SIB) to the prostate area. A total of 110 patients entered our study, 37 patients presented with localized prostate cancer and radiological evidence of node metastases or ≥15% estimated risk of lymph node (LN) involvement, while 73 patients underwent postoperative adjuvant or salvage irradiation for [...]

Cet article fait le point sur le traitement chirurgical des métastases hépatiques dont l'origine n'est pas un cancer colorectal

Surgical management of noncolorectal cancer liver metastases

Page, Andrew J. ; Weiss, Matthew J. ; Pawlik, Timothy M.

The number of hepatectomies performed for metastatic cancer has dramatically increased over the past 2 decades. Hepatectomy for stage IV colorectal cancer is now considered the standard of care for resectable patients with isolated hepatic disease and acceptable performance status. However, the indications for resection of noncolorectal origin liver metastases are not as clearly defined. This review focuses on emerging data for the resection of noncolorectal metastatic disease to the liver, [...]

Menée in vitro, cette étude identifie des mécanismes permettant de rendre compte, via l'activation de plusieurs voies de signalisation (MET, HER3, IGF-AR et INSR), d'une absence de réponse au lapatinib dans le traitement des patients atteints d'un cancer avancé de l'estomac HER2+

Functional Genetic Approach Identifies MET, HER3, IGF-1R, INSR Pathways as Determinants of Lapatinib Unresponsiveness in HER2-positive Gastric Cancer

Zhang, Zhe ; WANG, JIPING ; JI, DONGMEI ; WANG, CHENCHEN ; LIU, RUJIAO ; Wu, Zheng ; LIU, LIAN ; ZHU, DAN ; Chang, Jinjia ; GENG, RUIXUAN ; XIONG, LEI ; FANG, QIANGYI ; Li, Jin

Purpose: Targeting HER2 therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, as seen in recent clinical trails, most of HER2-positive GC are actually unresponsive to HER2-targeted agents, including lapatinib. The aim of the present study is to identify the responsible RTKs potentially conferring lapatinib unresponsiveness in HER2-positive GC and elucidate the molecular mechanism underlying this RTKs-induced resistance. Experimental [...]

Menée à l'aide de modèles murins de cancer du sein et du côlon, cette étude met en évidence des mécanismes par lesquels un inhibiteur de COX-2 augmente l'efficacité d'un traitement anti-angiogénique et prévient la formation de métastases

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

Xu, Lihong ; Stevens, Janine ; Hilton, Mary Beth ; Seaman, Steven ; Conrads, Thomas P. ; Veenstra, Timothy D. ; Logsdon, Daniel ; Morris, Holly ; Swing, Deborah A. ; Patel, Nimit L. ; Kalen, Joseph ; Haines, Diana C. ; Zudaire, Enrique ; St. Croix, Brad

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'afatinib éradique les cellules souches cancéreuses et suggère l'intérêt de cette thérapie ciblée, en combinaison avec le topotecan, pour le traitement des cancers

Afatinib enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem-like cells

Wang, Xiao-kun ; He, Jie-hua ; Xu, Jing-hong ; Ye, Sheng ; Wang, Fang ; Zhang, Hui ; Huang, Zhen-cong ; To, Kenneth Kin Wah ; Fu, Li-wu

Cancer stem-like cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ABCG2 confers chemoresistance to CSC where it serves as a potential biomarker and therapeutic target. Here we show that afatinib, a small molecule inhibitor of the tyrosine kinases EGFR, HER-2 and HER-4, preferentially eliminated side population (SP) cells with CSC [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par les protéines à bromodomaine BET dans la régulation de la voie de signalisation Hedghehog et suggère l'intérêt d'inhibiteurs de ces protéines pour le traitement de tumeurs résistantes aux inhibiteurs de Smoothened

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Tang, Yujie ; Gholamin, Sharareh ; Schubert, Simone ; Willardson, Minde I. ; Lee, Alex ; Bandopadhayay, Pratiti ; Bergthold, Guillame ; Masoud, Sabran ; Nguyen, Brian ; Vue, Nujsaubnusi ; Balansay, Brianna ; Yu, Furong ; Oh, Sekyung ; Woo, Pamelyn ; Chen, Spenser ; Ponnuswami, Anitha ; Monje, Michelle ; Atwood, Scott X. ; Whitson, Ramon J. ; Mitra, Siddhartha ; Cheshier, Samuel H. ; Qi, Jun ; Beroukhim, Rameen ; Tang, Jean Y. ; Wechsler-Reya, Rob ; Oro, Anthony E. ; Link, Brian A. ; Bradner, James E. ; Cho, Yoon-Jae

Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain [...]

Menée in vitro et in vivo, cette étude évalue la faisabilité d'une technologie permettant, à l'aide d'ultrasons et d'hydrogels, de contrôler à distance l'exposition des cellules cancéreuses à des molécules cytotoxiques

Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy

Huebsch, Nathaniel ; Kearney, Cathal J. ; Zhao, Xuanhe ; Kim, Jaeyun ; Cezar, Christine A. ; Suo, Zhigang ; Mooney, David J.

Biological systems are exquisitely sensitive to the location and timing of physiologic cues and drugs. This spatiotemporal sensitivity presents opportunities for developing new therapeutic approaches. Polymer-based delivery systems are used extensively for attaining localized, sustained release of bioactive molecules. However, these devices typically are designed to achieve a constant rate of release. We hypothesized that it would be possible to create digital drug release, which could be [...]

Menée à l'aide de modèles murins de myélome multiple, cette étude évalue l'activité antitumorale de nanoparticules comportant du bortezomib et met en évidence leurs capacités à modifier le micro-environnement osseux

Engineered nanomedicine for myeloma and bone microenvironment targeting

Swami, Archana ; Reagan, Michaela R. ; Basto, Pamela ; Mishima, Yuji ; Kamaly, Nazila ; Glavey, Siobhan ; Zhang, Sufeng ; Moschetta, Michele ; Seevaratnam, Dushanth ; Zhang, Yong ; Liu, Jinhe ; Memarzadeh, Masoumeh ; Wu, Jun ; Manier, Salomon ; Shi, Jinjun ; Bertrand, Nicolas ; Lu, Zhi Ning ; Nagano, Kenichi ; Baron, Roland ; Sacco, Antonio ; Roccaro, Aldo M. ; Farokhzad, Omid C. ; Ghobrial, Irene M.

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of [...]

A partir d'échantillons de tumeurs primitives et de métastases prélevés à l'autopsie sur 36 patients atteints d'un cancer du pancréas, puis menée in vitro et in vivo, cette étude suggère l'intérêt d'une stratégie thérapeutique basée sur l'inhibition de la signalisation JNK

Functional p38 MAPK Identified by Biomarker Profiling of Pancreatic Cancer Restrains Growth through JNK Inhibition and Correlates with Improved Survival

Zhong, Yi ; Naito, Yoshiki ; Cope, Leslie ; Naranjo-Suarez, Salvador ; Saunders, Tyler ; Hong, Seung-Mo ; Goggins, Michael ; Herman, Joseph M. ; Wolfgang, Christopher L ; Iacobuzio-Donahue, Christine A.

Purpose: Numerous biomarkers for pancreatic cancer have been reported. We determined the extent to which such biomarkers are expressed throughout metastatic progression, including those that effectively predict biologic behavior. Experimental Design: Biomarker profiling was performed for 35 oncoproteins in matched primary and metastatic pancreatic cancer tissues from 36 rapid autopsy patients. Proteins of significance were validated by immunolabeling in an independent sample set, and functional [...]

Cet article passe en revue les travaux récents sur les mécanismes de résistance aux thérapies ciblées, notamment les inhibiteurs de tyrosine kinase, chez les patients atteints d'un cancer avancé du poumon non à petites cellules

Acquired resistance to TKIs in solid tumours: learning from lung cancer

Camidge, D. Ross ; Pao, William ; Sequist, Lecia V.

The use of advanced molecular profiling to direct the use of targeted therapy, such as tyrosine kinase inhibitors (TKIs) for patients with advanced-stage non-small-cell lung cancer (NSCLC), has revolutionized the treatment of this disease. However, acquired resistance, defined as progression after initial benefit, to targeted therapies inevitably occurs. This Review explores breakthroughs in the understanding and treatment of acquired resistance in NSCLC, focusing on EGFR mutant and ALK [...]

Cet article passe en revue les travaux récents sur l'intérêt d'associer un inhibiteur de MET, par son action sur les cellules souches cancéreuses, à un inhbiteur d'EGFR pour le traitement d'un cancer colorectal métastatique

MET-Mediated Resistance to EGFR Inhibitors: An Old Liaison Rooted in Colorectal Cancer Stem Cells

Boccaccio, Carla ; Luraghi, Paolo ; Comoglio, Paolo M.

Inhibitors of EGFR are currently approved for the therapy of metastatic colorectal cancer (as well as other tumors), but their benefits are limited by inherent and acquired resistance, whose mechanisms are the subject of intense investigation. It is known that such resistance relies on a handful of genetic lesions and/or extracellular signals bypassing the requirement of EGF for cell proliferation and survival. As recently shown, these mechanisms may imply oncogenic activation of MET or its [...]

A partir de données issues du "Molecular Taxonomy of Breast Cancer International Consortium", puis menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude suggère l'intérêt de cibler une intégrine, à l'aide d'un composé appelé 264RAD, pour le traitement des patientes atteintes d'un cancer du sein résistant au trastuzumab

Therapeutic Targeting of Integrin αvβ6 in Breast Cancer

Moore, Kate M. ; Thomas, Gareth J. ; Duffy, Stephen W. ; Warwick, Jane ; Gabe, Rhian ; Chou, Patrick ; Ellis, Ian O. ; Green, Andrew R. ; Haider, Syed ; Brouilette, Kellie ; Saha, Antonio ; Vallath, Sabari ; Bowen, Rebecca ; Chelala, Claude ; Eccles, Diana ; Tapper, William J. ; Thompson, Alastair M. ; Quinlan, Phillip ; Jordan, Lee ; Gillett, Cheryl ; Brentnall, Adam ; Violette, Shelia ; Weinreb, Paul H. ; Kendrew, Jane ; Barry, Simon T. ; Hart, Ian R. ; Jones, J. Louise ; Marshall, John F.

Background : Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer. Methods : Protein expression of integrin subunit beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical [...]

Menée à l'aide d'un modèle murin, cette étude suggère l'intérêt d'une immunothérapie pour le traitement des gliomes présentant la mutation R132H du gène IDH1

A vaccine targeting mutant IDH1 induces antitumour immunity

Schumacher, Theresa ; Bunse, Lukas ; Pusch, Stefan ; Sahm, Felix ; Wiestler, Benedikt ; Quandt, Jasmin ; Menn, Oliver ; Osswald, Matthias ; Oezen, Iris ; Ott, Martina ; Keil, Melanie ; Balsz, Jorg ; Rauschenbach, Katharina ; Grabowska, Agnieszka K. ; Vogler, Isabel ; Diekmann, Jan ; Trautwein, Nico ; Eichmuller, Stefan B. ; Okun, Jurgen ; Stevanovic, Stefan ; Riemer, Angelika B. ; Sahin, Ugur ; Friese, Manuel A. ; Beckhove, Philipp ; von Deimling, Andreas ; Wick, Wolfgang ; Platten, Michael

Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation More than 70% of diffuse grade II and grade III [...]

Mené sur 546 patients atteints d'un carcinome hépatocellulaire de stade avancé, cet essai international de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'everolimus après l'échec d'un traitement par sorafenib

Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: The evolve-1 randomized clinical trial

Zhu, A. X. ; Kudo, M. ; Assenat, E. ; et al.,

Importance  : Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. Objective  : To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. Design, Setting, and Participants  : EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and [...]

Mené sur 39 patients atteints d'un cancer de la prostate résistant à la castration et non métastatique, cet essai de phase II évalue l'efficacité, du point de vue du pourcentage de patients dont le niveau de PSA est inférieur à 0,2 ng/ml après trois mois, et la toxicité de l'orteronel en monothérapie

Phase II Study of Single Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen

Hussain, Maha ; Corn, Paul G ; Michaelson, M. Dror ; Hammers, Hans ; Alumkal, Joshi J. ; Ryan, Charles J ; Bruce, Justine Y ; Moran, Susan ; Lee, Shih-Yuan ; Lin, H Mark ; George, Daniel J

Purpose: Orteronel (TAK-700) is an investigational, non-steroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17α-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M0). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary [...]

Cet article passe en revue les controverses et les perspectives concernant la stadification et le traitement d'un mélanome avec métastases ganglionnaires

Contemporary controversies and perspectives in the staging and treatment of patients with lymph node metastasis from melanoma, especially with regards positive sentinel lymph node biopsy

Pasquali, Sandro ; Spillane, Andrew

The management of melanoma lymph node metastasis particularly when detected by sentinel lymph node biopsy (SLNB) is still controversial. Results of the only randomized trial conducted to assess the therapeutic value of SLNB, the Multicenter Selective Lymphadenectomy Trial (MSLT), have not conclusively proven the effectiveness of this procedure but are interpreted by authors and guidelines as indicating SLNB is standard of care. After surgery, interferon alpha had a small survival benefit and [...]

A partir de données issues de 53 essais de phase I publiés entre janvier 2003 et septembre 2013, cette étude passe en revue les protocoles adaptatifs de recherche de dose guidés par un modèle

Adaptive Dose-Finding Studies: A Review of Model-Guided Phase I Clinical Trials

Iasonos, Alexia ; O’Quigley, John

Purpose : We provide a comprehensive review of adaptive phase I clinical trials in oncology that used a statistical model to guide dose escalation to identify the maximum-tolerated dose (MTD). We describe the clinical setting, practical implications, and safety of such applications, with the aim of understanding how these designs work in practice. Methods We identified 53 phase I trials published between January 2003 and September 2013 that used the continual reassessment method (CRM), CRM [...]

A partir de données portant sur l'inclusion de patients dans des essais cliniques de traitement des cancers en Grande-Bretagne entre 2005 et 2010, cet article propose une stratégie pour améliorer le taux de participation des adolescents et jeunes adultes

Available, accessible, aware, appropriate, and acceptable: a strategy to improve participation of teenagers and young adults in cancer trials

Fern, Lorna A. ; Lewandowski, Jennifer A. ; Coxon, Katy M. ; Whelan, Jeremy

Under-representation of teenagers and young adults in clinical trials for cancer is acknowledged internationally and might account for the lower survival gains noted for this group. Little research has focused on strategies to increase participation of teenagers and young adults in clinical trials. We applied a conceptual framework for barriers to recruitment of under-represented populations to data for cancer clinical trials in teenagers and young adults. We did a systematic analysis of data [...]

A partir de données portant sur 481 projets soumis à évaluation dans le cadre du Programme hospitalier de recherche clinique français en 2000, cette étude analyse l'association entre l'obtention d'un soutien financier, le démarrage de l'essai envisagé, son achèvement et la publication des résultats

Fate of Protocols Submitted to a French National Funding Scheme: A Cohort Study

Decullier, Evelyne ; Huot, Laure ; Chapuis, François R.

Background : The fate of clinical research projects funded by a grant has been investigated, but there is no information on the projects which did not receive funding. The fate of these projects is not known: do they apply for and/or receive funding from other sources or are they carried out without specific funding? Purpose : The aim of the study was to describe all clinical research projects submitted to a French national funding scheme (PHRC 2000) and to assess project initiation, completion [...]

A partir de données portant sur 522 essais de phase I menés dans un Centre américain de luttte contre le cancer entre 1988 et 2012, cette étude analyse l'évolution récente de leurs objectifs scientifiques et du nombre de patients inclus

Evaluation of Statistical Designs in Phase I Expansion Cohorts: The Dana-Farber/Harvard Cancer Center Experience

Dahlberg, Suzanne E. ; Shapiro, Geoffrey I. ; Clark, Jeffrey W. ; Johnson, Bruce E.

Background : Phase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess endpoints in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined. Methods : Adult therapeutic phase I trials opened within [...]