Menée sur 91 patients atteints d'un glioblastome ayant progressé après une première radiothérapie, cette étude évalue, du point de vue du taux de survie sans progression, l'intérêt d'ajouter à une nouvelle radiothérapie une protéine de fusion inhibant la voie CD95 (APG101)

A phase II, randomised, study of weekly APG101 + reirradiation versus reirradiation in progressive glioblastoma

Wick, Wolfgang ; Fricke, Harald ; Junge, Klaus ; Kobyakov, Grigory ; Martens, Tobias ; Heese, Oliver ; Wiestler, Benedikt ; Schliesser, Maximilian G ; von Deimling, Andreas ; Pichler, Josef ; Vetlova, Elena ; Harting, Inga ; Debus, Juergen ; Hartmann, Christian ; Kunz, Claudia ; Platten, Michael ; Bendszus, Martin ; Combs, Stephanie Elisabeth

Purpose : Preclinical data indicate antiinvasive activity of APG101, a CD95-ligand (CD95L)-binding fusion protein, in glioblastoma. Experimental Design : Patients (N=91)with glioblastoma at first or second progression were randomised 1:2 between second radiotherapy (rRT) (36 Gy; 5 times 2 Gy per week; rRT) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N=84 (26 patients rRT, 58 patients rRT + APG101)] were balanced. Results : PFS-6 rates were 3.8% (95%-CI: 0.1 - 19.6) rRT and [...]

Menée sur 24 patients atteints d'un mésothéliome traité entre 2009 et 2013 par pleurectomie avec décortication ou par pneumonectomie extrapleurale (durée médiane de suivi : 12,2 mois), cette étude évalue l'efficacité, du point de vue de la survie sans progression, de la survie globale, des délais avant récidive locorégionale ou survenue de métastases distantes, et la toxicité d'une radiothérapie hémithoracique avec modulation d'intensité

Hemithoracic Intensity Modulated Radiation Therapy After Pleurectomy/Decortication for Malignant Pleural Mesothelioma: Toxicity, Patterns of Failure, and a Matched Survival Analysis

Chance, William W. ; Rice, David C. ; Allen, Pamela K. ; Tsao, Anne S. ; Fontanilla, Hiral P. ; Liao, Zhongxing ; Chang, Joe Y. ; Tang, Chad ; Pan, Hubert Y. ; Welsh, James W. ; Mehran, Reza J. ; Gomez, Daniel R.

Purpose : To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT). Methods and Materials : In 2009-2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels l'expression de gènes mutés JAK1 et JAK3 favorise l'apparition d'une résistance à un traitement à base d'inhibiteurs de JAK tels que le ruxolitinib ou le CMP6

Cooperating JAK1 and JAK3 mutants increase resistance to JAK inhibitors

Springuel, Lorraine ; Hornakova, Tekla ; Losdyck, Elisabeth ; Lambert, Fanny ; Leroy, Emilie ; Constantinescu, Stefan N. ; Flex, Elisabetta ; Tartaglia, Marco ; Knoops, Laurent ; Renauld, Jean-Christophe

The acquisition of growth signal self-sufficiency is one of the hallmarks of cancer. We previously reported that the murine IL-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the JAK-STAT pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3 or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation, and that their [...]

Cet article passe en revue les perspectives thérapeutiques offertes par les connaissances récentes sur le rôle de la protéine de choc thermique Hsp70 dans le développement et la progression d'une tumeur

Hsp70 in cancer: back to the future

Sherman, M. Y. ; Gabai, V. L.

Mechanistic studies from cell culture and animal models have revealed critical roles for the heat shock protein Hsp70 in cancer initiation and progression. Surprisingly, many effects of Hsp70 on cancer have not been related to its chaperone activity, but rather to its role(s) in regulating cell signaling. A major factor that directs Hsp70 signaling activity appears to be the co-chaperone Bag3. Here, we review these recent breakthroughs, and how these discoveries drive drug development efforts.

Cet article présente un logiciel qui, à partir de données issues des projets "The Cancer Genome Atlas" et "Cancer Cell Line Encyclopedia", facilite l'identification de médicaments susceptibles de cibler des sous-types moléculaires de cancer

Cancer in silico Drug Discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes

San Lucas, F. Anthony ; Fowler, Jerry ; Chang, Kyle ; Kopetz, Scott ; Vilar, Eduardo ; Scheet, Paul

Large-scale cancer data sets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and [...]

Cet article passe en revue les perspectives offertes par l'application du principe de létalité synthétique pour le développement de thérapies ciblées des cancers

Applying Synthetic Lethality for the Selective Targeting of Cancer

McLornan, Donal P. ; List, Alan ; Mufti, Ghulam J.

Synthetic lethality refers to the requirement that two defects be present for cell death to occur. When an agent damages DNA, its effects on the cell can be amplified if the efforts of the cell to repair the damage are inhibited. Clinical application of this idea is just beginning.

Cet article passe en revue les travaux récents sur le développement d'immunothérapies pour le traitement de patients pédiatriques atteints de divers types de cancer

Immune-based therapies for childhood cancer

Mackall, Crystal L. ; Merchant, Melinda S. ; Fry, Terry J.

After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive [...]

Cet article passe en revue les perspectives thérapeutiques offertes par le développement de composés visant à restaurer les propriétés de suppresseur de tumeurs d'un gène p53 muté dans divers types de cancer

p53 as a target for the treatment of cancer

Duffy, Michael J. ; Synnott, Naoise C. ; McGowan, Patricia M. ; Crown, John ; O’Connor, Darran ; Gallagher, William M.

TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as “undruggable”. [...]

Cet article présente un modèle mathématique permettant de quantifier l'hétérogénéité des mutations présentes dans une lésion métastatique en association avec une résistance thérapeutique

Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers

Bozic, Ivana ; Nowak, Martin A.

Targeted therapies provide an exciting new approach to combat human cancer. The immediate effect is a dramatic reduction in disease burden, but in most cases, the tumor returns as a consequence of resistance. Various mechanisms for the evolution of resistance have been implicated, including mutation of target genes and activation of other drivers. There is increasing evidence that the reason for failure of many targeted treatments is a small preexisting subpopulation of resistant cells; [...]

Menée in vitro et in vivo, cette étude suggère l'intérêt d'un composé appelé AT13387, un inhibiteur de HSP90, pour surmonter une résistance à un traitement par inhibiteur de BRAF et/ou inhibiteur de MEK chez les patients atteints d'un mélanome présentant un gène BRAF muté

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to dual BRAF and MEK Inhibition in Melanoma Models

Smyth, Tomoko ; Paraiso, Kim H.T. ; Hearn, Keisha ; Rodriguez-Lopez, Ana M ; Munck, Joanne M ; Haarberg, H. Eirik ; Sondak, Vernon K. ; Thompson, Neil T ; Azab, Mohammad ; Lyons, John F ; Smalley, Keiran S.M. ; Wallis, Nicola G

Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor, AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par les lymphocytes NK dans la réponse à un traitement par inhibiteur de BRAF, ce qui suggère l'intérêt d'une immunothérapie complémentaire pour le traitement des patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF

Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E mutant metastatic melanoma

de Andrade, Lucas F ; Ngiow, Shin Foong ; Stannard, Kimberley ; Rusakiewicz, Sylvie ; Kalimutho, Murugan ; Khanna, Kum Kum ; Tey, Siok-Keen ; Takeda, Kazuyoshi ; Zitvogel, Laurence ; Martinet, Ludovic ; Smyth, Mark J.

BRAFV600E is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAFV600E by oncogene targeting therapy increases overall survival of melanoma patients, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAFV600E inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse. Tumor [...]

Menée à l'aide d'un modèle murin, cette étude suggère l'intérêt de combiner un inhbiteur de PARP avec l'irinotecan et le temozolomide pour le traitement de patients atteints d'un sarcome d'Ewing

Targeting the DNA Repair Pathway in Ewing Sarcoma

Stewart, Elizabeth ; Goshorn, Ross ; Bradley, Cori ; Griffiths, Lyra M ; Benavente, Claudia ; Twarog, Nathaniel R ; Miller, Gregory M ; Caufield, William ; Freeman, Burgess B, III ; Bahrami, Armita ; Pappo, Alberto ; Wu, Jianrong ; Loh, Amos ; Karlström, Åsa ; Calabrese, Chris ; Gordon, Brittney ; Tsurkan, Lyudmila ; Hatfield, M.  Jason ; Potter, Philip M ; Snyder, Scott E ; Thiagarajan, Suresh ; Shirinifard, Abbas ; Sablauer, Andras ; Shelat, Anang A ; Dyer, Michael A

Ewing sarcoma (EWS) is a tumor of the bone and soft tissue that primarily affects adolescents and young adults. With current therapies, 70% of patients with localized disease survive, but patients with metastatic or recurrent disease have a poor outcome. We found that EWS cell lines are defective in DNA break repair and are sensitive to PARP inhibitors (PARPis). PARPi-induced cytotoxicity in EWS cells was 10- to 1,000-fold higher after administration of the DNA-damaging agents irinotecan or [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes de cancer du pancréas, cette étude évalue les mécanismes liés à l'activité antitumorale d'un composé appelé YM155, développé initialement pour réduire l'expression de la survivine

Small molecule inhibitor YM155-mediated activation of death receptor 5 is crucial for chemotherapy-induced apoptosis in pancreatic carcinoma

Zhao, Xiangxuan ; Puszyk, William M ; Lu, Zaiming ; Ostrov, David ; George, Thomas ; Robertson, Keith ; Liu, Chen

Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor which has shown anti-tumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the anti-tumor effect of YM155 with in vitro studies in the cultured cells, and in vivo studies using a [...]

Menée sur des lignées cellulaires et à l'aide d'un modèle murin génétiquement modifié d'adénocarcinome canalaire du pancréas, cette étude évalue l'activité antitumorale d'un traitement combinant un inhibiteur de MEK et un inhibiteur de PI3K

Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer

Alagesan, Brinda ; Contino, Gianmarco ; Guimaraes, Alexander R ; Corcoran, Ryan B ; Desphande, Vikram ; Wojtkiewicz, Gregory R ; Hezel, Aram F. ; Wong, Kwok-Kin ; Loda, Massimo ; Weissleder, Ralph ; Benes, Cyril H ; Engelman, Jeffrey A ; Bardeesy, Nabeel

Purpose: Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being employed in clinical trials for PDAC patients, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMMs). Experimental Design: We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels le cabozantinib permet de surmonter une résistance au crizotinib des cellules de cancer du poumon non à petites cellules présentant des réarrangements ROS1

Cabozantinib overcomes crizotinib resistance in ROS1 fusion positive cancer

Katayama, Ryohei ; Kobayashi, Yuka ; Friboulet, Luc ; Lockerman, Elizabeth L. ; Koike, Sumie ; Shaw, Alice T. ; Engelman, Jeffrey A. ; Fujita, Naoya

Purpose: ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase 1 trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib resistance mechanisms in ROS1 rearranged NSCLC and [...]

Menée in vitro, in vivo et sur plusieurs cohortes de patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels la production d'interféron de type I par les cellules tumorales contribue à l'efficacité d'un traitement à base d'anthracycline

Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Sistigu, Antonella ; Yamazaki, Takahiro ; Vacchelli, Erika ; Chaba, Kariman ; Enot, David P. ; Adam, Julien ; Vitale, Ilio ; Goubar, Aicha ; Baracco, Elisa E. ; Remedios, Catarina ; Fend, Laetitia ; Hannani, Dalil ; Aymeric, Laetitia ; Ma, Yuting ; Niso-Santano, Mireia ; Kepp, Oliver ; Schultze, Joachim L. ; Tuting, Thomas ; Belardelli, Filippo ; Bracci, Laura ; La Sorsa, Valentina ; Ziccheddu, Giovanna ; Sestili, Paola ; Urbani, Francesca ; Delorenzi, Mauro ; Lacroix-Triki, Magali ; Quidville, Virginie ; Conforti, Rosa ; Spano, Jean-Philippe ; Pusztai, Lajos ; Poirier-Colame, Vichnou ; Delaloge, Suzette ; Pénault-Llorca, Frédérique ; Ladoire, Sylvain ; Arnould, Laurent ; Cyrta, Joanna ; Dessoliers, Marie-Charlotte ; Eggermont, Alexander ; Bianchi, Marco E. ; Pittet, Mikael ; Engblom, Camilla ; Pfirschke, Christina ; Preville, Xavier ; Uze, Gilles ; Schreiber, Robert D. ; Chow, Melvyn T. ; Smyth, Mark J. ; Proietti, Enrico ; Andre, Fabrice ; Kroemer, Guido ; Zitvogel, Laurence

Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-[alpha] and IFN-[beta] receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via le transfert d'exosomes entre des cellules stromales et des cellules de cancer du sein, les tumeurs acquièrent une résistance aux traitements

Exosome Transfer from Stromal to Breast Cancer Cells Regulates Therapy Resistance Pathways

Boelens, Mirjam C ; Wu, Tony J ; Nabet, Barzin Y ; Xu, Bihui ; Qiu, Yu ; Yoon, Taewon ; Azzam, Diana J ; Twyman-Saint Victor, Christina ; Wiemann, Brianne Z ; Ishwaran, Hemant ; ter Brugge, Petra J ; Jonkers, Jos ; Slingerland, Joyce ; Minn, Andy J

Stromal communication with cancer cells can influence treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance. Upon heterotypic interaction, exosomes are transferred from stromal to BrCa cells. RNA within exosomes, which are largely noncoding transcripts and transposable elements, stimulates the pattern recognition receptor RIG-I to activate STAT1-dependent antiviral signaling. In parallel, [...]

Cet article passe en revue les perspectives offertes par les connaissances récentes sur les quatre sous-types de médulloblastome pour le développement de nouveaux traitements

Medulloblastoma-translating discoveries from the bench to the bedside

Gajjar, Amar J. ; Robinson, Giles W.

Medulloblastoma is a form of brain cancer that mainly arises during infancy and childhood. Our understanding of this disease has transitioned rapidly; what was once thought of as a single disease entity is now known to be a compendium comprising at least four distinct subtypes of tumour (Wnt, sonic hedgehog [SHH], group 3, and group 4 medulloblastomas) that have characteristic molecular signatures, distinctive clinical features, and are associated with different outcomes. Importantly, [...]

Menée sur un modèle animal de cancer buccal (hamster), cette étude évalue l'activité antitumorale et la toxicité d'une thérapie de capture de neutrons par le bore à bases de liposomes enrichis en bore

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

Heber, Elisa M. ; Hawthorne, M. Frederick ; Kueffer, Peter J. ; Garabalino, Marcela A. ; Thorp, Silvia I. ; Pozzi, Emiliano C. C. ; Hughes, Andrea Monti ; Maitz, Charles A. ; Jalisatgi, Satish S. ; Nigg, David W. ; Curotto, Paula ; Trivillin, Verónica A. ; Schwint, Amanda E.

The application of boron neutron capture therapy (BNCT) mediated by liposomes containing 10B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] [...]

Mené sur 224 jeunes patients atteints d'un cancer hématologique (âge compris entre 1 et 21 ans), cet essai compare l'efficacité, du point de vue de la survie globale à 1 an, d'une mono-greffe et d'une double greffe de sang de cordon après chimiothérapie myéloablative et immunoprophylaxie pour la réaction du greffon contre l'hôte

One-Unit versus Two-Unit Cord-Blood Transplantation for Hematologic Cancers

Wagner, John E. ; Eapen, Mary ; Carter, Shelly ; Wang, Yanli ; Schultz, Kirk R. ; Wall, Donna A. ; Bunin, Nancy ; Delaney, Colleen ; Haut, Paul ; Margolis, David ; Peres, Edward ; Verneris, Michael R. ; Walters, Mark ; Horowitz, Mary M. ; Kurtzberg, Joanne

BACKGROUND : Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. METHODS : [...]

Mené sur 67 patients atteints d'une tumeur solide de stade avancé, cet essai de phase 1b évalue la dose maximale recommandée et la toxicité du trametinib, un inhibiteur de MEK, en combinaison avec l'everolimus

A Phase IB Trial of the Oral MEK Inhibitor Trametinib (GSK1120212) in Combination With Everolimus in Patients With Advanced Solid Tumors

Tolcher, A. W. ; Bendell, J. C. ; Papadopoulos, K. P. ; Burris, H. A. ; Patnaik, A. ; Jones, S. F. ; Rasco, D. ; Cox, D. S. ; Durante, M. ; Bellew, K. M. ; Park, J. ; Le, N. T. ; Infante, J. R.

Background : This phase 1b trial investigated the safety, tolerability, and recommended phase 2 dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic characterization and evaluation of clinical activity. Patients and methods : A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a [...]

Menée sur 165 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë B à haut risque, cette étude compare des paramètres pharmacocinétiques et pharmacodynamiques de deux formes pégylées de L-asparaginase

Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children’s Oncology Group Study AALL07P4

Angiolillo, Anne L. ; Schore, Reuven J. ; Devidas, Meenakshi ; Borowitz, Michael J. ; Carroll, Andrew J. ; Gastier-Foster, Julie M. ; Heerema, Nyla A. ; Keilani, Taha ; Lane, Ashley R. ; Loh, Mignon L. ; Reaman, Gregory H. ; Adamson, Peter C. ; Wood, Brent ; Wood, Charlotte ; Zheng, Hao W. ; Raetz, Elizabeth A. ; Winick, Naomi J. ; Carroll, William L. ; Hunger, Stephen P.

Purpose : Asparaginase is a critical agent used to treat acute lymphoblastic leukemia (ALL). Pegaspargase (SS-PEG), a pegylated form of Escherichia coli L-asparaginase with a succinimidyl succinate (SS) linker, is the first-line asparaginase product used in Children’s Oncology Group (COG) ALL trials. Calaspargase pegol (SC-PEG) replaces the SS linker in SS-PEG with a succinimidyl carbamate linker, creating a more stable molecule. COG AALL07P4 was designed to determine the pharmacokinetic and [...]

Mené sur 345 patientes atteintes d'un cancer du sein HR+ sans envahissement ganglionnaire avant la ménopause, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans maladie et de la survie globale, de l'ajout au tamoxifène d'un traitement supprimant la fonction ovarienne

Phase III Comparison of Tamoxifen Versus Tamoxifen Plus Ovarian Function Suppression in Premenopausal Women With Node-Negative, Hormone Receptor–Positive Breast Cancer (E-3193, INT-0142): A Trial of the Eastern Cooperative Oncology Group

Tevaarwerk, Amye J. ; Wang, Molin ; Zhao, Fengmin ; Fetting, John H. ; Cella, David ; Wagner, Lynne I. ; Martino, Silvana ; Ingle, James N. ; Sparano, Joseph A. ; Solin, Lawrence J. ; Wood, William C. ; Robert, Nicholas J.

Purpose The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS. Patients and Methods Premenopausal women with axillary node-negative, hormone receptor–positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were [...]

Mené sur 519 patientes atteintes d'un cancer métastatique du sein triplement négatif, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de l'ajout d'iniparib à un traitement combinant gemcitabine et carboplatine

Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer

O’Shaughnessy, Joyce ; Schwartzberg, Lee ; Danso, Michael A. ; Miller, Kathy D. ; Rugo, Hope S. ; Neubauer, Marcus ; Robert, Nicholas ; Hellerstedt, Beth ; Saleh, Mansoor ; Richards, Paul ; Specht, Jennifer M. ; Yardley, Denise A. ; Carlson, Robert W. ; Finn, Richard S. ; Charpentier, Eric ; Garcia-Ribas, Ignacio ; Winer, Eric P.

Purpose : There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. Patients and [...]

Mené sur 295 patientes atteintes d'un cancer métastatique du sein HR+ après la ménopause, cet essai randomisé de phase III évalue l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de l'ajout de lapatinib au fulvestrant

Endocrine Therapy With or Without Inhibition of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib for Postmenopausal Women With Hormone Receptor–Positive Advanced Breast Cancer—CALGB 40302 (Alliance)

Burstein, Harold J. ; Cirrincione, Constance T. ; Barry, William T. ; Chew, Helen K. ; Tolaney, Sara M. ; Lake, Diana E. ; Ma, Cynthia ; Blackwell, Kimberly L. ; Winer, Eric P. ; Hudis, Clifford A.

Purpose : CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor–positive metastatic breast cancer treated with fulvestrant. Patients and Methods : Eligible women had estrogen receptor–positive and/or progesterone receptor–positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed [...]

Cet article analyse la pertinence des essais cliniques récents sur les stratégies thérapeutiques combinant un agent anti-androgénique avec une radiothérapie pour traiter un cancer localisé de la prostate

Combination of Androgen Deprivation Therapy and Radiotherapy for Localized Prostate Cancer in the Contemporary Era

D’Angelillo, Rolando M. ; Franco, Pierfrancesco ; De Bari, Berardino ; Fiorentino, Alba ; Arcangeli, Stefano ; Alongi, Filippo

Currently, Androgen Deprivation Therapy (ADT) has a well-defined role when administered together with radiotherapy (RT): neo-adjuvant and concurrent combination for intermediate risk-disease and adjuvant therapy for high risk disease. Evidence of this association was generated by randomized trials designed and led approximately 30 years ago; thus the question which arises is how relevant and portable are these data in our current clinical practice? In the present review, we examine the pitfalls [...]

Menée à partir de données portant sur 243 patients atteints d'un glioblastome traité entre 2004 et 2013 (âge : 65 ans ou plus), cette étude compare l'efficacité, du point de vue de la survie sans progression et de la survie globale, et la toxicité de deux protocoles de radiothérapie (radiothérapie standard de 60 Gy ou radiothérapie de courte durée de 40 Gy) en combinaison avec une chimiothérapie concomitante ou adjuvante par témozolomide

Standard (60 Gy) or Short-Course (40 Gy) Irradiation Plus Concomitant and Adjuvant Temozolomide for Elderly Patients With Glioblastoma: A Propensity-Matched Analysis

Minniti, Giuseppe ; Scaringi, Claudia ; Lanzetta, Gaetano ; Terrenato, Irene ; Esposito, Vincenzo ; Arcella, Antonella ; Pace, Andrea ; Giangaspero, Felice ; Bozzao, Alessandro ; Enrici, Riccardo Maurizi

Purpose : To evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged ≥65 years with newly diagnosed glioblastoma (GBM). Methods and Materials : Patients aged ≥65 years with Karnofsky performance status (KPS) ≥60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score [...]

Mené sur 100 patientes présentant des métastases cérébrales ayant pour origine un cancer du sein (âge médian : 55 ans ; durée médiane de suivi : 9,4 mois), cet essai de phase II évalue, du point de vue du taux de réponse objective à 6 semaines, de la survie sans progression et de la survie globale, l'efficacité d'une radiothérapie du cerveau entier avec ou sans chimiothérapie concomitante par témozolomide

Phase II Randomized Study of Whole-Brain Radiation Therapy with or without Concurrent Temozolomide for Brain Metastases from Breast Cancer

Cao, K. I. ; Lebas, N. ; Gerber, S. ; Lévy, C. ; Le Scodan, R. ; Bourgier, C. ; Pierga, J.-Y. ; Gobillion, A. ; Savignoni, A. ; Kirova, Y. M.

Background : To improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. Patients and Methods : This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal brain metastases from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy x [...]

Menée sur 128 patients atteints d'un carcinome rhinopharyngé de stade localement avancé et résidant dans une région où les infections au virus d'Epstein-Barr sont endémiques (durée médiane de suivi : 53 mois), cette étude taïwanaise évalue, du point de vue de la survie sans maladie, du contrôle locorégional de la maladie et de la survie globale, l'intérêt d'une chimioradiothérapie concomitante par rapport à une chimiothérapie néoadjuvante suivie d'une radiothérapie

Comparison of concurrent chemoradiotherapy versus neoadjuvant chemotherapy followed by radiation in patients with advanced nasopharyngeal carcinoma in endemic area: experience of 128 consecutive cases with 5 year follow-up

Wu, Shang-Yin ; Wu, Yuan-Hua ; Yang, Ming-Wei ; Hsueh, Wei-Ting ; Hsiao, Jenn-Ren ; Tsai, Sen-Tien ; Chang, Kwang-Yu ; Chang, Jeffrey ; Yen, Chia-Jui

Background : Combined radiotherapy and chemotherapy is considered the standard of care for locally advanced nasopharyngeal carcinoma (LA-NPC) in Epstein-Barr virus infection endemic area. This study compared the long-term outcomes between LA-NPC patients treated with neoadjuvant chemotherapy followed by radiotherapy (NACT) and those treated with concurrent chemoradiotherapy (CCRT). Methods : From 2003 to 2007, a total of 128 histopathologically proven LA-NPC patients receiving either NACT or [...]

Cet article présente une méthodologie pour identifier, à partir d'une analyse du génome tumoral d'un patient, les cibles moléculaires les plus susceptibles de faire l'objet d'une thérapie ciblée

Prioritising Targets for Precision Cancer Medicine

Andre, Fabrice ; Mardis, Elaine ; Salm, Max ; Soria, Jean-Charles ; Siu, Lillian L. ; Swanton, Charles

The implementation of cancer genomic testing into the clinical setting has brought major opportunities. However, as our understanding of cancer initiation, maintenance and progression improves through detailed cancer genomic studies, the challenges associated with driver identification and target classification in the clinical setting become clearer. Here we review recent insights into cancer genomic testing in the clinical setting, and suggest a target classification approach that considers [...]

Menée à partir des données de mesures tumorales et de survie portant sur 1 471 patients atteints d'un cancer colorectal métastatique et inclus dans un essai de phase III évaluant différentes chimiothérapies, cette étude évalue la performance du délai avant croissance tumorale pour déterminer la supériorité d'une chimiothérapie par rapport à une autre dans le cadre d'un essai de phase II

Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

Sharma, Manish R. ; Gray, Elizabeth ; Goldberg, Richard M. ; Sargent, Daniel J. ; Karrison, Theodore G.

Purpose : The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and [...]

A partir d'une revue systématique de la littérature (29 essais identifiés, ayant inclus un total de 16 641 patientes atteintes d'un cancer du sein), cette étude évalue l'intérêt d'utiliser, dans les essais cliniques de traitements néoadjuvants, le critère de réponse pathologique complète en substitution aux critères de survie sans maladie ou de survie globale

Pathologic Complete Response As a Potential Surrogate for the Clinical Outcome in Patients With Breast Cancer After Neoadjuvant Therapy: A Meta-Regression of 29 Randomized Prospective Studies

Berruti, Alfredo ; Amoroso, Vito ; Gallo, Fabio ; Bertaglia, Valentina ; Simoncini, Edda ; Pedersini, Rebecca ; Ferrari, Laura ; Bottini, Alberto ; Bruzzi, Paolo ; Sormani, Maria Pia

Purpose To assess the role of pathologic complete response (pCR) after neoadjuvant therapy as surrogate end point of disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, we performed a trial-based meta-regression of randomized studies comparing different neoadjuvant systemic treatments. Methods The systematic literature search included electronic databases and proceedings of oncologic meetings. Endocrine therapy trials were excluded. Treatment effects on DFS and [...]