Menée sur 66 patients atteints d'un ou plusieurs paragangliomes de la tête et du cou traités entre 1990 et 2009 (âge : de 15 à 84 ans ; durée médiane de suivi : 4,1 ans), cette étude française évalue l'efficacité, du point de vue du taux de contrôle actuariel à 5 ou 10 ans, et la sécurité d'une radiothérapie externe

Treatment of Head and Neck Paragangliomas With External Beam Radiation Therapy

Dupin, Charles ; Lang, Philippe ; Dessard-Diana, Bernadette ; Simon, Jean-Marc ; Cuenca, Xavier ; Mazeron, Jean-Jacques ; Feuvret, Loïc

To retrospectively assess the outcomes of radiation therapy in patients with head and neck paragangliomas. From 1990 to 2009, 66 patients with 81 head and neck paragangliomas were treated by conventional external beam radiation therapy in 25 fractions at a median dose of 45 Gy (range, 41.4-68 Gy). One case was malignant. The median gross target volume and planning target volume were 30 cm3 (range, 0.9-243 cm3) and 116 cm3 (range, 24-731 cm3), respectively. Median age was 57.4 years (range, [...]

Menée sur diverses populations cellulaires microbiennes et sur des lignées cellulaires cancéreuses, cette étude évalue les capacités d'un modèle, basé sur des lois d'échelle, à prédire l'apparition d'une résistance à des traitements en combinaison

Uncovering Scaling Laws to Infer Multidrug Response of Resistant Microbes and Cancer Cells

Wood, Kevin B ; Wood, Kris C ; Nishida, Satoshi ; Cluzel, Philippe

Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here, we simplify the picture of drug resistance by identifying scaling laws that unify the multidrug responses of drug-sensitive and -resistant cells. On the basis of these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously [...]

Menée sur des lignées cellulaires et à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale d'un anticorps bi-spécifique (CD3/CD 33) appelé AMG 330 pour le traitement d'une leucémie myéloïde aiguë

Preclinical characterization of AMG 330, a CD3/CD33-bispecific T-cell-engaging antibody with potential for treatment of acute myelogenous leukemia

Friedrich, Matthias ; Henn, Anja ; Raum, Tobias ; Bajtus, Monika ; Matthes, Katja ; Hendrich, Larissa ; Wahl, Joachim ; Hoffmann, Patrick ; Kischel, Roman ; Kvesic, Majk ; Sloostra, Jerry W ; Baeuerle, Patrick A ; Kufer, Peter ; Rattel, Benno

There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell engaging (BiTE®) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3ε of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between [...]

Menée à partir d'échantillons sanguins prélevés sur 38 patients atteints d'une leucémie myéloïde chronique et 15 témoins, puis in vitro et in vivo, cette étude met notamment en évidence des mécanismes par lesquels la signalisation IL-33/ST2 favorise la résistance à l'imatinib

BCR-ABL-induced deregulation of the IL-33/ST2 pathway in CD34(+) progenitors from chronic myeloid leukemia patients

Levescot, Anaïs ; Flamant, Stephane ; Basbous, Sara ; Jacomet, Florence ; Feraud, Olivier ; Bourgeois, Elvire ; Bonnet, Marie-Laure ; Giraud, Christine ; Roy, Lydia ; Barra, Anne ; Chomel, Jean-Claude ; Turhan, Ali ; Guilhot, François ; Girard, Jean-Philippe ; Gombert, Jean-Marc ; Herbelin, Andre

Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myeloid leukemia (CML) and resistance to imatinib mesylate (IM) treatment remain poorly investigated. Here, we report that CD34(+) progenitors from CML patients at diagnosis are selectively targeted by the cytokine/alarmin IL-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, [...]

Menée sur 16 échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique présentant la mutation V600E du gène BRAF, cette étude met en évidence des mécanismes par lesquels, en exprimant le récepteur EGFR, les tumeurs développent une résistance aux inhibiteurs de BRAF ou MEK puis, après une période de "vacances thérapeutiques", sont suceptibles de retrouver une sensibilité aux traitements

Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma

Sun, Chong ; Wang, Liqin ; Huang, Sidong ; Heynen, Guus J. J. E. ; Prahallad, Anirudh ; Robert, Caroline ; Haanen, John ; Blank, Christian ; Wesseling, Jelle ; Willems, Stefan M. ; Zecchin, Davide ; Hobor, Sebastijan ; Bajpe, Prashanth K. ; Lieftink, Cor ; Mateus, Christina ; Vagner, Stephan ; Grernrum, Wipawadee ; Hofland, Ingrid ; Schlicker, Andreas ; Wessels, Lodewyk F. A. ; Beijersbergen, Roderick L. ; Bardelli, Alberto ; Di Nicolantonio, Federica ; Eggermont, Alexander M. M. ; Bernards, Rene

Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes permettant de rendre compte de la faible efficacité clinique d'un traitement combinant inhibiteurs de MEK et de PI3K chez les patients atteints d'un cancer du poumon non à petites cellules avec mutations du gène KRAS

Failure to induce apoptosis via BCL-2 family proteins underlies lack of efficacy of combined MEK and PI3K inhibitors for KRAS mutant lung cancers

Hata, Aaron N ; Yeo, Alan ; Faber, Anthony C ; Lifshits, Eugene ; Chen, Zhao ; Cheng, Katherine A ; Walton, Zandra ; Sarosiek, Kristopher A ; Letai, Anthony ; Heist, Rebecca S ; Mino-Kenudson, Mari ; Wong, Kwok-Kin ; Engelman, Jeffrey A

Although several groups have demonstrated that concomitant use of MEK and PI3K inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS mutant non-small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biological heterogeneity in the response of KRAS mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we [...]

Menée in vitro et in vivo, cette étude analyse l'efficacité du ceritinib pour surmonter l'apparition d'une résistance au crizotinib dans les tumeurs du poumon non à petites cellules avec réarrangements du gène ALK

The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer

Friboulet, Luc ; Li, Nanxin ; Katayama, Ryohei ; Lee, Christian C ; Gainor, Justin F. ; Crystal, Adam S. ; Michellys, Pierre-Yves ; Awad, Mark M ; Yanagitani, Noriko ; Kim, Sungjoon ; Pferdekamper, AnneMarie C ; Li, Jie ; Kasibhatla, Shailaja ; Sun, Frank ; Sun, Xiuying ; Hua, Su ; McNamara, Peter ; Mahmood, Sidra ; Lockerman, Elizabeth L ; Fujita, Naoya ; Nishio, Makoto ; Harris, Jennifer L ; Shaw, Alice T ; Engelman, Jeffrey A

Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients [...]

Menée à l'aide d'une tomographie par émission de positrons sur un modèle murin de cancer du poumon non à petites cellules, cette étude met en évidence les effets, sur le réseau vasculaire tumoral, d'un traitement anti-angiogénique de courte durée par un inhibiteur de VEGFR/PDGFR appelé PTK787

Transient anti-angiogenic treatment improves delivery of cytotoxic compounds and therapeutic outcome in lung cancer

Chatterjee, Sampurna ; Wieczorek, Caroline ; Schöttle, Jakob ; Siobal, Maike ; Hinze, Yvonne ; Franz, Thomas ; Florin, Alexandra ; Adamczak, Joanna ; Heukamp, Lukas ; Neumaier, Bernd ; Ullrich, Roland T

Extensive oncologic experience argues that the most efficacious applications of anti-angiogenic agents rely upon a combination with cytotoxic drugs. Yet there remains a lack of clarity about how to optimize scheduling for such drug combinations. Prudent anti-angiogenic therapy might transiently normalize blood vessels to improve tumor oxygenation and drug exposure. Using [15O]H2O Positron Emission Tomography (PET) imaging in a preclinical mouse model of non-small cell lung cancer, we observed [...]

Menée sur des lignées cellullaires et des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer primitif du sein, cette étude met en évidence des mécanismes permettant de rendre compte, par un phénomène de distorsion de la ségrégation des chromosomes, de la cytotoxicité du paclitaxel

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

Zasadil, Lauren M. ; Andersen, Kristen A. ; Yeum, Dabin ; Rocque, Gabrielle B. ; Wilke, Lee G. ; Tevaarwerk, Amye J. ; Raines, Ronald T. ; Burkard, Mark E. ; Weaver, Beth A.

The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme épigénétique impliquant le gène HOXC10 dans la résistance aux inhibiteurs d’aromatase pour le traitement d’un cancer du sein

Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer

Pathiraja, Thushangi N. ; Nayak, Shweta R. ; Xi, Yuanxin ; Jiang, Shiming ; Garee, Jason P. ; Edwards, Dean P. ; Lee, Adrian V. ; Chen, Jian ; Shea, Martin J. ; Santen, Richard J. ; Gannon, Frank ; Kangaspeska, Sara ; Jelinek, Jaroslav ; Issa, Jean-Pierre J. ; Richer, Jennifer K. ; Elias, Anthony ; McIlroy, Marie ; Young, Leonie S. ; Davidson, Nancy E. ; Schiff, Rachel ; Li, Wei ; Oesterreich, Steffi

Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)–positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term [...]

Menée in vitro et l'aide d'un modèle murin, cette étude suggère l'intérêt d'une combinaison pemetrexed-gemcitabine pour le traitement d'un sous-type de médulloblastome

Pemetrexed and Gemcitabine as Combination Therapy for the Treatment of Group3 Medulloblastoma

Morfouace, Marie ; Shelat, Anang ; Jacus, Megan ; Freeman, Burgess B, III ; Turner, David ; Robinson, Sarah ; Zindy, Frederique ; Wang, Yong-Dong ; Finkelstein, David ; Ayrault, Olivier ; Bihannic, Laure ; Puget, Stéphanie ; Li, Xiao-Nan ; Olson, James M ; Robinson, Giles W ; Guy, R.  Kiplin ; Stewart, Clinton F ; Gajjar, Amar ; Roussel, Martine F

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased [...]

Mené sur 83 patients japonais atteints d'un cancer du poumon non à petites cellules après 70 ans, cet essai de phase II compare l'efficacité, du point de vue du taux de réponse objective, et la toxicité du docétaxel en monothérapie par rapport à une combinaison carboplatine-paclitaxel

Randomized Phase II Trial Comparing Carboplatin Plus Weekly Paclitaxel and Docetaxel Alone in Elderly Patients With Advanced Non-Small Cell Lung Cancer: North Japan Lung Cancer Group Trial 0801

Maemondo, Makoto ; Inoue, Akira ; Sugawara, Shunichi ; Harada, Toshiyuki ; Minegishi, Yuji ; Usui, Kazuhiro ; Miwa, Koji ; Morikawa, Naoto ; Kambe, Mariko ; Ube, Kenji ; Watanabe, Kana ; Ishimoto, Osamu ; Sakakibara, Tomohiro ; Gemma, Akihiko ; Nukiwa, Toshihiro

Background : Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. Methods : [...]

A partir de données portant sur 808 patientes atteintes d'un cancer métastatique du sein HER2+ et incluses dans l'essai CLEOPATRA d'évaluation du pertuzumab en complément d'une combinaison trastuzumab-docétaxel, cette étude analyse les effets du pertuzumab sur le nombre de métastases cérébrales et le délai avant leur survenue

Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA

Swain, S. M. ; Baselga, J. ; Miles, D. ; Im, Y.-H. ; Quah, C. ; Lee, L. F. ; Cortés, J.

Background : Results from the phase III trial CLEOPATRA in HER2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We performed exploratory analyses of the incidence and time to development of CNS metastases in patients from CLEOPATRA. Patients and methods : Patients received pertuzumab/placebo: 840 mg in Cycle 1, then 420 mg; [...]

A partir de données portant sur 827 patientes atteintes d'un cancer métastatique du sein et incluses dans 3 essais cliniques, cette étude évalue l'efficacité et la toxicité de l'eribuline en monothérapie selon l'âge des patientes

Eribulin Monotherapy in Patients Aged 70 Years and Older With Metastatic Breast Cancer

Muss, Hyman ; Cortés, Javier ; Vahdat, Linda T. ; Cardoso, Fatima ; Twelves, Chris ; Wanders, Jantien ; Dutcus, Corina E. ; Yang, Jay ; Seegobin, Seth ; O’Shaughnessy, Joyce

Purpose : Following the demonstrated efficacy and safety of eribulin mesylate in heavily pretreated patients with metastatic breast cancer, an exploratory analysis was performed to investigate the effect of age in these patients. Methods : Data were pooled from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin mesylate at 1.4 mg/m2 as 2- to 5-minute intravenous infusions on days 1 and 8 of a 21-day cycle. The effect of age on [...]

Menée aux Etats-Unis auprès de 353 patientes atteintes d'un cancer métastatique du sein HER2+, cette étude analyse les bénéfices cliniques, en termes de taux de réponse et de survie globale, du trastuzumab selon que les patientes ont reçu une thérapie adjuvante ou néo-adjuvante par trastuzumab pour leur cancer primitif

Effect of adjuvant/neoadjuvant trastuzumab on clinical outcomes in patients with HER2-positive metastatic breast cancer

Murthy, Rashmi K. ; Varma, Ankur ; Mishra, Priyankana ; Hess, Kenneth R. ; Young, Elliana ; Murray, James L. ; Koenig, Kimberly H. ; Moulder, Stacy L. ; Melhem-Bertrandt, Amal ; Giordano, Sharon H. ; Booser, Daniel ; Valero, Vicente ; Hortobagyi, Gabriel N. ; Esteva, Francisco J.

BACKGROUND The purpose of the current study was to describe the outcomes of patients with human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified (HER2+) early breast cancer who received adjuvant or neoadjuvant trastuzumab-based therapy and were subsequently retreated with trastuzumab for metastatic disease. METHODS A total of 353 patients with metastatic HER2+ breast cancer who were treated with trastuzumab as part of their first-line treatment for metastatic disease were [...]

Cet article passe en revue les avancées récentes concernant les traitements médicamenteux et chirurgicaux du mélanome

Recent developments in the medical and surgical treatment of melanoma

Saranga-Perry, Vita ; Ambe, Chenwi ; Zager, Jonathan S. ; Kudchadkar, Ragini R.

Answer questions and earn CME/CNE Increasing knowledge of the biology of melanoma has led to significant advances in drug development to fight this disease. Surgery is the primary treatment for localized disease and is an integral part of management in patients with more advanced disease. The last decade has become the era of targeted therapy in melanoma and has revolutionized the treatment of this disease. Since 2011, 4 new agents have been approved for the treatment of patients with [...]

Cet article passe en revue les différentes stratégies thérapeutiques pour traiter un cancer localisé de l'œsophage chez les personnes âgées

Management of Localized Esophageal Cancer in the Older Patient

Won, Elizabeth ; Ilson, David H.

Most patients with gastroesophageal cancers are older than 65 years of age. The management of older patients poses challenges because they have multiple comorbidities and physiological changes associated with aging. Furthermore, data are limited on tolerance of cancer therapy and the use of combined-modality treatments in this patient population to guide their treatment. In this article, we focus on the management of older patients with localized esophageal cancer, highlighting the role of [...]

Mené sur 70 patients atteints d'un cancer du poumon non à petites cellules de stade III (âge médian : 61 ans), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, du taux de contrôle de la maladie et du taux de survie à 1 et 2 ans, et la toxicité d'un traitement comportant une chimiothérapie d'induction à base de cisplatine et de vinorelbine, administrée par intraveineuse puis par voie orale, suivie d'une chimiothérapie par vinorelbine orale et cisplatine en combinaison avec une radiothérapie concomitante

A phase II study of cisplatin with intravenous and oral vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy with oral vinorelbine and cisplatin for locally advanced non-small cell lung cancer

Lerouge, Delphine ; Riviere, Alain ; Dansin, Eric ; Chouaid, Christos ; Dujon, Cecile ; Schott, Roland ; Lavole, Armelle ; Le Pennec, Vincent ; Fabre, Elizabeth ; Crequit, Jacky ; Martin, Francis ; Dehette, Stephanie ; Fournel, Pierre ; Precheur-Agulhon, Benedicte ; Lartigau, Eric ; Zalcman, Gerard

Background : Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. Methods : Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 [...]

Menée sur 110 patients atteints d'un adénocarcinome du poumon avec mutation du gène EGFR, cette étude compare, du point de vue de la survie globale, l'efficacité de l'erlotinib, d'une radiothérapie du cerveau entier et d'une radiochirurgie stéréotaxique pour traiter des métastases cérébrales

Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

Gerber, Naamit K. ; Yamada, Yoshiya ; Rimner, Andreas ; Shi, Weiji ; Riely, Gregory J. ; Beal, Kathryn ; Yu, Helena A. ; Chan, Timothy A. ; Zhang, Zhigang ; Wu, Abraham J.

Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo [...]

A partir de données portant sur 110 essais cliniques de phase III ou IV, cette étude compare, entre la base ClinicalTrials.gov et les publications associées, les informations sur les événements indésirables des traitements évalués

Reporting Discrepancies Between the ClinicalTrials.gov Results Database and Peer-Reviewed Publications

Hartung, Daniel M. ; Zarin, Deborah A. ; Guise, Jeanne-Marie ; McDonagh, Marian ; Paynter, Robin ; Helfand, Mark

Background: ClinicalTrials.gov requires reporting of result summaries for many drug and device trials. Purpose: To evaluate the consistency of reporting of trials that are registered in the ClinicalTrials.gov results database and published in the literature. Data Sources: ClinicalTrials.gov results database and matched publications identified through ClinicalTrials.gov and a manual search of 2 electronic databases. Study Selection: 10% random sample of phase 3 or 4 trials with results in the [...]

Cet article passe en revue les travaux récents sur les traitements personnalisés des patientes atteintes d'un cancer du sein

Personalized medicine: present and future of breast cancer management

Sabatier, Renaud ; Gonçalves, Anthony ; Bertucci, François

Breast cancer is the first cause of cancer in women worldwide. Recent molecular analyses have shown that it is not a single disease but a mixture of several diseases with different biological behaviors, which should lead to treatment customization for each patient. Personalized medicine is based on tumor and/or patient molecular profiles. This new way to think oncology is currently applied at different stages of breast cancer management, including prognosis, prediction of treatment efficacy, [...]