Book de publications
Transcription
Book de publications
Book de publications R&D Unicancer 2011 Publications scientifiques, Communications orales, Poster scientifiques 2 book de publicationS — 2011 r&d UNICANCER book de publicationS — 2011 r&d UNICANCER 3 Publications et communications de R&D UNICANCER : en 2011, 15 publications dans des revues scientifiques internationales –– Ce document répertorie les publications et communications qui ont été répertoriées au cours de l’année 2011. Ces publications concernent les études cliniques et translationnelles en cancérologie, promues par R&D UNICANCER. L’effort de R&D UNICANCER en 2011 a porté tout particulièrement sur les publications d’articles, tout en maintenant l’effort sur les communications en congrès scientifiques, afin de mettre l’accent sur la valorisation des activités de recherche clinique. Ainsi, 15 articles ont été publiés dont 2 dans la revue New England Journal of Medicine et 18 abstracts ont été présentés en posters ou en communications orales à des congrès internationaux, dont l’ASCO. Les 3 grandes réussites de R&D UNICANCER en termes de publications des résultats en 2011 sont : –– Accord 11 : avancée majeure dans le traitement du cancer du pancréas métastatique ; étude publiée dans le N.E.J.M. –– Présentation orale de l’étude GEP 2 à l’ASCO 2011 : activité de l’association lapatinib-capécitabine chez les patientes porteuses de métastases cérébrales d’un cancer du sein, avant radiothérapie, –– MAP 3 : utilité de l’examestane dans la prévention contre le cancer du sein chez les femmes ménopausées à risque ; étude internationale publiée dans le N.E.J. M., à laquelle UNICANCER a participé. 4 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 5 SOMMAIRE 07 Publications Scientifiques 10 BREAST GROUP (UCBG) 10PACS 01 Protein expression, survival and docetaxel benefit in nodepositive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial J. Jacquemier, J-M. Boher, H. Roché, B. Esterni, D. Serin, P. Kerbrat, F. André, P. Finetti, E. Charafe-Jauffret, A-L. Martin, M. Campone, P. Viens, D. Birnbaum, F. Penault-Llorca, F. Bertucci. Breast Cancer Research and Treatment. 11 ACS 01 P Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer F. Bertucci, N. Borie, H. Roché, T. Bachelot, J-M. Le Doussal, G. Macgrogan, S. Debono, A. Martinec, I. Treilleux, P. Finetti, B. Esterni, J-M. Extra, J. Genève, F. Hermitte, C. Chabannon, J. Jacquemier, A-L. Martin, M. Longy, D. Maraninchi, V. Fert, D. Birnbaum, P. Viens. Breast Cancer Research and Treatment. 11PACS 01 A refined molecular taxonomy of breast cancer M. Guedj, L. Marisa, A. de Reynies, B. Orsetti, R. Schiappa, F. Bibeau, G. Macgrogan, F. Lerebours, P. Finetti, M. Longy, P. Bertheau, F. Bertrand, F. Bonnet, A-L. Martin, J-P.Feugeas, I. Bièche, J. Lehmann-Che, R. Lidereau , D. Birnbaum, F. Bertucci, H. de Thé, C. Theillet. Oncogene. 12 ACS 04 P Transparency in the presentation of trial results may not increase patients' trust in medical researchers J. Mancini, D. Genre, F. Dalenc, F. Maylevin, A-L. Martin, P. Viens, C. Julian-Reynier. Clinical Trials. 13PACS 06 High rate if extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer E. Brain, C. Levy, D. Serin, H. Roché, M. Spielmann, R. Delva, C. Veyret, L. Mauriac, M. Rios, A-L. Martin, M. Jimenez, B. Asselain, M. Gauthier, F. Bonnetain, P. Fumoleaut. British Journal of Cancer. 14PREV 01/MAP.3 Exemestane for breast cancer prevention in postmenopausal women P-E. Goss, J-N. Ingle, J-E. Alés-Martínez, A-M. Cheung, R-T. Chlebowski, J. Wactawski-Wende, A. McTiernan, J. Robbins, K-C. Johnson, L-W. Martin, E. Winquist, G-E. Sarto, J-E. Garber, C-J. Fabian, P. Pujol, E. Maunsell, P. Farmer, K-A. Gelmon, D. Tu, H. Richardson; NCIC CTG MAP.3 Study Investigators. The New england Journal of Medecine. 15 Groupe FEDEGYN 15FEDEGYN Cancers gynécologiques P. Cottu La lettre du cancérologue. 16 G ASTRO INTESTINAL GROUP (UCGI) - (ACCORD) 16ACCORD 09 Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/090201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival Lucie Oberic, Frédéric Viret, Charlotte Baey, Marc Ychou, Jaafar Bennouna, Antoine Adenis, Didier Peiffert, Françoise Mornex, Jean-Pierre Pignon, Patrice Celier, Jocelyne Berille,Michel Ducreux. Radiation Oncology. 17ACCORD 11 FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer Thierry Conroy, Françoise Desseigne, Marc Ychou, Olivier Bouché, Rosine Guimbaud, Yves Bécouarn, Antoine Adenis, Jean-Luc Raoul, Sophie Gourgou-Bourgade, Christelle de la Fouchardière, Jaafar Bennouna, Jean-Baptiste Bachet, Faiza Khemissa-Akouz, Denis Péré-Vergé, Catherine Delbaldo, Eric Assenat, Bruno Chauffert, Pierre Michel, Christine MontotoGrillot, M.Chem., and Michel Ducreux, for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup. The New England Journal of Medecine. 18ACCORD 11 Perioperative Chemotherapy Compared With Surgery Alone for Resectable Gastroesophageal Adenocarcinoma : An FNCLCC and FFCD Multicenter Phase III Triall Marc Ychou, Valérie Boige, Jean-Pierre Pignon, Thierry Conroy, Olivier Bouche, Gilles Lebreton,Muriel Ducourtieux, Laurent Bedenne, Jean-Michel Fabre, Bernard Saint-Aubert, Jean Genève, Philippe Lasser, Philippe Rougier. Journal of Clinical Oncology. 19GETUG 19GETUG 06 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial Véronique Beckendorf, Stéphane Guerif, Elisabeth Le Prisé, Jean-Marc Cosset, Agnes Bougnoux, Bruno Chauvet, Naji Salem, Olivier Chapet, Sylvain Bourdain, Jean-Marc Bachaud, Philippe Maingon, Jean-Michel Hannoun-Levi, Luc Malissard, Jean-Marc Simon, Pascal Pommier, Men Hay, Bernard Dubray, Jean-Léon Lagrange, Elisabeth Luporsi, Pierre Bey. Int J Radiation Oncol Biol Phys. 20 Groupe GERICO 20GERICO 02 Effect of XELOX on functional ability among elderly patients with metastatic colorectal cancer: Results from the FNCLCC/ GERICO 02 phase II study Frédérique Rousseau, Roland Bugat, Michel Ducreux, Frédérique Cvitkovic, Elisabeth Carola, Mathilde Gisselbrecht, Frédéric Viret, Benjamin Esterni, Jean Genève, Etienne Brain. Journal of Geriatric Oncology. 21GERICO 06 Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial Etienne G.C. Brain, Cécile Mertens, Véronique Girre, Frédérique Rousseau, Emmanuel Blot, Sophie Abadie, Lionel Uwer, Emmanuelle Bourbouloux, Isabelle Van Praagh-Doreau, Loic Mourey, Sylvie Kirscher, Brigitte Laguerre, Emmanuelle Fourme, Sylvia Luneau, Jean Genève, Marc Debled. Critical Reviews in Oncology Hematology. 22GERICO GERICO : dix ans de recherche clinique en oncogériatrie V. Girre, C. Orsini, E.G.C. Brain. Oncologie. 23 Groupe des essais précoces (GEP) 23LAPNAV/GEP 01 Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients K. Rezai, S. Urien, N. Isambert, H. Roche, V. Dieras, J. Berille, J. Bonneterre, E. Brain, F. Lokiec Cancer Chemother Pharmacol. 6 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 7 SOMMAIRE 25 Communications orales et posters scientifiques 27 ASCO Genito-urinary cancers symposium 28GETUG 15 (Présentation orale) Survival analysis of a randomized phase III trial comparing androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in hormone-naive metastatic prostate cancer (GETUG-AFU 15/0403) Gwenaelle Gravis, Karim Fizazi, Florence Joly, Stéphane Oudard, Franck Priou, Igor Latorzeff, Remy Delva, Ivan Krakowski, Brigitte Laguerre, Frederic Rolland, Christine Theodore, Gael Deplanque, Jean Marc Ferrero, Loic Mourey, Damien Pouessel, Philippe Beuzeboc, Sylvie Zanetta, Benjamin Esterni, Muriel Habibian, Michel Soulie; Journal of Clinical Oncology. 31 AACR ANNUAL MEETING 33GEP01 (Poster) A phase I pharmacokinetic study of lapatinib and IV vinorelbine in the treatment of her2-positive locally advanced or metastatic breast cancer K. Rezai, N. Isambert, E. Brain, F. Dalenc, S.Urien, V. Diéras, L. Vanlemmens, M. Jimenez, H. Roché, P. Tresca, P. Fumoleau, F. Lokiec, 37 ASCO Annual Meeting 38GETUG 12 (Présentation orale) Docetaxel-estramustine in high- risk localized prostate cancer: First results of the French Genito-Urinary Tumor Group phase III trial (GETUG 12) Karim Fizazi, Francois Lesaunier, Remy Delva, Gwenaëlle Gravis, Frederic Rolland, Frank Priou, Jean-Marc Ferrero, Nadine Houede, Loïc Mourey, Christine Theodore, Ivan Krakowski, Jean-François Berdah, Jean-Louis Davin, Jocelyne Berille, Muriel Habibian, JeanLaurent Ichante, Agnès Laplanche, Stephane Culine. Journal of Clinical Oncology. 40GETUG 14 (Poster discussion) Does short-term androgen depletion add to high dose radiotherapy (80 Gy) in localized intermediate risk prostate cancer? Intermediary analysis of GETUG 14 randomized trial. B. Dubray, V. Beckendorf, S. Guerif, E. Le Prisé, A. ReynaudBougnoux, J-M. Hannoun-Levy, T-D. Nguyen, C. Hennequin, J. Cretin, M. Fayolle-Campana, J-L. Lagrange, J-M. Bachaud, D. Azria, A. Grandgirard, P. Pommier, J-M. Simon, V. Harter, M. Habibian, for the French Genito-Urinary Tract Tumours Study Group (GETUG) 44PACS 01 (Poster discussion) Foxp3 expression in breast cancer cells : a new predictor of response to anthracycline versus docetaxel in primary breast cancer treated with adjuvant chemotherapy in the Phase III trial FNCLCC/PACS O1 François Ghiringhelli, Pierre Fumoleau, Grégoire Mignot, Laurent Arnould, Henri Roché, Marc Spielmann, Christelle Lévy, Alain Lortholary, Françoise Eichler, Christel Mesleard, Sylvain Ladoire 49PACS 09 / BEVERLY 01 (Poster) Early drop of circulating tumor cells (CTC) and increase of circulating endothelial cells (CEC) during neoadjuvant chemotherapy (CT) combined with bevacizumab in her2 negative inflammatory breast cancer (IBC) in multicentre phase II trial beverly 1 J.Y. Pierga, F. C. Bidart, F. André, T. Petit, F. Dalenc, T. Delozier, G. Romieu, J. Bonneterre, J-M. Ferrero, P. Kerbrat, A-L. Martin, P. Viens 52PREV 01 / MAP 03 (Communication orale) Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial. P. E. Goss, J. N. Ingle, J. Ales-Martinez, A. Cheung, R. T. Chlebowski, J. Wactawski-Wende, A. McTiernan, J. Robbins, K. Johnson, L. Martin, E. Winquist, G. Sarto, J. E. Garber, C. J. Fabian, P. Pujol, E. Maunsell, P. Farmer, K. A. Gelmon, D. Tu, H. Richardson; Journal of Clinical Oncology. 54SARCOME 01/EWING 99 (Communication orale) Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing’s tumor (ET). Results of the Euro-EWING.99-R1 trial. Oberlin O, Le Deley MC, Dirksen U, Lewis I, Ranft A, Michon J, Paulussen M, Whelan J, Ladenstein R, Brennan B, Marec Bérard P, Laurence V, Van den Berg H, Hjorth L, Douglas C, Wheatley K, Van Glabbeke M, Judson I, Craft A, Juergens H. Journal of Clinical Oncology. 57GEP 02 (Poster) Circulating tumor cells (CTC) monitoring during phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastses from her2-positive (+) metastaic breast cancer (MBC) before whole brain radiotherapy (WBR) : lanscape study T-D. Bachelot, G. Romieu, M. Campone, V. Dieras, C. Cropet, H-H. Roche, M. Jimenez, E. Le Rhun, J-Y. Pierga, A. Gonçalves, M. Leheurteur, J. Domont, M. Gutierrez, H. Cure, J-M. Ferrero, C. Labbe 61 I CCH (International Conference on Communication in Healthcare) 62PACS 04 (Communication orale) Lack of involvement in Decision-making is Associated with Regret after Participation in a Clinical Trial Julien Mancini, Dominique Genre, Florence Dalenc, Pierre Kerbrat, Patrice Viens, Anne-Laure Martin, Claire Julian-Reynier. Medical Encounter. 65EMUC (European Multidisciplinary Meeting on Urological Cancers) 66GETUG 20 (Poster) A phase III randomised, open-label, multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/0310) F. Rozet, M. Habibian, J. Berille, L. Roca, L. Salomon, M. Soulie, S. Culine 69 Pascal Pujol, Christine Lasset, Pascaline Berthet, Catherine Dugast, Suzette Delaloge, Jérôme Lemonnier, Lise Roca, Sylvie Mijonnet, Karen Baudry, Catherine Nogues, AnneLaure Martin, on behalf the French Federation of Cancer Centers (UNICANCER) SABCS San Antonio Breast Cancer Symposium 70GEP 02 (Communication orale) Circulating Tumor Cells (CTC) monitoring during phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases from HER2-positive (+) metastatic breast cancer (MBC) before whole brain radiotherapy (WBR): LANDSCAPE study J. Y. Pierga, C. Cropet, P. Tresca, F. Dalenc, G. Romieu, M. Campone, C. Mahier Aït-Oukhatar, E. Le Rhun, A. Gonçalves, M. Leheurteur, J. Domont, M. Gutierrez, H. Cure, J. M. Ferrero, C. Labbe-Devilliers, FC Bidard, T. D. Bachelot. Cancer Research. 73GRT 01 (Poster) SAFIR01: screening approach for individualized regimen UNICANCER (former French Federation of Cancer Centers F. André, C. Peletekian, M. Jimenez, J-M. Ferrero, S. Delaloge, S. Roman, P. Dessen, H. Bonnefoi 77ONCO 03/LIBER (Poster) Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers : the LIBER trial 81PACS 08/TAViX (Poster) Safety profile of lxabepilone as adjuvant treatment for poor prognosos early breast cancer : first results of the UnicancerPACS 08 trial Mario Campone, Marc Spielmann, Hans Wildiers, Paul Cottu, Pierre Kerbrat, Christelle Levy, Françoise Mayer, Thomas Bachelot, Winston Tan, Jean-Christophe Eymard, Lionel Uwer, Jean-Pascal Machiels, Didier Verhoeven, Dominique Jaubert, Thomas Facchini, Hubert Orfeuvre, Jean-Luc Canon, Bernard Asselain, Lise Roca, Magali Lacroix-Triki, Anne-Laure Martin, Henri Roché 85PACS 09/BEVERLY 01 (Poster) Multicentric Phase II PACS 09/ Beverly1 Trial: First Efficacy And Safety Results Of Neoadjuvant Chemotherapy Combined With Bevacizumab In HER2-Negative Patients With NonMetastatic Inflammatory Breast Cancer P. Viens,T. Petit, F. Dalenc, J-Y. Pierga, T. Delozier, G. Romieu, J. Bonneterre, J-M. Ferrero, P. Kerbrat, M. Mouret-Reynier, T. Bachelot, P. Soulié, F. Lerebours, J-C. Eymard, M. Deblock, A. Lortholary, A-C. Hardy Bessard, J-M. Boher, B. Asselain, E. Charafe Jauffret, J. Lemonnier, A-L. Martin, F. André 89PACS 09/BEVERLY 01 (Poster) Correlation of circulating tumor cells (CTC) and circulating endothelial cells (CEC) with pathological Complete Reponse (pCR) during neoadjuvant chemotherapy (CT) combined with bevacizumab in HER2 negative inflamatory breast cancer (IBC) : ancillary study of phase II trial BEVERLY 1 J-Y. Pierga, F-C. Bidart, F. André, T. Petit, F. Dalenc, T. Delozier, G. Romieu, J. Bonneterre, J-M. Ferrero, P. Kerbrat, J. Lemonnier, P. Viens 93 AACR New Horizons in Cancer Research 95ONCO 03/LIBER (Poster) Uptake of a randpmized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutation carriers the liber trial Pascal Pujol, Christine Lasset, Pascaline Berthet, Catherine Dugast, Suzette Delaloge, Jérôme Lemonnier, Lise Roca, Sylvie Mijonnet, Karen Baudry, Catherine Nogues, Anne-Laure Martin, on behalf the UNICANCER Breast Group Publications scientifiques 10 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 11 BREAST GROUP PACS 01 PACS 01 Jocelyne Jacquemier, Jean-Marie Boher, Henri Roche, Benjamin Esterni, Daniel Serin, Pierre Kerbrat, Fabrice Andre, Pascal Finetti, Emmanuelle Charafe-Jauffret, Anne-Laure Martin, Mario Campone, Patrice Viens, Daniel Birnbaum, Frédérique Penault-Llorca, François Bertucci François Bertucci, Nathalie Borie, Henri Roche, Thomas Bachelot, Jean-Marc Le Doussal, Gaëtan Macgrogan, Stéphane Debono, Agnès Martinec, Isabelle Treilleux, Pascal Finetti, Benjamin Esterni, Jean-Marc Extra, Jean Geneve, Fabienne Hermitte, Christian Chabannon, Jocelyne Jacquemier, Anne-Laure Martin, Michel Longy, Dominique Maraninchi, Vincent Fert, Daniel Birnbaum, Patrice Viens Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial Introduction Conclusions The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves diseasefree survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel’s benefit. In patients with node-positive EBC receiving adjuvant anthracyclinebased chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity. Methods adjuvant docetaxel, breast cancer, Ki67, molecular subtypese – – Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested. – Keywords – Breast Cancer Research 2011, 13:R109 Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer Abstract – Prognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CTwithout taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the ‘‘goodprognosis’’ group and 56% in the ‘‘poor-prognosis’’ group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens. Breast Cancer Research and Treatment, 2011;127(2):363-73. Results – Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67- positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively. PACS 01 A refined molecular taxonomy of breast cancer M. Guedj, L. Marisa, A. de Reynies, B. Orsetti, R. Schiappa, F. Bibeau, G. Macgrogan, F. Lerebours, P. Finetti, M. Longy, P. Bertheau, F. Bertrand, F. Bonnet, A-L. Martin, J-P.Feugeas, I. Bièche, J. Lehmann-Che, R. Lidereau, D. Birnbaum, F. Bertucci, H. de Thé, C. Theillet Abstract – The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ERþ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ERþ/PRþ/ARþ, one was ER /PR /ARþ and one was triple negative (AR / ER /PR ). ERBB2amplified tumors were split between the ER /PR /ARþ subgroup and the highly proliferative ERþ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapsefree survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent welldefined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer. Oncogene, 2012;31(9):1196-206 12 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 13 PACS 04 PACS 06 Julien Mancini, Dominique Genre, Florence Dalenc, Françoise Maylevin, Anne-Laure Martin, Patrice Viens, Claire Julian-Reynier E. Brain, C. Levy, D. Serin, H. Roché, M. Spielmann, R. Delva, C. Veyret, L. Mauriac, M. Rios, A-L. Martin, M. Jimenez, B. Asselain, M. Gauthier, F. Bonnetain, P. Fumoleau Transparency in the presentation of trial results may not increase patients' trust in medical researchers Background Limitations One of the expected benefits of sharing trial results with participants is that it may enhance trust in medical researchers (TMRs). The results obtained here on the disclosure of final results to breast cancer patients via the Internet cannot be generalized to all situations involving the disclosure of phase III randomized controlled trial results. – Purpose – In a prospective study on a sample of clinical trial participants, we investigated the effect on the participants’ TMRs of providing final trial results to participants via the Internet Methods – Participants in the FNCLCC-PACS04 trial (ClinicalTrials.gov Identifier: NCT00054587) were surveyed on average 6 years after enrollment, when the trial results were available. In the current study, they were randomized to receive (experimental group) or not to receive (control group) a letter informing them that the results of the trial could be consulted on a specific website. TMRs was measured before randomization and 6 months later using mailed self-administered questionnaires. Results – The response rate was 93% (N=107). TMRs remained unchanged in the control group (mean effect size = -0.06, 95% confidence interval (CI): -0.28 to 0.17, p=0.617) but decreased in the experimental group (-0.30, 95% CI: -0.53 to -0.06, p=0.015). However, the difference between the two effect sizes was not statistically significant (p=0.144) – Conclusions – Transparency is an ethical research requirement, but it may not enhance participants’ TMRs. Clinical Trials, 2012;9(1):90-3. http://ctj.sagepub.com High rate if extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer Background Result A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes based chemotherapy. In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B:18.9%) Methods Conclusion Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mgm 2, epirubicin 100 mgm 2, cyclophosphamide 500 mgm 2 (FEC 100) followed by three cycles of docetaxel 100 mgm 2 delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. Sequential dose-dense FEC 100 followed by docetaxel 100 mgm 2 is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration. – – – – British Journal of Cancer (2011) 105, 1480–1486. doi:10.1038/bjc.2011.414 www.bjcancer.com 14 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 15 Groupe FEDEGYN PREV 01/MAP.3 FEDEGYN Paul E. Goss, James N. Ingle, José E. Alés-Martínez, Angela M. Cheung, Rowan T. Chlebowski, Jean Wactawski-Wende, Anne McTiernan, John Robbins, Karen C. Johnson, Lisa W. Martin, Eric Winquist, Gloria E. Sarto, Judy E. Garber, Carol J. Fabian, Pascal Pujol, Elizabeth Maunsell, Patricia Farmer, Karen A. Gelmon, Dongsheng Tu, and Harriet Richardson, for the NCIC CTG MAP.3 Study Investigators* Paul E. Goss, James N. Ingle, José E. Alés-Martínez, Angela M. Cheung, Rowan T. Chlebowski, Jean Wactawski-Wende, Anne McTiernan, John Robbins, Karen C. Johnson, Lisa W. Martin, Eric Winquist, Gloria E. Sarto, Judy E. Garber, Carol J. Fabian, Pascal Pujol, Elizabeth Maunsell, Patricia Farmer, Karen A. Gelmon, Dongsheng Tu, and Harriet Richardson, for the NCIC CTG MAP.3 Study Investigators* Exemestane for breast cancer prevention in postmenopausal women Background Conclusion Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.) – Methods – In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. Result – A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P = 0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P = 0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = 0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatmentrelated deaths. Minimal quality-of-life differences were observed. – T h e N e w En g l a n d J o u r n a l o f M e d i c i n e, 2011;36 4(25): 2381- 91. http://www.nejm.org/ Cancers gynécologiques Extrait – "Nous revoyons ici les principaux essais concernant les cancers gynécologiques publiés ou présentés en 2010." Points forts – - Le bévacizumab prolonge la survie sans progression en première ligne thérapeutique des cancers tubo-ovariens. - Le concept de BRCAness commence à trouver une définition clinique et moléculaire. - La vaccination anti-HPV continue à prouver son efficacité sur toutes les formes de lésions cervicales. - La curiethérapie vaginale est le traitement adjuvant de référence des cancers endométriaux à risque haut ou intermédiaire. La lettre du cancérologue, janvier 2011, pages 18-22 16 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 17 GASTRO INTESTINAL ACCORD 09 Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/090201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival Lucie Oberic, Frédéric Viret, Charlotte Baey, Marc Ychou, Jaafar Bennouna, Antoine Adenis, Didier Peiffert, Françoise Mornex, Jean-Pierre Pignon, Patrice Celier, Jocelyne Berille, Michel Ducreux. ACCORD 11 FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer Thierry Conroy, Françoise Desseigne, Marc Ychou, Olivier Bouché, Rosine Guimbaud, Yves Bécouarn, Antoine Adenis, Jean-Luc Raoul, Sophie Gourgou-Bourgade, Christelle de la Fouchardière, Jaafar Bennouna, Jean-Baptiste Bachet, Faiza Khemissa-Akouz, Denis Péré-Vergé, Catherine Delbaldo, Eric Assenat, Bruno Chauffert, Pierre Michel, Christine Montoto-Grillot, M.Chem., and Michel Ducreux, for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup. Background Conclusions As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.) – Background Conclusion To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. – Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. Trial Registration Methods ClinicalTrials.gov: NCT00112697 We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. – Methods – Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m2/day (protracted IV) and docetaxel (DCT) 20 mg/m2/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/ m2, plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial’s primary endpoint was the 6-month crude nonprogression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. Result – Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). – The New England Journal of Medicine http://www.nejm.org/ – Results – The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). – The New England Journal of Medicine, 2011, 364 (19): 1817-1824. http://www.nejm.org/ 18 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 19 GETUG ACCORD 11 Perioperative Chemotherapy Compared With Surgery Alone for Resectable Gastroesophageal Adenocarcinoma : An FNCLCC and FFCD Multicenter Phase III Trial Marc Ychou, Valérie Boige, Jean-Pierre Pignon, Thierry Conroy, Olivier Bouche, Gilles Lebreton,Muriel Ducourtieux, Laurent Bedenne, Jean-Michel Fabre, Bernard Saint-Aubert, Jean Genève, Philippe Lasser, Philippe Rougier GETUG 06 70 Gy Versus 80 Gy in Localized Prostate Cancer: 5-Year Results of GETUG 06 Randomized Trial l Véronique Beckendorf, Stéphane Guerif, Elisabeth Le Prisé, Jean-Marc Cosset, Agnes Bougnoux, Bruno Chauvet, Naji Salem, Olivier Chapet, Sylvain Bourdain, Jean-Marc Bachaud, Philippe Maingon, Jean-Michel Hannoun-Levi, Luc Malissard, JeanMarc Simon, Pascal Pommier, Men Hay, Bernard Dubray, Jean-Léon Lagrange, Elisabeth Luporsi, Pierre Bey. Purpose Conclusions Purpose Conclusions After curative resection, the prognosis of gastroesophageal adenocarcinoma is poor. This phase III trial was designed to evaluate the benefit in overall survival (OS) of perioperative fluorouracil plus cisplatin in resectable gastroesophageal adenocarcinoma. In patients with resectable adenocarcinoma of the lower esophagus, GEJ, or stomach, perioperative chemotherapy using fluorouracil plus cisplatin significantly increased the curative resection rate, disease-free survival, and OS. To perform a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. High-dose radiotherapy provided a better 5-year biochemical outcome with slightly greater toxicity. Patients and Methods Int. J. Radiation Oncology Biol. Phys.2011;80(4):1056-63. Patients and Methods Journal of Clinical Oncology, 2011, 29 (13): 1715-1721. A total of 306 patients with localized prostate cancer were randomized. No androgen deprivation was allowed. The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions. Toxicity was graded using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective, objective, management, analytic scales (LENT-SOMA) scales. The patients’ quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item cancer-specific and 25-item prostatespecific modules. – – Overall, 224 patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction (GEJ), or stomach were randomly assigned to either perioperative chemotherapy and surgery (CS group; n = 113) or surgery alone (S group; n = 111). Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m2) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m2/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. The primary end point was OS. Results – Compared with the S group, the CS group had a better OS (5-year rate 38% v 24%; hazard ratio [HR] for death: 0.69; 95% CI, 0.50 to 0.95; P = .02); and a better disease-free survival (5-year rate: 34% v 19%; HR, 0.65; 95% CI, 0.48 to 0.89; P = .003). In the multivariable analysis, the favorable prognostic factors for survival were perioperative chemotherapy (P = .01) and stomach tumor localization (P < .01). Perioperative chemotherapy significantly improved the curative resection rate (84% v 73%; P = .04). Grade 3 to 4 toxicity occurred in 38% of CS patients (mainly neutropenia) but postoperative morbidity was similar in the two groups. – – – Results – The median follow-up was 61 months. According to the 1997-American Society for Therapeutic Radiology and Oncology definition, the 5-year biochemical relapse rate was 39% and 28% in the 70- and 80-Gy arms, respectively (p = .036). Using the Phoenix definition, the 5-year biochemical relapse rate was 32% and 23.5%, respectively (p = .09). The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level >15 ng/mL. At the last follow-up date, 26 patients had died, 10 of their disease and none of toxicity, with no differences between the two arms. According to the Radiation Therapy Oncology Group scale, the Grade 2 or greater rectal toxicity rate was 14% and 19.5% for the 70- and 80Gy arms (p =.22), respectively. The Grade 2 or greater urinary toxicity was 10% at 70 Gy and 17.5% at 80 Gy (p = .046). Similar results were observed using the LENT-SOMA scale. Bladder toxicity was more frequent at 80 Gy than at 70 Gy (p =.039). The quality-of-life questionnaire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms. – 20 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 21 Groupe GERICO GERICO 02 Effect of XELOX on functional ability among elderly patients with metastatic colorectal cancer: Results from the FNCLCC/GERICO 02 phase II study Frédérique Rousseau, Roland Bugat, Michel Ducreux, Frédérique Cvitkovic, Elisabeth Carola, Mathilde Gisselbrecht, Frédéric Viret, Benjamin Esterni, Jean Genève, Etienne Brain Objectives Conclusion This study investigated the effect of capecitabine–oxaliplatin (XELOX) on functional independence in patients aged ≥70 years with histologically proven metastatic colorectal cancer (mCRC). Materials and methods: Patients received capecitabine 750 mg/ m2 bid d1–14+oxaliplatin 90 mg/m2 d1, every 3 weeks; doses were increased to 1000 and 120 mg/m2, respectively, in the absence of significant toxicity. The primary endpoint was stabilization/ improvement of Katz Activities of Daily Living (ADL) scale. This study demonstrates the feasibility of XELOX in elderly mCRC patients, with no impairment of independence among patients who remained on therapy.Clinical Trials, 2012;9(1):90-3./http://ctj. sagepu – Results – Sixty patients were enrolled. ADL was stabilized/improved in 36/40 patients (90%) after 3 cycles, and in 25/27 patients (93%) after 6 cycles. Capecitabine and oxaliplatin doses were increased in 31% of patients. The objective response rate was 37% (1 complete and 21 partial responses). Toxicity included grade 3/4 diarrhea (13%), neurotoxicity (grade 1/2 in 68%, grade 3/4 in 2%), and grade 3/4 anemia (7%). GERICO 06 Impact of liposomal doxorubicin-based adjuvant chemotherapy on autonomy in women over 70 with hormone-receptor-negative breast carcinoma: A French Geriatric Oncology Group (GERICO) phase II multicentre trial Etienne G.C. Brain, Cécile Mertens, Véronique Girre, Frédérique Rousseau, Emmanuel Blot, Sophie Abadie, Lionel Uwer, Emmanuelle Bourbouloux, Isabelle Van Praagh-Doreau, Loic Mourey, Sylvie Kirscher, Brigitte Laguerre, Emmanuelle Fourme, Sylvia Luneau, Jean Genève, Marc Debled – Journal of Geriatric Oncology, 2011, 2: 105-111 Rationale Results Breast cancer is a disease of ageing. Functional independence in elderly patients, measured with the Katz activities of daily living (ADL) scale, predicts overall survival and the need for welfare support. Few prospective studies have examined the feasibility of adjuvant chemotherapy and its impact on autonomy in women over 70 years of age with high-risk breast cancer. This multicentre phase II trial was designed to assess the impact of adjuvant anthracycline-based chemotherapy on these patients’ autonomy. Forty patients (median age 75 [70–82]) were enrolled between February 2006 and November 2007. Chemotherapy had no deleterious impact on ADL, cognition, mental status, or the frequency of comorbidities. In contrast, the number of patients at risk of malnutrition, based on the Mini Nutritional Assessment, more than doubled between baseline and the end of chemotherapy, rising from 15% to 38%. Quality-of-life deteriorated in terms of social and role functioning, likely owing to fatigue, loss of appetite, nausea and vomiting. Treatment acceptability was good. The main adverse effect was neutropenia, 15% of the patients experiencing febrile neutropenia. No cardiac toxicity or toxic deaths occurred. – Design and methods – In a two-stage Fleming design, women aged ≥70 years with histologically proven hormone-receptor-negative early breast cancer and a significant risk of recurrence (pN+ or “high risk” pN0) received 4 cycles of nonpegylated liposomal doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks postoperatively, on an outpatient basis. The primary endpoint was the change in the ADL score during chemotherapy. Secondary endpoints include comprehensive geriatric, quality-of-life and acceptability assessments, tolerability, and long-term outcome. The results for the primary endpoint and other scales at completion of adjuvant chemotherapy are reported here, while long-term follow-up is not yet complete. – Conclusion – This study demonstrates the feasibility of an adjuvant chemotherapy regimen combining nonpegylated liposomal doxorubicin and cyclophosphamide in fit elderlywomen <85 years with breast cancer. Although chemotherapy had an impact on social and role functioning, autonomy was not impaired and toxicity was acceptable. Special attention should be paid to nutritional status before and after treatment. Critical Reviews in Oncology Hematology, 2011 Oct; 80(1): 160-170 22 book de publication — 2011 r&d UNICANCER book de publication — 2011 r&d UNICANCER 23 Groupe des essais précoces (GEP) GERICO GERICO: 10 years of clinical research in geriatric oncology V. Girre, C. Orsini, E.G.C. Brain Clinical research in geriatric oncology is under active development, since aging is heterogeneous and requires specific programs addressing both old and new therapeutic strategies in elderly cancer patients. The group of geriatric oncology, GERICO, launched in 2002 by the French National Federation of Cancer Centres (FNCLCC), has acquired and demonstrated this specific experience. Convinced of the need to integrate the dimensions of functional status and quality of life—key issues in the elderly—it has built several trials on primary endpoints derived from geriatric assessment, different from the traditional tumour response and survival. Today it plans to integrate again classical criteria with geriatric ones. It militates in favour of inclusion of a lower selection of populations and takes into consideration life expectancy which remains so difficult to estimate. Oncologie, 2011 ; 13: 102–105. LAPNAV/GEP01 Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients K. Rezai, S. Urien, N. Isambert, H. Roche, V. Dieras, J. Berille, J. Bonneterre, E. Brain, F. Lokiec Purpose Results T he objec tives of this s tudy were to inves tigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote intercompartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. – Methods – Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a nonlinear mixed effect model program (Monolix version 3.1 s). – Conclusion – The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8. Cancer Chemother Pharmacol. 2011; 68(6):1529-36. Communications orales & Posters scientifiques ASCO GENITO-URINARY CANCERS SYMPOSIUM orlando, 17-19 février 2011 book de publication — 2011 r&d UNICANCER 29 GETUG 15 Communication orale Survival analysis of a randomized phase III trial comparing androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in hormone-naive metastatic prostate cancer (GETUG-AFU 15/0403) GETUG 15 Survival analysis of a randomized phase III trial comparing androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in hormone-naive metastatic prostate cancer (GETUG-AFU 15/0403) Gwenaelle Gravis, Karim Fizazi, Florence Joly, Stéphane Oudard, Franck Priou, Igor Latorzeff, Remy Delva, Ivan Krakowski, Brigitte Laguerre, Frederic Rolland, Christine Theodore, Gael Deplanque, Jean Marc Ferrero, Loic Mourey, Damien Pouessel, Philippe Beuzeboc, Sylvie Zanetta, Benjamin Esterni, Muriel Habibian, Michel Soulie; Department of Medical Oncology, Institut Paoli Calmettes, INSERM UMR 891, Marseille, France; Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Centre François Baclesse, Caen, France; Hôpital Européen Georges Pompidou, Paris, France; Centre Hospitalier Departemental Les Oudairies, La Roche sur Yon, France; Clinique Pasteur, Toulouse, France; CLCC Paul Papin, Angers, France; Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France; Centre Eugène Marquis, Rennes, France; Institut de Cancérologie de l’Ouest , Nantes, France; Hospital Foch, Suresnes, France; Groupe Hospitalier St. Joseph, Paris, France; Centre Antoine-Lacassagne, Nice, France; Institut Claudius Regaud, Toulouse, France; Hopital Saint-Louis, Paris, France; Institut Curie, Paris, France; Centre Georges-François Leclerc, Dijon, France; Department of Biostatistics, Institut Paoli-Calmettes, Marseille, France; UNICANCER, Paris, France; Centre Hospitalier Universitaire Rangueil, Toulouse, France Background Results Androgen deprivation therapy (ADT) is the standard treatment of hormone naive metastatic prostate cancer (HNMPC). We initiated a phase III multicentre trial comparing ADT with or without docetaxel (D) in HNMPC (GETUG 15). From October 2004 to December 2008, 385 pts were included. The median age was 63 years (43-84), median PSA 26.8 ng/ml (0.111900), Gleason score ≥ 8: 57%. Prognosis classification [Glass TR, et al J Urol 2003] was as follows: good prognosis (49%), intermediate prognosis (29%) and poor prognosis (22%). Majority of patients were upfront metastatic (72%), 28% were metastatic after local treatment failure. Bone metastases were 81%, nodes 55%, lung 11%. Median number of cycles was 9 (range 0-9). Toxicity included grade 3-4 neutropenia (27%) with febrile neutropenia in 3 %; 3 toxic death occurred 2 pts due to febrile neutropenia and one due to multi-organ failure. After 215 pts accrued, systematic G-CSF day 5 to 10 was administered and no subsequent toxic death occurred. Higher 6 months PSA response (≥ 50%) was observed in arm A (p=0.01) and 6 months PSA progression (≥ 25%) was higher in arm B (p=0.002). With a median follow up duration of 50 months, final analysis will be completed in march 2012. Overall survival will be compared using a stratified log rank test. Biological and clinical progression-free survival will be also provided. – Methods – Patients (pts) with HNMPC were randomly assigned to either arm A (ADT plus D: 75mg/m² q3w, 9 cycles) or arm B (ADT). The primary endpoint was overall survival. The planned number of patients was 378 to detect a 15% difference in overall survival with a power of 80% and an alpha risk of 0.05 (two-sided test). Survival analysis is planned after 146 deaths will occur. Secondary end points were biological and clinical progression-free survival, toxicity and QOL, previously presented. – Journal of Clinical Oncology, 29: 2011, 7; Abstract 10 AACR Annual meeting orlando, 2-6 avril 2011 GEP01 Poster A phase I pharmacokinetic study of lapatinib and IV vinorelbine in the treatment of her2-positive locally advanced or metastatic breast cancer WSHZTHSHWH[PUPIUNT3 +VZLTN [PTLHM[LYKVZPUNO ASCO Annual meeting Mc CORMICK Place, CHICAGO, 3-7 juin 2011 book de publication — 2011 r&d UNICANCER 39 GETUG 12 Communication orale Docetaxel-estramustine in high- risk localized prostate cancer: First results of the French Genito-Urinary Tumor Group phase III trial (GETUG 12) GETUG 12 Docetaxel-estramustine in high- risk localized prostate cancer: First results of the French Genito-Urinary Tumor Group phase III trial (GETUG 12) Karim Fizazi, Francois Lesaunier, Remy Delva, Gwenaëlle Gravis, Frederic Rolland, Frank Priou, Jean-Marc Ferrero, Nadine Houede, Loïc Mourey, Christine Theodore, Ivan Krakowski, Jean-François Berdah, Jean-Louis Davin, Jocelyne Berille, Muriel Habibian, Jean-Laurent Ichante, Agnès Laplanche, Stephane Culine. Background Results Docetaxel improves survival in patients (pts) with castrationresistant prostate cancer (CaP). This phase III trial assessed docetaxel-based chemotherapy in pts with high-risk localized CaP. 413 pts were accrued (207 DE arm, 206 H arm): T3-T4 (67%), GS ≥8 (42%), PSA > 20 ng/mL (59%), pN+ (29%). Local treatment consisted of radiotherapy in 358 pts (87%) (median dose 74 Gy). All characteristics were well balanced. 94% of the pts received the planned 4 cycles of docetaxel. Toxicity included grade 3-4 neutropenia (27%) with neutropenic fever in 2%. There was no toxicity-related death and no secondary leukemia. After 3 months of systemic treatment, the PSA response rate defined as a serum PSA ≤ 0.2 ng/mL was 34% in the DE arm vs 15% in the Harm (p< 0.0001). With a median follow-up of 4.6 years, the 4-year PFS rate is 85% [79–89] in the DE arm vs 81% [75–86] in the H arm (p=NS). The adjusted hazard ratio for PFS between the two arms is 0.79 [0.53-1.18], (p=0.26). With a total of 44 deaths, the 4-year overall survival rate is 94% [91–96]. – Methods – Eligibility included non-pretreated high-risk localized CaP (defined as ≥1 of the following criteria: T3-T4, Gleason score (GS) ≥8, PSA ≥ 20 ng/mL, pN+). All pts had a staging pelvic lymph node dissection. This prospective, randomized trial was stratified on the four abovementioned prognostic factors. Pts were randomly assigned to either goserelin 10.8 mg every 3 months for 3 years and 4 cycles of docetaxel 70 mg/m2 q3w + estramustine 10 mg/kg/d d1-5 (DE arm) or goserelin alone (H arm). Local therapy was administered at 3 months. The primary endpoint was progression-free survival (PFS). The hypothesis was based on an expected 70% 4-year PFS rate in the control arm. The planned number of pts was 400, to detect a 12% difference with a power of 80% and a type I error of 0.05 (two-sided Logrank Test). – Conclusions – Docetaxel-estramustine can be safely combined with standard therapy in high-risk localized CaP and significantly improves the PSA response rate. With a lower than expected number of events in both arms, the observed difference in 4-year PFS did not reach significance. A longer follow-up is required. Journal of Clinical Oncology, 30, 2012, 5; Abstract4513 book de publication — 2011 r&d UNICANCER 41 GETUG 14 POSTER DISCUSSION Does short-term androgen depletion add to high dose radiotherapy (80 Gy) in localized intermediate risk prostate cancer? Intermediary analysis of GETUG 14 randomized trial. GETUG 14 Does short-term androgen depletion add to high dose radiotherapy (80 Gy) in localized intermediate risk prostate cancer? Intermediary analysis of GETUG 14 randomized trial B. Dubray1, V. Beckendorf2, S. Guerif3, E. Le Prisé4, A. Reynaud-Bougnoux5, JM. Hannoun-Levy6, TD. Nguyen7, C. Hennequin8, J. Cretin9, M. Fayolle-Campana10, JL. Lagrange11, JM. Bachaud12, D. Azria13, A. Grandgirard14, P.Pommier15, JM. Simon16, V. Harter2, M. Habibian17, for the French Genito-Urinary Tract Tumours Study Group (GETUG). 1-CRLCC Henri Becquerel, Rouen, France • 2-CRLCC Alexis Vautrin, Nancy, France • 3-CHU La Milétrie, Poitiers, France • 4-CRLCC Eugène Marquis, Rennes, France • 5-CHU Bretonneau, Tours, France • 6-CRLCC Antoine Lacassagne, Nice, France • 7-CRLCC Jean Godinot, Reims, France • 8-CHU Saint-Louis, Paris, France • 9-Clinique Valdegour, Nimes, France • 10-HIA Val de Grace, Paris, France • 11-CHU Henri Mondor, Créteil, France • 12-CRLCC Claudius Regaud, Toulouse, France • 13-CRLCC Val d’Aurelle, Montpellier, France • 14-Hôpital du Hasenrain, Mulhouse, France • 15-CRLCC Léon Bérard, Lyon, France • 16-CHU Pitié-Salpêtrière, Paris, France • 17-FNCLCC, Paris, France Purpose Results Randomized trial to evaluate the addition of 4-month androgen deprivation to high dose radiotherapy in localized intermediate risk prostate adenocarcinoma patients. 377 patients were entered between October 2003 and July 2010. The trial was prematurely closed, due to slow accrual. Intention-totreat analysis included 366 patients (188 RT, 178 AD-RT). Prognostic factors were well balanced between groups. The median follow-up duration was 37 months (range: 0 to 63). At 3 years, biochemical or clinical control probabilities were 86% [95% CI: 80% – 92%] and 92% [87% – 97%] in RT and AD-RT groups respectively (p = 0.09). Biochemical control probabilities were 91% [86% – 96%] and 97% [94% – 99.6%] in RT and AD-RT groups respectively (p = 0.04). The cumulative hazards of grade 3-4 toxicities were 6.4% and 2.8% (p=0.41) for digestive tract, 2.6% and 6.1% (p=0.14) for urinary tract, in RT and AD-RT groups respectively. – Methods – Eligible patients were randomly assigned to high dose radiotherapy (prostate 80 Gy; seminal vesicles 46 Gy) either alone (group RT) or in combination with 4-month androgen deprivation (flutamide + triptoreline starting 2 months before radiotherapy, group AD-RT). Lymphadenectomy was mandatory when the risk of node involvement was > 10% (Partin). The primary endpoint was biochemical (Phoenix definition) or clinical control. Secondary endpoints included survival, toxicity (CTCAE v3) and quality of life. The a-priori sample size was 450 patients (0.90 power to detect an increase from 75 to 85%, bilateral α = 0.05). An intermediate analysis was planned 6 months after the last patient inclusion (bilateral α = 0.005). – Conclusions – The observed difference in favour of AD-RT did not reach statistical significance as defined for the present intermediary analysis. The final analysis is schedule in 2013.. Funding – Programme Hospitalier de Recherche Clinique 2002, IPSENPharma Journal of Clinical Oncology, 29: 2011,5;Abstract 4521 RANDOMIZATION PATIENTS’ SELECTION ➡ Arm 1 RADIOTHERAPY (RT) Arm 2 ANDROGEN DEPRIVATION + RADIOTHERAPY (AD-RT) RADIOTHERAPY (8 weeks) Prostate : 80Gy, seminal vesicles : 46Gy 2 Gy/f, 5 times/week ANDROGEN DEPRIVATION (4 months) - Triptoreline 3mg every 4 weeks - Flutamide 3x250mg/day every day RADIOTHERAPY (8 weeks) same as in RT arm starting 8 weeks after AD PACS 01 Poster discussion Foxp3 expression in breast cancer cells : a new predictor of response to anthracycline versus docetaxel in primary breast cancer treated with adjuvant chemotherapy in the Phase III trial FNCLCC/PACS O1 Foxp3 expression in breast cancer cells: a new predictor of response to anthracycline versus docetaxel in primary breast cancer treated with adjuvant chemotherapy in the Phase III trial FNCLCC/PACS 01. Francois Ghiringhelli1,2, Pierre Fumoleau1, Gregoire Mignot2, Laurent Arnould1, Henri Roché3, Marc Spielmann4, Christelle Levy5, Alain Lortholary6, Françoise Eichler7, Christel Mesleard8, Sylvain Ladoire1,2 1.Centre Georges-François Leclerc, Dijon, France; 2.INSERM 866 AVENIR Team 3.Institut Claudius Regaud, Toulouse, France; 4.Institut Gustave Roussy, Villejuif, France 5.Centre François Baclesse, Caen, France; 6.Centre Paul Papin, Angers, France; 7.CHRU, Strasbourg, France 8. Fédération Nationale des Centres de Lutte Contre le Cancer, Paris, France. Results Background FOXP3 belongs to the family of forkhead box (FOX) Patients charracteristics HER2 infiltration in tumor predicted reduced survival in cancer patients. cancers cells of a nonhematopoietic origin, raising questions about Arm SBR its role in carcinogenesis. Recently FOXP3 staining was observed in normal and carcinoma breast tissue (Zuo Cell 2006). FOX P 3 gene may act as a tumor suppressor by repressing various oncogenes Hormone receptor Node status such as SKP2 and HER2. In addition recent biological study link the expression of Foxp3 in tumor cells with sensitivity to DNA damaging T Stage agent and Topoisomerase inhibitors (Jung J Bol Chem 2010). So we Foxp3 positive N=692 692 N=405 0 405 (36.9%) 0 692 0 916 (83.7%) 570 (82.5%) 346 (85.9%) 1 178 (16.3%) 121 (17.5%) 57 (14.1%) 6 FEC 547 (49.9%) 357 (51.6%) 190 (46.9%) 3FEC 3T 550 (50.1%) 335 (48.4%) 215 (53.1%) SBR I/II 579 (55.7%) 331 (50.5%) 248 (64.6%) SBR III 460 (44.3%) 324 (49.5%) 136 (35.4%) 692 (63.1%) 1 Négative P value According to study, Foxp3 expression is a new independant factor associated good response to anthracycline for breast 226 (20.7%) 153 (22.2%) 73 (18.1%) Positive 868 (79.3%) 537 (77.8%) 331 (81.9%) N1 683 (62.3%) 411 (59.4%) 272 (67.2%) N2 332 (30.3%) 222 (32.1%) 110 (27.2%) N3 82 (7.5%) 59 (8.5%) 23 (5.7%) T1 521 (52.2%) 319 (50.7%) 202 (54.7%) T2 T3 438 (43.9%) 39 (3.9%) 284 (45.2%) 26 (4.1%) 154 (41.7%) 13 (3.5%) cancer treated in adjuvant setting. 0.146 0.135 A previous study (Merlo et al J Clin Oncol 2006) investigate the prognostic role of Foxp3 expression in breast cancer cells in untreated patients. This study contrast with our 0.106 results and underline and intrinsic poor prognosis of Foxp3 0.026 expression tumors. 0.458 In vitro proof of concept: studies underline the anti-oncogene property of Foxp3 gene So we test the capacity of low dose of Valproic acid (and HDAC inhibitor to induce Foxp3 expression in Breast cancer cells line in breast cancer thus wondering this capacity to control make the hypotheseis that Foxp3 expression in breast cancer cells Foxp3/cyclophiline mRNA (RAU) 6 may be a predictive factor of response to anthracycline. Our present study analysis the prognostic impact of FOXP3 expression in breast cancer cells in the collected material from PACS01 trial and HR IC 95% p-value 181/953 FOXP3 PACS01 is a study that compared in node positive breast cancer the T stage 1 IC 95% fox 0 arm 6FEC 80/308 1 fox 0 arm 3FEC 3 T 50/292 0.62 0.011 [0.43;0.88] 0.008 p-value 0.0162 [0.42;0.9] 0.012 fox 1 arm 6FEC 27/171 0.62 [0.4;0.97] 0.035 [0.39;0.99] 0.045 fox 1 arm 3FEC 3 T 24/182 0.57 [0.36;0.9] 0.016 [0.35;0.91] 0.02 5 T1 62/499 1 0.001 T2 110/420 1.85 [1.34;2.54] T3 9/34 1.69 [0.82;3.45] N1 76/601 1 N2 78/284 2.08 [1.51;2.86] [1.49;2.89] N3 27/68 2.89 [1.83;4.57] [1.77;4.72] MCF7 5 cancer growth. Foxp3 could inhibit HER2 or SKP2 oncogene 4 and thus induces activation of p21 and p27 to gene involved 3 cancer cell senescence. Importantly Skp2 down regulation 2 1 and p27 induction were previoulsy involved in anthracycline 0 6 MDA -MB-231 4 sensitivity. Thus giving a rational that Foxp3 expression in Hs578T 5 breast cancer cells may be a predictive factor of response to 4 3 anthracycline. 3 2 2 1 1 0 0 0.001 1 0 5 1 0 17 SBR SBR I/II 69/526 1 SBR III 112/427 1.81 AIC Harrell'C statistic <0.0001 <0.0001 <0.0001 [1.31;2.49] 100 80 80 60 0.7037 ** 2000 replications 20 Kaplan-Meier analysis and Cox proportional regression modeling 0 were used to assess overall survival (OS). 1 5 10 50 100 Epirubicin (mM) Insert Footer or Copyright Information Here References test HDAC inhibitors and especially valproate acid to 60 enhance sensitivity of Foxp3 negative breast cancer to 40 anthracycline regimens. 20 0 In conclusion, up to our knowledge, this study may provide the first biomarker of sensitivity to anthracycline. In addition this study propose a rational to DOCETAXEL 100 40 2307.243 17 [0.78;3.63] <0.0001 [1.32;2.46] 5 HDAc enhance anthracycline cytotoxic effect but not docetaxel effect [1.33;2.56] ANTHRACYCLINE Node status obtain material sufficient material for 1097 patients. We studied by immunohistochemistry the Foxp3 expression in breast cancer cells. 2 % cell death (3FEC100 and 3 docetaxel 100). For this study that included 1999 3 Acide valproïque (mM) the sequential treatment with anthracyline followed by taxane patients a tumor collection was made for 1190 patients. We could Bootstrapping* Foxp3/cyclophiline mRNA (RAU) Death/n effect of adjuvant antracycline regimen (6 cycle of FEC100) versus 4 6 Prognostic factors associated with OS in multivariate analysis anthracycline. Patients and Methods 6 HBL100 5 0 identified FOXP3 expression as a predictive marker of response to In opposition to this study, biological HDAC inhibitor have the capacity to induce Foxp3 expression in leucocytes (Tao R. Nat Med 2006) Foxp3/cyclophiline mRNA R(AU) Foxp3 protein expression was recently demonstrated in in Foxp3 negative 0 % cell death and many studies reported that increased Foxp3 lymphocytes Whole popolation N=1097 Foxp3 Foxp3/cyclophiline m RNA(RAU) transcription factors and is the most specific marker for regulatory T lymphocytes. As FOXP3 lymphocytes are immunosuppressive cells Conclusions 0 0 1 5 10 50 Docetaxel(mM) 100 PACS 09/ BEVERLY 01 Poster Early drop of circulating tumor cells (CTC) and increase of circulating endothelial cells (CEC) during neoadjuvant chemotherapy (CT) combined with bevacizumab in her2 negative inflammatory breast cancer (IBC) in multicentre phase II trial beverly 1 book de publication — 2011 r&d UNICANCER 53 PREV 01/MAP 03 Communication orale Exemestane for primary prevention of breast cancer in postmenopausal women : NCIC CTG MAP.3- A randomized, placebo-controlled clinical trial PREV 01/MAP 03 Exemestane for primary prevention of breast cancer in postmenopausal women: NCIC CTG MAP.3—A randomized, placebo-controlled clinical trial. P. E. Goss, J. N. Ingle, J. Ales-Martinez, A. Cheung, R. T. Chlebowski, J. Wactawski-Wende, A. McTiernan, J. Robbins, K. Johnson, L. Martin, E. Winquist, G. Sarto, J. E. Garber, C. J. Fabian, P. Pujol, E. Maunsell, P. Farmer, K. A. Gelmon, D. Tu, H. Richardson; Massachusetts General Hospital, Boston, MA; Mayo Clinic, Rochester, MN; Hosp Ruber Internacional, Madrid, Spain; Universtiy Health Network, Toronto, ON, Canada; Harbor-UCLA Medical Center, Torrance, CA; University of Buffalo, Buffalo, NY; Fred Hutchinson Cancer Research Center, Seattle, WA; University of California, Davis, Sacramento, CA; University of Tennessee Health Science Center, Memphis, TN; George Washington University School of Medicine, Washington, DC; London Health Sciences Centre, London, ON, Canada; Center for Women's Health and Health Research, Madison, WI; Dana-Farber Cancer Institute, Boston, MA; Kansas University Medical Center, Kansas City, KS; CHU-Hopital Arnaud de Villeneuve, Montpellier, France; Laval University, Quebec City, QC, Canada; Queen's University Pathology and Molecular Medicine, Kingston, ON, Canada; British Columbia Cancer Agency, Vancouver, BC, Canada; NCIC Clinical Trials Group, Kingston, ON, Canada Background Results Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. From 2004-2010, 4,560 women were randomized: age 62.5 yrs (3790); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. – Methods – NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. – Conclusions – Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation. Journal of Clinical Oncology, 29, 2011 5; Abstract LBA504 book de publication — 2011 r&d UNICANCER 55 SARCOME 01/ EWING 99 Communication orale Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing’s tumor (ET). Results of the EuroEWING.99-R1 trial SARCOME 01/EWING 99 Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing’s tumor (ET). Results of the Euro-EWING.99-R1 trial Oberlin O, Le Deley MC, Dirksen U, Lewis I, Ranft A, Michon J, Paulussen M, Whelan J, Ladenstein R, Brennan B, Marec Bérard P, Laurence V, Van den Berg H, Hjorth L, Douglas C, Wheatley K, Van Glabbeke M, Judson I, Craft A, Juergens H. Background Results Anthracyclines and alkylating agents are the main effective drugs known for ET. Ifosfamide and cyclophosphamide are widely used, have different toxicity profiles and unknown relative efficiency. The Euro-EWING.99-R1 trial compared, in SR localized ET, two consolidation regimens combining either ifosfamide or cyclophosphamide with vincristine and D-actinomycin (VAI vs VAC courses) given after an intense induction CT combining vincristine, ifosfamide, doxorubicin and etoposide (VIDE) (NCT00020566). 856 pts were recruited between 02/2000 and 08/2010 in 202 European pediatric and adult oncology centers in 11 countries: 424 VAI and 432 VAC. With a median FU of 4.6 years, the main results were: 3-y EFS = 77.1 and 76.0% respectively, 3-y EFS difference = -1.1% (-6.3; +4.2), hazard ratio (HR) of event = 1.06 (0.83; 1.36), HR of death = 1.05 (0.78; 1.41) (intention to treat). Results were stable on the per protocol population. Major modifications of CT were significantly more frequent in the VAI arm (13%) than in the VAC arm (6%) due to toxicity but also to an inferior compliance. We observed more thrombocytopenia in the VAC arm but more grade 2-4 acute tubular renal toxicity in the VAI arm (31 vs 16%). – Methods – SR tumors were localized ET with either a good histological response to VIDE chemo, or small tumors (< 200 ml) resected at diagnosis or receiving radiotherapy alone as local treatment. Pts entered the trial after 6 VIDE + 1 VAI courses. Allocated treatment was either 7 VAI courses with ifo = 6 g/m²/course or 7 VAC courses with cyclo = 1.5 g/m²/course. Randomization was stratified by gender, age, local treatment and data center. It was a non-inferiority trial comparing VAC to VAI with a limit of noninferiority set at -8.5% for 3-year event-free survival rate (EFS). Overall, 806 pts were required to achieve 80%-power with alpha = 5% unilateral. 91.4%-confidence intervals (CI) are given for this final analysis performed after 3 interim analyses. – Conclusions – Cyclophosphamide and ifosfamide have a similar efficacy in consolidation treatment of standard risk Ewing’s tumor. Late effects studies are on-going to compare renal and gonadal toxicity of both arms. Journal of Clinical Oncology 29, 2011,5; Abstract 9517 GEP 02 Poster Circulating tumor cells (CTC) monitoring during phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastses from her2-positive (+) metastaic breast cancer (MBC) before whole brain radiotherapy (WBR) : lanscape study CIRCULATING TUMOR CELLS (CTC) MONITORING DURING PHASE II STUDY WITH LAPATINIB (L) AND CAPECITABINE (C) IN PATIENTS WITH BRAIN METASTASES FROM HER2-POSITIVE (+) METASTATIC BREAST CANCER (MBC) BEFORE WHOLE BRAIN RADIOTHERAPY (WBR): LANSCAPE STUDY J-Y Pierga1, C Cropet2, P Tresca1, F Dalenc3, G Romieu4, M Campone5, C Mahier Aït-Oukhatar6, E Le Rhun7, A Gonçalves8, M Leheurteur9, J Domont10, M Gutierrez11, H Curé12, J-M Ferrero13, C Labbe-Devilliers5, F-C Bidard1, T Bachelot2. Curie & Universite Paris Descartes, Paris 2Centre Léon Bérard, Lyon 3Institut Claudius Regaud, Toulouse 4Centre Val d'Aurelle, Montpellier 5Institut de Cancérologie de l'Ouest, Nantes 6R&D Unicancer, Paris 7Centre Oscar Lambret, Lille Paoli Calmettes, Marseille 9Centre Henri Becquerel, Rouen 10Institut Gustave Roussy, Villejuif 11Institut Curie - Hôpital René Huguenin, Saint-Cloud 12Institut Jean Godinot, Reims 13Centre Antoine Lacassagne, Nice, France. Landscape protocole This analysis is a preplanned secondary endpoint of the LANDSCAPE study. Key Inclusion Criteria in the absence of: increasing steroid use, progressive neurologic symptoms, progressive extra-CNS disease Lapatinib (L): 1,250 mg/d, PO, continuous Capecitabine (C): 2,000 mg/m²/d, PO, d1–14 q3weeks 250 • After 21 days of treatment, a disappearance of CTC was observed in 11 pts (31%). 200 100 50 Clinical assessment (including NSS) every 3 weeks 0 Cerebral and systemic imaging every 6 weeks D1 Circulating tumor cells CTC were detected in 7.5 ml of blood using the CellSearch® system , combining EpCAM immunomagnetic selection (IMS) followed by anti-cytokeratin (A45B/B3) fluorescently staining for CTC at baseline and at day (D) 21, before cycle 2 Results From 04 /2009 to 08/2010, 45 pts were enrolled, 41 were evaluable for CTC at baseline and 38 at D21. Median age was 56 (range 35 to 79). PS was >1 only in 2 pts. CTC/7.5ml at baseline and changes under treatment Secondary endpoints • Time to progression (CNS and extra-CNS), Safety,Time to WBR • Prognostic and predictive value of circulating tumor cell(CTC) at baseline and day 21 300 150 Treatment Primary endpoint Centrally assessed CNS objective response (CNS-OR defined as a ≥50% volumetric reduction of CNS lesions • CTC were detected in pts with (18/37) or without disease outside SNC (2/6) (p=0.63). 350 • HER2+ MBC • Newly diagnosed brain metastases, at least 1 cm in diameter (T1 gado. MRI) • Not candidate for brain surgery • Any previous treatment except WBR, lapatinib or capecitabine • ECOG PS status 0-2 Date of sampling Baseline (n=41) Day 21 (n=38) ≥1 (%) Median ≥ 5 (%) Range 20 (48.8)* 7 (18.4)* *p=0.006 9 (22) 3 (7.9) 3 (1-301) 3 (1-50) Time to progression D21 • At D21, only 7 (18.4%) pts had 1CTC and 3 (8%) 5 CTC (p=0.006, D21 vs. baseline). • In 43 evaluable pts, CNS-OR rate was 67% (95%CI 51-81), with a median time from inclusion to response of 1.8 month. • Absence of CTC was not correlated with CNS-OR rate at baseline (17/21 (81%) vs. 11/19 (58%), NS). • Strikingly, remaining positivity for CTC at D 21 ( 1CTC) was correlated with a poor response rate in CNS: 2/6 (33.3%) vs. 25/31 (80.6%) in pts with 0 CTC, p=0.03. Correlation with CNS-OR, (n=40) Baseline (n=41) Day 21 (n=38) 1.0 0.9 0.8 0.7 0.6 0.5 0 >=1 CTC 0.4 0.3 0.2 0.1 CTC changes & CNS objective response Date of sampling •At a median follow-up of 10 months (range 2.916.5), median TTP was 6.0 months [95% CI 4.9; 7.4] vs. 4.3 [2.8; 5.9] months for pts without and with CTC at baseline respectively (p=0.14). Probability of survival • Decrease of CTC level during treatment in MBC has been reported as an independent prognostic and predictive factor of patients' outcome. • Monitoring CTC in addition to clinical response criteria is currently evaluated in early clinical trials in various cancer types. • We sought to evaluate the clinical interest of peripheral blood CTC for patients included in the LANDSCAPE study which assessed the efficacy of upfront systemic treatment with Lapatinib + Capecitabine for newly diagnosed brain metastasis. CTC changes under treatment Methods CTC Status CNS-OR (%) 0 at baseline 17 / 21 ( 81) ≥ 1 at baseline 11 / 19 (57.9) 0 at day 21 25 / 31 (80.6) ≥ 1 at day 21 2 / 6 (33.3) p NS 0.03 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Months Conclusion • Early decrease (at D 21) in CTC level is correlated with a high response rate in newly diagnosed BM to L + C and underlines the predictive value of this blood marker in MBC pts even for brain metastasis. • Longer follow-up is needed to assess its prognostic value under antiHER2 targeted therapy. v Background vvv 8Institut v 1Institut Acknowlegments • Patients and families • Participating centers • GSK France staff ICCH International Conference on Communication in Healthcare CHICAGO, octobre 2011 book de publication — 2011 r&d UNICANCER 63 PACS 04 Communication orale Lack of involvement in Decisionmaking is Associated with Regret after Participation in a Clinical Trial PACS 04 Lack of involvement in Decision-making is Associated with Regret after Participation in a Clinical Trial Julien Mancini, Dominique Genre, Florence Dalenc, Pierre Kerbrat, Patrice Viens, Anne-Laure Martin, Claire Julian-Reynier Abstract – Though it should be personal, some patients prefer to leave the decision to participate in a randomized controlled trial (RCT) to their doctors. A completely passive role can be considered as a procedure indicator of insufficient quality of decision- making and unmotivated participation might be associated with regret. The aim of this analysis was to identify the factors associated with long-term regret after participation in a RCT with a particular interest for the patient participation in decision-making. Breast cancer participants in a RCT (FNCLCC-PACS-04) comparing trastuzumab to simple observation were surveyed on average 6 years after their trial inclusion. Among the 115 HER2-positive women from 21 centres, 93 (81%) answered a self-administrated questionnaire measuring involvement in decision-making about trial participation and including the decision regret scale (DRS). A quarter of women (25.6%) declared that decision about trial participation has been taken by the doctor alone without their participation, and 29.7% declared that they would have preferred a more active role. Their DRS scores (Cronbach’s alpha = 0.82) ranged from 0 to 55 with an average score of 16.8 (±15.9). Regret about RCT participation was significantly higher for patients that had been randomized in the Observation arm of FNCLCC-PACS04 trial (21.8±16.0 vs 13.0±14.9; p=0.007), and who did not participate in decision-making (26.7±16.3 vs 12.8±13.7, p<0.001). Regret was also significantly correlated with age (r=0.26; p=0.013) but not with delay since trial inclusion (r=0.03, p=0.761). Multivariate analysis (ordinal regression) confirmed that exclusive medical decision-making was associated with increased regret independently of others factors. Considering RCT participation, exclusive medical decision was frequently declared and associated with ling-term regret. More efforts should been done to recall that participation in research must remain a personal decision. Therefore participants might benefit more fully of their trial participation. Keyword – Decision-making, regret, clinical trials, breast cancer Medical Encounter, 2011, 25(3):51; Abstract 1141 emuc European Multidisciplinary Meeting on Urological Cancers BARCELONA, 4-6 novembre 2011 GETUG 20 Communication orale A phase III randomised, open-label, multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/0310) SABCS SAN ANTONIO BREAST CANCER SYMPOSIUM SYMPOSIUM, 6-10 décEMBRE 2011 book de publication — 2011 r&d UNICANCER 71 GEP 02 Communication orale Circulating Tumor Cells (CTC) monitoring during phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases from HER2-positive (+) metastatic breast cancer (MBC) before whole brain radiotherapy (WBR): LANDSCAPE study GEP 02 Circulating Tumor Cells (CTC) monitoring during phase II study with lapatinib (L) and capecitabine (C) in patients with brain metastases from HER2-positive (+) metastatic breast cancer (MBC) before whole brain radiotherapy (WBR): LANDSCAPE study J. Y. Pierga, C. Cropet, P. Tresca, F. Dalenc, G. Romieu, M. Campone, C. Mahier Aït-Oukhatar, E. Le Rhun, A. Gonçalves, M. Leheurteur, J. Domont, M. Gutierrez, H. Cure, J. M. Ferrero, C. Labbe-Devilliers, FC Bidard, T. D. Bachelot; Background Results Decrease of CTC level during treatment in MBC has been reported as an independent prognostic and predictive factor of patients’ outcome. Monitoring CTC in addition to clinical response criteria is currently evaluated in early clinical trials in various cancer types. We sought to evaluate the clinical interest of peripheral blood CTC for patients included in the LANDSCAPE study which assessed the efficacy of upfront systemic treatment with L+C for newly diagnosed brain metastasis. From 04 /2009 to 08/2010, 45 pts were enrolled, 41 were evaluable for CTC at baseline and 38 at D21. Median age was 56 (range 35 to 79). PS was >1 only in 2 pts. At baseline, 20/41 (48.8%) pts had ≥ 1CTC and 9 (22%) ≥ 5CTC (range 1-301, median 3). CTC were detected in pts with (18/37) or without disease outside SNC (2/6) (p=0.63). At a median follow-up of 10 months (range 2.9-16.5), median TTP was 6.0 months [95% CI 4.9; 7.4] vs 4.3 [2.8; 5.9] months for pts without and with CTC at baseline respectively (p=0.14). After 21 days of treatment, a disappearance of CTC was observed in 11pts (31%). At D21, only 7 (18.4%) pts had ≥ 1CTC and 3 (8%) ≥ 5 CTC (p=0.006, D21 vs baseline). In 43 evaluable pts, CNS-OR rate was 67% (95%CI 51-81), with a median time from inclusion to response of 1.8 month. Absence of CTC was not correlated with CNS-OR rate at baseline (17/21 (81%) vs 11/19 (58%), NS). Strikingly, remaining positivity for CTC at D 21 (≥ 1CTC) was correlated with a poor response rate in CNS: 2/6 (33.3%) vs 25/31 (80.6%) in pts with 0 CTC, p=0.03. – Methods – This analysis is a preplanned secondary end-point of the LANDSCAPE study Eligible pts had HER2+ MBC with BM not previously treated with WBR, C or L. Pts received L1250 mg/day and C2000 mg/m2/day, days 1-14, every 21 days. The primary endpoint was a centrally assessed CNS objective response (CNSOR) defined as a ≥50% volumetric reduction of CNS lesions in the absence of increasing steroid use, progressive neurologic symptoms or progressive extra-CNS disease. CTC were detected in 7.5 ml of blood using the CellSearch System, combining EpCAM immunomagnetic selection (IMS) followed by anticytokeratin (A45B/B3) fluorescently staining for CTC at baseline and at day (D) 21, before cycle 2. – Conclusions – Early decrease (at D 21) in CTC level is correlated with a high response rate in newly diagnosed BM to L + C and underlines the predictive value of this blood marker in MBC pts even for brain metastasis. Longer follow-up is needed to assess its prognostic value under antiHER2 targeted therapy. Cancer Research, 2011, 71 (24) suppl; Abstract P1-06-12 GRT 01 Poster SAFIR01: screening approach for individualized regimen UNICANCER (former French Federation of Cancer Centers) SAFIR01: Screening Approach For Individualized Regimen UNICANCER (former French Federation of Cancer Centers) Background: SAFIR01 trial: logistics Need for enrichement of phase I/II trials in patients with molecular alterations in order to early detect Responders = need for molecular screening Investi gation center Patient inclusion DNA extraction Hybridization Hot spot mutations Genomic unit Curie (Affy 6.0) Previous studies have suggested that molecular Screening testing a few targets are not feasible There is therefore a need to propose a molecular Screening with high throughput approaches in Patients who do not present a PD at the time of analyses TRIAL DESIGN Molecular screening: Which candidate target ? Phase I / II trials Target identification Quantification genetic instability Genomic unit Gustave Roussy (Agilent 4*44) Genomic unit Lyon (Affy 6.0) Biopsy of metastatic sites Frozen sample CGH/hot spot mutations (PIK3CA/AKT) PS=0-1, eligible for phase I SD / PR under treatment n=400 SAFIR01 trial: Illustration of a CGH array report Devlopment of phase II on the « rare » diseases detected during the program = SAFIR02 Trial D Trial E Trials X,Y… Perspectives Multiple site biopsies (ongoing amendment) Trial C Trial F Amendment to Limit inclusions to 1st and 2nd line (not enough slots for phase I/II) Next generation sequencing (Q2 2012) Funding: French NCI Primary endpoint: % of patients included in phase I/II trial according to the profile Monthly Accrual rate Monthly tumor board Trial B Target identification Genomic unit Marseille Agilent Bioinformatics Trial A SAFIR 01 (UNICANCER) Accrual Rate Therapy Randomized trial comparing high throughput approaches to standard of care ONCO 03/LIBER Poster Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers : the LIBER trial Uptake of a randomized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutations carriers: the LIBER trial Pascal Pujol1,2, Christine Lasset3, Pascaline Berthet4, Catherine Dugast5, Suzette Delaloge6, Jerome Lemonnier7, Lise Roca2, Sylvie Mijonnet7, Karen Baudry1, Catherine Nogues8, Anne Laure Martin7, on behalf the French Federation of Cancer Centres (Unicancer). 1Unité d'oncogénétique University hospital CHU Arnaud de Villeneuve, 371, av G. Giraud, 34295 Montpellier Cedex 5, France, Phone : 33 467 33 58 75 , e-mail: [email protected] 2 INSERM 896 CRCM Val d'Aurelle 34295 Montpellier. 3 Centre Léon Bérard, Lyon. 4 Centre Francois Baclesse, Caen. 5 Centre Eugene Marquis Rennes. 6 Institut Gustave Roussy, Villejuif. 7 Unicancer, 101 rue de Tolbiac, Paris. 8 Institut Curie, Paris, France Abstract Conclusion Results Background: Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations have a 56-80% life-time risk of developing breast cancer. Prophylactic mastectomy provides a valid option to reduce it, but impacts the quality of life [1-3]. Medical prevention by aromatase inhibitors (AI) has recently been shown to have preventive effect [4]. It may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial evaluating the efficacy of 5years letrozole vs placebo to decrease breast cancer incidence in postmenopausal BRCA1/2 mutation carriers (trial registration NCT00673335). Methods: We compared characteristics of women in the LIBER trial (n=113) to those of women enrolled in the prospective ongoing national GENEPSO cohort of BRCA1/2 mutation carriers (n=1505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 of the 20 (85%) centres [5]. Study design Cumulative number of enrollments Post-menopausal women with a BRCA1/2 deleterious mutation •According to the characteristics of the women included in the GENEPSO cohort and the survey, approximately one third of BRCA1/2 mutation carriers were eligible for the trial. •Out of the 534 women eligible from chart review informed by mail about the trial, 44% came to a dedicated medical visit. •Uptake of drug prevention trial was 32 % of orally informed women and 15 % of overall eligible women. •The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. •Previous unilateral breast cancer and prophylactic oophorectomy were more frequently observed in women enrolled in the trial than in the French cohort (93% vs 60% and 50 % vs 39 %, respectively). Acceptability Eligibility Eligible women N= 798 (BRCA1/2, 40<age<70, no bilateral mastectomy, no previous BC) 534 women informed by mail Informed consent •The overall uptake of the study is 15%, a rate similar to the uptake of other preventive trials [6,7]. •Women with previous unilateral breast cancer or prophylactic oophorectomy are more likely to enter a medical prevention trial. •A greater and wider information of the trial should be offered to women with BRCA1/2 mutation for better recruitment. •Breast cancer prevention by AIs deserves to be evaluated since it could provide a precious alternative to bilateral mastectomy in postmenopausal patients. •The study has been proposed to other countries (Spain, Canada). Women with BRCA1/2 mutation N= 336 Women deceased N= 29 (9%) Alive at time of screening N = 307 (91%) Randomization Arm 1 40 > age >70 N= 73 (22%) Women with positive answer and informed during a visit at investigational site N= 237 (44%) Arm 2 letrozole placebo 1 tablet (2.5 mg/day) 1 tablet/day Treatment: 5 years Follow-up: 5years Enrollment Criteria • Women who carry a characterized germline BRCA1 or 2 deleterious mutation • Women who have not undergone and do not wish to undergo prophylactic mastectomy • Unaffected women or women who have suffered from unilateral invasive breast cancer diagnosed more than 5 years before enrollment with no previous aromatase inhibitor and no evidence of recurrence • 40 < age < 70 • ECOG performance status <2 • Post-menopausal women (spontaneous menopause or following bilateral oophorectomy) • No cancer detected by mammography and MRI during the current year • No osteoporosis, measured by bone densitometry during the last 2 years (T score > -2.5 DS) • Normal hematological, liver, kidney and cardiovascular functions • No hormone replacement therapy during the 3 months before enrollment Women refusal after solicitation or no answer 40 ≤ age <70 N= 234 (70%) N = 292 (55 %) Women with bilateral mastectomy N= 58 (17%) Patients' characteristics LIBER trial Patients' characteristics Type of mutation BRCA1 BRCA2 BRCA1+BRCA2 Oophorectomy (>40) Yes No Prior breast cancer Yes No Age > 40 and < 50 > 50 and < 70 Without bilateral mastectomy N= 176 (52%) GENEPSO Cohort n=113 % N=1505 % 63 49 1 56 43 1 949 556 0 63 37 0 103 10 91 9 527 337 61 39 56 57 49 51 580 925 39 61 41 72 36 64 418 446 28 30 Women with Criteria not validated (Tscore >-2,5 , no menopause) N= 29 (12% of informed women) Without previous invasive cancer< 5 years or concomitant HT N= 128 (38%) Women who signed the participation consent N= 75 (32% of orally informed women, 15% of mail informed women) Main Inclusion criteria validated N= 124 (37%) 1. Meijers-Heijboer, H., et al. N Engl J Med, 2001. 345(3): 159-64. 2. Gahm, J., et al., Breast, 2010 Dec;19(6):462-9. 3. Brandberg, Y., et al., J Clin Oncol, 2008. 26(24): p. 3943-9. Other inclusion criteria N= 4 (1 %) Women refusal after information visit N=134 (56% of orally informed women) References Women with invasive cancer history < 5 years or concomitant HT N= 48 (14%) 4. Goss PE, et al.; N Engl J Med. 2011 Jun 23;364(25):2381-91 5. Pujol P. et al., Fam Cancer (in press). 6. Evans, D., et al., Lancet, 2001. 358(9285): 889-90. 7. Evans D, et al., J Med Genet. 2010 ;47(12):853-5. Printed by PACS 08/TAViX Poster Safety profile of lxabepilone as adjuvant treatment for poor prognosos early breast cancer : first results of the Unicancer-PACS 08 trial Safety profile of Ixabepilone as adjuvant treatment for poor prognosis early breast cancer: first results of the Unicancer-PACS 08 trial. CAMPONE Mario1, SPIELMANN Marc2, WILDIERS Hans3, COTTU Paul4, KERBRAT Pierre5, LEVY Christelle6, MAYER Françoise7, BACHELOT Thomas8, TAN Winston9, EYMARD Jean-Christophe 10, UWER Lionel 11, MACHIELS Jean-Pascal 12, VERHOEVEN Didier13, JAUBERT Dominique14, FACCHINI Thomas15, ORFEUVRE Hubert16, CANON Jean-Luc17, ASSELAIN Bernard4, ROCA Lise 18, LACROIX-TRIKI Magali 19, MARTIN Anne-Laure 20, ROCHÉ Henri19. 1 Institut de Cancérologie de l’Ouest-René Gauducheau, Nantes, France; 2 Institut Gustave Roussy, Villejuif, France; 3Katholike Universiteit, Leuven, Belgium; 4 Institut Curie, Paris, France ; 5 Centre Eugène Marquis, Rennes, France ; 6 Centre François Baclesse, Caen, France ; 7 Centre Georges-François Leclerc, Dijon, France; 8 Centre Léon Bérard, Lyon, France ; 9 Mayo Clinic Florida, Jacksonville ; 10 Institut Jean Godinot, reims, France ; 11 Centre Alexis Vautrin, Nancy, France ; 12 Saint Luc University, Bruxelles, Belgium; 1 3 AZ Klina Oncology, Brasschaat, Belgium ; 1 4 Clinique Tivoli, Bordeaux, France ; 15 Polyclinique de Courlancy, Reims, France ; 16 CH de Fleyriat, Bourg en Bresse, France ; 17 Grand Hopital de Charleroi, Charleroi, Belgium; 18 Centre Val d’Aurelle, Montpellier, France; 19 Institut Claudius Regaud, Toulouse, France; 20 R&D Unicancer, Paris # P5-18-04 Patient population INTRODUCTION The PACS01 trial demonstrated that the sequential use of Docetaxel significantly improved DFS and OS compared to 6 cycles of FEC 100. This advantage was more significant for patients with 1-3 involved nodes and age ≥50 years (1). Both triple negative (ER/PR/HER2 negative) and PR/HER2 negative profiles are significantly associated to a worse prognosis. Between October 2007 and September 2010, 762 patients* with TNBC or ER+/PR-/HER2- breast cancer were included in the study. The analysis was of 760 patients. Baseline characteristics are well balanced between the two arms (Table 1). Roché et al. demonstrated that Ixa is active in “triple negative” (ER/PR/HER2 negative) patients in neoadjuvant and metastatic setting (4). STUDY DESIGN & METHODS OBJECTIVES Primary objective: Open label multicentric, randomized, phase III study. To assess the benefit from the sequential administration 3 FEC 100 + 3 Ixa versus standard 3 FEC 100 + 3 Doc on the Disease-free survival (DFS) at 5 years. - Screening - Regional re-assessment of IHC parameters by referent pathologists - Randomization to either Arm A or Arm B - Randomization was stratified on Center, Menopausal status, Triple negative tumors vs the remainder of the population (HER2-, PR-, ER+). Secondary objectives: Efficacy: Distant metastasis free survival (DMFS); Disease-free survival (DFS); Event free survival (EFS), overall survival (OS) for the Whole Population, the Triple Negative subgroup and the ER+/PR-/HER2subgroup. Safety (CTCAE version 3.0) Translational research studies The treatment schema (Figure 1): Arm A: Sequential regimen 3 FEC 100 + 3 Doc Arm B: Sequential regimen 3 FEC 100 + 3 Ixa N- S U R G E R Y SBR II/III T2-3 ER- PR- HER2- T1-3 N0-1 N+ ER- PR- HER2or ER+PR- HER2- M0 Validation of pathological eligibility criteria 7 days R A N D O M I Z A T I O N Arm A 3 FEC100 q3w + 3 Doc q3w F 500 mg/m² E 100 mg/m² C 500 mg/m² Doc 100 mg/m² Arm B 3 FEC100 q3w + 3 Ixa q3w RT +/HT (ER+) Figure 1: Trial Scheme F 500 mg/m² E 100 mg/m² C 500 mg/m² Ixa 40 mg/m² 49 days Characteristic Main inclusion criteria : - Women aged from 18 to 70 years; - Histologically proven invasive unilateral BC as defined as: - Triple-negative tumors [ER- / PR- / HER2–]: N+ => irrespective of the grade and Tumor size N- => only SBR II / III and pT > 20 mm - [ER+ / PR- / HER2–] Tumors N+ patients only - No residual macro or microscopic tumor after surgical excision; - No clinically or radiologically detectable metastases - Start of CT no later than day 49 after initial surgery ; - Signed Informed Consent HR negativity = ER<10% , PR<10% HER2 negativity = IHC 0-1+, or [IHC 2+ & FISH or CISH -] Median age, years (range) Arm A (396 pts) Arm B (364 pts) Total (760 pts) 53.5 (24-70) 53.0 (26-71) 53.0 (24-71) ECOG performance status, n (%) 0 1 Missing 309 (89.8) 35 (10.2) 52 277 (89.9) 31 (10.1) 56 586 (89.9) 66 (10.1) 108 Menopausal Status, n (%) Premenauposal Postmenopausal 163 (41.6) 229 (58.4) 155 (42.9) 206 (57.1) 318 (42.2) 435 (57.8) Type of Surgery, n (%) Mastectomy Quadrantectomy Tumorectomy 120 (30.3) 49 (12.4) 227 (57.3) 120 (33.0) 42 (11.5) 202 (55.5) 240 (31.6) 91 (12.0) 429 (56.4) pT classification, n (%) pT1 pT2 pT3 pT4 128 (32.5) 245 (62.2) 20 (5.1) 1 (0.2) 128 (35.6) 209 (58.0) 23 (6.4) 0 (0) 256 (34.0) 454 (60.2) 43 (5.7) 1 (0.1) Scarff-Bloom-Richardson grade, n (%) 1 2 3 Missing 0 20 (18.0) 91 (82.0) 1 2 (1.9) 18 (17.5) 83 (80.6) 1 2 (0.9) 38 (17.8) 174 (81.3) 2 Stage pN after regional re-assessment, n (%) N0 N+ TNBC, n (%) - Bilateral BC or patient with controlateral DCIS; - HER2 overexpression; - Previous history of cancer (except cutaneous baso-cellular epithelioma or uterin peripheral ephitelioma) in the preceding 5 years, including invasive controlateral BC; - Concomittant treatment with strong inhibitors of CYP3A4 from 72 hours prior to the initiation of study therapy until end of treatment with Ixabepilone or Docetaxel REFERENCES 1- Roché et al., J. Clin. Oncol., 2006 2- Roché et al., ASCO Annual meeting Proceeding, 2005 3- Jacquemier et al., ASCO Annual meeting Proceeding, 2006 4- Roché et al., ESMO 2006. Neutropenia % 25 All Graphic Values are in Percentages; Per patient analysis performed on C4-C6 6 10 4 5 2 0 0 C1 C2 ER+/PR-/HER2-, n N+ C3 C4 C5 70 158 (39.9) 238 (60.1) 156 (42.9) 208 (57.1) 314 (41.3) 446 (58.7) 157 (51.3) 149 (48.7) 156 (54.9) 128 (45.1) 313 (53.1) 277 (46.9) 89 80 169 Treatment exposure - 755 patients were evaluable for safety (at least one dose of chemotherapy) - 5 patients have never received a dose of chemotherapy (3 were finally not eligible, 1 investigator decision, 1 adverse event) - Overall, 679 (89.9%) patients completed all 6 cycles of adjuvant therapy according to the protocol. - 26 patients from Arm A discontinued treatment before cycle 6. among them, 8 received the FEC sequence only. - 50 patients from Arm B discontinued treatment before cycle 6, among them, 16 received the FEC sequence only. C4 C5 6 3 4 30 2 25 Hepatic Toxicity C2 C3 C4 C5 C6 Thrombopenia % 1.5 30 1 2 20 0.5 C1 C2 C3 C4 C5 C1 Sensory Neurotoxicity % 25 20 20 15 15 10 10 5 5 0 0 C1 C2 C3 C4 C5 C6 Cutaneous % C2 20 15 15 10 10 5 5 0 C5 C1 C6 % C2 C3 C4 C5 C2 C3 C4 C5 C6 Mucitis 5 Safety C2 C3 C4 C5 C6 C6 Per Patient Anemia C2 C3 C4 C5 C6 ns C1 C2 C3 C4 C5 Edema C5 1 C2 C3 C4 C5 C6 Per Patient Motor Neurotoxicities % 2 ns C1 Whereas Gr3/4 sensory neurotoxicities and thrombopenia were reported in Ixa arm, none of these toxicities was reported in the Doc arm. There were also significantly more Gr3/4 neutropenia on day 21 in Ixa arm (Figure 3). C3 C4 C5 C6 Per Patient Mucitis ns C1 C2 C3 C4 C5 C6 Per Patient Edema ns 0.8 0.2 0 In total, 562 patients (74.9 %) experienced a grade ≥3 adverse event during adjuvant therapy. During FEC 100 sequence, toxicities were well balanced between the two arms (Figure 2 & 3) C2 2 0.4 C2 C3 C4 C5 C6 0 C1 Per Patient Fewer cutaneous toxicities were observed in Ixa arm (Figure 2 & 3); % 1 SUSAR were reported during the 1st cycle of Ixa : -> Bullous Dermatitis grade IV 3 2 deaths due to septic shock occurred in Ixa arm (both at cycle 4): however no obvious precipitating factor questioning the Ixa arm was identified. C4 Date Hepatic assessment date 29/07/09 18/08/09 07/09/09 28/09/09 0 0 0 2 17/08/09 02/9/09 23/9/09 5/10/09 Main toxicity reasons reported for Ixa arm are: hematological (33%), peripheral neuropathies (33%) and hypersensitivity reactions (17%). b- The increased of discontinuation in arm B is due to BMS decision to stop Ixa development in adjuvant setting. CONCLUSION 0.4 C1 C3 (18%), cutaneous (18%) and peripheral neuropathies (9%). 1 0.2 C2 a- Main toxicity reasons reported for Doc arm are: hypersensitivity reactions (28%), hematological C1 4 C6 C1 82 0.6 C5 88 Patient 2 139 0.6 C4 67 19 17 0.8 C3 26 31 16 6 C2 42 19 16 8 C1 23 SGOT (N<31 UI/l) SGOT (N<31 UI/l) % ns SGPT ( N<34 UI/l) 0.4 Per Patient Ungueal % 60 154 % C6 0 21May08 97 15 0 C4 0 15May08 85 150 1 C3 0 24Apr08 85 15 0.5 C2 0 3Apr08 171 1.5 C1 C4 15May08 13 0 C6 C3 24Apr08 PAL (50 - 130 UI/l) Hepatic toxicity (Gr) 0 C2 03Apr08 183 2.5 1 Hepatic toxicity (Gr) C1 13Mar08 SGPT ( N<31 UI/l) Per Patient Cutaneous b 15 5 0 C1 Reasons of discontinuation a 10 1 0 Patient 1 Date PAL (N<240 UI/l) Per Patient 0.5 0 C1 C5 Sensory Neurotoxicities % 2 0 C4 <0.05 0.6 1.5 10 10 C6 0.8 p = 0.024 % 15 C3 2 C6 Ungueal % C2 1 0 C1 C5 p < 0.001 % 20 C4 2 30 25 C3 Motor NeuroToxicity C1 25 C4 0.0 0 0 C6 C3 0.2 1 0 C2 % 1.0 4 p 49 (13%) 20 C1 Per Patient p = 0.001 3 % 0 C1 Ixa Arm, n (%) 26 (7%) Hepatic assessment date 4 C6 5 20 RESULTS C3 Doc Arm, n (%) p = 0.001 8 0 C2 Febril Neutropenia 10 1 % 40 % p = 0.020 (at Day 21) 2 C1 50 25 7 % 5 C6 Anemia Neutropenia % Figure 5: Two Septic Shocks at Cycle 4 in Ixa arm Figure 4: Discontinuation Figure 3: Reported grade 3/4 toxicities 6 8 15 30 NN+ 10 (Day 21) 20 % Thrombopenia % 10 Table 1: Patients’characteristics (n=760 pts) Main exclusion criteria : Figure 2: Reported grade 1/2 toxicities 60 * 2 patients have no data in the database at the time of this analysis ELIGIBILITY Ixa Arm Value This sequential regimen does not improve significantly the outcome of these subgroups (2) (3). Ixabepilone (Ixa) demonstrated activity in metastatic setting for patients resistant to anthracycline or resistant to anthracyclines and taxanes or resistant to anthracyclines-taxanes and capecitabine Doc Arm RESULTS C2 C3 C4 C5 C6 Per Patient Hepatic Toxicities 5 ns 4 2 These data suggest that: Despite a higher rate of febrile neutropenia under Doc, Ixa is significantly associated with a high rate of Gr 3/4 neutropenia at day 21. There was no significant difference between the two drugs with regards to motor neurotoxicities although there is a trend toward higher rate in Ixa arm compared to Doc arm; Doc had a higher rate of cutaneous toxicites compared to Ixa; There also more patients on the Ixa arm that discontinued treatment due to toxicities mainly due to hematological and peripheral neuropathies; Ixa may still represent a promising therapeutic option for patients in the adjuvant setting especially for poor prognosis breast cancer. ACKNOWLEDGMENTS Patients 58 Participating French centers: I. G. Roussy, Villejuif; I. C. Regaud, Toulouse; I. Curie, Paris; C. R. Gauducheau, Nantes; C. E. Marquis, Rennes; C. F. Baclesse, Caen; C. G-F Leclerc, Dijon; C. L. Bérard, Lyon; I. J. Godinot, Reims; C. A. Vautrin, Nancy; I. Curie, Saint-Cloud; Cl. Tivoli, Bordeaux; C. P. Papin, Angers; I. Bergonié, Bordeaux; Polycl. Courlancy, Reims; I. Paoli-Calmettes, Marseille; C. J. Perrin, Clermont Ferrand; PolyCl. du Parc, Toulouse; CH - Hôpital Fleyriat, Bourg-en-Bresse; Cl. Armoricaine de Radiologie, Saint-Brieuc; CMC Les Ormeaux, Le Havre; C. H. Becquerel, Rouen; Cl. C. Bernard, Metz; Cl. Saint-Jean Languedoc, Toulouse; CHU - Hôpital A. Morvan, Brest; C. A. Lacassagne, Nice; I. Cancérologie Loire, Saint-Priest en Jarez; Pôle Hospitalier Mutualiste, SaintNazaire; GH Saint-Joseph - Site Saint-Michel, Paris; CHI, Créteil; C. P. Strauss, Strasbourg; Cl. de l'Union, Saint-Jean; CH - Hôpital A. Mignot, Le Chesnay; PolyCl. des 4 Pavillons, Lormont; CHR Metz-Thionville; Hôpital Bon Secours; Polycl. de l'Ormeau, Tarbes; PolyCl. Francheville, Périgueux; CHU, Poitiers; Cl. Pasteur, Toulouse; CHU - Hôpital Rangueil, Toulouse; CH, Dax; CH, Mont-de-Marsan; I. Sainte-Catherine, Avignon; Cl. C. Bernard, Albi; Cl. du Pont de Chaume, Montauban; CHR, Annecy; CH, Pau; C. Oncologie Saint-Yves, Vannes; CHU J. Minjoz, Besançon; CHG, Brive-La-Gaillarde; Cl. Hartmann, Neuilly-sur-Seine; CHU Bretonneau, Tours; Cl. d'Occitanie, Muret; CH, Auxerre; CH, Beauvais; Cl. C. Bernard, Ermont; C. O. Lambret, Lille; CHU Dupuytren, Limoges. 31 Participating Belgium centers: Katholieke Universiteit Leuven /U.Z. Gasthuisberg_Leuven; CL Cl. Univ. Saint-Luc, Bruxelles; AZ KLINA Oncology, Brasschaat; CH PELTZER-LA TOURELLE, Verviers; UZ GENT, Gent; I. Jules BORDET, Bruxelles; Cl. Sainte-Elisabeth, Namur; Grand Hôpital, Charleroi; IMELDA Ziekenhuis, Bonheiden; CHA, Libramont; CHC Cl. Saint-Joseph, Liège; Notre Dame Site RHMS, Tournai; Cl. du Sud Luxembourg, Arlon; CH JOLIMONT, Haine Saint-Paul; CHR de la Citadelle, Liège; Cl. Saint-Pierre, Ottignies; AZ Groeninge -campus Maria's Voorzienigheid, Kortrijk; CHR CH Hutois, Huy; Cl. Notre Dame de GRACE, Gosselies; Cl. Universitaires UCL Mont-Godinne, Mont-Yvoir; C. de Santé des Fagnes, Chimay; Cl. Saint-Joseph, Mons. 9 Participating US centers: Cancer Center of Kansas_Wichita; Dayton Clinical Oncology Program, Dayton; Colorado Cancer Research Program, Denver; Meritcare Hospital CCOP_Fargo (North Dakota); Northern Indiana Cancer Research Consortium, South Bend; Mayo Clinic, Scottsdale; Mayo Clinic, Jacksonville ; Missouri Valley Cancer Consortium, Omaha; Green Bay Oncology, Green Bay. 1 0 C1 C2 C3 C4 C5 C6 Per Patient Sponsored by FNCLCC With the financial support of La Ligue Nationale Contre le Cancer ; BMS; AMGEN PACS 09/ BEVERLY01 Poster Multicentric Phase II PACS 09/ Beverly1 Trial: First Efficacy And Safety Results Of Neoadjuvant Chemotherapy Combined With Bevacizumab In HER2-Neg ative Patients With NonMetastatic Inflammatory Breast Cancer Multicentric Phase II PACS 09/Beverly1 Trial: First Efficacy And Safety Results Of Neoadjuvant Chemotherapy Combined With Bevacizumab In HER2-Negative Patients With Non-Metastatic Inflammatory Breast Cancer. VIENS P1, PETIT T2, DALENC F3, PIERGA JY4, DELOZIER T5, ROMIEU G6, BONNETERRE J7, FERRERO JM8, KERBRAT P9, MOURET REYNIER M10, BACHELOT T11, SOULIE P12, LEREBOURS F13, EYMARD JC14, DEBLOCK M15, LORTHOLARY A16, HARDY BESSARD AC17, BOHER JM1, ASSELAIN B4, CHARAFE-JAUFFRET E1, LEMONNIER J18, MARTIN AL18, ANDRE F19. 1 Institut Paoli Calmette, Marseille, France, 2 Centre Paul Strauss, Strasbourg, France ; 3 Institut Claudius. Regaud, Toulouse, France ; 4 Institut Curie, Paris, France ; 5 Centre François Baclesse, Caen, France ; 6 Centre Val d'Aurelle, Montpellier, France ; 7 Centre Oscar Lambret, Lille, France ; 8 Centre Antoine Lacassagne, Nice, France ; 9 Centre Eugène Marquis, Rennes, France ; 10 Centre Jean Perrin, Clermont Ferrand, France ; 11 Centre Leon Berard, Lyon, France ; 12 Centre Paul Papin, Angers, France; 1 3Institut Curie, Saint-Cloud, France ; 1 4 Institut Jean Godinot, Reims, France ; 15 Centre Alexis Vautrin, Nancy, France ; 16 Centre Catherine de Sienne, Nantes, France ; 17 Clinique Armoricaine, StBrieuc, France; 18 R&D Unicancer, Paris ; 19 Institut Gustave Roussy, Villejuif, France. Several angiogenesis-related genes are upregulated in IBC Vascular endothelial growth factor (VEGF) is a secreted molecule that promotes endothelial cell growth and viability among many other properties. Because this disease exhibits angiogenic properties, inhibiting VEGF may block endothelial cell proliferation, decreased vascular permeability and vasodilatation. Bevacizumab (BEV), a humanized monoclonal antibody targeting all isoforms of VEGF, significantly improves progression-free survival and response rate in patients with advanced breast cancer, as demonstrated in three randomized, phase III trials in the firstline setting 4-6. In the RIBBON-1 trial, the combination of bev with anthracycline-based combination therapy was found to be tolerable, with no substantial increase in risk of cardiac effects 6. A pilot study has shown that in inflammatory and locally advanced breast cancer BEV has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells 7. Moreover BEV induces significant modifications in angiogenic/apoptotic genes profile expression 8. BEV may improves the efficacy of neoadjuvant chemotherapy (CT) in IBC. The BEVERLY 1 study was designed to evaluate bevacizumab in combination with chemotherapy in patients with HER2-negative IBC. STUDY DESIGN & OBJECTIVES Primary objective: To assess the rate of pathologic complete response (pCR) according to Sataloff classification. Secondary objectives: Disease-free survival (DFS) at 3 and 5 years; Overall survival (OS) at 3 and 5 years; Safety (CTCAE version 3.0); Translational research studies FEC 1 2 3 4 DOC (Docetaxel) 100 mg/m2 q3w, 4 cycles 5 6 7 8 RESULTS Patient population Between December 2008 and September 2010, 101 patients were included in the study. Baseline characteristics are summarized in Table 1. Treatment exposure BEVERLY 1 is a multicenter single-arm phase II study evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy in HER2-negative IBC. (epirubicin 100 mg/m2 + cyclophosphamide 500 mg/m2 + 5FU 500 mg/m2) q3w, 4 cycles Characteristic Surgery 4–6 weeks Radiotherapy (4–6 weeks) 2–4 weeks Neoadjuvant bevacizumab 15 mg/kg q3w (24 weeks) Patients are followed until 5 years after enrollment of the last patient. FIGURE 1: Treatment Scheduled in Beverly1 Endocrine therapy if estrogen receptor positive Adjuvant bevacizumab 15 mg/kg q3w (30 weeks) Overall, 85 patients completed all 8 cycles of neoadjuvant therapy according to the protocol. 3 patients discontinued neoadjuvant therapy during BEV + FEC sequence. 12 patients discontinued neoadjuvant therapy during BEV + DOC sequence Efficacy Median age, years (range) ECOG performance status, n 0 1 Missing Value 49 (21-75) 88 7 5 Lymph node involvement, n N0 N1 N2 N3 Not evaluable 26 46 12 9 7 Scarff-Bloom-Richardson grade, n 1 2 3 Unknown 3 32 61 4 Estrogen receptor positive, n Progesterone receptor positive, n 42 37 Table 1: Patients’characteristics (n=100 pts) A total of one hundred patients (100) were evaluable for efficacy as initially planned The primary endpoint was pCR status defined as complete response on tumor site (TA) with evidence of therapeutic effect without nodal metastasis (NA,NB) according to Sataloff classification The pCR rate was 27 % (95% CI 18–36%) according to Sataloff classification This is significantly higher than the pre-planned 15% pCR rate considered insufficient to continue evaluation of the combination Confirmation by central review is required. Data are not yet available and will be reported in the near future. Response to treatment was more pronounced in the HR-negative patients : HR - : 21/55 (38%) vs HR + : 6/45 (13%) ; p=0.007; Surgical outcome: 90 patients underwent complete mastectomy, 4 had a breast-conservative surgery. NA NB NC ND TA 21 6 7 0 TOTAL 34 TB 3 3 20 8 34 TC 0 2 14 4 20 TD 0 0 0 12 12 TOTAL 24 11 41 24 100 100 Cycles 1 - 8 80 60 40 20 Table 2: pCR rate according to Sataloff classification, investigator assessment (n=100) Primary site response Axillary lymph node response TA, total or near total therapeutic effect; TB, subjectively >50% therapeutic effect but less than total or near total; TC, >50% therapeutic effect, but effect evident; TD, no therapeutic effect. Table 3: pCR rate is increased in HRnegative group according to Sataloff classification investigator assessment (n=100) NA, evidence of therapeutic effect, no metastatic disease; NB, no nodal metastasis or therapeutic effect; NC, evidence of therapeutic effect but nodal metastasis still present; ND, viable metastasis disease, no therapeutic effect. pCR 95% CI HR-negative 38 % [25-52] HR-positive 13 % [5-25] p<0.007 42 patients experienced non hematological toxicities grade ≥3 adverse event not related to Bev during neoadjuvant therapy. 3 patients experienced non hematological toxicities grade ≥3 adverse event related to Bev during neoadjuvant therapy. 72 patients experienced hematological toxicities grade ≥3 adverse event during neoadjuvant therapy. Neither gr3/4 HTA nor cardiac failure or proteinuria was reported. The median interval between last bevacizumab dose and surgery was 35 days (range 21-194 days). There were no treatment-related deaths. 100 80 60 40 20 0 100 During BEV + DOC cycles (5-8) 80 60 40 20 Anemia Neutropenia Febrile Mucitis Neutropenia Cutaneous 0 Anemia Neutropenia Febrile Mucitis Neutropenia Figure 2. Grade ≥3 adverse events occurring in >1 patient 100 80 60 40 20 0 Non-hematological Not related to Bev Non-hematological related to Bev hematological During BEV + FEC cycles (1-4) CONCLUSION 80 These data suggest that: 60 Anemia Neutropenia Febrile Mucitis Neutropenia Cutaneous 100 80 60 The combination of neoadjuvant chemotherapy and bevacizumab has a good 40 40 safety profile in IBC. 20 27% pCR is one of the higher described in Her220 The IBC. However, the place of bevacizumab remain to 0 0 be precized, specially in RH+ Anemia Neutropenia Febrile Mucitis Cutaneous Anemia Neutropenia Febrile Mucitis Cutaneous tumours. Neutropenia Neutropenia Long terms survival data are needed to confirm these results. REFERENCES Safety (Figure 2 & 2bis) During BEV + FEC cycles (1-4) 0 Cycles 1 - 8 100 Patients (%) Primary chemotherapy is used to render these patients operable. Standard local control is achieved with mastectomy followed by radiation Primary site response Patients (%) Compared with non–inflammatory breast cancer (IBC) breast tumors, IBC is more frequently estrogen receptor (ER) negative and progesterone receptor (PgR) negative 2,3. Figure 2bis. Grade ≥3 adverse events occurring in >1 patient during neoadjuvant therapy Axillary Lymph node response Patients (%) IBC tends to be highly angiogenic 1 Patients (%) Inflammatory breast cancer (IBC) is relatively rare but is the most aggressive form of locally advanced breast cancer with significantly lower overall survival than non-IBC. % of Patients Treatment schema: Treatment consists of 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by 4 cycles of docetaxel plus trastuzumab, with bevacizumab 15 mg/kg q3w administered throughout neoadjuvant therapy (Figure 1). At baseline, patients underwent computed tomography scan of the thorax, abdomen, and pelvis, bone scintigraphy, and bilateral breast ultrasound to confirm the absence of metastasis Patients participating in the translational research study were required to provide a separate written informed consent Main eligibility criteria : Histologically confirmed breast cancer and confirmed IBC (T4d any N; Institut Gustave Roussy PEV2 or PEV3; or skin biopsy with tumor emboli in the lymph vessels of the superficial derma) HER2-negative disease; No metastasis Normal hematologic, hepatic, renal, coagulation, and cardiac function No prior chemotherapy for breast cancer Female, aged ≥18 years; ECOG performance status ≤2. The sample size of 100 patients was calculated based on a twostage T. Fleming method with the following assumptions: ≥30% pCR rate considered as proof of efficacy <15% pCR rate considered insufficient to continue evaluation of the combination α=0.04; β=0.04. Patients (%) METHODS INTRODUCTION Patients (%) # P4-20-01 Cutaneous 1. Lerebours F, et al. Breast Cancer Res 2005, 7:52-58 2. Kleer CG, et al. Breast Cancer Res. 2000; 2(6):423-9. 3. Wu M, Merajver SD. Breast Dis. 2005-2006;22:25-34 4. Miller K, et al. N Engl J Med 2007;357:2666–76. 5. Miles D, et al. J Clin Oncol 2010;28:3239–47. 6. Robert N, et al. J Clin Oncol 2009;27(15S):1005. 7. Wedam SB, et al. J Clin Oncol. 2006; 24 (5): 769-77. 8. Yang SX, et al. Clin Cancer Res. 2008; 14(18): 5893-9. ACKNOWLEDGMENTS Patients 21 Participating centers Insitut Gustave Roussy, Villejuif, France Centre Paul Strauss, Strasbourg, France Institut Claudius Regaud, Toulouse, France Institut Curie, Paris, France Centre François Baclesse, Caen, France Centre Val d'Aurelle, Montpellier, France Centre Oscar Lambret, Lille, France Centre Antoine Lacassagne, Nice, France Centre Eugene Marquis, Rennes, France Centre Jean Perrin, Clermont Ferrand, France Centre Léon Bérard, Lyon, France Centre Paul Papin Center, Angers, France Centre René Huguenin, Saint Cloud, France Institut Jean Godinot, Reims, France Centre Alexis Vautrin, Nancy, France Centre Catherine de Sienne, Nantes, France Clinique Armoricaine, Saint Brieuc, France Centre René Gauducheau, Nantes, France Hôpital Civil, Strasbourg, France Institut Bergonié, Bordeaux, France Institut Paoli Calmettes, Marseille, France Sponsored by FNCLCC With the financial support of The Ligue Nationale Contre le Cancer ; Roche; Chugai Pharma PACS 09/ BEVERLY01 Poster Correlation of circulating tumor cells (CTC) and circulating endothelial cells (CEC) with pathological Complete Reponse (pCR) during neoadjuvant chemotherapy (CT) combined with bevacizumab in HER2 negative inflamatory breast cancer (IBC) : ancillary study of phase II trial BEVERLY 1 Correlation of circulating tumor cells (CTC) and circulating endothelial cells (CEC) with pathological Complete Response (pCR) during neoadjuvant chemotherapy (CT) combined with bevacizumab in HER2 negative inflammatory breast cancer (IBC) : ancillary study of phase II trial BEVERLY 1. J. Y. Pierga1, F. C. Bidard1, F. André2, T. Petit3, F. Dalenc4, T. Delozier5, G. Romieu6, J. Bonneterre7, J. M. Ferrero8, P. Kerbrat9, J. Lemonnier10, P. Viens11 # P1-14-02 1.Institut Curie, Paris, France; 2. Institut Gustave Roussy, Villejuif, France; 3. Centre Paul Strauss, Strasbourg, France; 4. Institut Claudius Regaud, Toulouse, France; 5.Centre François Baclesse, Caen, France; 6. Centre Val d'Aurelle, Montpellier, France; 7.Centre Oscar Lambret, Lille, France; 8. Centre Antoine-Lacassagne, Nice, France; 9. Centre Eugene Marquis, Rennes, France; 10.Unicancer, Paris, France; 11.Institut Paoli-Calmettes, Marseille, France INTRODUCTION RESULTS Characteristic Median age, years (range) Inflammatory breast cancer (IBC) is a highly aggressive form of locally advanced breast cancer Patient population Representing up to 5% of breast cancers1 Between December 2008 and September 2010, 101 patients were included in the study. 1 out of 101 patients enrolled in the study has removed her informed consent form before starting the trial's treatment Baseline characteristics are summarized in Table 1. Characterized by high vascularity and increased microvessel density 5-year survival rate of approximately 40%1,2 Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and is involved in endothelial cell growth and motility, and blood vessel permeability The humanized monoclonal antibody bevacizumab targets all isoforms of VEGF In metastatic breast cancer, bevacizumab significantly improves progression-free survival (PFS) and response rate, as demonstrated in three randomized phase III trials without benefit in overall survival 3. The BEVERLY1 study is evaluating bevacizumab in combination with chemotherapy in patients with HER2-negative IBC An ancillary study is evaluating circulating tumor cells (CTCs) and circulating endothelial cells (CECs) as candidate predictive biomarkers CTC count is an independent prognostic factor in non-metastatic breast cancer4–6 In the REMAGUS 02 study in patients receiving neoadjuvant chemotherapy, 20–25% of patients had at least 1 CTC/7.5 mL6 A similar rate (22%) was reported in the German GeparQuattro trial. The trial also included evaluation of HER2 expression in CTCs7 However, neither CTC count nor change in CTC count was predictive for pathologic complete response (pCR) in these two neoadjuvant studies . Predictive value of CEC for response to antiangiogenic agents is unclear. In the ATHENA study, in which patients with metastatic breast cancer received first-line bevacizumab combined with chemotherapy: CTC counts decreased dramatically during therapy Treatment exposure Overall, 85 patients completed all 8 cycles of neoadjuvant therapy according to the protocol. - 3 patients discontinued neoadjuvant therapy during BEV + FEC sequence. - 12 patients discontinued neoadjuvant therapy during BEV + DOC sequence Baseline CTC and CEC counts At baseline, ≥1 CTC/7.5 mL was detected in 37 patients/92 (40%) - Median CTC count was 0 (range 0–559) CECs were detected in all patients - Median CEC count was 12 (range 1–696) No correlation was observed between baseline CTC and CEC counts In 40 patients, CTC HER2 status was analyzed at baseline Among the 18 patients in whom CTCs were detected at baseline (≥1CTC): - 12 patients with HER2 negative primary tumor had HER2 positive CTCs - HER2+ CTC count ranged from 1 to 32 - In 9/12 cases, > 50% of detectable CTC were HER2+. 88 7 5 Lymph node involvement, n N0 N1 N2 N3 Not evaluable 26 46 12 9 7 Scarff-Bloom-Richardson grade, n 1 2 3 Unknown 3 32 61 4 Estrogen receptor positive, n Progesterone receptor positive, n 42 37 BEVERLY 1 is a multicenter single-arm phase II study evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy in HER2-negative IBC (T4d) 500 400 (epirubicin 100 + cyclophosphamide 500 mg/m2 + 5FU 500 mg/m2) q3w, 4 cycles 1 2 mg/m2 3 4 evaluable because of DVD scratch. 0 27/11/2011 9 -100 Baseline CTC Before cycle 5 CTC Before surgery CTC Post Surgery CTC Figure 3. Change in CTC count during therapy, by patient DOC (Docetaxel) 10000 100 mg/m2 q3w, 4 cycles 5 6 7 8 Surgery 4–6 weeks Radiotherapy (4–6 weeks) 2–4 weeks Neoadjuvant bevacizumab 15 mg/kg q3w (24 weeks) Endocrine therapy if estrogen receptor positive Adjuvant bevacizumab 100 Base line CEC FIGURE 1: Treatment Scheduled in Beverly1 Figure 2b. Examples of CEC detection (n=83) (n=65) (n=63) (n=45) 37 (40) 5 (6) 7 (11) 2 (3) 7 (15) ≥2 CTCs/7.5 mL 25 (27) 1 (1) 6 (9) 1 (1.5) 3 (6) ≥5 CTCs/7.5 mL 17(18.5) 1 (1) 1 (1.5) 1 (1.5) 2 (4) Median No. of CTCs/7.5 mL (range) 0 (0–559) 0 (0–6) 0 (0–5) 0 (0–2) 0 (0–4950) CEC count (n=90) (n=84) (n=71) (n=63) (n=47) Median No. of CECs/4 mL (range) 12 (0–696) 18 (1–505) 125 (0–635) 39 (0–1243) 20 (3–359) TA, total or near total therapeutic effect; TB, subjectively >50% therapeutic effect but less than total or near total; TC, >50% therapeutic effect, but effect evident; TD, no therapeutic effect. Table 2. Changes in CTC and CEC counts % of Patients Axillary Lymph node response Primary site response NA Axillary lymph node response NB NC ND TOTAL TA 21 6 7 0 34 TB 3 3 20 8 34 TC 0 2 14 4 20 TD 0 0 0 12 12 TOTAL 24 11 41 24 100 The primary endpoint was pCR status defined as: - complete response on tumor site (TA) - with evidence of therapeutic effect without nodal metastasis (NA,NB) according to Sataloff classification The pCR rate was 27 % (95% CI 18–36%) according to Sataloff classification (Table 3) This is significantly higher than the pre-planned 15% pCR rate considered insufficient to continue evaluation of the combination - Confirmation by central review is required. Data are not yet available and will be reported in the near future REFERENCES 10 15 mg/kg q3w (30 weeks) 1 Patients are followed until 5 years after enrollment of the last patient. (n=92) ≥1 CTC/7.5 mL CTC level at any time or CTc variations were not associated with pCR (Table 4). Out of 7 patients with detectable CTC at the end of adjuvant Bev none had pCR. A higher level of CEC (>20/4ml) before C5 is significantly associated with higher probability of pCR (Fisher test, p=0.005; OR=4.85) as an increase of CEC from Baseline to C5 (p=0.038) (table 4). 1000 Before Cycle 5 Before Surgery Post Surgery Figure 4. Change in CEC count during therapy, by patient Parameter Cycle Number of patients Negative Positive P value OR CTC C1 N= pCR n (%) N= pCR n (%) N= pCR n (%) 54 19(35.2) 78 22(28.2) 51 17(33.3) 38 7(18.4) 5 0(0) 31 5(16.1) 0.1013 0.42(0.15-1.12) 0.3182 NA 0.1237 0.39(0.28-2.35) N= pCR n (%) N= pCR n (%) N= pCR n (%) 64 18(28.1) 46 6(13.0) 26 3(11.5) 25 6(24.0) 38 16(42.1) 54 17(31.5) 0.7945 0.81(0.28-2.35) 0.0053 4.87(1.66-14.18) 0.0347 3.57 (0.92-14.28) C5 Decrease from C1 to C5 Table 3: pCR rate according to Sataloff classification, investigator assessment (n=100) Efficacy (see also Poster #P4-20-01) 200 Weakly positive Figure 2a. Examples of HER2 staining class in patients with CTCs End of adjuvant Bev 300 100 CEC/ 4 ml of blood (log) FEC Strongly positive aNot CTC/7.5ml of blood The treatment schema is depicted in Figure 1 At baseline, patients underwent computed tomography scan of the thorax, abdomen, and pelvis, bone scintigraphy, and bilateral breast ultrasound to confirm the absence of metastasis Patients participating in the translational research study were required to provide a separate written informed consent CTCs were measured at baseline and during treatment using the CellSearch™ system (Veridex LLC, Raritan, NJ, USA) with EpCAM immunomagnetic selection followed by anti-cytokeratin (A45B/B3) and anti-HER2 fluorescence staining for CTCs in 7.5 mL blood samples CEC were measured by CD146 immunomagnetic selection and CD105 staining in 4 ml of blood The HER2 expression of CTCs (CB11 clone) was categorized (class 0–3) as described by Riethdorf et al.9 FISH Test was used to study the correlation between pCR and either CTC or CEC variation After surgery CTC count, n (%) NA, evidence of therapeutic effect, no metastatic disease; NB, no nodal metastasis or therapeutic effect; NC, evidence of therapeutic effect but nodal metastasis still present; ND, viable metastasis disease, no therapeutic effect. 600 Negative FEC Before Docetaxel Before surgery x4 x 4 cycle 5 S u r g e r y Characteristic Primary site response There was a significant increase of CEC median number from baseline (12) to preoperative sample (125) (p <0.001) and a decrease (39) (p=0.04) when CT and bevacizumab were interrupted for surgery (Figure 4). METHODS Baseline Table 1: Patients’characteristics (n=100 pts) A dramatic drop in CTC incidence (p<0.0001) was observed from baseline to the 1st follow-up analysis after 4 cycles (6%). (Table 2 and Figure 3). STUDY DESIGN 49 (21-75) ECOG performance status, n 0 1 Missing CTC and CEC kinetics CEC counts increased and showed predictive potential for time to progression 8 Bevacizumab Value 1. Dawood S. Expert Rev Anticancer Ther 2010;10:209–20. 2. Cristofanilli M, et al. Cancer 2007;110:1436–44. 3. O'Shaughnessy, J et al, J Clin Oncol 2010; 28 15s, (suppl; abstr 1005) 4. Rack BK, et al. SABCS 2010;Abstr S06-05. 5. Bidard FC, et al. Ann Oncol 2010;21:729–33. 6. Pierga JY, et al. Clin Cancer Res 2008;14:7004–10. 7. Riethdorf S, et al. Clin Cancer Res 2010;16:2634–45. 8. Bidard FC, et al. Ann Oncol 2010;21:1765–71. 9. Pierga J-Y, et al. SABCS 2010, Abstr. PD04-07 10. Mego M, et al. Ann Oncol 2009;20:1824–8. 11. Pierga J-Y, et al. Ann Oncol 2011 Jun 3. [Epub ahead of print]. 12. Riethdorf S, et al. SABCS 2010; Abstr. PD04-06. 13. Viens P, et al. ASCO 2011, PD. CEC C1 C5 Increase from C1 to C5 Table 4: Correlation between CTC and CEC and pCR, at C1, C5 and variations between C1 and C5 (Fisher exact test) CONCLUSION At baseline, we detected CTCs in 40% of patients with HER2-negative IBC treated in the BEVERLY 1 study - This rate is higher than in previous neoadjuvant studies but in line with BEVERLY2 trial in HER positive IBC (35% of CTC positive patients)9 - It does not support the hypothesis based on indirect findings that fewer CTCs may be present in IBC than in other early breast cancers10 There was a dramatic decline in CTC count after 4 cycles of chemotherapy combined with bevacizumab, suggesting a specific impact of bevacizumab on CTCs - This is consistent with observations from the ATHENA study8 and the IC 2006-04 study11 at metastatic setting and the Geparquinto trial in neoadjuvant setting12 CEC counts increased steadily during neoadjuvant therapy and decreased after surgery - This finding may be attributable to bevacizumab (started at cycle 1, discontinued 4–6 weeks before surgery) - Alternatively, chemotherapy may play a role in CEC kinetics - Comparison with the BEVERLY2 study in 52 patients with HER2-positive IBC may help in defining the role of trastuzumab in CEC kinetics - Efficacy results of BEVERLY1 study are presented at this meeting ( Poster #P4-20-01) Our results confirm the discrepancy of the HER2 status in CTC and corresponding primary tumors. CEC increased between C1 and C5 was significantly associated to a higher probability of pCR. CTC variations were not associated to pCR Baseline CTC and CEC levels were not predictive of pCR Detection of CTC at 8 months of follow up was associated with the absence of response to neoadjuvant chemotherapy. ACKNOWLEDGMENTS Patients 21 Participating centers Insitut Gustave Roussy, Villejuif, France Centre Paul Strauss, Strasbourg, France Institut Claudius Regaud, Toulouse, France Institut Curie, Paris, France Centre François Baclesse, Caen, France Centre Val d'Aurelle, Montpellier, France Centre Oscar Lambret, Lille, France Centre Antoine Lacassagne, Nice, France Centre Eugene Marquis, Rennes, France Centre Jean Perrin, Clermont Ferrand, France Centre Léon Bérard, Lyon, France Centre Paul Papin Center, Angers, France Centre René Huguenin, Saint Cloud, France Institut Jean Godinot, Reims, France Centre Alexis Vautrin, Nancy, France Centre Catherine de Sienne, Nantes, France Clinique Armoricaine, Saint Brieuc, France Centre René Gauducheau, Nantes, France Hôpital Civil, Strasbourg, France Institut Bergonié, Bordeaux, France Institut Paoli Calmettes, Marseille, France Sponsored by FNCLCC; With the financial support of The Ligue Nationale Contre le Cancer ; Roche; Chugai Pharma AACR NEW HORIZONS IN CANCER RESEARCH DELHI, 13-16 décEMBRE 2011 ONCO 03/ LIBER Poster Uptake of a randpmized breast cancer prevention trial comparing letrozole to placebo in BRCA1/2 mutation carriers the liber trial UPTAKE OF A RANDOMIZED BREAST CANCER PREVENTION TRIAL COMPARING LETROZOLE TO PLACEBO IN BRCA1/2 MUTATION CARRIERS THE LIBER TRIAL Pascal Pujol1,2, Christine Lasset3, Pascaline Berthet4, Catherine Dugast5, Suzette Delaloge6, Jerome Lemonnier7, Lise Roca2, Sylvie Mijonnet7, Karen Baudry1, Catherine Nogues8, Anne Laure Martin7, on behalf the UNICANCER Breast Group. 1Unité d'oncogénétique University hospital CHU Arnaud de Villeneuve, 371, av G. Giraud, 34295 Montpellier Cedex 5, France, Phone : 33 467 33 58 75 , e-mail: [email protected] 2 INSERM 896 CRCM Val d'Aurelle 34295 Montpellier. 3 Centre Léon Bérard, Lyon. 4 Centre François Baclesse, Caen. 5 Centre Eugene Marquis Rennes. 6 Institut Gustave Roussy, Villejuif. 7 Unicancer, 101 rue de Tolbiac, Paris. 8 Institut Curie, Paris, France ABSTRACT ABSTRACT Background: Women with germline BRCA1 or BRCA2 (BRCA1/2) mutations have a 56-80% life-time risk of developing breast cancer. Prophylactic mastectomy provides a valid option to reduce it, but impacts the quality of life [1-3]. RESULTS ACCEPTABILITY Eligible women N= 798 (BRCA1/2, 40<age<70, no bilateral mastectomy, no previous BC) 534 women informed by mail CUMULATIVE NUMBER OF ENROLLMENTS Medical prevention by aromatase inhibitors (AI) has recently been shown to have preventive effect [4]. It may thus be considered as an alternative. LIBER is an ongoing double-blind, randomized phase III trial evaluating the efficacy of 5-years letrozole vs placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (trial registration NCT00673335). Women refusal after solicitation or no answer N = 292 (55 %) Women with positive answer and informed during a visit at investigational site N= 237 (44%) Women with Criteria not validated (Tscore >-2,5 , no menopause) N= 29 (12% of informed women) Methods: We compared characteristics of women in the LIBER trial (n=113) to those of women enrolled in the prospective ongoing national GENEPSO cohort of BRCA1/2 mutation carriers (n=1505). Uptake was evaluated through a survey sent to all active centres, with responses obtained from 17 of the 20 (85%) centres [5]. Women refusal after information visit N=134 (56% of orally informed women) PATIENT’S CHARACTERISTICS ELIGIBILITY Informed consent LIBER tri a l Randomization Arm 1 Arm 2 Letrozole: 1 tablet (2.5 mg/day) Placebo: 1 tablet/day Treatment: 5 years Follow-up: 5years ENROLLMENT CRITERIA • Women who carry a characterized germline BRCA1 or 2 deleterious mutation • Women who have not undergone and do not wish to undergo prophylactic mastectomy • Unaffected women or women who have suffered from unilateral invasive breast cancer diagnosed more than 5 years before enrollment with no previous aromatase inhibitor and no evidence of recurrence • 40 < age < 70 • ECOG performance status <2 • Post-menopausal women (spontaneous menopause or following bilateral oophorectomy) • No cancer detected by mammography and MRI during the current year • No osteoporosis, measured by bone densitometry during the last 2 years (T score > -2.5 DS) • Normal hematological, liver, kidney and cardiovascular functions • No hormone replacement therapy during the 3 months before enrollment Patients' characteristics Type of mutation BRCA1 BRCA2 BRCA1+BRCA2 Oophorectomy (>40) Yes No Prior breast cancer Yes No Age > 40 a nd < 50 > 50 a nd < 70 GENEPSO Cohort n=113 % N=1505 % 63 49 1 56 43 1 949 556 0 63 37 0 103 10 91 9 527 337 61 39 56 57 49 51 580 925 39 61 41 72 36 64 418 446 28 30 Women with BRCA1/2 mutation N= 336 Women deceased N= 29 (9%) Alive at time of screening N = 307 (91%) 40 > age >70 N= 73 (22%) 40 ≤ age <70 N= 234 (70%) Women with bilateral mastectomy N= 58 (17%) Without bilateral mastectomy N= 176 (52%) Without previous invasive cancer< 5 years or concomitant HT N= 128 (38%) • The overall uptake of the study is 15%, a rate similar to the uptake of other preventive trials [6,7]. • Women with previous unilateral breast cancer or prophylactic oophorectomy are more likely to enter a medical prevention trial. • A greater and wider information of the trial should be offered to women with BRCA1/2 mutation for better recruitment. • Breast cancer prevention by AIs deserves to be evaluated since it could provide a precious alternative to bilateral mastectomy in postmenopausal patients. • The study has been proposed to other countries (Spain, Canada). REFERENCES 1. Meijers-Heijboer, H., et al. N Engl J Med, 2001. 345(3): 159-64. Women with invasive cancer history < 5 years or concomitant HT N= 48 (14%) Other inclusion Criteria N= 4 (1 %) Main Inclusion criteria validated N= 124 (37%) • According to the characteristics of the women included in the GENEPSO cohort and the survey, approximately one third of BRCA1/2 mutation carriers were eligible for the trial. • Out of the 534 women eligible from chart review informed by mail about the trial, 44% came to a dedicated medical visit. • Uptake of drug prevention trial was 32 % of orally informed women and 15 % of overall eligible women. • The main reasons of refusal were: potential side effects, probability to receive the placebo and lack of support from their physicians. • Previous unilateral breast cancer and prophylactic oophorectomy were more frequently observed in women enrolled in the trial than in the French cohort (93% vs 60% and 50 % vs 39 %, respectively). CONCLUSION Women who signed the participation consent N= 75 (32% of orally informed women, 15% of mail informed women) STUDY DESIGN Post-menopausal women with a BRCA1/2 deleterious mutation RESULTS 2. Gahm, J., et al., Breast, 2010 Dec;19(6):462-9. 3. Brandberg, Y., et al., J Clin Oncol, 2008. 26(24): p. 3943-9. 4. Goss PE, et al.; N Engl J Med. 2011 Jun 23;364(25):2381-91 5. Pujol P. et al., Fam Cancer (in press). 6. Evans, D., et al., Lancet, 2001. 358(9285): 889-90. 7. Evans D, et al., J Med Genet. 2010 ;47(12):853-5. Sponsored by FNCLCC With the financial support of The Ligue Nationale Contre le Cancer ; BMS; AMGEN