Book de publications

Transcription

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.
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;
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.
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;
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.
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
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
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
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
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
–
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.
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.
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.
–
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
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
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
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
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.
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
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
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
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
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
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
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
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
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+
Mucitis Cutaneous
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
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
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
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
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
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
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
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

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