1. Abstract Book
International Congress
On Anti-Cancer Treatment
Paris, France
Palais des Congrès
3rd – 6th February 2009
Presidents
Pr David KHAYAT – Paris, France
Pr Gabriel N. HORTOBAGYI – Houston, USA
Accredited by the EACCME
SMO Labeled Meeting
ESMO
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3. 1
Sponsors
20TH INTERNATIONAL CONGRESS ON ANTI-CANCER TREATMENT
With the support of:
Major Sponsors
Roche
Merck Serono
Sanofi Aventis
Abraxis BioScience
Antigenics
Sponsors
Astrazeneca
Bayer Schering Pharma
Bristol-Myers Squibb
GE Healthcare
Générale de Santé
GlaxoSmithKline
Guerbet
Institut National du Cancer
Janssen Cilag
Lilly Oncology
Median Technologies
Médithèque
Pharma Mar
Pierre Fabre Médicaments
Schering Plough
Siemens
Storz
4. 2
ORGANISATION
OFFICIAL CARRIER
I.M.E. (International Medical Events)*
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75016 Paris
Tel.: (33-1) 47 43 50 00 – Fax : (33-1) 47 43 22 26
*I.M.E. est une filiale d’EQUATOUR
The airlines of SKYTEAM, Official Alliance Network for 20th ICACT 2009, offer attractive airfares for
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5. 3
20TH ICACT SCIENTIFIC COMMITTEE
Africa & Middle East
AZIM Hamdy Mohandiesen Giza – Egypt
CHAHINE Georges Beyrouth – Lebanon
ROBINSON Eliezer Haifa – Israël
VOROBIOF Daniel A. Johannesburg – South Africa
America
ARMITAGE James O. Omaha – USA
BALDUCCI Lodovico Tampa – USA
BENJAMIN Robert S. Houston – USA
BERLIN Jordan D. Nashville – USA
BIZZARI Jean-Pierre Houston – USA
DE LA GARZA Jaime Mexico DF – Mexico
DE MEESTER Tom Los Angeles – USA
CAZAP Eduardo Buenos-Aires – Argentina
DESCHAMPS Claude Rocherster – USA
FORASTIERE Arlène Baltimore – USA
FREUE José-Mario Buenos-Aires – Argentina
HALLER Daniel Philadelphia – USA
HONG Waun Ki Houston – USA
HORTOBAGYI Gabriel N. Houston – USA
HUDIS Clifford New York – USA
KRIS Mark G. New York – USA
LENZ Heinz Joseph Los Angeles – USA
LEVITSKY Hyam L. Baltimore – USA
MARKMAN Maurie Houston – USA
MENDELSOHN John Houston – USA
PEREZ Edith Jacksonville – USA
ROTHENBERG Mace L. Vanderbilt – USA
SALTZ Leonard New York – USA
SHEPHERD Frances Toronto – Canada
SWAIN Sandra Washington – USA
TEMPERO Margaret A. San Francisco – USA
VOKES Everett E. Chicago – USA
WEINBERG Robert Cambridge – USA
WOLMARK Norman Pittsburgh – USA
WOOD Christopher Houston – USA
Asia & Pacific
AZIZ Zeba Lahore – Pakistan
CHI Yihebali Beijing – China
FUJIWARA Yasuhiro Tokyo – Japan
HAO Chun-Yi Beijing - China
HATAKE Kiyohiko Tokyo – Japan
JAMIESON Glyn Adelaïde – Australia
JIANG Zefei Beijing – China
MINAMI Hironobu Kobe – Japan
MOK Tony Hong Kong – China
THONGPRASERT Sumitra Chiang Mai – Thailand
WONG John Hong Kong – China
XU Rui-Hua Guangzhou - China
6. 4
20TH ICACT SCIENTIFIC COMMITTEE
Europe
AAPRO Matti S. Genolier – Switzerland
ABBOU Clément-Claude Créteil – France
ADAM René Villejuif – France
AIMARD Lydie Marseille – France
ALTWEGG Thierry Dijon – France
ANDRE Fabrice Paris – France
AUCLERC Gérard Paris – France
AURENGO André Paris – France
BAJETTA Emilio Milano – Italy
BALDEYROU Pierre Paris – France
BANZET Pierre Paris – France
BASELGA José Barcelona – Spain
BASTIAN Gérard Paris – France
BEGER Hans Günther Ulm – Germany
BENCHIMOL Daniel Nice – France
BISMUTH Henri Villejuif – France
BLAY Jean-Yves Lyon – France
BOTTO Henry Suresnes – France
BOUDJEMA Karim Rennes – France
BOYLE Peter Lyon – France
BRAMBILLA Elisabeth Grenoble – France
BRAMBILLA Christian Grenoble – France
BRASNU Daniel Paris – France
BRUHAT Maurice-Antoine Clermont-Ferrand – France
BUGAT Roland Toulouse – France
BUTHIAU Didier Paris – France
CADRANEL Jacques Paris – France
CALS Laurent Toulon – France
CALVO Fabien Paris – France
CARDE Patrice Villejuif – France
CASALI Paolo Giovanni Milano – Italy
CASCINELLI Natale Milano – Italy
CASTELLSAGUE Xavier Barcelona – Spain
CHIRAS Jacques Paris – France
CLOUGH Krishna Paris – France
CONTE Pier-Franco Modena – Italy
CORTES Javier Barcelona – Spain
CORTES FUNES Hernan Madrid – Spain
COSSET Jean-Marc Dublin – Ireland
CUNNIGHAM David London – UK
DALIVOUST Philippe Marseille – France
DANA Alain Paris – France
DAVYDOV Mikhail I. Moscow – Russia
DE GRAMONT Aimery Paris – France
DEAU Xavier Paris – France
DE BRAUD Filippo Milano – Italy
DELGADO Marian Paris – France
DEMIDOV Lev V. Moscow – Russia
DEPLANQUE Gaël Paris – France
DIAZ-RUBIO Eduardo Madrid – Spain
7. 5
20TH ICACT SCIENTIFIC COMMITTEE
DORVAL Thierry Paris – France
DOUILLARD Jean-Yves Nantes St Herblain – France
DROMAIN Clarisse Paris – France
DUCREUX Michel Villejuif – France
ESCUDIER Bernard Villejuif – France
EGGERMONT Alexander Rotterdam – The Netherlands
ETTORE Francette Nice – France
EXTRA Jean-Marc Marseille – France
FAIVRE Sandrine Villejuif – France
FITOUSSI Alfred Paris – France
FOULT Jean-Marc Neuilly s/Seine – France
FUMOLEAU Pierre Dijon – France
GANDJBAKHCH Iradj Paris – France
GEORGOULIAS Vassilis Heraklion , Crete – Greece
GERARD Jean-Pierre Nice – France
GIANNI Luca Milano – Italy
GLIGOROV Joseph Paris – France
GUASTALLA Jean-Paul Lyon – France
HANNOUN Laurent Paris – France
HAROUSSEAU Jean-Luc Nantes – France
HARPER Peter London – UK
HOCK Danielle Liège – Belgium
KHAYAT David Paris – France
KNOPF Alain Asnières – France
LACAU ST GUILY Jean Paris – France
LAUNOIS Bernard Paris – France
LE CHEVALIER Thierry London – UK
LECESNE Axel Villejuif – Paris
LEJEUNE Ferdy Lausanne – Switzerland
LICHINITSER Michael Moscow – Russia
LINK Karl Heinrich Wiesbaden – Germany
LOUVET Christophe Paris – France
LUCIDARME Olivier Paris – France
LUDWIG Heinz Vienna – Austria
MAGNE Nicolas Villejuif – France
MARTIN Miguel Madrid – Spain
MARTIN Jean-Pierre Lyon – France
MARTY Michel Paris – France
MAURIAC Louis Bordeaux – France
MAZERON Jean-Jacques Paris – France
MILANO Gérard Nice – France
MISSET Jean-Louis Paris – France
MONSONEGO Joseph Paris – France
MORERE Jean-François Bobigny – France
MORNEX Françoise Lyon Pierre Bénite – France
MOUSSEAU Mireille Grenoble – France
MULARONI Elena Cailungo – San Marino
MULDERS Peter Nijmegen – The Netherlands
NAMER Moise Nice – Paris
NIZRI Daniel Paris – France
PECORELLI Sergio Brescia – Italy
PENAULT-LLORCA F. Clermont-Ferrand – France
8. 6
20TH ICACT SCIENTIFIC COMMITTEE
PICCART Martine Brussels – Belgium
PINEDO Herbert M. Amsterdam – The Netherlands
PIVOT Xavier Besançon – France
POPESCU Irinel Bucharest – Romania
POSTON Graeme Liverpool – UK
RAY-COQUARD Isabelle Lyon – France
RENODY Nicole Saint-Cloud – France
RICHARD François Paris – France
ROSELL Rafael Baladona – Spain
ROUËSSE Jacques Saint-Cloud – France
ROUGIER Philippe Boulogne-Billancourt – France
SALMON Rémy Paris – France
SCAGLIOTTI Georgio Torino – Italy
SCHMOLL Hans-Joachim Halle/Salle – Germany
SCHNEIDER Maurice Nice – France
SCOTTE Florian Paris – France
SEITZ Jean-François Marseille – France
SMITH Ian Edward London – UK
SOBRERO Alberto Genoa – Italy
SORIA Jean-Charles Villejuif – France
SPANO Jean-Philippe Paris – France
SPIELMANN Marc Villejuif – France
STERNBERG Cora Roma – Italy
STUDER Urs Bern – Switzerland
TABERNERO Josep Barcelona – Spain
TAIEB Julien Paris – France
TAILLADE Laurent Paris – France
TAVITIAN Armand Paris – France
THATCHER Nicholas Manchester – UK
TOURNIGAND Christophe Paris – France
TRILLET-LENOIR V. Pierre Bénite – France
TUBIANA Maurice Paris – France
UNTEREINER Michel Esch Alzette – Luxembourg
UZAN Serge Paris – France
VALLANCIEN Guy Paris – France
VAN CUTSEM Eric Leuven – Belgium
VAN LANSCHOT Jan Rotterdam – The Netherlands
VIGNOT Stéphane Paris – France
VUILLEMIN Eric Vannes – France
YCHOU Marc Montpellier – France
Founding President
Pr Claude JACQUILLAT Paris – France
Honorary Presidents
Pr Pierre BANZET Paris – France
Pr James HOLLAND New York - USA
9. 7
ACCREDITATION
ESMO Labeled Meeting
The 20th ICACT « International Congress on Anti-Cancer Treatment » has been accredited with
25 ESMO-MORA points Category 1
UEMS – EACCME
The 20th ICACT is accredited by the European Accreditation Council for Continuing Medical
Education (EACCME) to provide the following CME activity for medical specialists. The EACCME is
an institution of the European Union of Medical Specialits (UEMS), www.uems.net.
The ICACT is designated for a maximum of, or up to
24 EUROPEAN CME CREDITS (ECMEC’s)
Each medical specialist should claim only those credits that he/she actually spent in the educational activity. ECMEC()’s
are recognized by the American Medical Association towards the Physicians Recognition Award (PRA). To convert ECMEC’s
Credit to AMA PRA category I credit, please contact the AMA
10. 8
AWARDS
17TH
C L AUD E J A CQ U I L L AT
AWARD
F O R C L I N I C A L
C A N C E R R E S E A R C H
16TH
Lodovico BALDUCCI
R AY M O N D B OU R G I N E
AWARD
F O R AC H I E V E M E NT S
I N CAN C E R R ES EARCH
Nagahiro SAIJO
S O M P S P O S T E R
A WA R D S
11. 9
AWARDS
Pr Lodovico Balducci is Professor of Medicine & Oncology, University of South Florida College
of Medicine, and Chief of the Division of Geriatric Oncology, Senior Adult Oncology Program, at
the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida. Dr. Balducci received his
medical degree from Catholic University, Rome, Italy, and his residency training and fellowship at the
University of Mississippi Medical Center, Jackson, Mississippi.
Dr. Balducci has edited five textbooks on geriatric oncology and completed editing two books on
geriatric hematology, which will be published in 2007. He currently leads one of the three existing
geriatric oncology program in the country and the world. Dr. Balducci has published over 250 articles
in various medical journals on the subject of geriatric oncology, and five monographs on geriatric
oncology. Dr. Balducci’s clinical research activities include cancer and aging, management of the frail
elderly, assessment of quality of life in the older cancer patient, prognostic assessment of the older
cancer patient, and interactions of comorbidity and function in the older cancer patient. Dr. Balducci
is a member of ASCO’s Grant Selection Committee, and ASCO’s Cancer & Aging Task Force and
Oncology Workforce Task Force.
In 2003, Dr. Balducci was selected to present the first Paul Calabresi Memorial Lecture by the The
International Society of Geriatric Oncology (SIOG) in Rome, Italy. In 2003, he also received the
ACCC award for Outstanding Achievement in Clinical Research, and was the 2003 Physician of the
Year at the H. Lee Moffitt Cancer Center. In 2007 he received the Medi Tavossoli Lecture Award for
Innovative Research in Hematology in the Elderly and the ASCO’s B.J. Kennedy Award and Lecture
for Scientific Excellence.
Dr. Balducci is board certified in Medical Oncology/Hematology. He is a member of the American
Geriatrics Society, the American Society of Clinical Oncology, American Association for Cancer
Research, American Society of Hematology, American Society of Breast Disease, and a fellow of
the American College of Physicians. Dr. Balducci has lectured throughout the USA, Europe, Asia,
Australia and South America.
Dr. Nagahiro Saijo is Deputy Director of the National Cancer Center Hospital East in Tokyo. Currently
he is the President of the International Association for Study of Lung Cancer, the immediate past
member of the Board of Directors of the American Society for Clinical Oncology (ASCO), President,
Director and Counsilor of the Japanese Society of Medical Oncology (JSMO) and vice president of the
Japanese Lung Cancer Society.
Dr. Saijo received his medical training at the Osaka University School of Medicine. After two years
as project investigator in the Department of Developmental Therapeutics at MD Anderson Hospital,
he completed his Doctor’s Degree at the Osaka University School of Medicine. During his scientific
career, he has been Head of the Department for Internal Medicine at the National Cancer Center
Hospital, Chief of the Pharmacology Division of the National Cancer Center Research Institute, Chief
of the Medical Oncology Division at the National Cancer Center and President of the Japanese Clinical
Oncology Group (JCOG). His specialties and research interests include Cancer Chemotherapy Trials,
Drug Resistance, Pharmacology of Anticancer Drugs and Tumor Immunology.
Dr. Saijo has been awarded the Tamiya Prize, the Award of Adult Disease Memorial Research
Foundation, the 5th Central European Lung Cancer Symposium Meritorious Award, a BMS Freedom
to Discovery grant and Sagawa Investigator awards. He has served as editor, associate editor, editorial
board member and reviewer for numerous international and national journals, and has published
more than 561 English publications and over 813 Japanese publications.
12. 10
EEXXHIHBIITBOITRSORS
352B
Hall Havane
Neuilly
Amphithéâtre
Havane
Niveau 3
Level 3
351
352B
352A
Palais des Congres
2, Place de la Porte Maillot
75017 PARIS
Hall Havane Niveau 3
H
B
Côté Neuilly
Neuilly side
Côté Paris
Paris side
Niveau 3
Level 3
13. 11
TABLE OF CONTENTS
AGENDA
TUESDAY FEBRUARY 3RD, 2009 .................................................................................................. 15
WEDNEDSAY FEBRUARY 4TH, 2009 .......................................................................................... 20
THURSDAY FEBRUARY 5TH, 2009 .............................................................................................. 23
FRIDAY FEBRUARY 6TH, 2009 ..................................................................................................... 26
CLINICAL SYMPOSIUM
CS ................................................................................................................................................... 33
EDUCATIONAL LECTURES
EL ................................................................................................................................................. 133
MEET THE PROFESSOR
MTP ............................................................................................................................................. 139
PRESIDENTIAL SESSION
PRESIDENTIAL SESSION .......................................................................................................... 183
TIAL SESSION
15. 13
TABLE OF CONTENTS
Miscellaneous
Poster & Publication ....................................................................................................... 393
Pharmacology & New Drugs
Poster & Publication ....................................................................................................... 407
Quality of Life & Psychology
Poster ....................................................................................................................................... 445
Sarcoma
Poster & Publication ....................................................................................................... 449
16.
17. 15
AGENDA - Tuesday February 3rd, 2009
Room 1
9:00-12:30 Clinical Symposium on Breast Cancer (1)
Chaired by Martine PICCART
Clifford HUDIS
HER2: Beyond Trastuzumab
Sandra SWAIN
Update of the Adjuvant Therapy of Breast Cancer for HER2 Negative Disease
Pier-Franco CONTE
Adjuvant Treatment of HER2 + Early Breast Cancer: Achievements & Perspectives
Break
Martine PICCART
The “seed and soil hypothesis” revisited 120 years later: should all women with early breast cancer
receive adjuvant bisphosphonates following the results of tria ABCSG12
Javier CORTES
Re-defining the Role of Anthracyclines in Metastatic Breast Cancer
14:00-17:30 Clinical Symposium on Breast Cancer (2)
Chaired by Gabriel N. HORTOBAGYI
Gabriel N. HORTOBAGYI
Biology-driven selection of Optimal Systemic Therapy of Primary Breast Cancer
John CROWN
Adjuvant Therapy for Premonopausal Breast Cancer
Vassilis GEORGOULIAS
Circulating Tumor Cells in Early Breast Cancer: Biological and Clinical Relevance
Break
Javier CORTES
NabTM Technology in the Treatment of Breast Cancer
Norman WOLMARK
NSABP – Trials in the Adjuvant Treatment of Breast Cancer: an update
Room 2
09:00-12:30 Clinical Symposium on Head & Neck Cancer
Chaired by J-Mario FREUE
Arlene FORASTIERE
The Changing Epidemiology of Oropharynx Cancer and Implications for Disease
Everett E. VOKES
Targeted Therapy in Head and Neck Cancer
Break
José-Mario FREUE
Organ Preservation in Localy Advanced Larynx & Hypopharinx Squamous Cell Carcinomas
Robert S. BENJAMIN
Sarcoma of the Head & Neck
14:00-17:30 Clinical Symposium on Lung Cancer
Chaired by Nagahiro SAIJO
Tony MOK
The Dilemma in first line Therapy for Advanced NSCLC
Nagahiro SAIJO
Chemotherapy for Eldery NSCLC
Break
Frances SHEPHERD
Angiogenesis Inhibitors in Lung Cancer
Kazuhiro NAKAGAWA
EGFR-TKIs on Treatment in Advanced NSCLC
18. 16
AGENDA - Tuesday February 3rd, 2009
Room 3
09:00-12:30 Clinical Symposium on Gastrointestinal Tumors (1)
Chaired by Daniel HALLER
Daniel HALLER
Update on the Management of Advanced Colorectal Cancer
Eric Van CUTSEM
The Role of Biologicals in Colorectal Cancer
Break
Chun-Yi HAO
Surgical Management of Colorectal Liver Metastases: Consensus & Controversies in 2009
Norman WOLMARK
The retreat from anthracyclines and the NSABP Clinical trials
12:45-13:45 Educational Lecture Session
Leonard SALTZ
Life Beyond VEGF and EGFR: Investigational approaches in Colorectal Cancer
14:00-17:30 Clinical Symposium on Gastrointestinal Tumors (2)
Chaired by H. Joachim SCHMOLL
Hans.G BEGER
Cystic Neoplastic Tumor of the Pancreas – Resection is a Pancreatic Cancer Preventive Treatment
Daniel HALLER
Adjuvant Chemotherapy for Colorectal Cancer
Break
Leonard SALTZ
Management of Neuroendocrine Cancers
Hans-Joachim. SCHMOLL
New Standards in Advanced Colorectal Cancer
17:30-20:30 Expert Statement Conference
optimizing front line therapeutic strategies in mcrc
Chaired by Daniel HALLER & Jean-Luc RAOUL
Daniel HALLER
The Change in Paradigm: From How to Use 5-FU to Targeted Therapies
René ADAM
The Change in Paradigm: Patients with Isolated Liver Metastases
J. TABERNERO
Pronostic/Predictive Markers in CRC
Eric VAN CUTSEM
The Contribution of Targeted Therapies
Graeme POSTON
The Contribution of Targeted Therapies in Isolated Liver Metastases
Julien TAIEB
How to Optimally Treat our Patients Today: Patients with Wild Type K-Ras
Jean-Philippe SPANO
How to Optimally Treat our Patients Today: Patients with Mutated K-Ras
Round Table with all Presenters, chaired by Daniel HALLER
19. 17
AGENDA - Tuesday February 3rd, 2009
Room 4
12:30-14:00 Satellite Symposium Sponsored by ABRAXIS BioScience
Nabpaclitaxel: New dimensions in taxane spectrum of activity
Chaired by Gabriel N. HORTOBAGYI & David KHAYAT
Gabriel N. HORTOBAGYI
NabTM Platform
Hernan CORTES-FUNES
Early Development of Abraxane in Breast Cancer
TBC
Emerging Areas of Investigation: Ovarian
A. HAUSCHILD
Emerging Areas of Investigation: Melanoma
Georgio SCAGLIOTTI
Emerging Areas of Investigation: Lung
Margaret A. TEMPERO
Emerging Areas of Investigation: Pancreatic
Gabriel N. HORTOBAGYI
Discussion & Summary
14:00-17:20 expert statement conference on urological tumors
“New hope in early stage renal cell carcinoma”
Chaired by Mikhail I. DAVYDOV & David KHAYAT
C. ABBOU
Any Progress in early stage RCC with IL-2 and IFNα?
Lev V. DEMIDOV
Ongoing clinical trials involving targeted agents
Hyam I. LEVITSKY
Anticancer vaccines: a specific approach in early stage RCC
Christopher WOOD
Results of a phase III clinical trial with personalized HSP based anticancer vaccine
Peter MULDERS
Improving 3 years RFS with personalized HSP based anticancer vaccine in intermediate risk
RCC
Peter HARPER
How to move with personalized drugs from clinical trials to daily practice?
20. 18
AGENDA - Tuesday February 3rd, 2009
Room 5
12:30-14:00 Expert Statement Conference supported by JANSSEN-CILAG
What’s new on Erythroiesis stimulating agent (e.s.a)
Chaired by David KHAYAT
Mario DICATO
Anemia in Oncology - any news on treatments (ASE, Transfusions, iron)
Jean-François MORERE
Benefit/Risk of ASE
Isabelle RAY-COQUARD
Overview and guidelines for ASE Usage in oncology
Daniel HALLER
Based on literature, does anaemia should be treated in all cancer patients? (Chemotherapy vs no
chemotherapy, Impact of age, Impact of Hb level at therapy initiation)
TBC
Based on literature, what is the benefit from transfusions in cancer patients?
Peter HARPER
Based on literature, how the ASE tolerance could be optimized? (Thrombosis, survival)
TBC
Benefit of iron supplementation during the ASE treatment ?
David KHAYAT
Conclusion
Room 6
14:30-16:30 Satellite Symposium on Sarcoma
Supported by PHARMA MAR
Chaired by Robert S. BENJAMIN
Robert S. BENJAMIN
Trabectidin – Perspectives from development of an active antisarcoma drug
Jean-Yves BLAY
Adjuvant Treatments in Soft Tissue Sarcoma: Achievements and Perspectives
Jean-Yves BLAY
Targeted Therapies in Sarcoma
21. 19
AGENDA - Tuesday February 3rd, 2009
Room 7
09:30-12:30 Clinical Symposium on gynecological cancer
Chaired by Sergio PECORELLI
Joseph MONSONEGO
Impact of Gardasil® on incidence of CIN, EGL, abnormal Pap tests and cervical procedures during
the Future I/II studies
Xavier CASTELLSAGUE
HPV Vaccines for the Prevention of Cervical Cancer and Beyond
Sergio PECORELLI
Adjuvant Treatment for Early Stage Endometrial Cancer
Maurie MARKMAN
Maintenance Therapy in Ovarian Cancer
12:30-13:30 Meet The Professor Session
Chaired by Roger MOUAWAD
Natale CASCINELLI
Cutaneous Melanoma: Is completion Node Dissection needed for Sentinel Node Positive patients?
14:00-16:00 Meet The Professor Session
Chaired by Roger MOUAWAD
Kiyohiko HATAKE
CDC & ADCC Assay for Monoclonal Antibody Therapy using Rituximab
Georgio SCAGLIOTTI
Molecular Predictive & Prognostic Factors in Lung Cancer
22. 20
AGENDA - Wednesday February 4th, 2009
Room 1
09:00-12:30 Clinical Symposium on Lung Cancer (2)
Chaired by Mark G.Kris
Daniel A. VOROBIOF
Update on the Management of Malignant Mesothelioma
Benjamin BESSE
Cisplatin resistance in NSCLC
Break
Mark G. KRIS
Personalized Therapy for Lung Cancer: For Now or the Future
Frances SHEPHERD
Predictive & Prognostic Factors in Early Stage Resected Non-SCLC
14:00-16:15 Clinical Symposium on Lung Cancer (3)
Chaired by Rafael ROSELL
Rafael ROSELL
Molecular Biomarkers for Predicting Chemotherapy Response in Lung Cancer
Nagahiro SAIJO
Recent Advances in the Treatment SCLC
Georgio SCAGLIOTTI
Improving Survival with front line treatment in Advanced NSCLC
Room 2
09:00-12:30 Clinical Symposium on Issues in New Drugs Development
Chaired by Michel MARTY
Filipo DE BRAUD
Upcoming issues in Early Clinical Development of New Drugs
Michel MARTY
Europeen Regulations in the Evaluation & Approval of New Drugs in Cancer
Yasuhiro FUJIWARA
Current Japanese Environment of Clinical Drug Development/Research in Japan
Break
Jean-Pierre BIZZARI
What are the Optimal Strategies in the Development of a New Drug in Cancer?
Hironobu MINAMI
Pharmacogenomics of irinotecan in Asian Patients
12:30-14:00 Poster Discussion ICACT & poster Awards
23. 21
AGENDA - Wednesday February 4th, 2009
Room 4
09:00-11:15 Clinical Symposium on Gastric Cancer
Chaired by Emilio BAJETTA
Roberto BUZZONI
State of the Art in Adjuvant Treatment of Gastric Cancer
Marc YCHOU
Role of Neoadjuvant Chemotherapy in Gastric Cancer
Rui-Hua XU
What have we known in the Treatment of Advanced Gastric Cancer Beyond 5-FU and Cisplatin?
14:00-16:15 Clinical Symposium on Melanoma
Chaired by Alexander EGGERMONT
Alexander EGGERMONT
Drug Developments in Melanoma
Natale CASCINELLI
Cutaneus Melanoma: is the time for Combined Treatments?
Ferdy LEJEUNE
New Therapeutical Tragets in Melanoma: any Success?
Room 6
12:00-14:00 Satellite symposium institut national du cancer
Is the Genomic revolution changing our approaches to cancer and treatment?
Fabien CALVO
Introduction
Gilles THOMAS
Genetic predisposition to breast and prostate cancer
Jessica ZUCMAN
Oncogenomic in hepatocellular carcinoma: from tools to clinical applications
Anne CAMBON-THOMSEN
Is the ethics landscape also changing?
Michael STRATTON
The current advances in the field of breast cancer genomics
Dominique MARANINCHI
Conclusion
24. 22
AGENDA - Wednesday February 4th, 2009
Room 7
09:00-13:00 Meet the Professor Session
Chaired by Michel UNTEREINER
James O. ARMITAGE
Improving Survival in Follicular Lymphoma
Maurie MARKMAN
Intraperitoneal Chemotherapy: Rational & Results
Everett E. VOKES
Targeted Therapies in Head and Neck Cancer
Rafael ROSELL
QPCR-Based gene signatures for predicting survival in stageI NSCLC
13:00-14:00 Meet the Professor Session
Chaired by Michel UNTEREINER
Mark G. KRIS
Optimal Management at Locally-Advanced Non-Small Cell Lung Cancer: How do you Choose?
14:00-17:00 Meet the Professor Session
Chaired by Roger MOUAWAD
Javier CORTES
Treatment of HER2-Positive Breast Cancer. Should all Patients receive Trastuzumab?
Kiyohiko HATAKE
CTC (Circulating Tumor Cell) Analys in CRC, BC and Gastric
Herbert M. PINEDO
Antiangiogenic Agents in Cancer
Room 8
12:00-14:00 Meet the Professor Session
Chaired by Maurice Schneider
Henk M.W. VERHEUL
Early Detection of Colorectal Cancer Patients?
Alexander EGGERMONT
Management of irresectable extremity tumors
25. 23
AGENDA - Thursday February 5th, 2009
Room 1
09:00-11:15 Clinical Symposium on Gastrointestinal Tumors (3)
Chaired by Leonard SALTZ
Daniel HOCK
The Role of Imaging in Colorectal Cancer Prevention & Screening
Aimery de GRAMONT
Metastatic Colorectal Cancer: Current Status & Future Direction
Leonard SALTZ
Biomakers in Colorectal Cancer: ready for Prime Time?
14:30-15:00 Claude Jacquillat Award Ceremony
Raymond Bourgine Award Ceremony
15:00-17 :30 Presidential Session
Chaired by Gabriel N. HORTOBAGYI & David KHAYAT
Maurie MARKMAN
Controversies in the management of Ovarian Cancer
Margaret A. TEMPERO
Management of the Advanced Pancreatic Cancer: State of the Art
Edith PEREZ
Management of the Node Negative Breast Cancer: State of the Art
José BASELGA
Targeting the PI3K Pathway in Cancer
Room 2
13:00-14:30 Poster Discussion & Poster Awards
Room 3
09:00-13:00 Clinical Symposium on Cancer Management in the Developing Countries
Chaired by Jaime DE LA GARZA
Jaime DE LA GARZA
State of the Art in the Use of Hormonal Neo-Adjuvant Treatment for Breast Cancer
Eduardo CAZAP
Clinical Trials in developing countries: Promoting Independent Cancer Research
Zefei JIANG
Access to Innovative Treatment in Developing Countries: The Asiatic Experience
Break
Zeba AZIZ
Challenges in the diagnosis and Management of Breast Cancer in Developing Countries
Sumitra THONGPRASERT
Roles of EGFR TKI in Non-Small Cell Lung Cancer: Focus in Asian Population
Hamdy AZIM
Optimization of Trastuzumab treatment in developing countries: The need for new studies
26. 24
AGENDA - Thursday February 5th, 2009
Room 4
09:00-13:00 Expert Conference on Pancreatic Cancer
Chaired by Margaret A.TEMPERO & David KHAYAT
Margaret A. TEMPERO
Advanced Pancreatic Cancer: where are we more than ten years after Burris Trial?
Jordan D. BERLIN
Accelerating the pace of research in Pancreatic Cancer Treatment: a report from the US NCI State of
the Science Meeting
Alberto SOBRERO
Are New Targets more likely to be successful?
H.-J. SCHMOLL
Prospective/Predictive Biomakers: can we expect them helping individualizing Pancreatic Cancer
Management
Facing the today reality: how to optimally treat our patients with Advanced Pancreatic cancer on a
day to day basis?:
Claude LE PEN (TBC)
Are economical considerations already impeeting day to day practice?
Daniel HALLER
The US experience
Eric VAN CUTSEM
The European experience
Peter HARPER
The UK Situation
Michel DUCREUX
The French Situation
Round Table Discussion
Can we define a common position based on Medical Evidence?
David KHAYAT
Conclusion
27. 25
AGENDA - Thursday February 5th, 2009
Room 5
09:00-11:00 Satellite Symposium GE Healthcare
Chaired by Didier BUTHIAU & Dr Jean-Marc FOULT
ONCOLOGIST
Role of imaging techniques in oncology daily workflow.
Didier BUTHIAU
5 years experience in anti-angiogenic treatment assessment using CT Perfusion.
RADIOLOGIST
Interventional radiology in oncology : Why, how and for which patients ? Which perspectives?
MICHEL GRIMAUD
Future developments in Interventional Radiology for oncology. Multimodality advantages.
11:15-12:30 Satellite Symposium GUERBET
Why and How Imaging Helps the Oncologists ?
Chaired by Didier BUTHIAU
Didier BUTHIAU
Introduction & Objectives
A. JEYARAJAH
The Oncologist point of view
C.A. CUENOD
Scanner in the anti-angiogenic answer in kidney tumors
O. PELLET
Peritoneal Carcinomatosis
Didier BUTHIAU
Questions & Conclusion
Room 7
09:00-10:00 Educational Lecture Session
Chaired by Nicolas MAGNE
Herbert M. PINEDO
Antiangiogenic in GU Tumors
10:00-13:00 Meet the Professor Session
Chaired by Nicolas MAGNE
Eliezer ROBINSON
Cancer Survivors-A Challenge to Health Services
Hernan CORTES FUNES
Role of Antiangiogenic Therapy
Karl Heinrich LINK
How to treat Peritoneal Metastases or Primary Tumors
28. 26
AGENDA - Friday February 6th, 2009
Room 1
09:00-09:20 Opening Ceremony & Surgical Oncology Award
Chaired by Jacques POILLEUX
09:20-10:45 Plenary Session
Chaired by Bernard LAUNOIS & David KHAYAT
Urs STUDER
Ileal bladder substitute: the Keys of Success
Raymond REDING
Biography of a Surgeon: Judah Folkman and the history of a discovery: Angiogenesis
David KHAYAT
What’s new in 2009?
Dominique STOPPA-LYONNET
Genetics and Cancer
16:15-17:45 Plenary Session
Chaired by Anne PODEUR & Jacques POILLEUX
Dominique MARANINCHI
Evolution of Cancer Surgery in French Health Institutions in 2009-2011
Claude DESCHAMPS
“Aeronautic Quality” (in search of 0 Fault) in Surgical Oncology
Yvon BERLAND (TBC)
Surgical Demography: a Dramatic and Imminent Menace for Cancer Surgery?
Xavier DEAU
New Trends in the organization of post-graduate Education
Jacques POILLEUX
Conclusions
29. 27
AGENDA - Friday February 6th, 2009
Room 2
09:00-11:00 Meet the Professor Session
Chaired by Roger MOUAWAD
Robert S. BENJAMIN
Update in Management of Soft Tissues Sarcoma
Georges CHAHINE
What is new with Taxanes in Breast Cancer?
11:15-12:45 Esophagus Cancer
Chaired by Jacques BAULIEUX & Jean-Marie COLLARD
Christian ELL
Endoscopic mucosal resection
Jean-Pierre TRIBOULET
Recommendations of the French National Society of Gastro-Enterology
Glyn G. JAMIESON
Methodological problems with regard to lymph nodes in the treatment of esophageal cancer
John WONG
Randomized and prospective trials in surgery of Esophageal cancer
Tom R. DE MEESTER
Neoadjuvant treatment in Esophageal cancer
12:45-14:15 Satellite Symposium STORZ: Ovarian Cancer
Chaired by Maurice-Antoine BRUHAT & Serge UZAN
Hervé CURÉ
What’s new in Chemotherapy?
Michel CANIS
Place of Laparoscopy in Diagnostic and Treatment
Antoine MAUBON
Imaging and Ovarian Cancer
Denis QUERLEU
Surgical Treatment in Advanced Cancers
14:15-15:45 Breast Cancer
Chaired by Rémy SALMON & Gilles HOUVENAEGHEL
Hiram S. CODY
Memorial Sloan Kettering’s experience of Sentinel node biopsy (SNB) for Breast Cancer
Gilles HOUVENAEGHEL
Experience of Cancer Hospital Centers in micro metastatic sentinel node biopsy (SNB)
Richard VILLET
Surgical Indications of Immediate breast reconstruction
Alain FOURQUET
Radiotherapy after RMI and Oncoplasty
30. 28
AGENDA - Friday February 6th, 2009
Room 3
09:00-11:00 Meet the Professor Session
James O. ARMITAGE
Case studies in Lymphoma
Laure CATENA
Management of Neuro Endocrine Tumors
11:15-12:45 Kidney Cancer & Bladder Tumors
Chaired by François RICHARD & Christian COULANGE
Jean-Jacques RAMBEAUD
Natural history of Kidney cancer: Is there a place for active surveillance?
Christian COULANGE
Place of non-surgical treatment in metastatic Kidney cancer
Stéphane CULINE
Anti-angiogenic treatment in metastatic Kidney cancer in 2009?
Jean-Louis DAVIN
Hexvix & Bladder tumors : shedding a new light
Morgan ROUPRÊT
Place of conservative treatment in upper urinary tract tumors?
14:15-15:45 Prostate Cancer, Testicule & Adrenal Cancer
Chaired by François RICHARD & Pascal RISCHMANN
Albert GELET
What is the place for local treatment by ultrasound in prostate cancer in 2009?
Pierre MOZER
Prostate Cancer: towards a local treatment
Yann NEUZILLET
Value of onco-geriatric evaluation in therapeutic management of Prostate cancer
Jean-Dominique DOUBLET
Guidelines for malignant Adrenal Tumors
Nicolas MOTTET
Management of a non-seminomatous germinal tumor of stageI: follow-up or treatment?
31. 29
AGENDA - Friday February 6th, 2009
Room 4
09:00-11:00 Meet the Professor Session
Jean-Philippe SPANO
HIV & Cancer
Georgio SCAGLIOTTI
Pharmacogenomic in Thoracic Oncology
11:15-12:45 Satellite Symposium Generale de Sante: Breast cancer & Enhancing
multidisciplinary towards optimal chemical practice
Chaired by Pierre BONNIER & Jacques MEURETTE
Xavier MARTIN
Place of the Surgical Oncologist
Elisabeth HODIN / Jacques MEURETTE
Place of the Plastic Surgeon
Axel DURIEUX
Place of the Medical Oncologist
Pierre BONNIER
Multidisciplinarity in day-to-day-practice: Experience of Beauregard Private Hospital Center’s
Department of Gynecologic and Breast Surgery and Oncology
14:15-15:45 Hepato-biliary and Pancreatic Tumors
Chaired by Henri BISMUTH & Laurent HANNOUN
Laurence CHICHE
Adenomatosis: a rare and non-benign diagnosis of multinodular liver
Karim BOUDJEMA
Portal embolisation and biliary drainage in Cholangiocarcinoma of the confluence: Rennes
experience
Pierre-Alain CLAVIEN
Strategy for the safest Liver Surgery
Eliano BONACCORSI-RIANI
Liver transplantation for malignant vascular hepatic tumors
Christian PARTENSKY
Papillary and mucinous intracanalar tumors of the Pancreas
15:45-16:15 Poster discussion &Awards
32. 30
AGENDA - Friday February 6th, 2009
Room 5
11:15-12:45 Colorectal Cancer
Chaired by Eric RULLIER & Michel MALAFOSSE
Philippe ROUANNET
“A la carte” Treatment of locally advanced Rectal cancers
Angelita HABR-GAMA
“Wait and see” policy for complete clinical response after rectal cancer radio-chemotherapy
Phil QUIRKE
Oncological problems in colorectal surgery: optimizing surgery?
Dominique ELIAS
Peritoneal carcinomatosis in colorectal cancer: can we cure the patient?
12:45-14:00 Meet the Professor Session
Joël LEROY
Mesorectum Resection
14:15-15:45 Thoracic Cancers
Chaired by Iradj GANDJBAKHCH & Pierre FUENTES
Pascal THOMAS
Extended Surgery of Malignant Tumors of Mediastinum
Roger GIUDICELLI
Impact of guidelines on the practice of bronchus cancer surgery
Marc RIQUET
Value of Surgery in the treatment of Infra-thoracic lymphatic metastases of extra thoracic neoplasms
Jérôme MOUROUX
Why and how should we evaluate meetings of the Cancer Multidisciplinary Committee in Thoracic
Oncology?
Room 6
11:15-12:45 Malignant Tumors in Children
Chaired by Christine GRAPIN & Raymond REDING
Raymond REDING
Therapeutic modalities of hepatoblastoma: Evolution of Concepts
Michèle LARROQUET
Surgical treatment of bronchus tumors in children
Christine GRAPIN
Surgical indications in neuroblastoma
Pierre HELARDOT
Sacro-coccygeal teratoma: Pronostic factors
12:45-14:00 Meet the professor Session
Claude DESCHAMPS
Oesophageal Cancer
35. 33
Clinical Symposium
CLINICAL SYMPOSIUM
Clinical Symposium
BREAST CANCER (1)
Tuesday 3rd February – 09:00-12:30
HER2: Beyond Trastuzumab
Clifford HUDIS, MD
Chief, Breast Cancer Medicine Service
Attending Physician
MSKCC
Professor of Medicine
Weill Medical College of Cornell University
New York, NY, USA
The discovery of HER2 as a driver of growth in
a subset of human breast cancer coupled with the
development of a targeted therapy – trastuzumab – has
allowed us to identify this type of disease as a distinct
subset. The treatment of HER2 over-expressing breast
cancer is thus diverging from the treatment of all
other subtypes. Regardless of stage at presentation,
invasive breast cancers that overexpress HER2 at the
cell surface (3+ by immunohistochemistry) or have
amplification by FISH (>2.0 gene copy number) are
approached differently. 1 The key issue for all such
patients is now the role of trastuzumab because in
the first-line therapy metastatic setting such patients
given trastuzumab with chemotherapy (as opposed
to chemotherapy alone followed by trastuzumab at
disease progression) not only benefited with improved
time to progression and an increased response rate
but also gained overall survival. 2 This initial result
was then confirmed by a randomized phase 2 study
utilizing docetaxel as the chemotherapeutic agent. 3
These data directly influenced the development of
four large (and one smaller) randomized adjuvant
trials which in the aggregate demonstrated an
important reduction in risks of recurrence and death
for eligible patients with early stage disease. 4,5,6
These adjuvant results will have an important
implication going forward. While we can anticipate
an overall reduction in the incidence of HER2 positive
metastatic disease as a result of potential cures in the
adjuvant setting, those who do experience relapse
may be to some degree trastuzumab-refractory. The
situation for such patients will be similar to those we
already treat who have disease progression despite
treatment with trastuzumab for established metastatic
disease. Indeed, almost all who receive it as palliative
treatment for metastatic disease experience disease
progression. Hence it is important to accomplish
several tasks including the discovery of mechanisms
of resistance to trastuzumab, the development of
novel new agents targeting HER2, and clarification
of the role of continued trastuzumab beyond
progression.
The recent discovery that an oral tyrosine kinase
inhibitor targeting HER2 (along with HER1),
lapatinib, is active in trastuzumab-refractory
metastatic breast cancer suggests that HER2 itself
remains a viable target even when trastuzumab has
ceased to be effective. 7 A variety of additional TKIs
are in clinical development and may extend this
approach either because they are simply “better”
inhibitors of HER2 tyrosine kinase activity or because
they add important “off-target” (ie, pan-HER or pan-tyrosine
kinase) inhibition and activities. The activity
of these anti-HER2 agents, despite refractoriness to
prior trastuzumab, paradoxically lends some support
to the notion that continued trastuzumab, even
after progression of disease, might have some value
because for these patients HER2 still appears to be an
important driver of cell growth and survival. Until
recently, no randomized trial has been reported to
support the continued use of trastuzumab beyond
progression on this antibody although this approach
was frequently adopted in some parts of the world.
However, two prospective randomized trials testing
the role of continued trastuzumab beyond disease
36. 34
Clinical Symposium
progression have been attempted. A US trial initially
launched at MDAnderson and later extended
through the Southwest Oncology Group (SWOG)
using vinorelbine failed to accrue while a German
trial using capecitabine was recently reported
despite its failure to accrue its planned number of
patients. The latter trial is, however, informative
since it suggests that continued use of trastuzumab
(in this case with capecitabine) after progression on
trastuzumab-containing chemotherapy is associated
with significant clinical benefit.8 [1] Finally, another
recently reported study suggests that lapatinib plus
trastuzumab is superior to lapatinib alone in heavily
pre-treated patients. Together, these randomized
trials strongly suggest that HER2 remains a
potentially viable target and trastuzumab continues
to contribute benefit even after progression on other
trastuzumab-containing regimens.
The continued importance of HER2 as a driver
of cell growth and survival despite progression on
trastuzumab is underscored by the recent report
of activity for a several novel HER2 targeting
agents. Pertuzumab, a monoclonal antibody with
a unique mechanism of action is clearly active. 9
Unlike trastuzumab, pertuzumab appears to directly
inihibit receptor dimerization, leading to its earlier
development as a possible pan-HER inhibitor
(independent of HER2 expression level). This
antibody is associated with clinical activity when given
with trastuzumab in HER2 positive, trastuzumab-refractory
disease. 10 This observed activity begs the
question of the role of continued trastuzumab but a
practical issue for patients experiencing progression
on this antibody is that its long half-life makes it
likely that any “single agent” treatment administered
shortly after progression will, in fact, really consist
of a new drug added to remaining trastuzumab.
(This was a concern raised after the first report of
activity for lapatinib and capecitabine following
progression on trastuzumab). As a consequence,
continuing trastuzumab while testing new agents
can make practical sense. Furthermore, in some
cases preclinical models specifically predict that
the alternative mechanisms of action for different
anti-HER2 agents may be complementary and
therefore appropriate for combined use. At present,
the CLEOPATRA trial is testing the value of adding
pertuzumab to docetaxel and trastuzumab as first-line
therapy for HER2 positive metastatic breast
cancer. This trial has the potential to change the
standard of care for these patients.
A second new antibody approach consists of
trastuzumab bound directly to a highly potent
antimicrotubule agent (DM1, derived from
maytansine). This drug, (T-DM1) has clear activity
as a “single agent” in trastuzumab-refractory HER2
positive metastatic breast cancer. 11, 12
At the same time, there is clear evidence that
trastuzumab does not “convert” inert agents (ie,
celecoxib) into active ones. 13 Hence any activity seen
when a novel agent (or conventional chemotherapy
drug for that matter) is added to trastuzumab in
trastuzumab-refractory disease, can be interpreted
as evidence solely for the effect of the newly
introduced agent. We have taken this approach in
our development of heat shock protein 90 chaperone
molecule inhibitors as treatment for HER2 positive
breast cancer.
Heat shock protein 90 is a chaperone responsible for
the maintenance of structure and therefore function
of a variety of complex proteins including, among
others, HER2 and AKT. 14 Loss of HSP90 function
allows HER2 degradation via the ubiquitination
pathway thereby reducing the expression of HER2.
Geldanamycin, an ansamycin, is an HSP90 inhibitor
that is too toxic for clinical use. 17-allyl amino
geldanamycin (17-AAG, tanespimycin) is a modified
geldanamycin derivative with minimal toxicity that
maintains the HSP90 inhibitory effects of this class
of ansamycins. Pre-clinical experiments confirmed
the down-regulation of HER2 expression following
exposure to 17-AAG as well as the additive effects
of trastuzumab. Based on these trials our group has
been testing the combination of HSP90 inhibition
and trastuzumab in clinical trials.
In our first phase 1 study, Modi and colleagues
demonstrated safety for the combination of
trastuzumab and 17-AAG as well as significant
anti-tumor activity among a cohort of patients with
extensive prior trastuzumab-containing therapies. 15
A subsequent phase 2 trial, now accruing, confirms
this level of activity. A phase 1 study with a water
soluble derivative, 17-DMAG combined with
trastuzumab shows similar activity but a possibly
different toxicity profile. 16 Given this activity, as
well as evidence of activity in other disease settings
(ie, multiple myleloma) additional agents targeting
HSP90 are in development and a range of clinical
trials are now needed (and underway) to identify
their optimal integration into the management of
HER2 overexpressing breast cancer. With rational
combinations of antibodies, tyrosine kinase
inhibitors, and possibly HSP90 inhibition, it is
possible that the natural history of HER2 positive
breast cancer will continue to improve remarkably in
the near future.
37. 35
Clinical Symposium
References:
1. Hudis C. Drug Therapy: Trastuzumab. . New
England Journal of Medicine 2007;357:39-51.
2. Slamon DJ, Leyland-Jones B, Shak S, et al. Use
of Chemotherapy plus a Monoclonal Antibody
against HER2 for Metastatic Breast Cancer That
Overexpresses HER2. The New England journal of
medicine 2001;344(11):783-92.
3. Marty M, Cognetti F, Maraninchi D, et al.
Randomized Phase II Trial of the Efficacy and Safety of
Trastuzumab Combined With Docetaxel in Patients
With Human Epidermal Growth Factor Receptor
2-Positive Metastatic Breast Cancer Administered
As First-Line Treatment: The M77001 Study Group
10.1200/JCO.2005.04.173. J Clin Oncol
2005;23(19):4265-74.
4. Romond E, Perez E, Bryant J, et al. Trastuzumab
plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Eng J Med 2005;353(16):1673-
84.
5. Piccart-Gebhart M, Procter M, Leyland-Jones
B, et al. Trastuzumab after adjuvant chemotherapy
in HER2-positive breast cancer. N Eng J Med
2005;353(16):659-72.
6. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et
al. Adjuvant docetaxel or vinorelbine with or without
trastuzumab for breast cancer. The New England
journal of medicine 2006;354(8):809-20.
7. Geyer CE, Forster J, Lindquist D, et al. Lapatinib
plus capecitabine for HER2-positive advanced
breast cancer. The New England journal of medicine
2006;355(26):2733-43.
8. Von Minckwitz, G., C. Zielinski, E. Maarteense, and
e. al, Capecitabine vs. capecitabine + trastuzumab in
patients with HER2-positive metastatic breast cancer
progressing during trastuzumab treatment: The TBP
phase III study (GBG 26/BIG 3-05). J Clin Oncol,
2008. 26:47s. Abstract 1025.
9. Agus DB, Gordon MS, Taylor C, et al. Phase
I clinical study of pertuzumab, a novel HER
dimerization inhibitor, in patients with advanced
cancer. J Clin Oncol 2005;23(11):2534-43.
10. Gelmon, K., P. Fumoleau, S. Verma, and e. al,
Results of a phase II trial of trastuzumab (H) and
pertuzumab (P) in patients (pts) with HER2-positive
metastatic breast cancer (MBC) who had progressed
during trastuzumab therapy.. J Clin Oncol, 2008.
26:47s. Abstract 1026.
11. Holden, S., M. Beeram, I. Krop, I. Burris, HA, M.
Birkner, S. Girish, J. Tibbitts, S. Lutzker, and S. Modi,
A phase I study of weekly dosing of trastuzumab-
DM1 (T-DM1) in patients (pts) with advanced
HER2+ breast cancer (BC). J Clin Oncol, 2008.
26:48s. Abstract 1029.
12. Beeram, M., I. Burris, HA, S. Modi, M. Birkner, S.
Girish, J. Tibbitts, S. Holden, S. Lutzker, and I. Krop,
A phase I study of trastuzumab-DM1 (T-DM1), a
first-in-class HER2 antibody-drug conjugate (ADC),
in patients (pts) with advanced HER2+ breast cancer
(BC). J Clin Oncol. , 2008. 26:48s. Abstract 1028.
13. Dang CT, Dannenberg AJ, Subbaramaiah K, et
al. Phase II study of celecoxib and trastuzumab in
metastatic breast cancer patients who have progressed
after prior trastuzumab-based treatments. Clin
Cancer Res 2004;10(12 Pt 1):4062-7.
14. Solit DB, Zheng FF, Drobnjak M, et al.
17-Allylamino-17-demethoxygeldanamycin Induces
the Degradation of Androgen Receptor and HER-
2/neu and Inhibits the Growth of Prostate Cancer
Xenografts. Clin Cancer Res 2002;8(5):986-93.
15. Modi, S., A.T. Stopeck, M.S. Gordon, et al ,
Combination of Trastuzumab and Tanespimycin (17-
AAG, KOS-953) Is Safe and Active in Trastuzumab-
Refractory HER-2 Overexpressing Breast Cancer: A
Phase I Dose-Escalation Study. J Clin Oncol, 2007.
25(34): p. 5410-5417.
16. Miller K, Rosen L, Modi S, et al. Phase I trial
of alvespimycin (KOS-1022; 17-DMAG) and
trastuzumab (T). Journal of Clinical Oncology ASCO
Annual Meeting Proceedings Part I 2007;25(18S
(June 20 Supplement) Abs 1115).
Adjuvant Treatment of Her2 Positive
Early Breast Cancer Achievements and
Perspectives
Simona Giovannelli, PierFranco CONTE
Department of Oncology and Hematology, Hospital,
University of Modena- Italy
Among breast cancers diagnosed at any stage,
20%–30% are found to have amplification of the
human epidermal growth factor receptor (HER)-
2/neu gene (1). Overexpression of this protein, is
associated with aggressive biological characteristics
(high proliferative activity, metastatic potential and
neoangiogenesis) and poor survival (2).
Trastuzumab, the humanized monoclonal antibody
against HER2 receptor, is an essential component of
the treatment of patients with HER2-positive breast
cancer and its role in curative therapy of early breast
cancer is evolving rapidly (3).
The clinical benefits observed with trastuzumab in the
metastatic setting provided the rationale for assessing
trastuzumab in the treatment of early breast cancer
(4, 5). In the adjuvant setting, the results of 6 phase III
randomized trials have been published or presented
so far. In these trials, different chemotherapy
38. 36
Clinical Symposium
regimens and different modalities of trastuzumab
administration (in combination or sequentially
after chemotherapy) have been explored. Overall,
these trials have included > 10,000 women with
HER2-positive breast cancer; five of these trials have
demonstrated the superiority of adding trastuzumab
to chemotherapy compared with chemotherapy
alone (3, 6, 7, 8, 9, 10). The HERA trial recruited
5102 women and randomized them to observation
alone vs 1 year or 2 years of trastuzumab therapy.
One-year therapy with trastuzumab resulted in an
absolute DFS benefit of 6.3%, an absolute OS benefit
of 2.7%, and an absolute TDR event-free survival
benefit of 6.3%, all at 3 years from randomization
(3, 6). The BCIRG006 recruited 3222 patients and
randomly allocated them to three arms; AC therapy
followed by docetaxel was the control arm, versus
1-year trastuzumab therapy administered in two
intervention arms: following AC and concurrently
with docetaxel, or concurrently with six cycles of
docetaxel and carboplatin. Absolute DFS benefits
from years 2 to 4 from randomization were 6% and
5% for AC → D + H versus control and D + Pla + H
versus control, respectively. While AC → D + H
showed the greatest improvement in both DFS
and OS over control, when trastuzumab therapy
arms were directly compared (AC → D + H versus
D + Pla + H), there was no significant difference in
either DFS (p = 0.42) or OS (p = 0.58) (3, 7) . The North
NCCTG N9831 phase III trial randomised patients
to three arms, all of which included doxorubicin plus
cyclophosphamide followed by weekly paclitaxel for
twelve weeks, given either alone as control, or with
weekly trastuzumab for 1 year initiated sequentially
after chemotherapy, or concurrently with 12 weeks
of weekly paclitaxel (6,10). With similarities, the
NSABP trial B-31 randomized patients to receive
doxorubicin and cyclophosphamide followed by
paclitaxel every 21 days for four cycles alone or with
1 year of weekly trastuzumab initiated concurrently
with paclitaxel. The combined analysis of the two trials
(considering the sequential arm of the first one) found
a significant advantage to the concurrent addition
of trastuzumab to chemotherapy in comparison to
control for DFS, with OS and time to recurrence
(TTR) (3, 8). An unplanned interim analysis from
the N9831 trial comparing sequential trastuzumab
therapy to concurrent showed a significant advantage
in terms of DFS, but not OS, in favour of concurrent
therapy (3). Furthermore, no significant advantage
was found in terms of DFS or OS for the comparison
of sequential trastuzumab therapy to control arm
(3). The FinHer study compared primarily adjuvant
docetaxel (every 21 days for 4 cycles) to vinorelbine
(weekly for 8 cycles), with either being followed by
therapy with FEC (every twenty-one days for three
cycles). Trastuzumab was administered concurrently
with either docetaxel or vinorelbine, on a weekly
schedule for a total of only 9 weeks and was therefore
completed prior to therapy with FEC; despite the
short duration of admistration of trastuzumab this
study showed similar results (9). On the contrary,
the Programmes d’Actions Concertées Sein (PACS)
04 trial has shown no benefit for adding trastuzumab
at the completion of chemotherapy versus control
(10).
Both biologic and clinical data strongly support
the synergistic cytotoxic effects of trastuzumab and
chemotherapy on HER2 positive breast cancer cells,
while the sequential administration of trastuzumab
after chemotherapy seems to induce mainly a
cytostatic effect that might require longer treatment
to achieve maximum clinical benefit (11).
The HERA trial is the only one specifically
designed to test prospectively different durations of
trastuzumab administration (6). By now, on the basis
of the available results, one year of treatment with
trastuzumab is considered the gold standard.
Symptomatic congestive heart failure (CHF)
occurred in 1.5%-2.5% of the patients treated with
sequential trastuzumab (HERA trial, PACS 04, and
N9831 arm B) and in a percentage ranging from 0.4
(BCIRG 006 arm C, without anthracyclines) to 3.6 of
the patients in the trials in which trastuzumab was
started concomitantly with chemotherapy (BCIRG
006 arm B, N9831 arm C, NSABP B-31) (6-10, 11,
12). The FinHer (Finland Herceptin) trial is the only
adjuvant trastuzumab trial without episodes of CHF;
however, the limited number of patients included in
this trial does not allow concluding that a shorter
trastuzumab treatment is less cardiotoxic (9).
Many questions related to trastuzumab use in the
adjuvant setting still remain unanswered, regarding
to the optimum timing and duration of treatment,
its role in small node-negative tumors, the optimum
chemotherapy regimens (3).
A phase III multicentric, randomized trial (ShortHER
trial), has been designed in order to evaluate if 3
months of trastuzumab (9 weekly administrations)
is not inferior to 12 months of trastuzumab (18
3-weekly administrations), when administered in
combination with chemotherapy, in terms of DFS;
patients are randomised to receive AC or EC for
4 courses every 21 days followed by paclitaxel 175
mg/m2 or docetaxel 100 mg/m2 administered
concomitantly with trastuzumab every 21 days,
followed by trastuzumab alone for 14 additional
courses (long Arm); or docetaxel 100 mg/m2 I.V. on
day 1 every 21 days for 3 courses plus trastuzumab
weekly for 9 weeks followed by 3 courses of FEC60
(Short Arm) ; so far 143 patients have been enrolled,
69 in Arm A (Long) and 74 in Arm B (Short) (13).
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Other european trials are addressing the question of
shorter duration of Herceptin (PHARE trial, SOLD
trial, PERSEPHONE trial).
Adjuvant Lapatinib and/or Trastuzumab Treatment
Optimisation (ALTTO) is a four-arm randomized
trial designed to compare trastuzumab and lapatinib
in women with early-stage HER2-positive breast
cancer. Specifically, ALTTO will examine which anti-
HER2 agent is more effective and which is their best
schedule of administration, namely, what benefit will
be derived by taking the drugs separately, in tandem
order or in combination. Overall, 8000 patients will
be enrolled worldwide (14).
Primary systemic therapy is increasingly used in
operable disease and is replacing more conventional
postoperative adjuvant treatments in some subsets of
patients, because it can allow for breast conservative
surgery when up-front mastectomy would be
recommended, without jeopardizing survival, and
also permits an in vivo evaluation of treatment
efficacy (15).
Burstein et al. examined the safety and efficacy of
preoperative intravenous weekly trastuzumab and
paclitaxel (175 mg/m2 q 21 days×4) followed by
surgery and adjuvant AC in stage II and III breast
cancer patients. Pathologic CR was seen in 18% of all
patients, whereas the clinical response rate was 75%
(16).
In a prospective randomized phase III trial of Budzar
et al. the administration of 24 weeks of primary
systemic chemotherapy (PST) with paclitaxel and
FEC75 (fluorouracil, epirubicin, cyclophosphamide)
concurrently with trastuzumab in patients with
HER2-positive primary breast cancer resulted in
more than doubled pCR rate (66.7% vs 25%) as
compared to chemotherapy alone (17).
In a Multicenter phase II trial of neoadjuvant therapy
( GETN (A)-1 trial) 70 patients with HER-2-positive,
stage II/III, noninflammatory, operable breast cancer
received trastuzumab weekly, plus docetaxel 75 mg/
m2 every 3 weeks, and carboplatin AUC 6 for six
cycles before surgery. A complete or partial objective
clinical response occurred in 95% of patients (85%
and 10%, respectively). Tumor and nodal pCR were
seen in 27 (39%) of 70 patients (18).
In this setting, we are conducting a phase II
randomized trial in patients with tumors larger
than 2 cm. Patients with HER2 positive tumors are
randomized to receive: Arm A: chemotherapy plus
trastuzumab; Arm B: chemotherapy plus lapatinib;
Arm C: chemotherapy plus trastuzumab and
lapatinib (CHER-LOB trial). Patients enrolled will
receive chemotherapy with paclitaxel wkly for 12
wks, followed by 4 courses of FEC 75 every 3 wks.
Trastuzumab is administered at 2 mg/kg wkly in
arms A and C; Lapatinib is administered at 1500 mg
po daily in arm B, and at 1000 mg po daily in arm
C. Primary endpoint of this study is the percentage
of pCR (complete disappearance of invasive
tumoral cells in both breast and axillary nodes.
Secondary aims are: breast objective response, breast
conservative surgery, safety, molecular responses,
gene expression related to pCR. In this trial, as well
as in other similar ongoing studies, tumor samples
are collected for very important correlative studies
(19). Other studies (Neo ALTTO and NSABP-41
that will explore the concomitant chemotherapy
with lapatinib or trastuzumab or both, and the
sequential use of chemotherapy followed by L or H
or both respectively) are underway exploring the role
of neoadjuvant trastuzumab and also the possible
incorporation of lapatinib and will add elements to
enhance our understanding of which patients derive
the most benefit from trastuzumab (3).
References:
1. Bergman CI, Hung MC, et al. The neu oncogene
encodes an epidermal growth factor receptor-related
protein. Nature 1986; 319: 226-230.
2. Slamon DJ, Clark GM, Wong SG et al., Human
breast cancer: correlation of relapse and survival with
amplification of the HER-2/neu oncogene, Science
235 (1987), pp. 177-182. 3. Madarnas Y, Messersmith
H et al. Adjuvant/neoadjuvant trastuzumab therapy
in women with HER-2/neu-overexpressing breast
cancer: a systematic review. Cancer Treatment
reviews, 2008 Oct;34(6):539-57.
4. Slamon DJ, Leyland-Jones B, Shak S et al.,
Concurrent administration of anti-HER2 monoclonal
antibody and first-line chemotherapy for HER2-
overexpressing metastatic breast cancer. A phase III,
multinational, randomised controlled trial, N Engl J
Med 344 (2001), pp. 783-792.
5. Marty M, Cognetti F, Maraninchi D et al.,
Randomised phase II trial of the efficacy and safety
of trastuzumab combined with docetaxel in patients
with human epidermal growth factor receptor
2-positive metastatic breast cancer administered as
first-line treatment: the M77001 Study Group, J Clin
Oncol 23 (2005), pp. 4265-4274.
6. Piccart-Gebhart MJ, Procter M, Leyland-Jones
B et al., Trastuzumab after adjuvant chemotherapy
in HER2-positive breast cancer, N Engl J Med 353
(2005), pp. 1659-1672.
7. Slamon D, Eiermann W, Robert N et al. Phase
III randomized trial comparing doxorubicin and
cyclophosphamide followed by docetaxel (AC T)
with doxorubicin and cyclophosphamide followed
by docetaxel and trastuzumab (AC TH) with
docetaxel, carboplatin and trastuzumab (TCH) in
HER2 positive early breast cancer patients: BCIRG
40. 38
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006 study. Breast Cancer Res Treat 2005;94(suppl
1):S5.
8. Romond EH, Perez EA, Bryant J et al., Trastuzumab
plus adjuvant chemotherapy for operable HER2-
positive breast cancer, N Engl J Med 353 (2005), pp.
1673-1684.
9. Joensuu H, Kellokumpu-Lehtinen PL, Bono P
et al., Adjuvant docetaxel or vinorelbine with or
without trastuzumab for breast cancer, N Engl J Med
354 (2006), pp. 809-820.
10. Spielmann M, Roché H, Machiels JP, et al.
Trastuzumab following adjuvant chemotherapy
in node-positive, HER2-positive breast cancer
patients. 4-year followup results of the PACS-04 trial.
Presented at: the 29th Annual San Antonio Breast
Cancer Symposium; December 14-17, 2006; San
Antonio, TX. Abstract 72.
11. Suter TM, Procter M, van Veldhuisen DJ, et al.
Trastuzumab-associated cardiac adverse effects in
the Herceptin Adjuvant Trial. J Clin Oncol 2007;
25:3859-65.
12. Perez EA, Suman VJ, Davidson NE, et al. Cardiac
safety analysis of doxorubicin and cyclophosphamide
followed by paclitaxel with or without trastuzumab
in the North Central Cancer Treatment Group
N9831 adjuvant breast cancer trial. J Clin Oncol
2008,26:1231-8.
13.Guarneri V, Conte PF et al, Multicentric
randomised phsase III trial of two different
Adjuvant chemotherapy regimens plus Three versus
twelve months of trastuzumab in patients with
HER2- positive breast cancer (SHORT-HER trial;
NCT00629278). Clinical Breast Cancer 2008; 8; 5:
453-456.
14. Tomasello G, Piccart-Gebhart M et al. Jumping
higher: is it still possible? The ALTTO trial challenge.
Expert Rev Anticancer Ther, December 2008, Vol. 8,
No. 12, Pages 1883-1890 .
15. Guarneri V, Conte PF et al. Primary systemic
therapy for operable breast cancer: a review of
clinical trials and perspectives. Cancer Lett, 2007
Apr 18;248(2):175-85.
16. Burstein HJ, Harris LN, Gelman R, et al.
Preoperative therapy with trastuzumab and paclitaxel
followed by sequential adjuvant doxorubicin/
cyclophosphamide for HER2 overexpressing stage
II or III breast cancer: a pilot study. J Clin Oncol
2003;21(1):46–53.
17. Buzdar AU, Ibrahim NK, Francis D, et al.
Significantly higher pathologic complete remission
rate after neoadjuvant therapy with trastuzumab,
paclitaxel, and epirubicin chemotherapy: results of a
randomized trial in human epidermal growth factor
receptor 2-positive operable breast cancer. J. Clin.
Oncol. 23 (2005) 3676-3685.
18. Coudert BP, Namer M et al. Multicenter phase
II trial of neoadjuvant therapy with trastuzumab,
docetaxel, and carcoplatin for HER2 overexpressing
stage II or III breast cancer: results of the GETN(A)-1
trial. J Clin Oncol 2007; 25 (19): 2678-84.
19 Guarneri V, Conte PF et al. Preoperative
Chemotherapy plus Lapatinib or Trastuzumab or
Both in HER2-Positive Operable Breast Cancer
(CHERLOB Trial) . Clinical Breast Cancer, Vol. 8,
No. 2, 192-194, 2008.
The “seed and soil hypothesis” revisited
120 years later: should all women with
early breast cancer receive adjuvant
bisphosphonates following the results of
trial ABCSG-12?
Martine PICCART
JULES BORDET INSTITUTE
Medicine Department - 1 rue Heger-Bordet
1000 BRUSSELS - BELGIUM
Bisphosphonates have a clearly established role
in the prevention of skeletal-related events and
symptom management for breast cancer patients
with metastatic bone disease. In early disease, three
prior adjuvant trials with clodronate produced
mixed results. The ABCSG-12 trial randomized 1803
premenopausal women in a 2x2 manner to three years
of monthly goserelin with tamoxifen or goserelin with
anastrozole and either three years of six-monthly
zoledronic acid 4mg or no bisphosphonate therapy.
The anastrozole versus tamoxifen comparison did
not show any difference in DFS or OS, although
the study was underpowered to detect a clinically
significant difference between tamoxifen and an
aromatase inhibitor. The addition of zoledronic acid
reduced the risk of relapse (HR 0.64, p=0.011) with
a trend toward improved overall survival (HR 0.60,
p=0.10). Surprisingly, all categories of DFS events
(distant recurrences, locoregional recurrences, and
contralateral primaries) appeared to be reduced
by the addition of zoledronic acid. This finding
raises many important questions regarding the
underlying mechanism of action of bisphosphonates
in early disease. Namely, seen in the light of Stephen
Paget’s 120 year old “seed and soil” hypothesis, do
bisphosphonates target the seed, soil, or both? In
preclinical studies, bisphosphonates have direct
anti-tumor activity, with well documented pro-apoptic,
anti-angiogenic, and immune modulating
effects. However, the schedule of zoledronic acid
administered in ABCSG-12 may not have been potent
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enough to invoke eradication of the seed as the sole
cause of a 36% reduction in the risk of a DFS event.
Zoledronic acid has previously shown to reverse the
profound bone mineral destabilization induced by
the combination of goserelin and either anastrozole
or tamoxifen, raising the intriguing possibility that
zoledronic acid may alter the fertile soil of the bone
microenvironment for dormant disseminated cancer
cells. Before these results of ABCSG-12 are broadly
applied to clinical practice, it should be kept in mind
that this analysis was based on 137 DFS events and
42 deaths. In addition, only three years of adjuvant
systemic endocrine therapy were used in this trial
which is not universally accepted. The soon to be
reported, larger BIG 1-04/AZURE and NSABP B-34
studies of adjuvant zoledronic acid and clodronate
respectively in broader disease populations should
provide further guidance regarding the role of
adjuvant bisphosphonates. As the first test of a new
wave of promising bone microenvironment-directed
therapies -- such as inhibitors of RANLK, cathespin
K, src, and αvß3 integrins -- ABCSG-12 has ushered
in a new paradigm for breast cancer therapy, by
demonstrating that targeting both the seed and the
soil can improve the outcome of women diagnosed
with early disease.
Re-defining the Role of Anthracyclines in
Metastatic Breast Cancer
Javier CORTES
Val D’hebron University Hospital, Barcelona - Spain
Anthracyclines are being widely used in early breast
cancer cases, and meta-analyses conducted in 1995
showed them to be significantly more effective than
the standard CMF (cyclophosphamide, methotrexate,
fluorouracil) regimen in reducing disease recurrence
and mortality (1). The efficacy of anthracycline-containing
regiments such as FAC and FEC in
adjuvant treatment was established in a subsequent
meta-analysis conducted in 2005 (2).
One important risk associated with anthracycline
use in early breast cancer is that of cardiotoxicity,
particularly late-onset cardiomyopathy, which can
result in impairment of left-ventricular ejection
fraction (LVEF) and the development of congestive
heart failure (CHF). A major risk factor for the
development of such cardiac events is the cumulative
dose of anthracycline that patients receive (3, 4).
The use of these agents is often avoided in patients
with increased cardiovascular risk. Furthermore,
when anthracyclines are prescribed, current
practice is generally to keep the dose of doxorubicin
and epirubicin below the recommended total
lifetime dose (around 450 mg/m2 and 900 mg/m2,
respectively), in order to reduce cardiovascular
risk. Some risk factors, such as prior chest-wall
radiotherapy, advanced age, female gender and
prior cardiovascular disease, can increase the risk of
CHF. As would be expected, combination therapy
of anthracyclines with other cardiotoxic agents also
increases the incidence of cardiac events in these
patients. Thus, a retrospective review of seven Phase
II and III clinical trials with trastuzumab found that
concomitant administration of anthracycline and
trastuzumab was associated with a large increase in
the incidence of cardiac dysfunction (incidence 27%),
compared with the combination of paclitaxel and
trastuzumab (13%), or trastuzumab alone (3–7%)
(5). Similarly, administration of trastuzumab with
paclitaxel after doxorubicin plus cyclophosphamide
for adjuvant therapy of HER2-positive localised
breast cancer increased the incidence of CHF and
cardiac dysfunction, with a cumulative 1-year
incidence of cardiac dysfunction of 3.8%, compared
with 0.9% in the control arm (6).
Anthracycline-containing regimens have
demonstrated good efficacy in metastatic breast
cancer (MBC) through improved tumor response
rates and time to progression. However, the utility of
these agents might be complicated in those patients
pre-treated with anthracyclines. Strategies designed
to reduce the cardiotoxic effects of anthracyclines
include maintenance of a cumulative dose below
450 mg/m2 for doxorubicin and 900 mg/m2 for
epirubicin, modification of the dosing schedule,
use of the iron chelator dexrazoxane, and the use of
liposomal delivery systems for the anthracyclines.
Two forms of liposomal anthracyclines have been
developed in the treatment of MBC. Non-pegylated
liposomal doxorubicin (Myocet®, Cephalon) and
pegylated liposomal doxorubicin (Caelyx®, Schering-
Plough; Doxil®, Ortho Biotech).
Data from two Phase III studies have confirmed that
non-pegylated liposomal doxorubicin has similar
efficacy in MBC to conventional doxorubicin,
while reducing cardiovascular risk. A third Phase
III study compared combination therapy with non-pegylated
liposomal doxorubicin or epirubicin plus
cyclophosphamide (7-9).
Non-pegylated liposomal doxorubicin plus
cyclophosphamide (MC) was compared with
conventional doxorubicin and cyclophosphamide
(AC) in 297 patients with MBC (7). The two treatment
combinations achieved similar overall response rates
and median survival times. However, the incidence
of cardiotoxicity was significantly lower in patients
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receiving MC than in those receiving AC (p =
0.0001). A randomised comparison of monotherapy
with non-pegylated liposomal doxorubicin or with
conventional doxorubicin in 224 patients who had
not previously received chemotherapy for metastatic
disease also reported similar efficacy in the two
treatment arms (8). Significantly fewer patients
who received the liposomal formulation developed
cardiac events that prompted their removal from
the study compared with those who received
conventional doxorubicin (p = 0.0001). In a second
study of the MC combination therapy, this was
compared with epirubicin plus cyclophosphamide
(EC) in 160 patients who had not previously received
anthracycline therapy (9). The two treatment groups
had similar objective response rates and median
overall survival. However, the median time to
disease progression was significantly longer with
MC compared with EC (7.7 versus 5.6 months, p =
0.022).
This drug has also been tested in combination
with other chemotherapeutic agents including
trastuzumab. In the largest combination study, non-pegylated
doxorubicin was tested with paclitaxel
and trastuzumab in patients with HER2-positive,
locally advanced breast cancer (LABC) or MBC. The
overall response rate was 98%, with a median time
to progression of 22 months (10). Eight patients
discontinued therapy due to asymptomatic decreases
in LVEF to below 50%, but there were no cases of
symptomatic heart failure related to this regimen.
In light of these results, a Phase III study is ongoing
to compare non-pegylated liposomal doxorubicin,
trastuzumab and paclitaxel against trastuzumab and
paclitaxel for first-line therapy of HER2-positive
MBC.
Two Phase III studies have been conducted with
pegylated liposomal doxorubicin. In the first, this
agent was compared with conventional doxorubicin
in 509 patients with MBC (11). The risk of developing
cardiotoxicity, assessed in a subset of 339 patients,
was significantly lower with pegylated liposomal
doxorubicin than conventional doxorubicin
(hazard ratio 0.32, p < 0.001). The second study
compared pegylated liposomal doxorubicin versus
vinorelbine (the main comparator) or mitomycin
C plus vinblastine in 301 patients with taxane-refractory
advanced breast cancer (12). Progression-free
survival was similar for pegylated liposomal
doxorubicin and vinorelbine (median 2.9 versus 2.5
months, respectively).
In summary, the development of liposomal
anthracyclines has increased the therapeutic index of
the conventional anthracyclines in MBC. However,
there is still a need for improved patient selection in
order to maximize benefits and minimize risks. The
near future use of gene expression profiling might
help to better define which patients should receive
anthracyclines and when.
Clinical Symposium
BREAST CANCER (2)
Tuesday 3rd February, 14:00-17:30
Biology-driven Selection of Optimal
Systemic Therapy of Primary Breast
Cancer
Gabriel N. HORTOBAGYI, M.D., F.A.C.P.,
Department of Breast Medical Oncology,
The University of Texas M. D. Anderson Cancer
Center,
Houston, Texas, USA
Combined modality therapy is the therapeutic
approach of choice for the management of early
breast cancer. Systemic therapies, surgical resection
and radiotherapy all have important functions in
this strategy. Systemic therapy includes endocrine
treatments, chemotherapy and HER-2-targeted
therapies. Whether administered before optimal
local-regional treatments or following local therapy,
systemic treatments are estimated to reduce annual
odds of recurrence by 50% to 60% and annual
odds of death by about 40% to 50%.(1) While
endocrine therapy is unarguably the oldest of all
systemic treatments, wide acceptance of adjuvant
endocrine therapy did not occur until the mid
to late 1980s. Combination chemotherapy was
the first successful and fully validated adjuvant
systemic intervention. Initial regimens included
variations of cyclophosphamide, methotrexate
and fluorouracil (CMF): CMF-type regimens are
clearly effective, regardless of age, menopausal
status and nodal status. In subsequent generations
of adjuvant therapy regimens, anthracyclines were
substituted for methotrexate, with a 20% to 30%
improvement in outcomes compared to CMF-like
regimens. The introduction of taxanes produced
another incremental improvement in relapse-free
and overall survival. Chemotherapy research over
the past decade has focused on issues of dose, dose-density
and scheduling, with varying degrees of
success. The initial endocrine adjuvant therapies
were designed for unselected patients with primary
breast cancer, since the estrogen receptor was only
discovered in the 1960s. By the mid-1980s, there
was fairly compelling evidence that tamoxifen,
administered for several years, reduced significantly
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Clinical Symposium
the risk of recurrence, and in some trials, the risk
of death, especially in postmenopausal women.
Subsequent clinical trials established that around five
years of adjuvant tamoxifen were optimal. Clinical
trials conducted in the same era, also demonstrated
that for hormone receptor-positive tumors, the
combination of tamoxifen and chemotherapy was
more effective than either component, and this
approach was eventually adopted as the standard of
care. The initial trials of adjuvant ovarian ablation
were underpowered, and accrual to such trials
was quite challenging. Definitive evidence of the
therapeutic activity of ovarian ablation/suppression
was provided by the Oxford meta-analysis in the early
1990s. It was also the meta-analysis that provided
definitive support for the effectiveness of adjuvant
tamoxifen in the management of premenopausal
patients with breast cancer, and that the expression
of the estrogen receptor in tumor tissue was the most
effective predictor of benefit from endocrine therapy;
conversely, the evidence also indicated that patients
with estrogen receptor-negative tumors did not
benefit from hormonal therapy. Progress during the
1990s was incremental in nature: the development
of adjuvant selective aromatase inhibitors (AIs)
and the introduction of taxanes. AIs are clearly
more effective than tamoxifen, and considered to
be the first choice for adjuvant endocrine therapy
of postmenopausal women with hormone receptor-positive
breast cancer. In fact, the AIs are now the
subject of intensive investigation in the prevention
of breast cancer in women at high risk of developing
this disease. The recent presentation of the first
analysis of the BIG1-98 trial suggested that the
administration of adjuvant AIs up front was the best
strategy, and performed better than a sequential
tamoxifen-to-AI (or AI to tamoxifen) sequential
strategy. Ongoing clinical trials will soon establish the
optimal duration of adjuvant endocrine therapy for
postmenopausal women. While there is considerable
uncertainty and ongoing controversy about optimal
endocrine therapy for premenopausal women with
hormone receptor-positive breast cancer several
well-designed clinical trials (SOFT and TEXT) to
define the best strategy are approaching completion.
Clinical trials have clearly established that ovarian
ablation or suppression (using gonadotropin
analogs) has equivalent therapeutic activity to some
first-generation chemotherapy regimens (CMF).
Trials have also suggested that, for patients with
hormone receptor-positive tumors, ovarian ablation/
suppression might have superior activity to that of
CMF. However, these answers provide incomplete
guidance for optimal management of premenopausal
women with hormone-responsive breast cancer. The
endocrine therapy and chemotherapy used in the
relevant clinical trials are now of historical interest
only, since they have largely been replaced by more
effective regimens. Thus, the optimal integration
of aromatase inhibitors into the management of
premenopausal women has not been determined,
and no endocrine therapy has been directly compared
with modern chemotherapy regimens (TAC, dose-dense
AC+T, etc.). Even more importantly, the
most important question is not whether endocrine
therapy is better or worse than chemotherapy, but
whether and what combination of endocrine and
chemotherapy will offer the highest probability of
long-term disease control to both premenopausal
and postmenopausal women with hormone-sensitive
breast cancer.
The incorporation of taxanes into adjuvant and
neoadjuvant therapy was accomplished in a relatively
short time interval. It is now generally accepted
that the optimal schedule of administration for
paclitaxel is the weekly schedule, while the 3-weekly
schedule appears to have the best therapeutic index
for docetaxel. Nab-paclitaxel is currently under
evaluation in the adjuvant and neoadjuvant settings.
Retrospective analyses suggest that the incremental
benefit of adjuvant taxanes is greater for patients with
hormone receptor-negative tumors than for hormone
receptor-positive breast cancer. This observation has
not been reported for docetaxel-based regimens, so
there is substantial uncertainty about the relevance
of the initial reports to clinical practice. Perhaps a
more important line of investigation is to determine
whether there are subsets of hormone receptor
positive tumors that derive little or no benefit from
chemotherapy. For premenopausal women, these
issues are somewhat more complicated, because
chemotherapy affects ovarian function, and therefore,
has endocrine effects for some, but perhaps not all
premenopausal women. This observation explains, at
least in part, why combinations of endocrine therapy
and chemotherapy do not provide the same additive
benefit observed in postmenopausal patients. This
is particularly true for ovarian ablation added to
chemotherapy. Retrospective analyses suggest, but
do not establish, that the benefit of ovarian ablation
after chemotherapy might be limited to those
premenopausal women whose menses persist during
and after adjuvant chemotherapy.
Two other important development in the 1990s
were not incremental, but paradigm changing. The
discovery and validation of HER2 amplification/
overexpression as an adverse prognostic factor, and
the development of a monoclonal antibody to the
HER2 cell surface oncoprotein, and more recently
small molecule tyrosine kinase inhibitors with
similar (although not identical) effects, opened
entirely new avenues of therapeutic research. Several
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Clinical Symposium
large, prospective randomized trials documented the
marked antitumor efficacy of these drugs, both in the
metastatic and the adjuvant settings. Simultaneously
with these developments, technological advances
made possible the simultaneous evaluation of not
2 or 3, but thousands of genes (the entire human
genome, in fact) on the same tissue. Our increased
understanding of the heterogeneity of primary breast
cancer, and the identification of discrete, molecularly
defined subgroups of breast cancer with distinct
natural histories, drug sensitivities and specific
molecular therapeutic targets has revolutionalized
our conceptual and therapeutic approach to breast
cancer. Thus, it is apparent today, that luminal, basal,
HER2-like and perhaps other, smaller molecular
subsets can be reproducibly identified by microarray
technology. Somewhat more simplistically (and less
accurately), the use of three immunohistochemical
assays (estrogen receptor [ER], progesterone
receptor [PR] and HER2) defines similar, although
not identical groups of tumors. These three markers
are today considered and integral component
of the diagnosis of breast cancer, and represent
prognostic indicators as well as selectors of optimal
therapy for individual patients. We no longer design
clinical trials for “breast cancer”: instead, clinical
trials focus on HER2-positive tumors, or hormone
receptor-positive/HER2 negative breast cancer,
or “triple-negative” malignancies. Increasingly, as
part of therapeutic trials, we incorporate biological
correlative studies in an attempt to identify within
relatively homogeneous populations the operative
mechanisms of resistance. The challenge of future
drug development will be to generate compelling
biological and clinical evidence of safety and efficacy
in populations of smaller and smaller size.
Another important collateral benefit of multigene
assays is the ability to identify genetic “profiles” or
“signatures” associated with improved or adverse
prognosis or response to therapies. One such example
it the Oncotype Dx assay. This is an RT-PCR-based
assay that measures the expression of 21 genes: 16
related to the estrogen signaling pathway, proliferation
markers, invasion and metastasis and HER2. The
other five are “housekeeping genes”. Retrospective
analyses of paraffin-embedded tumors samples of
patients with estrogen receptor-positive tumors
have shown that the Recurrence Score, derived from
Oncotype Dx is linearly associated with the risk of
recurrence, whether the patient received tamoxifen
or not, and regardless of nodal status. Additional
analyses provide preliminary evidence suggesting
that patients with low Recurrence Score tumors
might not benefit from adjuvant chemotherapy,
while those with high Recurrence Scores might not
benefit from tamoxifen, despite a positive estrogen
receptor assay. A large prospective validation trial
is ongoing and should provide more compelling
answers to these and potentially other outstanding
questions. Another is being planned for patients
with ER-positive, lymph node-positive breast cancer.
The Recurrence Score also predicts the probabiltity
of achieving a pathological complete remission after
neoadjuvant chemotherapy. Other genomic assays
(Mammaprint, and others) are also available for more
accurate determination of prognosis and are under
evaluation to predict therapeutic benefit. Modern
technology should provide us with better and better
methods to select the most appropriate therapies for
individual patients and thus increase efficacy, while
limiting toxicity. The era of personalized medicine is
upon us, although the validation of these intuitively
attractive concepts will take a good part of the next
decade.
Today, the aggregate available evidence suggests the
following:
1) Patients with hormone receptor-positive, HER2
negative tumors:
a. premenopausal women benefit from adjuvant
or neoadjuvant ovarian ablation/suppression
or tamoxifen; chemotherapy (CMF, FAC/FEC,
AC+T, TAC, etc.) provides incremental benefit
above that achieved by endocrine therapy for
many patients.
b. Postmenopausal women benefit from adjuvant
or neoadjuvant aromatase inhibitors (AI, alone
or followed by tamoxifen); chemotherapy of the
same type shown for premenopausal women
provides incremental benefit, although to a
lesser extent than for premenopausal women;
2) Patients with HER2-positive tumors, any ER/
PR or menopausal status: the administration of
one year of trastuzumab in combination with
chemotherapy is associated with about a 50%
reduction in odds of recurrence and about a
30% reduction in odds of death. The optimal
timing and duration of trastuzumab is under
investigation, although trastuzumab has been
given in the adjuvant and neoadjuvant situations
with apparently similar benefits. Whether other
molecular markers can identify those patients
with HER2-positive tumors that will benefit
from trastuzumab, and what the role of lapatinib
is in the management of primary breast cancer
is also under investigation.
3) Because of the increased cardiac toxicity observed
with simultaneous or sequential combinations
of an anthracycline and trastuzumab, some have
proposed that anthracyclines have limited or
no role in the management of primary breast
cancer. This concept is being hotly debated;
there is no reliable or reproducible marker
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Clinical Symposium
of anthracycline benefit that would serve to
identify the population most and least likely to
benefit from this group of drugs.
4) Patients with “triple-negative” breast cancer:
chemotherapy with an anthracycline,
cyclophosphamide and a taxane is the treatment
of choice for patients with HR-negative,
HER2-negative tumors; platinum-based,
non-anthracycline-containing regimens are
under evaluation; bevacizumab is active in the
metastatic setting in this group, and is under
evaluation in clinical trials in the adjuvant and
neoadjuvant settings.
5) There is much interest in identifying those patients
who will benefit more from anthracyclines than
other agents, and those who need a taxane for
optimal results. The incremental benefit of
chemotherapy for women with high HR content
is under renewed investigation.
6) Clinical and pathological factors are commonly
used to determine risk of recurrence and
death from breast cancer.(7) These factors are
reasonably accurate in predicting prognosis
for groups of patients, but much less so for
individual patients. An on-line program,
Adjuvant!Online considers multiple clinical and
pathological factors to predict risk of recurrence
and mortality.(8) In addition, this program
incorporates the effect of comorbid conditions
in the determination of prognosis and benefit
from various therapeutic interventions. This
program is available on-line at no cost to the
user. Adjuvant!Online has been independently
validated by Canadian investigators, and
the concordance with actual recurrence and
mortality rates was within 1% of predictions
based on this model.(9)
7) Multigene predictors of prognosis and
responsiveness to therapy are currently under
development and clinical validation.(10;11) The
Oncotype Dx assay seems to be most advanced in
validation trials and has been used in over 20,000
patients in the practice setting. Some require
fresh or fresh-frozen tumor samples; others can
be performed on paraffin-embedded archival
material, increasing the possibility of general
use in the community. Preliminary analyses
suggest that combinaed use of the Oncotype DX
assay and Adjuvant!Online provides even more
accurate prognostic information thatn each
component alone.
8) The results of current trials will determine
whether more precise determination of prognosis
and identification of patients most likely and
least likely to benefit from specific therapies
can improve the efficacy and reduce the toxicity
of systemic treatments. As individual tumors
are molecularly characterized and molecularly
targeted therapies are clinically validated,
“personalized” adjuvant therapy will become a
reality in the not too distant future.(12)
Reference List
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(3) Early Breast Cancer Trialists’ Collaborative
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(4) Jonat W, Kaufmann M, Sauerbrei W, Blamey
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(6) Early Breast Cancer Trialists’ Collaborative
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(7) McGuire WL. Prognostic factors for recurrence
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Clin Oncol 2001; 19(4):980-991.
(9) Olivotto IA, Bajdik C, Ravdin PM, Norris B,
Coldman AJ, Speers C et al. An independent
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(10) Paik S, Shak S, Tang G, Kim C, Baker J, Cronin
M et al. A multigene assay to predict recurrence
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Hart AA, Voskuil DW et al. A gene-expression
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cancer 2004 [Review]. Am J Clin Pathol 2004;
122(4):598-609.
Clinical relevance of disseminated and
circulating tumor cells in patients with
breast cancer
Vassilis A. Georgoulias MD, PhD
Department of Medical Oncology
University General Hospital of Heraklion
PO Box 1352, 711 10 Heraklion, Crete, Greece
Abstract: The presence of lymph node involvement is
an unfavorable prognostic factor during the diagnosis
of an epithelial malignant tumor. In several tumors,
however, distant metastasis could also be developed
even in the absence of lymph node involvement,
indicating that hematogenous spread may play an
important role in the metastatic process of cancer
cells. Using immunochemical and molecular assays
it is now possible to detect single metastatic tumor
cells in both the bone marrow (disseminated tumor
cells; DTCs) and the peripheral blood (circulating
tumor cells; CTCs) of patients with different
epithelial malignant tumors either in the absence
of overt clinical metastasis or during the metastatic
phase of the disease. In breast cancer patients,
several recent studies have clearly demonstrated
that the detection of DTCs and/or CTCs at primary
diagnosis is an independent prognostic factor for
unfavorable outcome. In addition, the development
of a semiautomated system allowing the enrichment
of the blood sample for CTCs permitted the
evaluation of the efficacy of chemotherapy as early
as three or four weeks after the initiation of the
treatment. Therefore, the study of DTCs/CTCs may
allow to address important questions of systemic
tumor cell dissemination during the early steps of
the metastatic cascade; moreover, their study during
the advanced disease may help to better select
therapeutic approaches according to the biological
characteristics of tumor cells.
Methods for tumor cell detection: Several methods
have been developed in order to identify occult
tumor cells in the bone marrow and the peripheral
blood of patients with solid tumors. The likehood
to detect isolated breast cancer cells at diagnosis by
using histological evaluation of the bone marrow
and peripheral blood is very low (less than 4% and
1%, respectively). Conversely, immunocytochemical
evaluation of mononuclear cells after Ficoll density
gradient centrifugation using antibodies against
cytokeratins (CK), which are expressed on epithelial
but not on mesenchymal hematopoietic cells,
has been revealed to be a reliable method for the
detection of DTCs and CTCs. Numerous recent
studies demonstrated that immunocytochemistry
can detect occult tumor cells in 19%-48% of the
patients without overt metastatic disease. Several
methodological parameters may influence the results
of the detection of such rare cells. The International
Society of Cell Therapy and the National Cancer
Institute have recognized the need for standardization
of the immunocytochemical assay. The use of highly
specific anti-CK monoclonal antibodies, the use of
a sufficient number of mononuclear cells and the
exclusion of CD45+ lymphocytes are limiting factors
for the immunocytochemical detection of DTCs
and CTCs. In addition, new enrichment techniques
based on improved methods and procedures of cell
separation (i.e. immunoseparation) may increase the
sensitivity of immunocytohemical assays improving
the prognostic relevance of DTCs and CTCs. In
addition, enrichment techniques have the advantage
that the tumor cells remain viable and can be used for
further biological studies. The immunocytochemical
characterization of DTCs/CTCs also gives the
possibility to evaluate the expression of different
molecules on these cells (i.e. HER2, EGFR, EpCAM,
UPA-R etc) which may be interesting potential
targets for systemic “secondary adjuvant” therapeutic
approaches aiming to eliminate these cells.
The molecular methods for the detection of DTCs
and CTCs are based on the reverse transcriptase
polymerase chain reaction (RT-PCR). Using this
assay, tumor-associated mRNA transcripts, which
are not expressed on hematopoietic cells, can be
detected. The limiting factor for these assays is
the illegitime low-level transcription of tumor-or
epithelial-associated genes in normal cells. This
limitation implies a thorough evaluation of each
marker in normal subjects. Several markers (CK,
mucin, CEA, β-hCG, mammaglobulin, EGFR etc)
have been used for the detection of DTCs/CTCs.
Quantitative real-time PCR offers the opportunity to
discriminate between the low-level expression of the
marker gene in normal and cancer cells allowing an
increase of the specificity of this molecular approach.
Although real-time PCR may also provide a method
to evaluate the tumor cell load, it is important to
mention that the amount of marker transcript
may vary considerably between tumor cells of an