1. Abstract BookInternational CongressOn Anti-Cancer TreatmentParis, FrancePalais des Congrs3rd 6th February 2009PresidentsPr David KHAYAT Paris, FrancePr Gabriel N. HORTOBAGYI Houston, USAAccredited by the EACCMESMO Labeled MeetingESMO

2. Creating TreatmentsAs Unique As You.Antigenics is developing heat shock protein-basedpatient-specific therapeutic cancer vaccinces thatare designed to target and destroy tumor cells.For more information, please call +1 781.674.4280 or emailclinicalaffairs@antigenics.comsmart science. smart medicine.08-gp96-0047 Rev. 01 3. 1Sponsors20TH INTERNATIONAL CONGRESS ON ANTI-CANCER TREATMENTWith the support of:Major SponsorsRocheMerck SeronoSanofi AventisAbraxis BioScienceAntigenicsSponsorsAstrazenecaBayer Schering PharmaBristol-Myers SquibbGE HealthcareGnrale de SantGlaxoSmithKlineGuerbetInstitut National du CancerJanssen CilagLilly OncologyMedian TechnologiesMdithquePharma MarPierre Fabre MdicamentsSchering PloughSiemensStorz 4. 2ORGANISATIONOFFICIAL CARRIERI.M.E. (International Medical Events)*124, Boulevard Exelmans75016 ParisTel.: (33-1) 47 43 50 00 Fax : (33-1) 47 43 22 26*I.M.E. est une filiale dEQUATOURThe airlines of SKYTEAM, Official Alliance Network for 20th ICACT 2009, offer attractive airfares forparticipants.SKYTEAM comprises 10 leading international airlines: Aeroflot, Aeromexico, AirFrance, Alitalia,Continental, CSA Czech Airlines, Delta, KLM, Korean Air, Northwest Airlines, serving 728 cities in149 countries with over 15000 flights daily.To benefit from these special offers, link up with www.skyteam.com/Global Meetings and quote theIdentifier Code 0684S.Through this site you can also access the schedules of all SkyTeam partners to plan your flights on theairline of your choice.As an added benefit you can earn miles everytime you travel on a member airline. 5. 320TH ICACT SCIENTIFIC COMMITTEEAfrica & Middle EastAZIM Hamdy Mohandiesen Giza EgyptCHAHINE Georges Beyrouth LebanonROBINSON Eliezer Haifa IsralVOROBIOF Daniel A. Johannesburg South AfricaAmericaARMITAGE James O. Omaha USABALDUCCI Lodovico Tampa USABENJAMIN Robert S. Houston USABERLIN Jordan D. Nashville USABIZZARI Jean-Pierre Houston USADE LA GARZA Jaime Mexico DF MexicoDE MEESTER Tom Los Angeles USACAZAP Eduardo Buenos-Aires ArgentinaDESCHAMPS Claude Rocherster USAFORASTIERE Arlne Baltimore USAFREUE Jos-Mario Buenos-Aires ArgentinaHALLER Daniel Philadelphia USAHONG Waun Ki Houston USAHORTOBAGYI Gabriel N. Houston USAHUDIS Clifford New York USAKRIS Mark G. New York USALENZ Heinz Joseph Los Angeles USALEVITSKY Hyam L. Baltimore USAMARKMAN Maurie Houston USAMENDELSOHN John Houston USAPEREZ Edith Jacksonville USAROTHENBERG Mace L. Vanderbilt USASALTZ Leonard New York USASHEPHERD Frances Toronto CanadaSWAIN Sandra Washington USATEMPERO Margaret A. San Francisco USAVOKES Everett E. Chicago USAWEINBERG Robert Cambridge USAWOLMARK Norman Pittsburgh USAWOOD Christopher Houston USAAsia & PacificAZIZ Zeba Lahore PakistanCHI Yihebali Beijing ChinaFUJIWARA Yasuhiro Tokyo JapanHAO Chun-Yi Beijing - ChinaHATAKE Kiyohiko Tokyo JapanJAMIESON Glyn Adelade AustraliaJIANG Zefei Beijing ChinaMINAMI Hironobu Kobe JapanMOK Tony Hong Kong ChinaTHONGPRASERT Sumitra Chiang Mai ThailandWONG John Hong Kong ChinaXU Rui-Hua Guangzhou - China 6. 420TH ICACT SCIENTIFIC COMMITTEEEuropeAAPRO Matti S. Genolier SwitzerlandABBOU Clment-Claude Crteil FranceADAM Ren Villejuif FranceAIMARD Lydie Marseille FranceALTWEGG Thierry Dijon FranceANDRE Fabrice Paris FranceAUCLERC Grard Paris FranceAURENGO Andr Paris FranceBAJETTA Emilio Milano ItalyBALDEYROU Pierre Paris FranceBANZET Pierre Paris FranceBASELGA Jos Barcelona SpainBASTIAN Grard Paris FranceBEGER Hans Gnther Ulm GermanyBENCHIMOL Daniel Nice FranceBISMUTH Henri Villejuif FranceBLAY Jean-Yves Lyon FranceBOTTO Henry Suresnes FranceBOUDJEMA Karim Rennes FranceBOYLE Peter Lyon FranceBRAMBILLA Elisabeth Grenoble FranceBRAMBILLA Christian Grenoble FranceBRASNU Daniel Paris FranceBRUHAT Maurice-Antoine Clermont-Ferrand FranceBUGAT Roland Toulouse FranceBUTHIAU Didier Paris FranceCADRANEL Jacques Paris FranceCALS Laurent Toulon FranceCALVO Fabien Paris FranceCARDE Patrice Villejuif FranceCASALI Paolo Giovanni Milano ItalyCASCINELLI Natale Milano ItalyCASTELLSAGUE Xavier Barcelona SpainCHIRAS Jacques Paris FranceCLOUGH Krishna Paris FranceCONTE Pier-Franco Modena ItalyCORTES Javier Barcelona SpainCORTES FUNES Hernan Madrid SpainCOSSET Jean-Marc Dublin IrelandCUNNIGHAM David London UKDALIVOUST Philippe Marseille FranceDANA Alain Paris FranceDAVYDOV Mikhail I. Moscow RussiaDE GRAMONT Aimery Paris FranceDEAU Xavier Paris FranceDE BRAUD Filippo Milano ItalyDELGADO Marian Paris FranceDEMIDOV Lev V. Moscow RussiaDEPLANQUE Gal Paris FranceDIAZ-RUBIO Eduardo Madrid Spain 7. 520TH ICACT SCIENTIFIC COMMITTEEDORVAL Thierry Paris FranceDOUILLARD Jean-Yves Nantes St Herblain FranceDROMAIN Clarisse Paris FranceDUCREUX Michel Villejuif FranceESCUDIER Bernard Villejuif FranceEGGERMONT Alexander Rotterdam The NetherlandsETTORE Francette Nice FranceEXTRA Jean-Marc Marseille FranceFAIVRE Sandrine Villejuif FranceFITOUSSI Alfred Paris FranceFOULT Jean-Marc Neuilly s/Seine FranceFUMOLEAU Pierre Dijon FranceGANDJBAKHCH Iradj Paris FranceGEORGOULIAS Vassilis Heraklion , Crete GreeceGERARD Jean-Pierre Nice FranceGIANNI Luca Milano ItalyGLIGOROV Joseph Paris FranceGUASTALLA Jean-Paul Lyon FranceHANNOUN Laurent Paris FranceHAROUSSEAU Jean-Luc Nantes FranceHARPER Peter London UKHOCK Danielle Lige BelgiumKHAYAT David Paris FranceKNOPF Alain Asnires FranceLACAU ST GUILY Jean Paris FranceLAUNOIS Bernard Paris FranceLE CHEVALIER Thierry London UKLECESNE Axel Villejuif ParisLEJEUNE Ferdy Lausanne SwitzerlandLICHINITSER Michael Moscow RussiaLINK Karl Heinrich Wiesbaden GermanyLOUVET Christophe Paris FranceLUCIDARME Olivier Paris FranceLUDWIG Heinz Vienna AustriaMAGNE Nicolas Villejuif FranceMARTIN Miguel Madrid SpainMARTIN Jean-Pierre Lyon FranceMARTY Michel Paris FranceMAURIAC Louis Bordeaux FranceMAZERON Jean-Jacques Paris FranceMILANO Grard Nice FranceMISSET Jean-Louis Paris FranceMONSONEGO Joseph Paris FranceMORERE Jean-Franois Bobigny FranceMORNEX Franoise Lyon Pierre Bnite FranceMOUSSEAU Mireille Grenoble FranceMULARONI Elena Cailungo San MarinoMULDERS Peter Nijmegen The NetherlandsNAMER Moise Nice ParisNIZRI Daniel Paris FrancePECORELLI Sergio Brescia ItalyPENAULT-LLORCA F. Clermont-Ferrand France 8. 620TH ICACT SCIENTIFIC COMMITTEEPICCART Martine Brussels BelgiumPINEDO Herbert M. Amsterdam The NetherlandsPIVOT Xavier Besanon FrancePOPESCU Irinel Bucharest RomaniaPOSTON Graeme Liverpool UKRAY-COQUARD Isabelle Lyon FranceRENODY Nicole Saint-Cloud FranceRICHARD Franois Paris FranceROSELL Rafael Baladona SpainROUSSE Jacques Saint-Cloud FranceROUGIER Philippe Boulogne-Billancourt FranceSALMON Rmy Paris FranceSCAGLIOTTI Georgio Torino ItalySCHMOLL Hans-Joachim Halle/Salle GermanySCHNEIDER Maurice Nice FranceSCOTTE Florian Paris FranceSEITZ Jean-Franois Marseille FranceSMITH Ian Edward London UKSOBRERO Alberto Genoa ItalySORIA Jean-Charles Villejuif FranceSPANO Jean-Philippe Paris FranceSPIELMANN Marc Villejuif FranceSTERNBERG Cora Roma ItalySTUDER Urs Bern SwitzerlandTABERNERO Josep Barcelona SpainTAIEB Julien Paris FranceTAILLADE Laurent Paris FranceTAVITIAN Armand Paris FranceTHATCHER Nicholas Manchester UKTOURNIGAND Christophe Paris FranceTRILLET-LENOIR V. Pierre Bnite FranceTUBIANA Maurice Paris FranceUNTEREINER Michel Esch Alzette LuxembourgUZAN Serge Paris FranceVALLANCIEN Guy Paris FranceVAN CUTSEM Eric Leuven BelgiumVAN LANSCHOT Jan Rotterdam The NetherlandsVIGNOT Stphane Paris FranceVUILLEMIN Eric Vannes FranceYCHOU Marc Montpellier FranceFounding PresidentPr Claude JACQUILLAT Paris FranceHonorary PresidentsPr Pierre BANZET Paris FrancePr James HOLLAND New York - USA 9. 7ACCREDITATIONESMO Labeled MeetingThe 20th ICACT International Congress on Anti-Cancer Treatment has been accredited with25 ESMO-MORA points Category 1UEMS EACCMEThe 20th ICACT is accredited by the European Accreditation Council for Continuing MedicalEducation (EACCME) to provide the following CME activity for medical specialists. The EACCME isan institution of the European Union of Medical Specialits (UEMS), www.uems.net.The ICACT is designated for a maximum of, or up to24 EUROPEAN CME CREDITS (ECMECs)Each medical specialist should claim only those credits that he/she actually spent in the educational activity. ECMEC()sare recognized by the American Medical Association towards the Physicians Recognition Award (PRA). To convert ECMECsCredit to AMA PRA category I credit, please contact the AMA 10. 8AWARDS17THC L AUD E J A CQ U I L L ATAWARDF O R C L I N I C A LC A N C E R R E S E A R C H16THLodovico BALDUCCIR AY M O N D B OU R G I N EAWARDF O R AC H I E V E M E NT SI N CAN C E R R ES EARCHNagahiro SAIJOS O M P S P O S T E RA WA R D S 11. 9AWARDSPr Lodovico Balducci is Professor of Medicine & Oncology, University of South Florida Collegeof Medicine, and Chief of the Division of Geriatric Oncology, Senior Adult Oncology Program, atthe H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida. Dr. Balducci received hismedical degree from Catholic University, Rome, Italy, and his residency training and fellowship at theUniversity of Mississippi Medical Center, Jackson, Mississippi.Dr. Balducci has edited five textbooks on geriatric oncology and completed editing two books ongeriatric hematology, which will be published in 2007. He currently leads one of the three existinggeriatric oncology program in the country and the world. Dr. Balducci has published over 250 articlesin various medical journals on the subject of geriatric oncology, and five monographs on geriatriconcology. Dr. Balduccis clinical research activities include cancer and aging, management of the frailelderly, assessment of quality of life in the older cancer patient, prognostic assessment of the oldercancer patient, and interactions of comorbidity and function in the older cancer patient. Dr. Balducciis a member of ASCOs Grant Selection Committee, and ASCOs Cancer & Aging Task Force andOncology Workforce Task Force.In 2003, Dr. Balducci was selected to present the first Paul Calabresi Memorial Lecture by the TheInternational Society of Geriatric Oncology (SIOG) in Rome, Italy. In 2003, he also received theACCC award for Outstanding Achievement in Clinical Research, and was the 2003 Physician of theYear at the H. Lee Moffitt Cancer Center. In 2007 he received the Medi Tavossoli Lecture Award forInnovative Research in Hematology in the Elderly and the ASCOs B.J. Kennedy Award and Lecturefor Scientific Excellence.Dr. Balducci is board certified in Medical Oncology/Hematology. He is a member of the AmericanGeriatrics Society, the American Society of Clinical Oncology, American Association for CancerResearch, American Society of Hematology, American Society of Breast Disease, and a fellow ofthe 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. Currentlyhe is the President of the International Association for Study of Lung Cancer, the immediate pastmember 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 theJapanese Lung Cancer Society.Dr. Saijo received his medical training at the Osaka University School of Medicine. After two yearsas project investigator in the Department of Developmental Therapeutics at MD Anderson Hospital,he completed his Doctors Degree at the Osaka University School of Medicine. During his scientificcareer, he has been Head of the Department for Internal Medicine at the National Cancer CenterHospital, Chief of the Pharmacology Division of the National Cancer Center Research Institute, Chiefof the Medical Oncology Division at the National Cancer Center and President of the Japanese ClinicalOncology 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 ResearchFoundation, the 5th Central European Lung Cancer Symposium Meritorious Award, a BMS Freedomto Discovery grant and Sagawa Investigator awards. He has served as editor, associate editor, editorialboard member and reviewer for numerous international and national journals, and has publishedmore than 561 English publications and over 813 Japanese publications. 12. 10EEXXHIHBIITBOITRSORS352BHall HavaneNeuillyAmphithtreHavaneNiveau 3Level 3351352B352APalais des Congres2, Place de la Porte Maillot75017 PARISHall Havane Niveau 3HBCt NeuillyNeuilly sideCt ParisParis sideNiveau 3Level 3 13. 11TABLE OF CONTENTSAGENDATUESDAY FEBRUARY 3RD, 2009 .................................................................................................. 15WEDNEDSAY FEBRUARY 4TH, 2009 .......................................................................................... 20THURSDAY FEBRUARY 5TH, 2009 .............................................................................................. 23FRIDAY FEBRUARY 6TH, 2009 ..................................................................................................... 26CLINICAL SYMPOSIUMCS ................................................................................................................................................... 33EDUCATIONAL LECTURESEL ................................................................................................................................................. 133MEET THE PROFESSORMTP ............................................................................................................................................. 139PRESIDENTIAL SESSIONPRESIDENTIAL SESSION .......................................................................................................... 183TIAL SESSION 14. 12TABLE OF CONTENTSPROFFERED PAPERSBREASTPoster & Publication....................................................................................................... 189Central Nervous System (CNS)Poster ...................................................................................................................................... 241Gastro-EnterologyPoster & Publication ....................................................................................................... 245Genito-UrinaryPoster & Publication ....................................................................................................... 291GYNECOLOGYPoster & Publication ...................................................................................................... 305Head & NeckPoster & Publication ...................................................................................................... 325HematologyPoster & Publication ....................................................................................................... 343LungPoster ....................................................................................................................................... 365Malignant MelanomaPoster ...................................................................................................................................... 385 15. 13TABLE OF CONTENTSMiscellaneousPoster & Publication ....................................................................................................... 393Pharmacology & New DrugsPoster & Publication ....................................................................................................... 407Quality of Life & PsychologyPoster ....................................................................................................................................... 445SarcomaPoster & Publication ....................................................................................................... 449 16. 15AGENDA - Tuesday February 3rd, 2009Room 19:00-12:30 Clinical Symposium on Breast Cancer (1)Chaired by Martine PICCARTClifford HUDISHER2: Beyond TrastuzumabSandra SWAINUpdate of the Adjuvant Therapy of Breast Cancer for HER2 Negative DiseasePier-Franco CONTEAdjuvant Treatment of HER2 + Early Breast Cancer: Achievements & PerspectivesBreakMartine PICCARTThe seed and soil hypothesis revisited 120 years later: should all women with early breast cancerreceive adjuvant bisphosphonates following the results of tria ABCSG12Javier CORTESRe-defining the Role of Anthracyclines in Metastatic Breast Cancer14:00-17:30 Clinical Symposium on Breast Cancer (2)Chaired by Gabriel N. HORTOBAGYIGabriel N. HORTOBAGYIBiology-driven selection of Optimal Systemic Therapy of Primary Breast CancerJohn CROWNAdjuvant Therapy for Premonopausal Breast CancerVassilis GEORGOULIASCirculating Tumor Cells in Early Breast Cancer: Biological and Clinical RelevanceBreakJavier CORTESNabTM Technology in the Treatment of Breast CancerNorman WOLMARKNSABP Trials in the Adjuvant Treatment of Breast Cancer: an updateRoom 209:00-12:30 Clinical Symposium on Head & Neck CancerChaired by J-Mario FREUEArlene FORASTIEREThe Changing Epidemiology of Oropharynx Cancer and Implications for DiseaseEverett E. VOKESTargeted Therapy in Head and Neck CancerBreakJos-Mario FREUEOrgan Preservation in Localy Advanced Larynx & Hypopharinx Squamous Cell CarcinomasRobert S. BENJAMINSarcoma of the Head & Neck14:00-17:30 Clinical Symposium on Lung CancerChaired by Nagahiro SAIJOTony MOKThe Dilemma in first line Therapy for Advanced NSCLCNagahiro SAIJOChemotherapy for Eldery NSCLCBreakFrances SHEPHERDAngiogenesis Inhibitors in Lung CancerKazuhiro NAKAGAWAEGFR-TKIs on Treatment in Advanced NSCLC 17. 16AGENDA - Tuesday February 3rd, 2009Room 309:00-12:30 Clinical Symposium on Gastrointestinal Tumors (1)Chaired by Daniel HALLERDaniel HALLERUpdate on the Management of Advanced Colorectal CancerEric Van CUTSEMThe Role of Biologicals in Colorectal CancerBreakChun-Yi HAOSurgical Management of Colorectal Liver Metastases: Consensus & Controversies in 2009Norman WOLMARKThe retreat from anthracyclines and the NSABP Clinical trials12:45-13:45 Educational Lecture SessionLeonard SALTZLife Beyond VEGF and EGFR: Investigational approaches in Colorectal Cancer14:00-17:30 Clinical Symposium on Gastrointestinal Tumors (2)Chaired by H. Joachim SCHMOLLHans.G BEGERCystic Neoplastic Tumor of the Pancreas Resection is a Pancreatic Cancer Preventive TreatmentDaniel HALLERAdjuvant Chemotherapy for Colorectal CancerBreakLeonard SALTZManagement of Neuroendocrine CancersHans-Joachim. SCHMOLLNew Standards in Advanced Colorectal Cancer17:30-20:30 Expert Statement Conferenceoptimizing front line therapeutic strategies in mcrcChaired by Daniel HALLER & Jean-Luc RAOULDaniel HALLERThe Change in Paradigm: From How to Use 5-FU to Targeted TherapiesRen ADAMThe Change in Paradigm: Patients with Isolated Liver MetastasesJ. TABERNEROPronostic/Predictive Markers in CRCEric VAN CUTSEMThe Contribution of Targeted TherapiesGraeme POSTONThe Contribution of Targeted Therapies in Isolated Liver MetastasesJulien TAIEBHow to Optimally Treat our Patients Today: Patients with Wild Type K-RasJean-Philippe SPANOHow to Optimally Treat our Patients Today: Patients with Mutated K-RasRound Table with all Presenters, chaired by Daniel HALLER 18. 17AGENDA - Tuesday February 3rd, 2009Room 412:30-14:00 Satellite Symposium Sponsored by ABRAXIS BioScienceNabpaclitaxel: New dimensions in taxane spectrum of activityChaired by Gabriel N. HORTOBAGYI & David KHAYATGabriel N. HORTOBAGYINabTM PlatformHernan CORTES-FUNESEarly Development of Abraxane in Breast CancerTBCEmerging Areas of Investigation: OvarianA. HAUSCHILDEmerging Areas of Investigation: MelanomaGeorgio SCAGLIOTTIEmerging Areas of Investigation: LungMargaret A. TEMPEROEmerging Areas of Investigation: PancreaticGabriel N. HORTOBAGYIDiscussion & Summary14:00-17:20 expert statement conference on urological tumorsNew hope in early stage renal cell carcinomaChaired by Mikhail I. DAVYDOV & David KHAYATC. ABBOUAny Progress in early stage RCC with IL-2 and IFN?Lev V. DEMIDOVOngoing clinical trials involving targeted agentsHyam I. LEVITSKYAnticancer vaccines: a specific approach in early stage RCCChristopher WOODResults of a phase III clinical trial with personalized HSP based anticancer vaccinePeter MULDERSImproving 3 years RFS with personalized HSP based anticancer vaccine in intermediate riskRCCPeter HARPERHow to move with personalized drugs from clinical trials to daily practice? 19. 18AGENDA - Tuesday February 3rd, 2009Room 512:30-14:00 Expert Statement Conference supported by JANSSEN-CILAGWhats new on Erythroiesis stimulating agent (e.s.a)Chaired by David KHAYATMario DICATOAnemia in Oncology - any news on treatments (ASE, Transfusions, iron)Jean-Franois MOREREBenefit/Risk of ASEIsabelle RAY-COQUARDOverview and guidelines for ASE Usage in oncologyDaniel HALLERBased on literature, does anaemia should be treated in all cancer patients? (Chemotherapy vs nochemotherapy, Impact of age, Impact of Hb level at therapy initiation)TBCBased on literature, what is the benefit from transfusions in cancer patients?Peter HARPERBased on literature, how the ASE tolerance could be optimized? (Thrombosis, survival)TBCBenefit of iron supplementation during the ASE treatment ?David KHAYATConclusionRoom 614:30-16:30 Satellite Symposium on SarcomaSupported by PHARMA MARChaired by Robert S. BENJAMINRobert S. BENJAMINTrabectidin Perspectives from development of an active antisarcoma drugJean-Yves BLAYAdjuvant Treatments in Soft Tissue Sarcoma: Achievements and PerspectivesJean-Yves BLAYTargeted Therapies in Sarcoma 20. 19AGENDA - Tuesday February 3rd, 2009Room 709:30-12:30 Clinical Symposium on gynecological cancerChaired by Sergio PECORELLIJoseph MONSONEGOImpact of Gardasil on incidence of CIN, EGL, abnormal Pap tests and cervical procedures duringthe Future I/II studiesXavier CASTELLSAGUEHPV Vaccines for the Prevention of Cervical Cancer and BeyondSergio PECORELLIAdjuvant Treatment for Early Stage Endometrial CancerMaurie MARKMANMaintenance Therapy in Ovarian Cancer12:30-13:30 Meet The Professor SessionChaired by Roger MOUAWADNatale CASCINELLICutaneous Melanoma: Is completion Node Dissection needed for Sentinel Node Positive patients?14:00-16:00 Meet The Professor SessionChaired by Roger MOUAWADKiyohiko HATAKECDC & ADCC Assay for Monoclonal Antibody Therapy using RituximabGeorgio SCAGLIOTTIMolecular Predictive & Prognostic Factors in Lung Cancer 21. 20AGENDA - Wednesday February 4th, 2009Room 109:00-12:30 Clinical Symposium on Lung Cancer (2)Chaired by Mark G.KrisDaniel A. VOROBIOFUpdate on the Management of Malignant MesotheliomaBenjamin BESSECisplatin resistance in NSCLCBreakMark G. KRISPersonalized Therapy for Lung Cancer: For Now or the FutureFrances SHEPHERDPredictive & Prognostic Factors in Early Stage Resected Non-SCLC14:00-16:15 Clinical Symposium on Lung Cancer (3)Chaired by Rafael ROSELLRafael ROSELLMolecular Biomarkers for Predicting Chemotherapy Response in Lung CancerNagahiro SAIJORecent Advances in the Treatment SCLCGeorgio SCAGLIOTTIImproving Survival with front line treatment in Advanced NSCLCRoom 209:00-12:30 Clinical Symposium on Issues in New Drugs DevelopmentChaired by Michel MARTYFilipo DE BRAUDUpcoming issues in Early Clinical Development of New DrugsMichel MARTYEuropeen Regulations in the Evaluation & Approval of New Drugs in CancerYasuhiro FUJIWARACurrent Japanese Environment of Clinical Drug Development/Research in JapanBreakJean-Pierre BIZZARIWhat are the Optimal Strategies in the Development of a New Drug in Cancer?Hironobu MINAMIPharmacogenomics of irinotecan in Asian Patients12:30-14:00 Poster Discussion ICACT & poster Awards 22. 21AGENDA - Wednesday February 4th, 2009Room 409:00-11:15 Clinical Symposium on Gastric CancerChaired by Emilio BAJETTARoberto BUZZONIState of the Art in Adjuvant Treatment of Gastric CancerMarc YCHOURole of Neoadjuvant Chemotherapy in Gastric CancerRui-Hua XUWhat have we known in the Treatment of Advanced Gastric Cancer Beyond 5-FU and Cisplatin?14:00-16:15 Clinical Symposium on MelanomaChaired by Alexander EGGERMONTAlexander EGGERMONTDrug Developments in MelanomaNatale CASCINELLICutaneus Melanoma: is the time for Combined Treatments?Ferdy LEJEUNENew Therapeutical Tragets in Melanoma: any Success?Room 612:00-14:00 Satellite symposium institut national du cancerIs the Genomic revolution changing our approaches to cancer and treatment?Fabien CALVOIntroductionGilles THOMASGenetic predisposition to breast and prostate cancerJessica ZUCMANOncogenomic in hepatocellular carcinoma: from tools to clinical applicationsAnne CAMBON-THOMSENIs the ethics landscape also changing?Michael STRATTONThe current advances in the field of breast cancer genomicsDominique MARANINCHIConclusion 23. 22AGENDA - Wednesday February 4th, 2009Room 709:00-13:00 Meet the Professor SessionChaired by Michel UNTEREINERJames O. ARMITAGEImproving Survival in Follicular LymphomaMaurie MARKMANIntraperitoneal Chemotherapy: Rational & ResultsEverett E. VOKESTargeted Therapies in Head and Neck CancerRafael ROSELLQPCR-Based gene signatures for predicting survival in stageI NSCLC13:00-14:00 Meet the Professor SessionChaired by Michel UNTEREINERMark G. KRISOptimal Management at Locally-Advanced Non-Small Cell Lung Cancer: How do you Choose?14:00-17:00 Meet the Professor SessionChaired by Roger MOUAWADJavier CORTESTreatment of HER2-Positive Breast Cancer. Should all Patients receive Trastuzumab?Kiyohiko HATAKECTC (Circulating Tumor Cell) Analys in CRC, BC and GastricHerbert M. PINEDOAntiangiogenic Agents in CancerRoom 812:00-14:00 Meet the Professor SessionChaired by Maurice SchneiderHenk M.W. VERHEULEarly Detection of Colorectal Cancer Patients?Alexander EGGERMONTManagement of irresectable extremity tumors 24. 23AGENDA - Thursday February 5th, 2009Room 109:00-11:15 Clinical Symposium on Gastrointestinal Tumors (3)Chaired by Leonard SALTZDaniel HOCKThe Role of Imaging in Colorectal Cancer Prevention & ScreeningAimery de GRAMONTMetastatic Colorectal Cancer: Current Status & Future DirectionLeonard SALTZBiomakers in Colorectal Cancer: ready for Prime Time?14:30-15:00 Claude Jacquillat Award CeremonyRaymond Bourgine Award Ceremony15:00-17 :30 Presidential SessionChaired by Gabriel N. HORTOBAGYI & David KHAYATMaurie MARKMANControversies in the management of Ovarian CancerMargaret A. TEMPEROManagement of the Advanced Pancreatic Cancer: State of the ArtEdith PEREZManagement of the Node Negative Breast Cancer: State of the ArtJos BASELGATargeting the PI3K Pathway in CancerRoom 213:00-14:30 Poster Discussion & Poster AwardsRoom 309:00-13:00 Clinical Symposium on Cancer Management in the Developing CountriesChaired by Jaime DE LA GARZAJaime DE LA GARZAState of the Art in the Use of Hormonal Neo-Adjuvant Treatment for Breast CancerEduardo CAZAPClinical Trials in developing countries: Promoting Independent Cancer ResearchZefei JIANGAccess to Innovative Treatment in Developing Countries: The Asiatic ExperienceBreakZeba AZIZChallenges in the diagnosis and Management of Breast Cancer in Developing CountriesSumitra THONGPRASERTRoles of EGFR TKI in Non-Small Cell Lung Cancer: Focus in Asian PopulationHamdy AZIMOptimization of Trastuzumab treatment in developing countries: The need for new studies 25. 24AGENDA - Thursday February 5th, 2009Room 409:00-13:00 Expert Conference on Pancreatic CancerChaired by Margaret A.TEMPERO & David KHAYATMargaret A. TEMPEROAdvanced Pancreatic Cancer: where are we more than ten years after Burris Trial?Jordan D. BERLINAccelerating the pace of research in Pancreatic Cancer Treatment: a report from the US NCI State ofthe Science MeetingAlberto SOBREROAre New Targets more likely to be successful?H.-J. SCHMOLLProspective/Predictive Biomakers: can we expect them helping individualizing Pancreatic CancerManagementFacing the today reality: how to optimally treat our patients with Advanced Pancreatic cancer on aday to day basis?:Claude LE PEN (TBC)Are economical considerations already impeeting day to day practice?Daniel HALLERThe US experienceEric VAN CUTSEMThe European experiencePeter HARPERThe UK SituationMichel DUCREUXThe French SituationRound Table DiscussionCan we define a common position based on Medical Evidence?David KHAYATConclusion 26. 25AGENDA - Thursday February 5th, 2009Room 509:00-11:00 Satellite Symposium GE HealthcareChaired by Didier BUTHIAU & Dr Jean-Marc FOULTONCOLOGISTRole of imaging techniques in oncology daily workflow.Didier BUTHIAU5 years experience in anti-angiogenic treatment assessment using CT Perfusion.RADIOLOGISTInterventional radiology in oncology : Why, how and for which patients ? Which perspectives?MICHEL GRIMAUDFuture developments in Interventional Radiology for oncology. Multimodality advantages.11:15-12:30 Satellite Symposium GUERBETWhy and How Imaging Helps the Oncologists ?Chaired by Didier BUTHIAUDidier BUTHIAUIntroduction & ObjectivesA. JEYARAJAHThe Oncologist point of viewC.A. CUENODScanner in the anti-angiogenic answer in kidney tumorsO. PELLETPeritoneal CarcinomatosisDidier BUTHIAUQuestions & ConclusionRoom 709:00-10:00 Educational Lecture SessionChaired by Nicolas MAGNEHerbert M. PINEDOAntiangiogenic in GU Tumors10:00-13:00 Meet the Professor SessionChaired by Nicolas MAGNEEliezer ROBINSONCancer Survivors-A Challenge to Health ServicesHernan CORTES FUNESRole of Antiangiogenic TherapyKarl Heinrich LINKHow to treat Peritoneal Metastases or Primary Tumors 27. 26AGENDA - Friday February 6th, 2009Room 109:00-09:20 Opening Ceremony & Surgical Oncology AwardChaired by Jacques POILLEUX09:20-10:45 Plenary SessionChaired by Bernard LAUNOIS & David KHAYATUrs STUDERIleal bladder substitute: the Keys of SuccessRaymond REDINGBiography of a Surgeon: Judah Folkman and the history of a discovery: AngiogenesisDavid KHAYATWhats new in 2009?Dominique STOPPA-LYONNETGenetics and Cancer16:15-17:45 Plenary SessionChaired by Anne PODEUR & Jacques POILLEUXDominique MARANINCHIEvolution of Cancer Surgery in French Health Institutions in 2009-2011Claude DESCHAMPSAeronautic Quality (in search of 0 Fault) in Surgical OncologyYvon BERLAND (TBC)Surgical Demography: a Dramatic and Imminent Menace for Cancer Surgery?Xavier DEAUNew Trends in the organization of post-graduate EducationJacques POILLEUXConclusions 28. 27AGENDA - Friday February 6th, 2009Room 209:00-11:00 Meet the Professor SessionChaired by Roger MOUAWADRobert S. BENJAMINUpdate in Management of Soft Tissues SarcomaGeorges CHAHINEWhat is new with Taxanes in Breast Cancer?11:15-12:45 Esophagus CancerChaired by Jacques BAULIEUX & Jean-Marie COLLARDChristian ELLEndoscopic mucosal resectionJean-Pierre TRIBOULETRecommendations of the French National Society of Gastro-EnterologyGlyn G. JAMIESONMethodological problems with regard to lymph nodes in the treatment of esophageal cancerJohn WONGRandomized and prospective trials in surgery of Esophageal cancerTom R. DE MEESTERNeoadjuvant treatment in Esophageal cancer12:45-14:15 Satellite Symposium STORZ: Ovarian CancerChaired by Maurice-Antoine BRUHAT & Serge UZANHerv CURWhats new in Chemotherapy?Michel CANISPlace of Laparoscopy in Diagnostic and TreatmentAntoine MAUBONImaging and Ovarian CancerDenis QUERLEUSurgical Treatment in Advanced Cancers14:15-15:45 Breast CancerChaired by Rmy SALMON & Gilles HOUVENAEGHELHiram S. CODYMemorial Sloan Ketterings experience of Sentinel node biopsy (SNB) for Breast CancerGilles HOUVENAEGHELExperience of Cancer Hospital Centers in micro metastatic sentinel node biopsy (SNB)Richard VILLETSurgical Indications of Immediate breast reconstructionAlain FOURQUETRadiotherapy after RMI and Oncoplasty 29. 28AGENDA - Friday February 6th, 2009Room 309:00-11:00 Meet the Professor SessionJames O. ARMITAGECase studies in LymphomaLaure CATENAManagement of Neuro Endocrine Tumors11:15-12:45 Kidney Cancer & Bladder TumorsChaired by Franois RICHARD & Christian COULANGEJean-Jacques RAMBEAUDNatural history of Kidney cancer: Is there a place for active surveillance?Christian COULANGEPlace of non-surgical treatment in metastatic Kidney cancerStphane CULINEAnti-angiogenic treatment in metastatic Kidney cancer in 2009?Jean-Louis DAVINHexvix & Bladder tumors : shedding a new lightMorgan ROUPRTPlace of conservative treatment in upper urinary tract tumors?14:15-15:45 Prostate Cancer, Testicule & Adrenal CancerChaired by Franois RICHARD & Pascal RISCHMANNAlbert GELETWhat is the place for local treatment by ultrasound in prostate cancer in 2009?Pierre MOZERProstate Cancer: towards a local treatmentYann NEUZILLETValue of onco-geriatric evaluation in therapeutic management of Prostate cancerJean-Dominique DOUBLETGuidelines for malignant Adrenal TumorsNicolas MOTTETManagement of a non-seminomatous germinal tumor of stageI: follow-up or treatment? 30. 29AGENDA - Friday February 6th, 2009Room 409:00-11:00 Meet the Professor SessionJean-Philippe SPANOHIV & CancerGeorgio SCAGLIOTTIPharmacogenomic in Thoracic Oncology11:15-12:45 Satellite Symposium Generale de Sante: Breast cancer & Enhancingmultidisciplinary towards optimal chemical practiceChaired by Pierre BONNIER & Jacques MEURETTEXavier MARTINPlace of the Surgical OncologistElisabeth HODIN / Jacques MEURETTEPlace of the Plastic SurgeonAxel DURIEUXPlace of the Medical OncologistPierre BONNIERMultidisciplinarity in day-to-day-practice: Experience of Beauregard Private Hospital CentersDepartment of Gynecologic and Breast Surgery and Oncology14:15-15:45 Hepato-biliary and Pancreatic TumorsChaired by Henri BISMUTH & Laurent HANNOUNLaurence CHICHEAdenomatosis: a rare and non-benign diagnosis of multinodular liverKarim BOUDJEMAPortal embolisation and biliary drainage in Cholangiocarcinoma of the confluence: RennesexperiencePierre-Alain CLAVIENStrategy for the safest Liver SurgeryEliano BONACCORSI-RIANILiver transplantation for malignant vascular hepatic tumorsChristian PARTENSKYPapillary and mucinous intracanalar tumors of the Pancreas15:45-16:15 Poster discussion &Awards 31. 30AGENDA - Friday February 6th, 2009Room 511:15-12:45 Colorectal CancerChaired by Eric RULLIER & Michel MALAFOSSEPhilippe ROUANNETA la carte Treatment of locally advanced Rectal cancersAngelita HABR-GAMAWait and see policy for complete clinical response after rectal cancer radio-chemotherapyPhil QUIRKEOncological problems in colorectal surgery: optimizing surgery?Dominique ELIASPeritoneal carcinomatosis in colorectal cancer: can we cure the patient?12:45-14:00 Meet the Professor SessionJol LEROYMesorectum Resection14:15-15:45 Thoracic CancersChaired by Iradj GANDJBAKHCH & Pierre FUENTESPascal THOMASExtended Surgery of Malignant Tumors of MediastinumRoger GIUDICELLIImpact of guidelines on the practice of bronchus cancer surgeryMarc RIQUETValue of Surgery in the treatment of Infra-thoracic lymphatic metastases of extra thoracic neoplasmsJrme MOUROUXWhy and how should we evaluate meetings of the Cancer Multidisciplinary Committee in ThoracicOncology?Room 611:15-12:45 Malignant Tumors in ChildrenChaired by Christine GRAPIN & Raymond REDINGRaymond REDINGTherapeutic modalities of hepatoblastoma: Evolution of ConceptsMichle LARROQUETSurgical treatment of bronchus tumors in childrenChristine GRAPINSurgical indications in neuroblastomaPierre HELARDOTSacro-coccygeal teratoma: Pronostic factors12:45-14:00 Meet the professor SessionClaude DESCHAMPSOesophageal Cancer 32. 31 33. 33Clinical SymposiumCLINICAL SYMPOSIUMClinical SymposiumBREAST CANCER (1)Tuesday 3rd February 09:00-12:30HER2: Beyond TrastuzumabClifford HUDIS, MDChief, Breast Cancer Medicine ServiceAttending PhysicianMSKCCProfessor of MedicineWeill Medical College of Cornell UniversityNew York, NY, USAThe discovery of HER2 as a driver of growth ina subset of human breast cancer coupled with thedevelopment of a targeted therapy trastuzumab hasallowed us to identify this type of disease as a distinctsubset. The treatment of HER2 over-expressing breastcancer is thus diverging from the treatment of allother subtypes. Regardless of stage at presentation,invasive breast cancers that overexpress HER2 at thecell surface (3+ by immunohistochemistry) or haveamplification by FISH (>2.0 gene copy number) areapproached differently. 1 The key issue for all suchpatients is now the role of trastuzumab because inthe first-line therapy metastatic setting such patientsgiven trastuzumab with chemotherapy (as opposedto chemotherapy alone followed by trastuzumab atdisease progression) not only benefited with improvedtime to progression and an increased response ratebut also gained overall survival. 2 This initial resultwas then confirmed by a randomized phase 2 studyutilizing docetaxel as the chemotherapeutic agent. 3These data directly influenced the development offour large (and one smaller) randomized adjuvanttrials which in the aggregate demonstrated animportant reduction in risks of recurrence and deathfor eligible patients with early stage disease. 4,5,6These adjuvant results will have an importantimplication going forward. While we can anticipatean overall reduction in the incidence of HER2 positivemetastatic disease as a result of potential cures in theadjuvant setting, those who do experience relapsemay be to some degree trastuzumab-refractory. Thesituation for such patients will be similar to those wealready treat who have disease progression despitetreatment with trastuzumab for established metastaticdisease. Indeed, almost all who receive it as palliativetreatment for metastatic disease experience diseaseprogression. Hence it is important to accomplishseveral tasks including the discovery of mechanismsof resistance to trastuzumab, the development ofnovel new agents targeting HER2, and clarificationof the role of continued trastuzumab beyondprogression.The recent discovery that an oral tyrosine kinaseinhibitor targeting HER2 (along with HER1),lapatinib, is active in trastuzumab-refractorymetastatic breast cancer suggests that HER2 itselfremains a viable target even when trastuzumab hasceased to be effective. 7 A variety of additional TKIsare in clinical development and may extend thisapproach either because they are simply betterinhibitors of HER2 tyrosine kinase activity or becausethey add important off-target (ie, pan-HER or pan-tyrosinekinase) inhibition and activities. The activityof these anti-HER2 agents, despite refractoriness toprior trastuzumab, paradoxically lends some supportto the notion that continued trastuzumab, evenafter progression of disease, might have some valuebecause for these patients HER2 still appears to be animportant driver of cell growth and survival. Untilrecently, no randomized trial has been reported tosupport the continued use of trastuzumab beyondprogression on this antibody although this approachwas frequently adopted in some parts of the world.However, two prospective randomized trials testingthe role of continued trastuzumab beyond disease 34. 34Clinical Symposiumprogression have been attempted. A US trial initiallylaunched at MDAnderson and later extendedthrough the Southwest Oncology Group (SWOG)using vinorelbine failed to accrue while a Germantrial using capecitabine was recently reporteddespite its failure to accrue its planned number ofpatients. The latter trial is, however, informativesince it suggests that continued use of trastuzumab(in this case with capecitabine) after progression ontrastuzumab-containing chemotherapy is associatedwith significant clinical benefit.8 [1] Finally, anotherrecently reported study suggests that lapatinib plustrastuzumab is superior to lapatinib alone in heavilypre-treated patients. Together, these randomizedtrials strongly suggest that HER2 remains apotentially viable target and trastuzumab continuesto contribute benefit even after progression on othertrastuzumab-containing regimens.The continued importance of HER2 as a driverof cell growth and survival despite progression ontrastuzumab is underscored by the recent reportof activity for a several novel HER2 targetingagents. Pertuzumab, a monoclonal antibody witha unique mechanism of action is clearly active. 9Unlike trastuzumab, pertuzumab appears to directlyinihibit receptor dimerization, leading to its earlierdevelopment as a possible pan-HER inhibitor(independent of HER2 expression level). Thisantibody is associated with clinical activity when givenwith trastuzumab in HER2 positive, trastuzumab-refractorydisease. 10 This observed activity begs thequestion of the role of continued trastuzumab but apractical issue for patients experiencing progressionon this antibody is that its long half-life makes itlikely that any single agent treatment administeredshortly after progression will, in fact, really consistof a new drug added to remaining trastuzumab.(This was a concern raised after the first report ofactivity for lapatinib and capecitabine followingprogression on trastuzumab). As a consequence,continuing trastuzumab while testing new agentscan make practical sense. Furthermore, in somecases preclinical models specifically predict thatthe alternative mechanisms of action for differentanti-HER2 agents may be complementary andtherefore appropriate for combined use. At present,the CLEOPATRA trial is testing the value of addingpertuzumab to docetaxel and trastuzumab as first-linetherapy for HER2 positive metastatic breastcancer. This trial has the potential to change thestandard of care for these patients.A second new antibody approach consists oftrastuzumab bound directly to a highly potentantimicrotubule agent (DM1, derived frommaytansine). This drug, (T-DM1) has clear activityas a single agent in trastuzumab-refractory HER2positive metastatic breast cancer. 11, 12At the same time, there is clear evidence thattrastuzumab does not convert inert agents (ie,celecoxib) into active ones. 13 Hence any activity seenwhen a novel agent (or conventional chemotherapydrug for that matter) is added to trastuzumab intrastuzumab-refractory disease, can be interpretedas evidence solely for the effect of the newlyintroduced agent. We have taken this approach inour development of heat shock protein 90 chaperonemolecule inhibitors as treatment for HER2 positivebreast cancer.Heat shock protein 90 is a chaperone responsible forthe maintenance of structure and therefore functionof a variety of complex proteins including, amongothers, HER2 and AKT. 14 Loss of HSP90 functionallows HER2 degradation via the ubiquitinationpathway thereby reducing the expression of HER2.Geldanamycin, an ansamycin, is an HSP90 inhibitorthat is too toxic for clinical use. 17-allyl aminogeldanamycin (17-AAG, tanespimycin) is a modifiedgeldanamycin derivative with minimal toxicity thatmaintains the HSP90 inhibitory effects of this classof ansamycins. Pre-clinical experiments confirmedthe down-regulation of HER2 expression followingexposure to 17-AAG as well as the additive effectsof trastuzumab. Based on these trials our group hasbeen testing the combination of HSP90 inhibitionand trastuzumab in clinical trials.In our first phase 1 study, Modi and colleaguesdemonstrated safety for the combination oftrastuzumab and 17-AAG as well as significantanti-tumor activity among a cohort of patients withextensive prior trastuzumab-containing therapies. 15A subsequent phase 2 trial, now accruing, confirmsthis level of activity. A phase 1 study with a watersoluble derivative, 17-DMAG combined withtrastuzumab shows similar activity but a possiblydifferent toxicity profile. 16 Given this activity, aswell as evidence of activity in other disease settings(ie, multiple myleloma) additional agents targetingHSP90 are in development and a range of clinicaltrials are now needed (and underway) to identifytheir optimal integration into the management ofHER2 overexpressing breast cancer. With rationalcombinations of antibodies, tyrosine kinaseinhibitors, and possibly HSP90 inhibition, it ispossible that the natural history of HER2 positivebreast cancer will continue to improve remarkably inthe near future. 35. 35Clinical SymposiumReferences:1. Hudis C. Drug Therapy: Trastuzumab. . NewEngland Journal of Medicine 2007;357:39-51.2. Slamon DJ, Leyland-Jones B, Shak S, et al. Useof Chemotherapy plus a Monoclonal Antibodyagainst HER2 for Metastatic Breast Cancer ThatOverexpresses HER2. The New England journal ofmedicine 2001;344(11):783-92.3. Marty M, Cognetti F, Maraninchi D, et al.Randomized Phase II Trial of the Efficacy and Safety ofTrastuzumab Combined With Docetaxel in PatientsWith Human Epidermal Growth Factor Receptor2-Positive Metastatic Breast Cancer AdministeredAs First-Line Treatment: The M77001 Study Group10.1200/JCO.2005.04.173. J Clin Oncol2005;23(19):4265-74.4. Romond E, Perez E, Bryant J, et al. Trastuzumabplus adjuvant chemotherapy for operable HER2-positive breast cancer. N Eng J Med 2005;353(16):1673-84.5. Piccart-Gebhart M, Procter M, Leyland-JonesB, et al. Trastuzumab after adjuvant chemotherapyin HER2-positive breast cancer. N Eng J Med2005;353(16):659-72.6. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, etal. Adjuvant docetaxel or vinorelbine with or withouttrastuzumab for breast cancer. The New Englandjournal of medicine 2006;354(8):809-20.7. Geyer CE, Forster J, Lindquist D, et al. Lapatinibplus capecitabine for HER2-positive advancedbreast cancer. The New England journal of medicine2006;355(26):2733-43.8. Von Minckwitz, G., C. Zielinski, E. Maarteense, ande. al, Capecitabine vs. capecitabine + trastuzumab inpatients with HER2-positive metastatic breast cancerprogressing during trastuzumab treatment: The TBPphase III study (GBG 26/BIG 3-05). J Clin Oncol,2008. 26:47s. Abstract 1025.9. Agus DB, Gordon MS, Taylor C, et al. PhaseI clinical study of pertuzumab, a novel HERdimerization inhibitor, in patients with advancedcancer. 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) andpertuzumab (P) in patients (pts) with HER2-positivemetastatic breast cancer (MBC) who had progressedduring 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 advancedHER2+ 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), afirst-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, etal. Phase II study of celecoxib and trastuzumab inmetastatic breast cancer patients who have progressedafter prior trastuzumab-based treatments. ClinCancer Res 2004;10(12 Pt 1):4062-7.14. Solit DB, Zheng FF, Drobnjak M, et al.17-Allylamino-17-demethoxygeldanamycin Inducesthe Degradation of Androgen Receptor and HER-2/neu and Inhibits the Growth of Prostate CancerXenografts. 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: APhase I Dose-Escalation Study. J Clin Oncol, 2007.25(34): p. 5410-5417.16. Miller K, Rosen L, Modi S, et al. Phase I trialof alvespimycin (KOS-1022; 17-DMAG) andtrastuzumab (T). Journal of Clinical Oncology ASCOAnnual Meeting Proceedings Part I 2007;25(18S(June 20 Supplement) Abs 1115).Adjuvant Treatment of Her2 PositiveEarly Breast Cancer Achievements andPerspectivesSimona Giovannelli, PierFranco CONTEDepartment of Oncology and Hematology, Hospital,University of Modena- ItalyAmong breast cancers diagnosed at any stage,20%30% are found to have amplification of thehuman epidermal growth factor receptor (HER)-2/neu gene (1). Overexpression of this protein, isassociated with aggressive biological characteristics(high proliferative activity, metastatic potential andneoangiogenesis) and poor survival (2).Trastuzumab, the humanized monoclonal antibodyagainst HER2 receptor, is an essential component ofthe treatment of patients with HER2-positive breastcancer and its role in curative therapy of early breastcancer is evolving rapidly (3).The clinical benefits observed with trastuzumab in themetastatic setting provided the rationale for assessingtrastuzumab in the treatment of early breast cancer(4, 5). In the adjuvant setting, the results of 6 phase IIIrandomized trials have been published or presentedso far. In these trials, different chemotherapy 36. 36Clinical Symposiumregimens and different modalities of trastuzumabadministration (in combination or sequentiallyafter chemotherapy) have been explored. Overall,these trials have included > 10,000 women withHER2-positive breast cancer; five of these trials havedemonstrated the superiority of adding trastuzumabto chemotherapy compared with chemotherapyalone (3, 6, 7, 8, 9, 10). The HERA trial recruited5102 women and randomized them to observationalone vs 1 year or 2 years of trastuzumab therapy.One-year therapy with trastuzumab resulted in anabsolute DFS benefit of 6.3%, an absolute OS benefitof 2.7%, and an absolute TDR event-free survivalbenefit of 6.3%, all at 3 years from randomization(3, 6). The BCIRG006 recruited 3222 patients andrandomly allocated them to three arms; AC therapyfollowed by docetaxel was the control arm, versus1-year trastuzumab therapy administered in twointervention arms: following AC and concurrentlywith docetaxel, or concurrently with six cycles ofdocetaxel and carboplatin. Absolute DFS benefitsfrom years 2 to 4 from randomization were 6% and5% for AC D + H versus control and D + Pla + Hversus control, respectively. While AC D + Hshowed the greatest improvement in both DFSand OS over control, when trastuzumab therapyarms were directly compared (AC D + H versusD + Pla + H), there was no significant difference ineither DFS (p = 0.42) or OS (p = 0.58) (3, 7) . The NorthNCCTG N9831 phase III trial randomised patientsto three arms, all of which included doxorubicin pluscyclophosphamide followed by weekly paclitaxel fortwelve weeks, given either alone as control, or withweekly trastuzumab for 1 year initiated sequentiallyafter chemotherapy, or concurrently with 12 weeksof weekly paclitaxel (6,10). With similarities, theNSABP trial B-31 randomized patients to receivedoxorubicin and cyclophosphamide followed bypaclitaxel every 21 days for four cycles alone or with1 year of weekly trastuzumab initiated concurrentlywith paclitaxel. The combined analysis of the two trials(considering the sequential arm of the first one) founda significant advantage to the concurrent additionof trastuzumab to chemotherapy in comparison tocontrol for DFS, with OS and time to recurrence(TTR) (3, 8). An unplanned interim analysis fromthe N9831 trial comparing sequential trastuzumabtherapy to concurrent showed a significant advantagein terms of DFS, but not OS, in favour of concurrenttherapy (3). Furthermore, no significant advantagewas found in terms of DFS or OS for the comparisonof sequential trastuzumab therapy to control arm(3). The FinHer study compared primarily adjuvantdocetaxel (every 21 days for 4 cycles) to vinorelbine(weekly for 8 cycles), with either being followed bytherapy with FEC (every twenty-one days for threecycles). Trastuzumab was administered concurrentlywith either docetaxel or vinorelbine, on a weeklyschedule for a total of only 9 weeks and was thereforecompleted prior to therapy with FEC; despite theshort duration of admistration of trastuzumab thisstudy showed similar results (9). On the contrary,the Programmes dActions Concertes Sein (PACS)04 trial has shown no benefit for adding trastuzumabat the completion of chemotherapy versus control(10).Both biologic and clinical data strongly supportthe synergistic cytotoxic effects of trastuzumab andchemotherapy on HER2 positive breast cancer cells,while the sequential administration of trastuzumabafter chemotherapy seems to induce mainly acytostatic effect that might require longer treatmentto achieve maximum clinical benefit (11).The HERA trial is the only one specificallydesigned to test prospectively different durations oftrastuzumab administration (6). By now, on the basisof the available results, one year of treatment withtrastuzumab is considered the gold standard.Symptomatic congestive heart failure (CHF)occurred in 1.5%-2.5% of the patients treated withsequential trastuzumab (HERA trial, PACS 04, andN9831 arm B) and in a percentage ranging from 0.4(BCIRG 006 arm C, without anthracyclines) to 3.6 ofthe patients in the trials in which trastuzumab wasstarted concomitantly with chemotherapy (BCIRG006 arm B, N9831 arm C, NSABP B-31) (6-10, 11,12). The FinHer (Finland Herceptin) trial is the onlyadjuvant trastuzumab trial without episodes of CHF;however, the limited number of patients included inthis trial does not allow concluding that a shortertrastuzumab treatment is less cardiotoxic (9).Many questions related to trastuzumab use in theadjuvant setting still remain unanswered, regardingto the optimum timing and duration of treatment,its role in small node-negative tumors, the optimumchemotherapy regimens (3).A phase III multicentric, randomized trial (ShortHERtrial), has been designed in order to evaluate if 3months of trastuzumab (9 weekly administrations)is not inferior to 12 months of trastuzumab (183-weekly administrations), when administered incombination with chemotherapy, in terms of DFS;patients are randomised to receive AC or EC for4 courses every 21 days followed by paclitaxel 175mg/m2 or docetaxel 100 mg/m2 administeredconcomitantly with trastuzumab every 21 days,followed by trastuzumab alone for 14 additionalcourses (long Arm); or docetaxel 100 mg/m2 I.V. onday 1 every 21 days for 3 courses plus trastuzumabweekly 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). 37. 37Clinical SymposiumOther european trials are addressing the question ofshorter duration of Herceptin (PHARE trial, SOLDtrial, PERSEPHONE trial).Adjuvant Lapatinib and/or Trastuzumab TreatmentOptimisation (ALTTO) is a four-arm randomizedtrial designed to compare trastuzumab and lapatinibin women with early-stage HER2-positive breastcancer. Specifically, ALTTO will examine which anti-HER2 agent is more effective and which is their bestschedule of administration, namely, what benefit willbe derived by taking the drugs separately, in tandemorder or in combination. Overall, 8000 patients willbe enrolled worldwide (14).Primary systemic therapy is increasingly used inoperable disease and is replacing more conventionalpostoperative adjuvant treatments in some subsets ofpatients, because it can allow for breast conservativesurgery when up-front mastectomy would berecommended, without jeopardizing survival, andalso permits an in vivo evaluation of treatmentefficacy (15).Burstein et al. examined the safety and efficacy ofpreoperative intravenous weekly trastuzumab andpaclitaxel (175 mg/m2 q 21 days4) followed bysurgery and adjuvant AC in stage II and III breastcancer patients. Pathologic CR was seen in 18% of allpatients, whereas the clinical response rate was 75%(16).In a prospective randomized phase III trial of Budzaret al. the administration of 24 weeks of primarysystemic chemotherapy (PST) with paclitaxel andFEC75 (fluorouracil, epirubicin, cyclophosphamide)concurrently with trastuzumab in patients withHER2-positive primary breast cancer resulted inmore than doubled pCR rate (66.7% vs 25%) ascompared 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 cancerreceived trastuzumab weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin AUC 6 for sixcycles before surgery. A complete or partial objectiveclinical response occurred in 95% of patients (85%and 10%, respectively). Tumor and nodal pCR wereseen in 27 (39%) of 70 patients (18).In this setting, we are conducting a phase IIrandomized trial in patients with tumors largerthan 2 cm. Patients with HER2 positive tumors arerandomized to receive: Arm A: chemotherapy plustrastuzumab; Arm B: chemotherapy plus lapatinib;Arm C: chemotherapy plus trastuzumab andlapatinib (CHER-LOB trial). Patients enrolled willreceive chemotherapy with paclitaxel wkly for 12wks, followed by 4 courses of FEC 75 every 3 wks.Trastuzumab is administered at 2 mg/kg wkly inarms A and C; Lapatinib is administered at 1500 mgpo daily in arm B, and at 1000 mg po daily in armC. Primary endpoint of this study is the percentageof pCR (complete disappearance of invasivetumoral cells in both breast and axillary nodes.Secondary aims are: breast objective response, breastconservative surgery, safety, molecular responses,gene expression related to pCR. In this trial, as wellas in other similar ongoing studies, tumor samplesare collected for very important correlative studies(19). Other studies (Neo ALTTO and NSABP-41that will explore the concomitant chemotherapywith lapatinib or trastuzumab or both, and thesequential use of chemotherapy followed by L or Hor both respectively) are underway exploring the roleof neoadjuvant trastuzumab and also the possibleincorporation of lapatinib and will add elements toenhance our understanding of which patients derivethe most benefit from trastuzumab (3).References:1. Bergman CI, Hung MC, et al. The neu oncogeneencodes an epidermal growth factor receptor-relatedprotein. Nature 1986; 319: 226-230.2. Slamon DJ, Clark GM, Wong SG et al., Humanbreast cancer: correlation of relapse and survival withamplification of the HER-2/neu oncogene, Science235 (1987), pp. 177-182. 3. Madarnas Y, MessersmithH et al. Adjuvant/neoadjuvant trastuzumab therapyin women with HER-2/neu-overexpressing breastcancer: a systematic review. Cancer Treatmentreviews, 2008 Oct;34(6):539-57.4. Slamon DJ, Leyland-Jones B, Shak S et al.,Concurrent administration of anti-HER2 monoclonalantibody and first-line chemotherapy for HER2-overexpressing metastatic breast cancer. A phase III,multinational, randomised controlled trial, N Engl JMed 344 (2001), pp. 783-792.5. Marty M, Cognetti F, Maraninchi D et al.,Randomised phase II trial of the efficacy and safetyof trastuzumab combined with docetaxel in patientswith human epidermal growth factor receptor2-positive metastatic breast cancer administered asfirst-line treatment: the M77001 Study Group, J ClinOncol 23 (2005), pp. 4265-4274.6. Piccart-Gebhart MJ, Procter M, Leyland-JonesB et al., Trastuzumab after adjuvant chemotherapyin HER2-positive breast cancer, N Engl J Med 353(2005), pp. 1659-1672.7. Slamon D, Eiermann W, Robert N et al. PhaseIII randomized trial comparing doxorubicin andcyclophosphamide followed by docetaxel (AC T)with doxorubicin and cyclophosphamide followedby docetaxel and trastuzumab (AC TH) withdocetaxel, carboplatin and trastuzumab (TCH) inHER2 positive early breast cancer patients: BCIRG 38. 38Clinical Symposium006 study. Breast Cancer Res Treat 2005;94(suppl1):S5.8. Romond EH, Perez EA, Bryant J et al., Trastuzumabplus adjuvant chemotherapy for operable HER2-positive breast cancer, N Engl J Med 353 (2005), pp.1673-1684.9. Joensuu H, Kellokumpu-Lehtinen PL, Bono Pet al., Adjuvant docetaxel or vinorelbine with orwithout trastuzumab for breast cancer, N Engl J Med354 (2006), pp. 809-820.10. Spielmann M, Roch H, Machiels JP, et al.Trastuzumab following adjuvant chemotherapyin node-positive, HER2-positive breast cancerpatients. 4-year followup results of the PACS-04 trial.Presented at: the 29th Annual San Antonio BreastCancer Symposium; December 14-17, 2006; SanAntonio, TX. Abstract 72.11. Suter TM, Procter M, van Veldhuisen DJ, et al.Trastuzumab-associated cardiac adverse effects inthe Herceptin Adjuvant Trial. J Clin Oncol 2007;25:3859-65.12. Perez EA, Suman VJ, Davidson NE, et al. Cardiacsafety analysis of doxorubicin and cyclophosphamidefollowed by paclitaxel with or without trastuzumabin the North Central Cancer Treatment GroupN9831 adjuvant breast cancer trial. J Clin Oncol2008,26:1231-8.13.Guarneri V, Conte PF et al, Multicentricrandomised phsase III trial of two differentAdjuvant chemotherapy regimens plus Three versustwelve months of trastuzumab in patients withHER2- positive breast cancer (SHORT-HER trial;NCT00629278). Clinical Breast Cancer 2008; 8; 5:453-456.14. Tomasello G, Piccart-Gebhart M et al. Jumpinghigher: 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 systemictherapy for operable breast cancer: a review ofclinical trials and perspectives. Cancer Lett, 2007Apr 18;248(2):175-85.16. Burstein HJ, Harris LN, Gelman R, et al.Preoperative therapy with trastuzumab and paclitaxelfollowed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stageII or III breast cancer: a pilot study. J Clin Oncol2003;21(1):4653.17. Buzdar AU, Ibrahim NK, Francis D, et al.Significantly higher pathologic complete remissionrate after neoadjuvant therapy with trastuzumab,paclitaxel, and epirubicin chemotherapy: results of arandomized trial in human epidermal growth factorreceptor 2-positive operable breast cancer. J. Clin.Oncol. 23 (2005) 3676-3685.18. Coudert BP, Namer M et al. Multicenter phaseII trial of neoadjuvant therapy with trastuzumab,docetaxel, and carcoplatin for HER2 overexpressingstage II or III breast cancer: results of the GETN(A)-1trial. J Clin Oncol 2007; 25 (19): 2678-84.19 Guarneri V, Conte PF et al. PreoperativeChemotherapy plus Lapatinib or Trastuzumab orBoth in HER2-Positive Operable Breast Cancer(CHERLOB Trial) . Clinical Breast Cancer, Vol. 8,No. 2, 192-194, 2008.The seed and soil hypothesis revisited120 years later: should all women withearly breast cancer receive adjuvantbisphosphonates following the results oftrial ABCSG-12?Martine PICCARTJULES BORDET INSTITUTEMedicine Department - 1 rue Heger-Bordet1000 BRUSSELS - BELGIUMBisphosphonates have a clearly established rolein the prevention of skeletal-related events andsymptom management for breast cancer patientswith metastatic bone disease. In early disease, threeprior adjuvant trials with clodronate producedmixed results. The ABCSG-12 trial randomized 1803premenopausal women in a 2x2 manner to three yearsof monthly goserelin with tamoxifen or goserelin withanastrozole and either three years of six-monthlyzoledronic acid 4mg or no bisphosphonate therapy.The anastrozole versus tamoxifen comparison didnot show any difference in DFS or OS, althoughthe study was underpowered to detect a clinicallysignificant difference between tamoxifen and anaromatase inhibitor. The addition of zoledronic acidreduced the risk of relapse (HR 0.64, p=0.011) witha trend toward improved overall survival (HR 0.60,p=0.10). Surprisingly, all categories of DFS events(distant recurrences, locoregional recurrences, andcontralateral primaries) appeared to be reducedby the addition of zoledronic acid. This findingraises many important questions regarding theunderlying mechanism of action of bisphosphonatesin early disease. Namely, seen in the light of StephenPagets 120 year old seed and soil hypothesis, dobisphosphonates target the seed, soil, or both? Inpreclinical studies, bisphosphonates have directanti-tumor activity, with well documented pro-apoptic,anti-angiogenic, and immune modulatingeffects. However, the schedule of zoledronic acidadministered in ABCSG-12 may not have been potent 39. 39Clinical Symposiumenough to invoke eradication of the seed as the solecause of a 36% reduction in the risk of a DFS event.Zoledronic acid has previously shown to reverse theprofound bone mineral destabilization induced bythe combination of goserelin and either anastrozoleor tamoxifen, raising the intriguing possibility thatzoledronic acid may alter the fertile soil of the bonemicroenvironment for dormant disseminated cancercells. Before these results of ABCSG-12 are broadlyapplied to clinical practice, it should be kept in mindthat this analysis was based on 137 DFS events and42 deaths. In addition, only three years of adjuvantsystemic endocrine therapy were used in this trialwhich is not universally accepted. The soon to bereported, larger BIG 1-04/AZURE and NSABP B-34studies of adjuvant zoledronic acid and clodronaterespectively in broader disease populations shouldprovide further guidance regarding the role ofadjuvant bisphosphonates. As the first test of a newwave of promising bone microenvironment-directedtherapies -- such as inhibitors of RANLK, cathespinK, src, and v3 integrins -- ABCSG-12 has usheredin a new paradigm for breast cancer therapy, bydemonstrating that targeting both the seed and thesoil can improve the outcome of women diagnosedwith early disease.Re-defining the Role of Anthracyclines inMetastatic Breast CancerJavier CORTESVal Dhebron University Hospital, Barcelona - SpainAnthracyclines are being widely used in early breastcancer cases, and meta-analyses conducted in 1995showed them to be significantly more effective thanthe standard CMF (cyclophosphamide, methotrexate,fluorouracil) regimen in reducing disease recurrenceand mortality (1). The efficacy of anthracycline-containingregiments such as FAC and FEC inadjuvant treatment was established in a subsequentmeta-analysis conducted in 2005 (2).One important risk associated with anthracyclineuse in early breast cancer is that of cardiotoxicity,particularly late-onset cardiomyopathy, which canresult in impairment of left-ventricular ejectionfraction (LVEF) and the development of congestiveheart failure (CHF). A major risk factor for thedevelopment of such cardiac events is the cumulativedose of anthracycline that patients receive (3, 4).The use of these agents is often avoided in patientswith increased cardiovascular risk. Furthermore,when anthracyclines are prescribed, currentpractice is generally to keep the dose of doxorubicinand epirubicin below the recommended totallifetime dose (around 450 mg/m2 and 900 mg/m2,respectively), in order to reduce cardiovascularrisk. Some risk factors, such as prior chest-wallradiotherapy, advanced age, female gender andprior cardiovascular disease, can increase the risk ofCHF. As would be expected, combination therapyof anthracyclines with other cardiotoxic agents alsoincreases the incidence of cardiac events in thesepatients. Thus, a retrospective review of seven PhaseII and III clinical trials with trastuzumab found thatconcomitant administration of anthracycline andtrastuzumab was associated with a large increase inthe incidence of cardiac dysfunction (incidence 27%),compared with the combination of paclitaxel andtrastuzumab (13%), or trastuzumab alone (37%)(5). Similarly, administration of trastuzumab withpaclitaxel after doxorubicin plus cyclophosphamidefor adjuvant therapy of HER2-positive localisedbreast cancer increased the incidence of CHF andcardiac dysfunction, with a cumulative 1-yearincidence of cardiac dysfunction of 3.8%, comparedwith 0.9% in the control arm (6).Anthracycline-containing regimens havedemonstrated good efficacy in metastatic breastcancer (MBC) through improved tumor responserates and time to progression. However, the utility ofthese agents might be complicated in those patientspre-treated with anthracyclines. Strategies designedto reduce the cardiotoxic effects of anthracyclinesinclude maintenance of a cumulative dose below450 mg/m2 for doxorubicin and 900 mg/m2 forepirubicin, modification of the dosing schedule,use of the iron chelator dexrazoxane, and the use ofliposomal delivery systems for the anthracyclines.Two forms of liposomal anthracyclines have beendeveloped in the treatment of MBC. Non-pegylatedliposomal doxorubicin (Myocet, Cephalon) andpegylated liposomal doxorubicin (Caelyx, Schering-Plough; Doxil, Ortho Biotech).Data from two Phase III studies have confirmed thatnon-pegylated liposomal doxorubicin has similarefficacy in MBC to conventional doxorubicin,while reducing cardiovascular risk. A third PhaseIII study compared combination therapy with non-pegylatedliposomal doxorubicin or epirubicin pluscyclophosphamide (7-9).Non-pegylated liposomal doxorubicin pluscyclophosphamide (MC) was compared withconventional doxorubicin and cyclophosphamide(AC) in 297 patients with MBC (7). The two treatmentcombinations achieved similar overall response ratesand median survival times. However, the incidenceof cardiotoxicity was significantly lower in patients 40. 40Clinical Symposiumreceiving MC than in those receiving AC (p =0.0001). A randomised comparison of monotherapywith non-pegylated liposomal doxorubicin or withconventional doxorubicin in 224 patients who hadnot previously received chemotherapy for metastaticdisease also reported similar efficacy in the twotreatment arms (8). Significantly fewer patientswho received the liposomal formulation developedcardiac events that prompted their removal fromthe study compared with those who receivedconventional doxorubicin (p = 0.0001). In a secondstudy of the MC combination therapy, this wascompared with epirubicin plus cyclophosphamide(EC) in 160 patients who had not previously receivedanthracycline therapy (9). The two treatment groupshad similar objective response rates and medianoverall survival. However, the median time todisease progression was significantly longer withMC compared with EC (7.7 versus 5.6 months, p =0.022).This drug has also been tested in combinationwith other chemotherapeutic agents includingtrastuzumab. In the largest combination study, non-pegylateddoxorubicin was tested with paclitaxeland trastuzumab in patients with HER2-positive,locally advanced breast cancer (LABC) or MBC. Theoverall response rate was 98%, with a median timeto progression of 22 months (10). Eight patientsdiscontinued therapy due to asymptomatic decreasesin LVEF to below 50%, but there were no cases ofsymptomatic heart failure related to this regimen.In light of these results, a Phase III study is ongoingto compare non-pegylated liposomal doxorubicin,trastuzumab and paclitaxel against trastuzumab andpaclitaxel for first-line therapy of HER2-positiveMBC.Two Phase III studies have been conducted withpegylated liposomal doxorubicin. In the first, thisagent was compared with conventional doxorubicinin 509 patients with MBC (11). The risk of developingcardiotoxicity, assessed in a subset of 339 patients,was significantly lower with pegylated liposomaldoxorubicin than conventional doxorubicin(hazard ratio 0.32, p < 0.001). The second studycompared pegylated liposomal doxorubicin versusvinorelbine (the main comparator) or mitomycinC plus vinblastine in 301 patients with taxane-refractoryadvanced breast cancer (12). Progression-freesurvival was similar for pegylated liposomaldoxorubicin and vinorelbine (median 2.9 versus 2.5months, respectively).In summary, the development of liposomalanthracyclines has increased the therapeutic index ofthe conventional anthracyclines in MBC. However,there is still a need for improved patient selection inorder to maximize benefits and minimize risks. Thenear future use of gene expression profiling mighthelp to better define which patients should receiveanthracyclines and when.Clinical SymposiumBREAST CANCER (2)Tuesday 3rd February, 14:00-17:30Biology-driven Selection of OptimalSystemic Therapy of Primary BreastCancerGabriel N. HORTOBAGYI, M.D., F.A.C.P.,Department of Breast Medical Oncology,The University of Texas M. D. Anderson CancerCenter,Houston, Texas, USACombined modality therapy is the therapeuticapproach of choice for the management of earlybreast cancer. Systemic therapies, surgical resectionand radiotherapy all have important functions inthis strategy. Systemic therapy includes endocrinetreatments, chemotherapy and HER-2-targetedtherapies. Whether administered before optimallocal-regional treatments or following local therapy,systemic treatments are estimated to reduce annualodds of recurrence by 50% to 60% and annualodds of death by about 40% to 50%.(1) Whileendocrine therapy is unarguably the oldest of allsystemic treatments, wide acceptance of adjuvantendocrine therapy did not occur until the midto late 1980s. Combination chemotherapy wasthe first successful and fully validated adjuvantsystemic intervention. Initial regimens includedvariations of cyclophosphamide, methotrexateand fluorouracil (CMF): CMF-type regimens areclearly effective, regardless of age, menopausalstatus and nodal status. In subsequent generationsof adjuvant therapy regimens, anthracyclines weresubstituted for methotrexate, with a 20% to 30%improvement in outcomes compared to CMF-likeregimens. The introduction of taxanes producedanother incremental improvement in relapse-freeand overall survival. Chemotherapy research overthe past decade has focused on issues of dose, dose-densityand scheduling, with varying degrees ofsuccess. The initial endocrine adjuvant therapieswere designed for unselected patients with primarybreast cancer, since the estrogen receptor was onlydiscovered in the 1960s. By the mid-1980s, therewas fairly compelling evidence that tamoxifen,administered for several years, reduced significantly 41. 41Clinical Symposiumthe risk of recurrence, and in some trials, the riskof death, especially in postmenopausal women.Subsequent clinical trials established that around fiveyears of adjuvant tamoxifen were optimal. Clinicaltrials conducted in the same era, also demonstratedthat for hormone receptor-positive tumors, thecombination of tamoxifen and chemotherapy wasmore effective than either component, and thisapproach was eventually adopted as the standard ofcare. The initial trials of adjuvant ovarian ablationwere underpowered, and accrual to such trialswas quite challenging. Definitive evidence of thetherapeutic activity of ovarian ablation/suppressionwas provided by the Oxford meta-analysis in the early1990s. It was also the meta-analysis that provideddefinitive support for the effectiveness of adjuvanttamoxifen in the management of premenopausalpatients with breast cancer, and that the expressionof the estrogen receptor in tumor tissue was the mosteffective predictor of benefit from endocrine therapy;conversely, the evidence also indicated that patientswith estrogen receptor-negative tumors did notbenefit from hormonal therapy. Progress during the1990s was incremental in nature: the developmentof adjuvant selective aromatase inhibitors (AIs)and the introduction of taxanes. AIs are clearlymore effective than tamoxifen, and considered tobe the first choice for adjuvant endocrine therapyof postmenopausal women with hormone receptor-positivebreast cancer. In fact, the AIs are now thesubject of intensive investigation in the preventionof breast cancer in women at high risk of developingthis disease. The recent presentation of the firstanalysis of the BIG1-98 trial suggested that theadministration of adjuvant AIs up front was the beststrategy, and performed better than a sequentialtamoxifen-to-AI (or AI to tamoxifen) sequentialstrategy. Ongoing clinical trials will soon establish theoptimal duration of adjuvant endocrine therapy forpostmenopausal women. While there is considerableuncertainty and ongoing controversy about optimalendocrine therapy for premenopausal women withhormone receptor-positive breast cancer severalwell-designed clinical trials (SOFT and TEXT) todefine the best strategy are approaching completion.Clinical trials have clearly established that ovarianablation or suppression (using gonadotropinanalogs) has equivalent therapeutic activity to somefirst-generation chemotherapy regimens (CMF).Trials have also suggested that, for patients withhormone receptor-positive tumors, ovarian ablation/suppression might have superior activity to that ofCMF. However, these answers provide incompleteguidance for optimal management of premenopausalwomen with hormone-responsive breast cancer. Theendocrine therapy and chemotherapy used in therelevant clinical trials are now of historical interestonly, since they have largely been replaced by moreeffective regimens. Thus, the optimal integrationof aromatase inhibitors into the management ofpremenopausal women has not been determined,and no endocrine therapy has been directly comparedwith modern chemotherapy regimens (TAC, dose-denseAC+T, etc.). Even more importantly, themost important question is not whether endocrinetherapy is better or worse than chemotherapy, butwhether and what combination of endocrine andchemotherapy will offer the highest probability oflong-term disease control to both premenopausaland postmenopausal women with hormone-sensitivebreast cancer.The incorporation of taxanes into adjuvant andneoadjuvant therapy was accomplished in a relativelyshort time interval. It is now generally acceptedthat the optimal schedule of administration forpaclitaxel is the weekly schedule, while the 3-weeklyschedule appears to have the best therapeutic indexfor docetaxel. Nab-paclitaxel is currently underevaluation in the adjuvant and neoadjuvant settings.Retrospective analyses suggest that the incrementalbenefit of adjuvant taxanes is greater for patients withhormone receptor-negative tumors than for hormonereceptor-positive breast cancer. This observation hasnot been reported for docetaxel-based regimens, sothere is substantial uncertainty about the relevanceof the initial reports to clinical practice. Perhaps amore important line of investigation is to determinewhether there are subsets of hormone receptorpositive tumors that derive little or no benefit fromchemotherapy. For premenopausal women, theseissues are somewhat more complicated, becausechemotherapy affects ovarian function, and therefore,has endocrine effects for some, but perhaps not allpremenopausal women. This observation explains, atleast in part, why combinations of endocrine therapyand chemotherapy do not provide the same additivebenefit observed in postmenopausal patients. Thisis particularly true for ovarian ablation added tochemotherapy. Retrospective analyses suggest, butdo not establish, that the benefit of ovarian ablationafter chemotherapy might be limited to thosepremenopausal women whose menses persist duringand after adjuvant chemotherapy.Two other important development in the 1990swere not incremental, but paradigm changing. Thediscovery and validation of HER2 amplification/overexpression as an adverse prognostic factor, andthe development of a monoclonal antibody to theHER2 cell surface oncoprotein, and more recentlysmall molecule tyrosine kinase inhibitors withsimilar (although not identical) effects, openedentirely new avenues of therapeutic research. Several 42. 42Clinical Symposiumlarge, prospective randomized trials documented themarked antitumor efficacy of these drugs, both in themetastatic and the adjuvant settings. Simultaneouslywith these developments, technological advancesmade possible the simultaneous evaluation of not2 or 3, but thousands of genes (the entire humangenome, in fact) on the same tissue. Our increasedunderstanding of the heterogeneity of primary breastcancer, and the identification of discrete, molecularlydefined subgroups of breast cancer with distinctnatural histories, drug sensitivities and specificmolecular therapeutic targets has revolutionalizedour conceptual and therapeutic approach to breastcancer. Thus, it is apparent today, that luminal, basal,HER2-like and perhaps other, smaller molecularsubsets can be reproducibly identified by microarraytechnology. Somewhat more simplistically (and lessaccurately), the use of three immunohistochemicalassays (estrogen receptor [ER], progesteronereceptor [PR] and HER2) defines similar, althoughnot identical groups of tumors. These three markersare today considered and integral componentof the diagnosis of breast cancer, and representprognostic indicators as well as selectors of optimaltherapy for individual patients. We no longer designclinical trials for breast cancer: instead, clinicaltrials focus on HER2-positive tumors, or hormonereceptor-positive/HER2 negative breast cancer,or triple-negative malignancies. Increasingly, aspart of therapeutic trials, we incorporate biologicalcorrelative studies in an attempt to identify withinrelatively homogeneous populations the operativemechanisms of resistance. The challenge of futuredrug development will be to generate compellingbiological and clinical evidence of safety and efficacyin populations of smaller and smaller size.Another important collateral benefit of multigeneassays is the ability to identify genetic profiles orsignatures associated with improved or adverseprognosis or response to therapies. One such exampleit the Oncotype Dx assay. This is an RT-PCR-basedassay that measures the expression of 21 genes: 16related to the estrogen signaling pathway, proliferationmarkers, invasion and metastasis and HER2. Theother five are housekeeping genes. Retrospectiveanalyses of paraffin-embedded tumors samples ofpatients with estrogen receptor-positive tumorshave shown that the Recurrence Score, derived fromOncotype Dx is linearly associated with the risk ofrecurrence, whether the patient received tamoxifenor not, and regardless of nodal status. Additionalanalyses provide preliminary evidence suggestingthat patients with low Recurrence Score tumorsmight not benefit from adjuvant chemotherapy,while those with high Recurrence Scores might notbenefit from tamoxifen, despite a positive estrogenreceptor assay. A large prospective validation trialis ongoing and should provide more compellinganswers to these and potentially other outstandingquestions. Another is being planned for patientswith ER-positive, lymph node-positive breast cancer.The Recurrence Score also predicts the probabiltityof achieving a pathological complete remission afterneoadjuvant chemotherapy. Other genomic assays(Mammaprint, and others) are also available for moreaccurate determination of prognosis and are underevaluation to predict therapeutic benefit. Moderntechnology should provide us with better and bettermethods to select the most appropriate therapies forindividual patients and thus increase efficacy, whilelimiting toxicity. The era of personalized medicine isupon us, although the validation of these intuitivelyattractive concepts will take a good part of the nextdecade.Today, the aggregate available evidence suggests thefollowing:1) Patients with hormone receptor-positive, HER2negative tumors:a. premenopausal women benefit from adjuvantor neoadjuvant ovarian ablation/suppressionor tamoxifen; chemotherapy (CMF, FAC/FEC,AC+T, TAC, etc.) provides incremental benefitabove that achieved by endocrine therapy formany patients.b. Postmenopausal women benefit from adjuvantor neoadjuvant aromatase inhibitors (AI, aloneor followed by tamoxifen); chemotherapy of thesame type shown for premenopausal womenprovides incremental benefit, although to alesser extent than for premenopausal women;2) Patients with HER2-positive tumors, any ER/PR or menopausal status: the administration ofone year of trastuzumab in combination withchemotherapy is associated with about a 50%reduction in odds of recurrence and about a30% reduction in odds of death. The optimaltiming and duration of trastuzumab is underinvestigation, although trastuzumab has beengiven in the adjuvant and neoadjuvant situationswith apparently similar benefits. Whether othermolecular markers can identify those patientswith HER2-positive tumors that will benefitfrom trastuzumab, and what the role of lapatinibis in the management of primary breast canceris also under investigation.3) Because of the increased cardiac toxicity observedwith simultaneous or sequential combinationsof an anthracycline and trastuzumab, some haveproposed that anthracyclines have limited orno role in the management of primary breastcancer. This concept is being hotly debated;there is no reliable or reproducible marker 43. 43Clinical Symposiumof anthracycline benefit that would serve toidentify the population most and least likely tobenefit from this group of drugs.4) Patients with triple-negative breast cancer:chemotherapy with an anthracycline,cyclophosphamide and a taxane is the treatmentof choice for patients with HR-negative,HER2-negative tumors; platinum-based,non-anthracycline-containing regimens areunder evaluation; bevacizumab is active in themetastatic setting in this group, and is underevaluation in clinical trials in the adjuvant andneoadjuvant settings.5) There is much interest in identifying those patientswho will benefit more from anthracyclines thanother agents, and those who need a taxane foroptimal results. The incremental benefit ofchemotherapy for women with high HR contentis under renewed investigation.6) Clinical and pathological factors are commonlyused to determine risk of recurrence anddeath from breast cancer.(7) These factors arereasonably accurate in predicting prognosisfor groups of patients, but much less so forindividual patients. An on-line program,Adjuvant!Online considers multiple clinical andpathological factors to predict risk of recurrenceand mortality.(8) In addition, this programincorporates the effect of comorbid conditionsin the determination of prognosis and benefitfrom various therapeutic interventions. Thisprogram is available on-line at no cost to theuser. Adjuvant!Online has been independentlyvalidated by Canadian investigators, andthe concordance with actual recurrence andmortality rates was within 1% of predictionsbased on this model.(9)7) Multigene predictors of prognosis andresponsiveness to therapy are currently underdevelopment and clinical validation.(10;11) TheOncotype Dx assay seems to be most advanced invalidation trials and has been used in over 20,000patients in the practice setting. Some requirefresh or fresh-frozen tumor samples; others canbe performed on paraffin-embedded archivalmaterial, increasing the possibility of generaluse in the community. Preliminary analysessuggest that combinaed use of the Oncotype DXassay and Adjuvant!Online provides even moreaccurate prognostic information thatn eachcomponent alone.8) The results of current trials will determinewhether more precise determination of prognosisand identification of patients most likely andleast likely to benefit from specific therapiescan improve the efficacy and reduce the toxicityof systemic treatments. As individual tumorsare molecularly characterized and molecularlytargeted therapies are clinically validated,personalized adjuvant therapy will become areality in the not too distant future.(12)Reference List(1) Hamilton A, Hortobagyi G. Chemotherapy:What progress in the last 5 years? J Clin Oncol2005; 23(8):1760-1775.(2) Early Breast Cancer Trialists CollaborativeGroup. Tamoxifen for early breast cancer:an overview of the randomised trials. Lancet1998; 351(9114):1451-1467.(3) Early Breast Cancer Trialists CollaborativeGroup. Ovarian ablation in early breast cancer:overview of the randomised trials. Lancet1996; 348(9036):1189-1196.(4) Jonat W, Kaufmann M, Sauerbrei W, BlameyR, Cuzick J, Namer M et al. Goserelinversus cyclophosphamide, methotrexate,and fluorouracil as adjuvant therapy inpremenopausal patients with node-positivebreast cancer: The Zoladex Early Breast CancerResearch Association Study. J Clin Oncol 2002;20(24):4628-4635.(5) The ATAC Trialists Group. Anastrozole aloneor in combination with tamoxifen versustamoxifen alone for adjuvant treatment ofpostmenopausal women with early breastcancer: first results of the ATAC randomisedtrial. Lancet 2002; 359(9324):2131-2139.(6) Early Breast Cancer Trialists CollaborativeGroup. Polychemotherapy for early breastcancer: an overview of the randomised trials.Lancet 1998; 352(9132):930-942.(7) McGuire WL. Prognostic factors for recurrenceand survival in human breast cancer. BreastCancer Res & Treat 1987; 10(1):5-9.(8) Ravdin PM, Siminoff LA, Davis GJ, Mercer MB,Hewlett J, Gerson N et al. Computer programto assist in making decisions about adjuvanttherapy for women with early breast cancer. JClin Oncol 2001; 19(4):980-991.(9) Olivotto IA, Bajdik C, Ravdin PM, Norris B,Coldman AJ, Speers C et al. An independentpopulation-based validation of the adjuvantdecision-aid for stage I-II breast cancer. J ClinOncol 22[14S], 8S (abst 522). 2004.(10) Paik S, Shak S, Tang G, Kim C, Baker J, CroninM et al. A multigene assay to predict recurrenceof tamoxifen-treated, node-negative breastcancer. New Engl J Med 2004; 351(27):2817-2826.(11) van de Vijver MJ, He YD, vant Veer LJ, Dai H,Hart AA, Voskuil DW et al. A gene-expression 44. 44Clinical Symposiumsignature as a predictor of survival in breastcancer. New Engl J Med 2002; 347(25):1999-2009.(12) Ross JS, Schenkein DP, Pietrusko R, Rolfe M,Linette GP, Stec J et al. Targeted therapies forcancer 2004 [Review]. Am J Clin Pathol 2004;122(4):598-609.Clinical relevance of disseminated andcirculating tumor cells in patients withbreast cancerVassilis A. Georgoulias MD, PhDDepartment of Medical OncologyUniversity General Hospital of HeraklionPO Box 1352, 711 10 Heraklion, Crete,