QOL primary endpoint primary endpoint NSABP B-18 AC(60/600) surgery surgery AC(60/600) Primary end points: disease free survival NSABP B-18 primary ch

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1 T T pc primary endpoint

2 QOL primary endpoint primary endpoint NSABP B-18 AC(60/600) surgery surgery AC(60/600) Primary end points: disease free survival NSABP B-18 primary chemotherapy in breast cancer: a five year update of the Aberdeen Trial PST adjuvant DFS, JCO 16: ,1998 Andrew W Hutcheon on behalf of the Aberdeen Breast Group University of Aberdeen and Grampian University Hospitals Aberdeen, Scotland

3 Survival (%) andomise Tax301 Study Conducted by the Aberdeen Breast Group First Phase Second Phase Tax301 Pathological esponse ates All Patients 4 cycles of CVAP (n=162) No esponse esponse 4 cycles of docetaxel (n=55) 4 cycles of docetaxel (n=52) 4 cycles of CVAP (n=52) Final Assessment / Surgery pn pc Miller & Payne Grade of Pathological esponse No Initial esponse n = 55 % Initial esponse CVAP n = 52 % * Not Evaluable n = 52 % (*P=0.06) Tax 301 Overall Survival Median Follow - up: 60 months 97% NSABP B-27 AC(60/600) x 4 AC(60/600) x 4 AC(60/600) x Log rank p= % CVAP surgery 75 x 4 surgery Time (months) surgery 75 x 4 Complete Phathologic Tumor esponse NSABP B-27 Overall Survival Grp.l (n=762) 26.1 * Grp.ll (n=752) Grp.lll (n=772) DCIS only No Tumor Journal of Clinical Oncology, Vol 21, No 22(November 15), 2003: pp % Surviving TT N Deaths Group I Group II Group III H=0.694 p=0.57 H=1.07 p= Years after Surgery

4 % Disease-free NSABP B-27: Disease-Free Survival Patients with cp after AC TT N Events Group I Group II H=0.68 p=0.003 Group III H=0.90 p= P = Partial esponse Years after Surgery % 80% 60% 40% 20% 0 Year B-18 Disease-Free and Overall Survival According to esponse pc pinv cp cn P= pc pinv cp cn P= Wolmark N: CDC, 2000 (pc andomised trial in HE2-positive BC: trial design P q3w x 4 Stage II IIIA breast cancer; HE2 positive andomisation H qw x 12 + P q3w x 4 FEC q3w x 4 H qw x 12 + FEC q3w x 4 Local therapy Appropriate endocrine therapy for patients with E+ disease FEC = fluorouracil, epirubicin, cyclophosphamide H = Herceptin ; P = paclitaxel Buzdar A, et al. Proc ASCO 2004;23:7 (Abstract 520) pc (%) andomised trial in HE2-positive operable BC: pc rates % CI (41 87%) p= % n= % n=16 DSMB reviewed data (n=34) 95% CI (43 84%) p= % n= % n=23 Final results (n=42) P + FEC alone H + (P FEC) Buzdar A, et al. Proc ASCO 2004;23:7 (Abstract 520) Herceptin PST compares favourably with anthracycline plus taxane-based PST Study Author n egimen C (%) NSABP B-27 Bear AC x 4 Doc x GeparDuo Minckwitz AT x 4 Doc x Aberdeen Smith CVAPd x 4 Doc x AGO Untch (E x 3 Pac x 3) q2w NA 18 ECTO Gianni APac x 4 CMF x MD Anderson* Buzdar Herceptin + (P FEC) NA 65 *HE2-positive patients pc (%)

5 C Clinical response n=90) P SD PD NE FEC 100 x 4 x 4 Cyclophosphamide 500 mg/m 2 75 mg/m 2 Epirubicin 100 mg/m 2 5FU 500 mg/m 2 FEC % 12% 43% 39% 4% 1% Surgery % 46% 20% 7% 2% Changes of effects : Improvement 30 pts (34.1%) (FEC ) No change 49 pts (55.7%) Progress 9 pts (10.2%) Primary Chemo adiation therapy pc + Near pc for Breast Cancer 5.6% 24.4 % PICA-BC 57.8% 15.6% 8.9% 12.2% pc : 14 Near pc : 8 pp : 11 S*/N: 52 NE : 5 * Slight esponse multiple cross-section specimens: median 21.5 (3-77) 2cm I-III 5cm US 2cm stagei-iiia :20-70, PS:0-1, JBCG 003 AC(60/600) 4 q3w PTX(80mg/m2) 12 q1w x 4 75 mg/m 2 FEC 100 x 4 Cyclophosphamide 500 mg/m 2 Epirubicin 100 mg/m 2 5FU 500 mg/m 2 45Gy/25 Fr + Boost 10Gy Surgery

6 TBCG 001 Locally advanced breast cancer 75mg/m2 Herceptin surgery IMAGE-BC JCOG) PST cp+cc Surgery 3.8% 1581 /M.D. Anderson Cancer Center Cancer 85: ,1999 Adjuvant chemotherapy Evidence

adical Mastectomy The First Milan Trial 386 node positive Breast Cancer A N D O

ecurrence reduces the risk of recurrence by 24% Death vs CMF Percentage elapse

006) 0 1 2 3 4 5 N+, Pre CEF:q4Wk x 6 CPA:75mg/m2 po,14d EPI:60mg/m2, d1&8

5-FU:600mg/m2, d1&8 Lancet. 1998;352:930-942.

7 adical Mastectomy The First Milan Trial 386 node positive Breast Cancer A N D O M I Z E No Treatment (179 pts) CMF 12 cycles (207 pts) CMF (Milan Trial) ecurrence reduces the risk of recurrence by 24% Death vs CMF Percentage elapse Free CMF Follow-up (Years) 57.3% 54.1% 3.2% (log-rank 2p = 0.006) N+, Pre CEF:q4Wk x 6 CPA:75mg/m2 po,14d EPI:60mg/m2, d1&8 5-FU:500mg/m2 d1&8 CMF: q4wk x 6 CPA:100mg/m2 po, 14d MTX:40mg/m2, d1&8 5-FU:600mg/m2, d1&8 Lancet. 1998;352: N+ cases FASG trial DFS EC: 60/500 q3w x 8 HEC:100/830 q3w x 8 CMF:classical CMF x 6 OS DFS OS JCO 19: ,2001 JCO 19: ,2001

Evidences of Chemotherapy (including Taxans) Trial CALGB9344 NSABP B-28 anthracyclin BCIG001 PACS-01 CALGB9840 NSABP B-27 CALGB9741 ECOG1199 results DFS E(-) P=0.001, :0.75 E(+) P=0.13, :0.

8 Evidences of Chemotherapy (including Taxans) Trial CALGB9344 NSABP B-28 anthracyclin BCIG001 PACS-01 CALGB9840 NSABP B-27 CALGB9741 ECOG1199 results DFS E(-) P=0.001, :0.75 E(+) P=0.13, :0.88 OS DFS TAC FAC DFS, OS FECx3 Dx3 FECx6 weekly P 3 week P AC AC D dose dense AC P AC P Hudis ATAC ANO / ITA axan BIG 1-98 (BIG FEMTA) Taxan MA-17 ICCG / IES TEAM NSABP B33 EXEM 027 Trial Strategies in Early Adjuvant Therapy: Aromatase Inhibitors Early Adjuvant setting 0 5 years Extended Adjuvant setting 5 10 years TAMOXIFEN ANASTOZOLE LETOZOLE PLACEBO EXEMESTANE Chronology of endocrine therapy Future S U G E Y Early Adjuvant Extended Adjuvant Tamoxifen Anastrozole Exemestane TEAM Letrozole Tamoxifen ANO BIG 1.98 Letrozole No treatment Placebo Letrozole 5y 10y 15y

9 NSABP B-31 Control: AC T Arm 1 Arm 2 Arm A Arm B Arm C NCCTG N9831 Investigational: AC T+H = doxorubicin/cyclophosphamide (AC) 60/600 mg/m 2 q 3 wk x 4 = paclitaxel (T) 175 mg/m 2 q 3 wk x 4 = paclitaxel (T) 80 mg/m 2 /wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51 % Disease-Free Survival AC T AC TH N Events AC T AC TH % 75% Years From andomization 85% 67% H=0.48, 2P=3x10-12 B31/N9831 B-31/N9831 Survival NCCTG N9831 Schema AC T 94% 92% AC TH 91% 87% N Deaths AC T AC TH H=0.67, 2P=0.015 A N D O M I Z E Arm A: AC q3w x 4 Paclitaxel qw x 12 Arm B: AC q3w x 4 Paclitaxel qw x 12 H qw x 52 Paclitaxel qw x 12 Arm C: AC q3w x 4 + H qw x 40 H qw x 12 adiation and/or hormonal therapy as indicated Years From andomization B31/N9831 Perez E. Protocol NCCTG-N9831. H=trastuzumab (4mg/kg loading dose, followed by 2mg/kg); doxorubicin dose 60mg/m 2 ; cyclophosphamide, 600mg/m 2 ; paclitaxel, 80mg/m 2 q3w=every 3 weeks; qw=weekly Disease-Free Survival: A vs C From the Joint Analysis Disease-Free Survival: A vs B N9831 % AC T Events=261 AC T + H H Events=134 Hazard ratio=0.48 Stratified logrank 2P=3x Years Number of patients followed A C % AC T Events=117 AC T H Events=103 Hazard ratio=0.87 Stratified logrank 2P= Years Number of patients followed A B

FIST ESULTS OF THE HEA TIAL ASCO, Scientific Session, May 16, 2005 ACCUAL: 5090 WOMEN 478 centers from 39 countries (2002-2005) A randomized three-arm multi-centre comparison of: 1 year Herceptin 2

10 FIST ESULTS OF THE HEA TIAL ASCO, Scientific Session, May 16, 2005 ACCUAL: 5090 WOMEN 478 centers from 39 countries ( ) A randomized three-arm multi-centre comparison of: 1 year Herceptin 2 years Herceptin or no Herceptin in women with HE-2 positive primary breast cancer who have completed adjuvant chemotherapy Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann La oche Ltd. CANADA CENTAL & SOUTH AMEICA 71.5% 5.5% NODIC COUNTIES EU SOUTH AFICA EASTEN EUOPE: 11% JAPAN 12% ASIA PACIFIC AUSTALIA NEW ZEALAND HEA TIAL DESIGN DISEASE-FEE SUVIVAL Women with HE2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT) ± radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region andomization Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 1 year Observation % alive and disease free year trastuzumab Observation 50 2-yr 40 Events DFS % H [95% CI] p value [0.43, 0.67] < No. Months from randomization at risk ACKNOWLEDGEMENTS BIG GOUPS ABCSG ACCOG ANZ BCTG BOOG BEAST CEEOG DBCG EOTC GABG GEICAM. Gelber M. Procter C. Ward M. Jahn GOCCHI GOIC GONO IBCSG ICCG NCIC-CTG NCI SAKK SBCG YBCG STATISTICS & DATAMANAGEMENT & MEDICAL SUPEVISION E. McFadden A. Spence BIG COODINATION S. Dolci S. Jonas P. Wermuth CADIAC ADVISOY BOAD T. Suter IDMC MEMBES WITING OF HEA POTOCOL C. Lohrish, H. Weber CENTAL HE-2 TESTING J. ueschoff, O. Stoss C. Straehle S. Guillaume, V. Greatorex L. Dal Lago G. Demonty C. Bernard M. Mano T. Suetoe MONITOING COOD TIAL DESIGN / DAY TO DAY SUPEVISION A. Goldhirsch, M. Piccart, B. egeer, B. Vanhauwere J. Baselga,. Bell, D. Cameron, M. Dowsett, L. Gianni, C. Jackisch, B. Leyland-Jones, I. Smith, M. Untch INVESTIGATOS WITH LAGEST ACCUAL NON BIG GOUPS AGO ASG&WSG BIOMED NO GIM IBCG MICHELANGELO NBCG SOLTI TCOG 91 Independent centers Evidence (guideline) St Gallen recommendation NIH consensus conference NCCN guideline M. Lichinitser, I. Lang, U. Nitz, H. Iwata, C. Thomssen

第11回CSPO CCセミナー 2005/9/17 9/18 乳がん臨床試験概説岩田広治 NCCN (The National Comprehensive Cancer network) 全米で１９施設 9th International Conference on Primary Therapy of Early Breast Cancer at St.

11 第11回CSPO CCセミナー 2005/9/17 9/18 乳がん臨床試験概説岩田広治 NCCN (The National Comprehensive Cancer network) 全米で１９施設 9th International Conference on Primary Therapy of Early Breast Cancer at St. Gallen,2005 Annals of On Prognosis estimate by microarray gene expression profiling 遺伝子解析による臨床試験の時代 Van t veer LJ, et al: Nature 2002:31: Van de Vijver MJ, et al: N Engl J Med 2002:347; New clinical trial (MINDACT Trial) Oncotype DX MINDACT: Microarray In Node-negative Disease may Avoid ChemoTherapy Standardization and validation phase ecruitment 5,000 patients last quarter of 2005 使用目的を研究者の自己学習用に限りその他への転用を禁じる 11

12 US intergroup PACT Trial N(-), E(+), Pg(+) S S S N-SAS-BC H alone H+Chemo H alone H+Chemo S : Oncotype DX (Paik et al:nejm, 2004:351; ) Comprehensive Support Project for Oncology esearch (C-SPO) C-SPO QOL CC / CC(Clinical esearch Coordinator) CC C-SPO

13 n0 high risk CC / C-SPO UFT 2Y CMF 6cycle N-SAS-BC 01 T TAM N-SAS BC 02 N-SAS BC 02 Stage I-IIIA 70 PS 0-1 paclitaxel A(E) C docetaxel paclitaxel ACP ACD PTX Adriamycin (Epi) 60 (75) mg/m 2 Cyclophosphamide 600 mg/m 2 q3wks x 4 Paclitaxel 175 mg/m 2 q3wks x 4 Adriamycin (Epi) 60 (75) mg/m 2 Cyclophosphamide 600 mg/m 2 75 mg/m 2 q3wks x 4 q3wks x 4 Paclitaxel 175 mg/m 2 q3wks x 8 docetaxel DTX 75 mg/m 2 q3wks x 8 N-SAS BC 02 2 * 2 design N-SAS BC 02 2 * 2 design A(E)C Paclitaxel A(E)C A(E)C Paclitaxel A(E)C Paclitaxel Paclitaxel 1,200 8

14 TAM H TAM 1 4Y N-SAS-BC03 TAM 5Y ANA 1 4Y 2, n0 high risk, n H+ N-SAS-BC 04 TAM 5Y TEAM trial EXE 5Y TAM 5Y EXE 5Y ANA 5Y TEAM Japan trial N-SAS-BC 04 (new) TAM 3Y EXE 2Y TEAM trial EXE 5Y JCOG trial TAM 3Y EXE 5Y ANA 5Y EXE 2Y TEAM Japan trial phaseii phaseii) Fuluvestlant (ICI182,780) TAS-108 Gemcitabine (LY188011) TSU-68 BNP7787 Ixabepilone(BMS ) Lapatinib (GW572016) EPOCH TBCG002 E+ or/and Pg+ and Her-2:3+ first line Trastuzumab uncertain EXE + Trastuzumab

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untitled 19CRC/2009.8.8-9 T0 T1 T2 T3 T4 M0 N0 M1 19CRC 2009.8.8 1 2 N1 N2 N3 Stage 0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Tis 3 4 5 6 1 19CRC/2009.8.8-9 7 8 Subtype of Breast Cancer