CSPOR CSPOR NEOS New primary Endocrine-therapy Origination Study 1 ~10%~ ~90%~ 2 CSPOR CSPOR ER/HER 3 N-SAS BC06 version CSPOR CSPOR St. Gallen

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1 NEOS New primary Endocrine-therapy Origination Study 1 ~10%~ ~90%~ 2 ER/HER 3 4 St. Gallen ER/HER 5 6

2 Low risk n0 2 cm Grade 1 ER(+) and/or PgR(+) and HER2(-) 35 Intermediate n0 risk 2 cm Grade 2-3 ER(-)/PgR(-) HER2(+) High risk 35 n(+) 1-3 ER(+) and/or PgR(+) and HER2(-) n(+) 1-3 ER(-)PgR(-) triple negative n(+) 1-3 HER2(+) n(+) 4 7 HER2 2005St. Gallen ACCMFAC ACMFFEC3 AC A FEC100 TAC AC ACMF CEF CAFday 1&84 FEC3 AC A FEC100 TAC 8 St. Gallen ER/HER ER == HER2 Herceptin ER/ HER2 Histological Grade Ki-67? Topo2? tau?? HER2(-) HER2(+) Incompletely *1 *1 ( ( ) ) Trastuzumab*2 +Trastuzumab *2 + +Trastuzumab* HER2 ER ER ER ER HER2 HER2 HER2 HER

3 ER ER HER % 10-15% HER2 20% ER ER HER2 HER pcr up intermediate~high >2cm N+ ER(-) HER2(+) JBCRG01 FEC100 x4 D75 x4 pcr ( )pcr (A-T)

chemotherapy 399 33% 8% Ring et al. chemotherapy x 6 435 22% 8% Gianni et al.

4 JBCRG-05 JBCRG-05, -06 primary endpoint? pcr pcr rate based on ER status Chemotherapy regimen n ER-negative ER-positive MDACC. Total (FACx3, FACx4, Tx4, 3wTx4FACx4, wtx12facx4, ADx4) % 5% ECTO: AT CMF % 12% NSABP B-27 : ACx4 1,533 14% 6% JBCRG-06 NSABP B-27 : ACx4Dx % 14% Colleoni et al. chemotherapy % 8% Ring et al. chemotherapy x % 8% Gianni et al. ATx3 wt x % 8% J Clin Oncol 24: ,2006 Br J Cancer 91: , ER/PR:negative pcr vs No pcr: 83.9% vs 67.4% (p=0.003) ER/PR:positive pcr vs No pcr:96.4% vs 84.5% (p=0.04) 22 vs N=239 PM women HR+ T2N0-2T3N0-1 T4N0 R A N D O M I Z E (n = 118) AT q 3w x 4 DXR60mg/m 2 PTX200mg/m 2 Median age 67 years (n = 121) 3 Median age 68 years MMG pcr 23 Semiglazov et al. Cancer 2007;110: AIs vs : Semiglazov et al. Cancer 2007;110:

AI n=121 n=118 G2-4) 0 0 51 43 0 0 6 5 G2-3) 0 0 2 2 G3) 0 0 8 7 0 0 8 7 G2-3) 0 0 37 32 0 0 93 79 LVEF<50%) 0 0 8 7 G2) 28 23 2 2 G2) 18 15 9 8 8 7 0 0

1 2007 Preoperative systemic therapy The primary objective of this therapy is to improve resectability and cosmesis Assessment of responsiveness to

5 AI n=121 n=118 G2-4) G2-3) G3) G2-3) LVEF<50%) G2) G2) G1-2) Semiglazov et al. Cancer 2007;110: B C 26 NCCN 2008ver Preoperative systemic therapy The primary objective of this therapy is to improve resectability and cosmesis Assessment of responsiveness to preoperative therapy may in the future be useful in selection of postoperative adjuvant therapy St.Gallen consensus RT-PCR Oncotype DX TM Paik S., NEJM.,351,2817,

Intermediate risk(rs 18-30) Low risk <18) (Recurrence

of Adjuvant Combination Chemotherapy and Hormonal Therapy

Previously Resected Axillary Node-Negative Breast Cancer With

and/or PgR +, HER2:0,1+, 1cmT5cm S N:10,046 pt RS:11 11RS25

6 Intermediate risk(rs 18-30) Low risk <18) (Recurrence Score[RS] High risk(rs > 30) Phase III Randomized Study of Adjuvant Combination Chemotherapy and Hormonal Therapy Versus Adjuvant Hormonal Therapy Alone in Women With Previously Resected Axillary Node-Negative Breast Cancer With Various Levels of Risk for Recurrence (TAILORx Trial) N0, ER and/or PgR +, HER2:0,1+, 1cmT5cm S N:10,046 pt RS:11 11RS25 RS:25 R Hormone therapy alone Chemo + hormone therapy Oncotype DX RS 35 36

case 58 US 2.4cm Bp+SLNB Invasive ductal carcinoma ( ) 2.0cm, n0(0/2) ER Allred score:7 PgR Allred Score:5 Her-2(-) HG:3 ly0, v0, St. Gallen: intermediate risk Adjuvant Online! Oncotype DX?

7 case 58 US 2.4cm Bp+SLNB Invasive ductal carcinoma ( ) 2.0cm, n0(0/2) ER Allred score:7 PgR Allred Score:5 Her-2(-) HG:3 ly0, v0, St. Gallen: intermediate risk Adjuvant Online! Oncotype DX? Letrozole (5~10y) ER+ Stage 2/3 Letrozole P024 4 months Final accrual 337 Tamoxifen S U R G E R Y Continued therapy with tamoxifen radiotherapy chemotherapy discretionary pcr 39 Overall tumor response Letrozole Tamoxifen P (CR+PR) Clinical 74 (60%) 52 (41%) Breast-conserving surgery 60 (48%) 45 (36%) % Response rate P024: Response Rates and ER Expression Total % of cases in each Allred category Allred ER Score Ellis et al. J Clin Oncol. 2001;19:3808. Reprinted with permission from the American Society of Clinical Oncology. Tamoxifen Letrozole (Femara ) 41 Response versus Outcome Survival Distribution Function P= Log Rank Test RFS by Clinical Response relapse free survival (months)

8 IMPACT Trial Prognostic Value of Ki67 Expression After Short-Term Presurgical Endocrine Therapy... Dowsett et al. J. Natl. Cancer Inst. 2007; 99: Relapse Free Survival by 2 week LnKi ER+ Stage 2/3 AstraZeneca: Clinical lead: Ian Smith Correlative Science: Mitch Dowsett Anastrozole Tamoxifen Combination S U R G E R Y Relapse Free Survival % =0.8 N=45 O=3 E= N=60 O=9 E= N=54 O=14 E=7.4 2 =8.65 df=1 p=0.003 = Years since Randomisation JFMC ER(+) S A PDprotocol off Research Question ER(+)HER2(-) Oncotype DX QoL PD (TAM) rescure 1. AI Bhatnagar et al. J Steroid Biochem Mol Biol. 2001, Geisler et al. J Clin Oncol. 2002, Dixon et al. J Clin Oncol # TAM TAM AI Eiermann et al. Ann Oncol AI Rose et al. Eur J Cancer Thürlimann et al. N Engl J Med

9 Neoadjuvant Aromatase Inhibitors for Postmenopausal Breast Cancer Letrozole Eiermann, et al 1) Anastrozole Smith, et al 2) Exemestane Takei, et al 3) Study Design Randomized, Randomized, Single arm, Open, Double-blind, Double-blind, Phase III Phase III Phase II N L=154 A= Age(median) Stage 68 IIA - IIIB 73.2 N.R. 60 IIA - IIIB Duration 4 months 3 months 4 months CRPR 55% LET > TAM 37% ANA = TAM 66% N/A P < P = 0.87 BCS rate 45% LET > TAM P = % ANA > TAM P = % N/A Duration of Neoadjuvant Letrozole Letrozole Paepke, et al 1) Letrozole Renshaw, et al 2) N Duration 4 months 8 months 3 months 6 months 12 months (N=29) Response Rate 4M: CR + PR 57% 8M: CR + PR 80% P = M: CR 9.5% 6M: CR 29 % 12M: CR 36 % 1) Ann Oncol 12, ) JCO 23, ) EBCC5:EJC (S)4, ) Proc ASCO 2003, #321 2) SABCS 2004, # Letrozole (Femara ) vs Anastrozole in Second-Line Treatment of MBC: FEM-INT-01 Postmenopausal women with progression on TAM R A N D O M I Z E Milestones Start date Dec 1997 Enrollment 713 Completion Nov 1999 MBC = metastatic breast cancer. Rose et al. Eur J Cancer. 2003;39:2318. Letrozole 2.5 mg od Anastrozole 1 mg od TTP ORR MDR Survival 51 Letrozole (Femara ) vs Anastrozole (FEM-INT-01): Response Rates Objective response rate (%) Rose et al. Eur J Cancer. 2003;39: % 12.4% 6.7% Letrozole, n=356 P= % 8.7% 3.6% Anastrozole, n=357 PR CR NEOS New primary Endocrine-therapy Origination Study T1c-T2N0M0 HER2 PS 0-1 LET LET 1 2 LET 4 CRPRSD LET PD LET 53 LET CR+PR/SD 60 /60 CL LET L LET PD 54

10 1. 2 Disease- Free Survival, DFS Health related qiality of lifehrqol (CR/PR/SD/PD) DFS Overall Survival, OS Primary endpoint Endpoints Disease-Free Survival; DFS Secondary endpoints Overall Survival; OS LET PRSD PD LET CR/PR/SD/PD DFS/OS HRQOL 1. HER2 N0 2. CR 3. LLET QOLCL LET Low risk n0 2 cm Grade 1 ER(+) and/or PgR(+) and HER2(-) 35 Intermediate n0 risk 2 cm Grade 2-3 ER(-)/PgR(-) HER2(+) 35 n(+) 1-3 ER(+) and/or PgR(+) and HER2(-) High risk n(+) 1-3 ER(-)PgR(-) triple negative n(+) 1-3 HER2(+) n(+) PD LET 4 LET CL 0.5 LET LET L LET CR / PR / SD 60

11 60 1) FSH FSH30 miu/ml 10 pg/ml ) TNM T1c-T2, N0, M0 8) 4 3) 3,000/mm IHC 10% 100,000/mm 3 GOTGPT 2.5 4) HER2IHC mg/dL FISH 5) 75 9) 6) PSECOG 0 1Performance Status 7) ) 2) 4 6 3) 4) 5 5) 1) 2) 3) 6) selective estrogen receptor modulator SERM 7) 4) 5) 8) 65 MRI CT X CT CT 66 66

12 6) 7) ERPR 8) HER2IHC FISH 9) 10) / 50 E2FSH 11) PS3.3 Performance Status 12) Hb GOTGPT 13) 14) HRQOL 3) GTPALP LET HRQOL LET 1 4 1) 2) 4) 5) 6) HRQOL1 4 7) PD LET 1) 70 2) 1 LET 1 MRI CT 2 3) PD 5 6 MRI CT LET 7 PD LET - 3) PD 4) PS 5) 6) 4 6 FAX LET LET RECIST LET MRI CT 15 PD

13 LET 4 confirmation 1) CRComplete Response LET 1 4 2) PRPartial Response 1 30% 3) SDStable Disease PR PD 4) PDProgressive Disease 20% 73 N-SAS CR, PR, SD 1) 2) 3) CR, PR 13 SD CL LET LLET 11 1) CL LET 1) LET CR, PR / SD 2) PgR / 3) / 4) 60 / 60 5) 2) LLET 77 78

14 CL CL LET 2 1) CL chemotherapyletrozole L letrozole ) 3) CL 4) 80 CMF 4 6 CL CPA MTX 5-FU mg (p.o.) d mg/m 2 d 1& mg/m 2 d 1&8 DXR ADR AC mg/m2 60 mg/m 2 EC 3 4 TC mg/m mg/m 2 EPI PTXPAC DTX DOC 600 mg/m mg/m 2 FAC mg/m2 500 mg/m 2 50 mg/m 2 FEC mg/m2 500 mg/m mg/m 2 AC-T/EC-T mg/m2 60 mg/m 2 ( mg/m 2 ) FEC-T mg/m 2 ( mg/m 2 /w) 500 mg/m mg/m 2 100mg/m 2 ( (175 mg/m 2 ) mg/m 2 /w) ( mg/m 2 ) mg/m 2 TAC mg/m2 50 mg/m 2 mg/m PS6 HRQOL 2 1) 2) PS 3) 4) 5) HRQOL 6) 7) HRQOL 1 1) 2) PS 1) 3) 4) 2) PS 5) 3) 4) 5) HRQOL 6) 7)

15 :1 : CL CL LET LLET 2-1 LET LET LET LET 78 LLET 5DFS 85.20% 87 (a) LET LET 5DFS 86.6% (b) LET 5DFS 92.1% 88 DFS LET (a) (b) (a)(b) % DFS88% 3 8 LET SD 90%

16 N-SAS BC 06 NEOS New primary Endocrine-therapy Origination Study

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untitled 19 CSPOR CRC/2009.8.8-9 2009 8 8 ( ) - CSPOR CRC SEMINAR- twatanab@oncoloplan.com http://www.oncoloplan.com - Toru Watanabe MD - 2 Phase I: Dose Finding trial Phase II : Efficacy and Safety trial Phase