Seigo Nakamura,M.D.,Ph.D.

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1 Seigo Nakamura,M.D.,Ph.D. Professor of Surgery Director of Breast Center Showa University Hospital Chairman of the board of directors Japan Breast Cancer Society

3 Inhibition of Estrogen-Dependent Growth Antiestrogens Estrogen biosynthesis Nucleus Estrogen biosynthesis Aromatase inhibitors Cancer cell Inhibition of growth

% Recurrence-free Tamoxifen: Improvement in Disease-Free Survival 100 90 80 70 Recurrence as First Event 87.4 74.9 79.2 Node -ve 75.6 64.3 Tamoxifen (~5 y) Placebo Tamoxifen (~5 y) Placebo 60 50 58.

4 % Recurrence-free Tamoxifen: Improvement in Disease-Free Survival Recurrence as First Event Node -ve Tamoxifen (~5 y) Placebo Tamoxifen (~5 y) Placebo Node +ve Node -ve: 14.9% SD 1.4: 2P< Node +ve: 15.2% SD 2.5: 2P< Absolute Recurrence Reduction 0 0 Years Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists Collaborative Group, 1451, 1998, with permission from Elsevier Science.

years of tam results in 47% relative reduction in recurrence risk at 10y

6 EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postmp pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk

7 Endocrine Therapy Reduces the risk of systemic recurrence Increased overall survival All women regardless of age, menopausal status, nodal involvement, tumour size, HER2 status or use of chemotherapy Therefore almost universal use across the population of HR +ve patients

8 Suppress plasma oestrogen levels by inhibiting or inactivating aromatase

9 Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only anastrozole, letrozole nonsteroidal exemestane steroidal

10 Early (Upfront) Adjuvant Trials Surgery 0-5 years ATAC TEAM R R TAM ANASTRO ANASTRO + TAM TAM EXEM BIG1-98 R TAM LETRO TAM LETRO LETRO TAM

DFS: Reduction of Event Rate in the Adjuvant Setting Follow-up (mo) Rel. Red. % Abs. Red. % Early TAM 5 vs none 120 47 12 (5 yrs) Early ANA 5 vs TAM 5 68 13 3.3 (6 yrs) Early LET 5 vs. TAM 5 25.

11 DFS: Reduction of Event Rate in the Adjuvant Setting Follow-up (mo) Rel. Red. % Abs. Red. % Early TAM 5 vs none (5 yrs) Early ANA 5 vs TAM (6 yrs) Early LET 5 vs. TAM (5 yrs) Early seq. Early seq. TAM 2 EXE 3 vs TAM 5 TAM 2 ANA 3 vs TAM (3 yrs) (3 yrs) Extended LETRO 5 vs placebo (4 yrs) Review: Mouridsen HT, January 2005 EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:

12 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI

13 Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group

14 AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE

15 Osteoporosis/Fractures Reported in Adjuvant AI Trials Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P A T AC 68 AN A T A M F r a c tu r e vs 7.7 < BIG L E T R O T A M F r a c tu r e 5.8 vs 4.1 N I IES 31 E X E M T A M F r a c tu r e O s te o por os i s 3.1 vs vs AR N O 28 AN A T A M F r a c tu r e M A L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 2.4 vs vs vs 4.5 N I ATAC Trialists Group Lancet 2005;365:60; Thürlimann et al. Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. Mouridsen 0305

16 ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis Anastrozole % of patients n=3092 Tamoxifen % of patients n=3094 p-value Joint Disorders 35.6 (27.8) 29.5 (21.2) < All Fractures 11.0 (5.8) 7.7 (3.7) < spine hip wrist (Bisphosphonate usage) ATAC Trialists Group. SABCS Lancet 2005; 365:

17 ATAC - Incidence of Polyps and Fibroids Anastrozol (n=2229) p< Patients (%)* 6 5 tamoxifen (n=2236) 118 (5.3%) (3.1%) 55 (2.5%) (0.7%) 8 (0.4%) 23 (1.0%) years years Total *Patients with an intact uterus at baseline. Patients can have an event more than once, but in different time categories Duffy S et al. Eur J Cancer Suppl 2005

18 Overall Incidence of Hysterectomy in the ATAC Trial Median 68 Months Follow-up Patients (%)* 6 5 Anastrozol (n=2229) tamoxifen (n=2236) *Patients with an intact uterus at baseline Duffy S et al. Eur J Cancer Suppl 2005

19 Annual Hazard of Recurrence Peaks at 2 Years Regardless of Baseline Prognostic Factors Hazard of recurrence by yearly interval Total Node 0 Node (+4) Tumour size >3 cm Tumour size <1 cm ER- ER+ Premenopausal Postmenopausal Time (years) Saphner T et al. J Clin Oncol 1996; 14:

20 Time to Recurrence: Smoothed Hazard Estimates HR+ Patients Annual hazard rates (%) Follow-up time (years) tamoxifen anastrozol The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53

21 Adjuvant Trial Designs Randomisation Initial adjuvant trial tamoxifen AI Randomisation Switching trial 2 3 years prior tamoxifen tamoxifen AI Randomisation Extended adjuvant trial Randomisation 5 years prior tamoxifen AI Placebo Sequencing trial tamoxifen AI tamoxifen AI tamoxifen AI 0 5 Time (years)

22 BIG 1-98 DFS OS Letrozole alone 78.6% 87.5% Letrozole2/ Tamoxifen % 87.7% Tamoxifen2 / Letrozole % 85.9%

Study Endocrine therapy and duration Relative risk of recurrence Relative Risk of mortality EBCTC Tamoxifen (5 years) 0.61 0.70 ATAC BIG 1-98 Sequential Therapy BIG 1-98 Anastrozole vs.

23 Study Endocrine therapy and duration Relative risk of recurrence Relative Risk of mortality EBCTC Tamoxifen (5 years) ATAC BIG 1-98 Sequential Therapy BIG 1-98 Anastrozole vs. Tamoxifen (5yr) Letrozole vs. Tamoxifen (5yr) Tamoxifen/ Letrozole vs. letrozole BIG 1-98 Letrozole/ Tamoxifen vs. Letrozole Extended Therapy NCIC CTG MA. 17 Tamoxifen (5 yrs) then Letrozole (5 yrs)

35 Conventional concept of 35 adjuvant chemotherapy DFS If there is a statistically significant difference all the patients should be given adjuvant chemotherapy. How can we select the patients who are not necessary given chemo? TAM+CMF TAM 年

36 36 Basic rule of Othello game No Advant age Win

37 37 NIH Consensus conference in 2000 Consensus development conference statement recommends: Adjuvant polychemotherapy for women with primary breast cancers > 1 cm in diameter, regardless of nodal, menopausal, or hormone receptor status Anthracycline-containing (ie, epirubicin or doxorubicin) adjuvant chemotherapy regimens 4 to 6 Courses of treatment

38 Proliferation Ki-67 STK15 Survivin Cyclin B1 MYBL2 Invasion Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 Oncotype DX 16 Cancer and 5 Reference Genes From 3 Studies Estrogen ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = x HER2 Group Score x ER Group Score x Proliferation Group Score x Invasion Group Score x CD x GSTM x BAG1 Category RS (0-100) Low RS RS <18 Inter RS RS High RS RS 31 Paik et al. N Engl J Med. 2004;351:

39 DRFS DRFS DRFS Chemotherapy Benefit by Recurrence Score yrs 96% 95% yrs 89% 90% Low-Risk Patients (RS < 18) Tam + chemo Tam N Events P = Yrs 10 yrs 88% Int-Risk Patients (RS 18-30) N Tam + chemo Tam Events N Events P =.71 p = Yrs % High-Risk Patients (RS 31) Tam + chemo Tam N Events P = Yrs Paik S, et al. J Clin Oncol. 2006;24:

40 Results Risk Classification by Oncotype DX, St Gallen 2007 and Adjuvant! Online (n) % (n=142) 65% % % Low Risk 10% 39% Intermediate Risk 13% High Risk 3% Adjuvant! Online St Gallen 2007 Oncotype DX

41 NSABP B-20: The Recurrence Score result can be high or low for any given tumor size 41 Paik S, et al. J Clin Oncol. 2006;24:

42 NSABP B-20: Significant proportion of high-grade tumors have a low Recurrence Score result and many low-grade tumors have a high result 42 Paik S, et al. J Clin Oncol. 2006;24:

43 Results Lymph Node Metastasis and Recurrence Score Spearman r = (95% CI = -0.36, -0.04)

44 Ki67

45 Results Ki-67 and Recurrence Score Spearman r = 0.41 (95% CI = 0.26, 0.54) Spearman r = 0.35 (95% CI = 0.20, 0.49)

46 LN positive: Responder Trial Presented By Banu Arun at 2014 ASCO Annual Meeting

47 Slide 21 Presented By Banu Arun at 2014 ASCO Annual Meeting

48 Potential of Personalized Medicine Future Health Care Spending Individual Health Care Spending Curve Current Practice Health Care $ Improved Quality of Life & Financial Savings Years Source: Deloitte Development LLC 2006

49 Adaptive design for clinical trials

50 Figure 1 Schematic representation for the ALTERNATE Trial Goncalves, R. et al. (2012) Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer Nat. Rev. Clin. Oncol. doi: /nrclinonc

52 RAD001 Plus Letrozole (Femara ): Phase II/III Adaptive Trial Design 4 mo 1. Phase II neoadjuvant therapy trial in patients with HR+ localized breast cancer Letrozole 2.5 mg/d +/- RAD mg/d Surgery Identification of predictive biomarkers 2. Phase III 1st-line therapy trial in postmenopausal women with HR+ advanced breast cancer Letrozole 2.5 mg/d +/- RAD mg/d Phase II B I O M A R K E R V A L I D A T I O N Full population OR Biomarker population Phase III HR = hormone receptor. Stage 1 Stage 2

53 Sky Tree ( New Tokyo Tower ) in 2015

Assessment of Risk Recurrence: Adjuvant Online, OncotypeDx & Mammaprint

Assessment of Risk Recurrence: Adjuvant Online, OncotypeDx & Mammaprint William J. Gradishar, MD Professor of Medicine Robert H. Lurie Comprehensive Cancer Center of Northwestern University Classical