1. BREAST CANCER Lawrence E. Flaherty M.D. Professor of Medicine and Oncology Karmanos Cancer Institute Wayne State University

3. Breast Cancer Risk Factors

15. Monthly Incidence 1998 thru 2002 (for women 50 and older) Stable Incidence Year of Diagnosis Incidence Per 100,000 Women / Month

16. Updated with an Additional Year of Data Monthly Incidence 1998 thru 2003 Decrease In 2003 Year of Diagnosis Incidence Per 100,000 Women / Month

17. Effect Seen in All SEER 9 Registries Relative Reduction (2003 vs 2000/2001) Relative reduction in incidence (%) San Franscisco Connecticut Detroit Hawaii Iowa New Mexico Seattle Utah Atlanta All Registries

18. Effect Only Evident In Subsets Of Patients 50 and Older Relative reduction in incidence (%) < 40 40 – 49 50 – 64 65 – 74 75 – 84 Any Age

19. Influence of ER Status Relative reduction in incidence (%) ER + ER – Any ER

20. Usage of Hormonal Agents in the US www.drugtopics.com/drugtopics/

21. % Of Population Treated Buist et al. Obstet Gynecol 2004;104:1042–50. Use and Decrease Mainly in Women 50 and Older 0 5 10 15 20 25 30 35 40 40-44 45 50 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Pre-WHI Dec-02 Change In Use The Prevalence Of Use Of HT Pre/Post WHI (Estimates Derived From HMO Data)

31. Breast Cancer Non-Invasive

39. Breast Cancer - Invasive

40. Breast Cancer - Invasive Lumpectomy + RT Mastectomy == Lymph Nodes Micrometastasis Risk Size Lymph node/# Grade ER/PR Her 2-neu Adjuvant Therapy Surgery Medical Oncology

41. Breast Cancer - Invasive Micrometastasis Risk (1-99%) Size Lymph node/# Grade ER/PR Her 2-neu Adjuvant Therapy Medical Oncology Hormonal Rx Chemotherapy >1.0 cm or node + or Her 2-neu + IV – 2-6 months 25-75% RRR ER or PR + Oral x 5yrs (+ ?) 33-50% RRR Pre – Tamoxifen Post - AIs

50. Molecular profiling Sorlie et al. PNAS 98:10869, 2001 Individual Genes 78 Individual Tumors & 4 Normal Breast

51. Molecular profiling Sorlie et al. PNAS 98:10869, 2001

52. Note: Does not include lobular CA (5-10% frequency) 85% 18% Basal-like (triple negative) 62% 14% Her-2+ 49% 20% Luminal B (weak ER/+/-PR and Her-2) 21% 52% Luminal A(ER/PR+/Her-2-) % High grade Frequency

61. Adjuvant! A program for aiding health professionals in making estimates of outcome of patients with invasive cancer who have undergone definitive local therapy (without prior radiation or systemic therapy) and who are now deciding on whether to get systemic adjuvant therapy.

62. Information Input Natural Mortality Br Ca Mortality Tx Efficacy

67. Integrating / Presenting Information The Biology Of The Patient Decision Treatment Efficacy / Toxicity The Biology Of The Tumor Doctor’s Opinions Patient’s Opinions

68. Adjuvant Guidelines (Never A Mention Of Numbers) A Relic Of The Empire !

70. How Much Of A Reduction In Breast Cancer Would Make The Adjuvant Worthwhile ? % Reduction Breast Cancer Mortality Minimally Acceptable Bimodal Distribution Of Answers North American Study Australian Study % Of Patients Responding

81. Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens Aromatase inhibitors

85. ATAC Trial: Probability of Recurrence in Receptor-Positive Population *Censoring non-BC deaths before recurrence No. of patients at risk AN TAM 2617 2598 2533 2516 2436 2386 2243 2180 1258 1210 602 574 Patients with recurrence* (%) 0 6 12 18 24 30 36 42 48 54 HR 95% CI p -value AN vs TAM 0.78 0.65-0.93 0.007 Time to event (months) Absolute difference 1.8% Absolute difference 2.6% Anastrozole (AN) Tamoxifen (TAM) Source: With permission from Buzdar A. Presentation. SABCS, 2002; Abstract 13 . 0 5 10 15 20

86. Significant Difference in Pre-defined Adverse Events * proportion with  10% gain in body weight from baseline to year 2 -10 -5 0 5 10 Difference between anastrozole and tamoxifen AEs (%) (-5.4%) (-1.8%) (-3.6%) (-8.6%) (-1.1%) (-1.4%) (-0.7%) Fractures of hip, spine, wrist Fractures MSK disorders (-0.4%) In favour of anastrozole Hot flushes Weight gain* Vag. bleeding (6.6%) (2.1%) (0.8%) Endo Ca ICVA VTE DVT Vag. discharge In favour of tamoxifen

92. 7 Years Follow-Up of NSABP-B-14: 5 versus > 5 Years of Adjuvant Tamoxifen: Node-Negative, ER-Positive Disease-free survival Relapse-free survival Survival Years p = 0.03 p = 0.13 p = 0.07 100 90 80 70 60 50 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 No. No. of of pts events 5 y 569 106 >5 y 583 137 No. of events 34 47 No. of deaths 39 57 Source: Fisher B et al. Five versus more than five years of Tamoxifen… J Natl Cancer Inst 2001;93:684-90, by permission of Oxford University Press. Abstract Percent Placebo Tamoxifen

93. Letrozole versus Placebo in Women Completing at Least 5 Years of Adjuvant Tamoxifen Source: Goss P et al. N Engl J Med 2003;349(19):1793-802. Abstract Protocol ID: CAN-NCIC-MA17 Accrual: 5,187 (Closed) Eligibility Postmenopausal ER- and/or PR-positive or unknown Previously treated with adjuvant tamoxifen for 4.5 to 6 years Letrozole x 5 y Placebo x 5 y R

97. Breast Cancer – Invasive Prognostic and Predictive Gene Assays

98. Oncotype DX 21 Gene Recurrence Score (RS) Assay RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1 PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies Paik S, et al. NEJM 2004 RS ≥ 31 High risk RS ≥ 18 and < 31 Intermediate risk RS < 18 Low risk RS (0 – 100) Category

100. Onco type DX ™ Clinical Validation: B-14 Results – DRFS (cont) Risk Group % of 10-yr Rate of 95% CI Patients Recurrence Low (RS <18) 51% 6.8% 4.0%, 9.6% Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3% High (RS ≥ 31) 27% 30.5% 23.6%, 37.4% Test for the 10-year DRFS comparison between the low-and high-risk groups: p <0.00001

101. All Patients (N = 645) B-14 Overall Benefit of Tamoxifen 0 2 4 6 8 14 16 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 DRFS Placebo Tamoxifen 12 10

102. B-14 Benefit of Tamoxifen By Recurrence Score Risk Category Low Risk (RS<18) N 171 142 Int Risk (RS 18-30) N 85 69 High Risk (RS ≥ 31) N 99 79 Interaction p=0.06 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10

104. B-20 Results 0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 All Patients Tam + Chemo Tam p = 0.02 N Events 424 33 227 31 DRFS Tam vs Tam + Chemo – All 651 Pts

108. Low RS<18 Int RS18-30 High RS ≥31 0 10% 20% 30% 40% B-20: Absolute % Increase in DRFS at 10 Years n = 353 n = 134 n = 164 % Increase in DRFS at 10 Yrs (mean ± SE)

109. 0 10 20 30 40 50 Recurrence Score 0.0 0.1 0.2 0.3 0.4 Distant Recurrence at 10 Years Recurrence Score Oncotype Dx 21 Gene Recurrence Score Assay: Predictive in NSABP B-20 and Informs TAILORx Benefit from CMF TAILORx Intergroup Trial Chemoendo vs endo Minimal, if any, Chemo Benefit Clear Chemo Benefit Sparano, TBCI San Antonio, 2005; Paik JCO 2006 Tam Tam + Chemo

111. Breast Cancer – Invasive The Role of Targeted Therapy -Herceptin

112. Joint Analysis of HER2+ Adjuvant Trials 2 Arms of Intergroup N9831 + NSABP-31 Control Group (n=1,979) : AC  T N9831 Group A B-31 Group 1 Trastuzumab Group (n= 1,989 ) : AC  T+H N9831 Group C B-31 Group 2 = AC (doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T (paclitaxel 80 mg/m 2 /wk × 12) = T (paclitaxel 175 mg/m 2 q3w × 4 or 80 mg/m 2 /wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) AC T H AC T AC T H AC T

113. Joint Analysis Disease-Free Survival 87% 85% 67% 75% N Events AC  T 1679 261 AC  TH 1672 134 % HR=0.48, 2P=3x10 -12 AC  TH AC  T Years From Randomization B31/N9831 ASCO 2005

114. Cardiac Toxicity Summary in 3 Adjuvant Trastuzumab Studies ASCO 2005 Special Session Percent Congestive Heart Failure 0.5 0 HERA 2.2-3.3 0 N9831 4.1 0.7 B-31 Trastuzumab arm Control Study

115. B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF LVEF (%) Age P(Age)=0.04 P(LVEF)<0.0001 1.3% 0.6% 65+ 5.2% 2.2% 55-64 19.1% 6.3% 50-54  50 <50

120. Breast Cancer – Invasive Pre-operative Rx - Neoadjuvant

135. ECOG 2100 Phase III Trial Progression-Free Survival HR = 0.51 (0.43-0.62) Log Rank Test P < 0.0001 Pac. + Bev. 11.4 mos Paclitaxel 6.11 mos 484 events reported Miller et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S6. Abstract 3. 0.0 0.2 0.4 0.6 0.8 1.0 Months PFS Probability 0 6 12 18 24 30

142. Breast Cancer Prevention Trial Results: P1 and STAR

143. BCPT Design: Schema Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Eligible Women at High Risk (5-yr risk  1.66%) Randomization n = 13,388 Tamoxifen 5 Years n = 6681 Placebo 5 Years n = 6707

145. BCPT Results: Cumulative Rate of Invasive Breast Cancer Placebo Tamoxifen 0 1 2 3 5 4 Placebo 175 43.4 Tamoxifen 89 22.0 Events Rate per 1000 Rate/1000 P < 0.00001 0 1 0 2 0 3 0 4 0 Years Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.

146. BCPT Results: Invasive Breast Cancer Cases in All Age Groups 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 T o t a l 3 5 - 4 9 5 0 - 5 9 6 0 + P l a c e b o Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Age Group Number of Invasive Breast Cancers 175 89 68 38 50 25 57 26 Tamoxifen

147. BCPT Results: Cumulative Rate of Noninvasive Breast Cancer* Placebo Tamoxifen 0 1 2 3 5 4 Placebo 69 15.9 Tamoxifen 35 7.7 Events Rate per 1000 Rate/1000 0 1 0 2 0 3 0 4 0 *Analysis included women who had LCIS at baseline. Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Years

149. BCPT Results: Vascular Events PE TIA DVT CVA 25 19 0 1 0 2 0 3 0 4 0 PE = pulmonary embolism; DVT = deep vein thrombosis; CVA = cerebral vascular accident (stroke); TIA = transient ischemic attack P l a c e b o Number of Events 18 22 35 38 24 6 Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Tamoxifen

151. STAR Average Annual Rate & Number of Invasive Breast Cancers 163 168 * # of events 312* 0 2 4 6 8 10 Gail Model Projection TAM Raloxifene Av Ann Rate per 1000

152. STAR: Cumulative Incidence of IBC Cumulative Incidence (per 1000) Time Since Randomization (months) At Risk by Year # of Rate/1000 Treatment 0 3 6 Events at 6 yrs. P-value Tamoxifen 9726 6653 809 163 25.1 0.83 Raloxifene 9745 6703 833 168 24.8 0 5 10 15 20 25 30 35 40 0 6 12 18 24 30 36 42 48 54 60 66 72

153. STAR: Average Annual Rate and # of Uterine Cancers 36* 23 * # of events RR = 0.62, 95% CI: 0.35 to 1.08 0 1 2 3 TAM Raloxifene Av Ann Rate per 1000

154. STAR: Endometrial Hyperplasia # Hysterectomies 244 111 13 72 w/o Atypia 1 12 with Atypia 14 84 Hyperplasia RAL TAM

155. STAR: Average Annual Rates of Cataracts 394* 313 RR = 0.79; 95% CI(0.68 – 0.92) * # of events 0 2 4 6 8 10 12 14 TAM Raloxifene Av ann rate per 1000

156. STAR: # of Osteoporotic Fractures 0.46-1.53 0.85 23 27 Radius 0.65-1.46 0.98 52 53 Spine 0.48-1.60 0.88 23 26 Hip RR 95% Confidence Interval Risk Ratio (RR) Raloxifene # Tamoxifen # Type of event

157. STAR: Thromboembolic Events Cumulative Incidence (per 1000) Time Since Randomization (months) At Risk by Year # of Rate/1000 Treatment 0 3 6 Events at 6 yrs. RR Tamoxifen 9726 6682 814 141 21.0 0.70 Raloxifene 9745 6764 836 100 16.0 P-value= 0.01 0 5 10 15 20 25 30 35 40 0 6 12 18 24 30 36 42 48 54 60 66 72

158. STAR: A verage Annual Rate and # of In Situ (DCIS & LCIS) Cancers 57* 80 * # of events RR = 1.40 95% CI: 0.98 to 2.00 0 1 2 3 TAM Raloxifene Av Ann Rate per 1000