Slide 1

Hormonally Sensitive Early-Stage Breast Cancer Current Considerations and New Directions Terry Mamounas, MD, MPH Professor of Surgery Northeastern Ohio Universities College of Medicine Medical Director Aultman Cancer Center Canton, OH Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer

Slide 2

Breast Cancer Mortality in US and UK WHO Mortality and UN Population Estimates

Slide 3

Factors Associated with Reduction In Breast Cancer Mortality Early Detection Mammography Adjuvant Systemic Therapy Hormonal Therapy and Chemotherapy Treatment of Advanced Disease Hormonal Therapy, Chemotherapy, Trastuzumab LR Therapy Surgery XRT

Slide 4

Overview Analysis: Benefit from Tamoxifen 2005 Overview Analysis

Slide 5

Current Considerations and New Directions with Endocrine Therapy Recurrence patterns of ER-positive BCRecurrence patterns of ER-positive BC Optimal tamoxifen durationOptimal tamoxifen duration Aromatase InhibitorsAromatase Inhibitors Overview of efficacy data Remaining questions Combinations of AIs with other promising agents:Combinations of AIs with other promising agents: EGFR Inhibitors mTOR Inhibitors Bisphosphonates

Slide 6

Saphner et al. J Clin Oncol. 1996;14:2738. Long-Term Risk of Breast Cancer Recurrence Remains High in ER+ Patients A substantial proportion of breast cancer recurrences occur >5 years postsurgeryA substantial proportion of breast cancer recurrences occur >5 years postsurgery The annual risk of late recurrence is higher in ER+ tumorsThe annual risk of late recurrence is higher in ER+ tumors 0 0.1 0.2 0.3 0123456789101112 Recurrence hazard rate Years ER (n=1,305) ER+ (n=2,257)

Slide 7

Recurrences Breast Cancer Deaths More Than Half of Breast Cancer Recurrences and Deaths Occur Post-Tamoxifen Adapted with permission. Early Breast Cancer Trialists Collaborative Group Meeting, 2000. Years 85.2 76.1 68.2 73.7 62.7 54.9 68% 55% 0 20 40 60 80 100 051015 TamoxifenControl 15%17% 0 20 40 60 80 100 051015 73% 64% 80.9 73.0 87.8 73.2 64.0 Years TamoxifenControl 9%18% 91.4 % of patients

Slide 8

NSABP B-14 Tamoxifen Duration Years TRT N Events PLAC 569 106 TAM 583 137 p=0.03 Disease-Free Survival 40 60 80 100 01234567 Fisher et al: JNCI, 2001 TAM X 5 yrs TAM X 5 yrs Placebo X 5 yrs Randomization Node-Negative ER-Positive Registration TAM X 5 yrs Placebo X 5 yrs

Slide 9

Adjuvant Tamoxifen Longer Against Shorter (ATLAS) RANDOMIZE Tamoxifen 20 mg PO qd 5 years Postmenopausal women with invasive tumors Tamoxifen 20 mg PO qd 10 years Peto R, et al. 30th Annual San Antonio Breast Cancer Symposium. December 13-16, 2007; San Antonio, TX. Abstract 48. Preliminary Data N = 11,500 Woman Years Number of Recurrences Annual Rate of Recurrence Years 5 - 942,00013533% Years 10 - 1480002113% Recurrence Annual Event Rate 3.4% 5-yr tamoxifen 2.9% 10-yr tamoxifen Rate Ratio 0.866 SE (0.048) Breast Cancer Mortality Annual Event Rate 1.5% 5-yr tamoxifen 1.4% 10-yr tamoxifen Rate Ratio 0.895 SE (0.070)

Slide 10

ATLAS Preliminary Results Partial data suggest About 12% risk reduction in breast cancer recurrence years 5 - 9 from diagnosis with continued tamoxifen Limitations Incomplete biomarker testing 59% confirmed ER(+) Adherence ~ 80% Incomplete toxicity profile Peto R, et al. 30th Annual San Antonio Breast Cancer Symposium. December 13-16, 2007; San Antonio, TX. Abstract 48.

Slide 11

Adjuvant Tamoxifen To Offer More (aTTom) RANDOMIZE Discontinue Tamoxifen 20 mg PO qd Postmenopausal women with invasive tumors who received 2 years of tamoxifen N = 6934 Tamoxifen 20 mg PO qd 5 additional years Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513. Preliminary Data N = 6952 Discontinued Tamoxifen Continued Tamoxifen Relative RiskP Value Disease Recurrence4474450.95NS Median Follow-up 4.2 Years of 15-Year Analysis

Slide 12

0123456789101112 40 35 30 25 20 15 10 5 0 % Recurred Years From Randomization continue stop RR = 0.95 (0.83 - 1.09; P = NS) 35% 34% At risk: continue346831522831232018031303916629422254139548 stop3484316028292308178612849166354122501224911 Primary Endpoint: Disease Recurrence Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513. No. Patients No. Obs. Events Exp. Continue3468437447-9 Stop3484456445-1

Slide 13

Preliminary aTTom Results Limitations Confirmed ER(+) = 40% Various durations of tamoxifen use Adherence ~ 80% Incomplete toxicity profile Statistically, only 68% of the true effect of 10-year tamoxifen will be observed Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513.

Slide 14

Adjuvant Aromatase Inhibitors Replacing 5 Years of Tamoxifen as the Gold Standard AIs as Initial Therapy AIs After 2-3 Yrs of TAM AIs After 5 Years of TAM TAM X 5 Yrs AI X 5 Yrs TAM X 2-3AI X 2-3 TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs Three Strategies

Slide 15

Relative Reductions in DFS Event in 8 Reported AI Adjuvant Trials Percent IES 55 m ITA 52 m MA.17 30 m Up-Front After 2-3 yrs of TAM After 5 yrs of TAM ATAC 68 m 13% 58% 42% 24% 0 10 20 30 40 50 60 70 19% BIG 26 m 40% ABCSG/ARNO 28 m Coombs et al. ASCO 2006 Boccardo et al. ASCO 2005 Jakesz et al. Lancet 2005. AnastrozoleLetrozoleExemestane ABCSG-6 60 m 36% Howell A, et al: SABCS 2004 Thurlimann et al. N Engl J Med 2005. Goss et al. JNCI 2005 Jakesz et al. ASCO 2005 Mamounas et al. SABCS 2006 32% B-33 30 m

Slide 16

75% Reductions in Contralateral BC in 7 Reported AI Adjuvant Trials Percent IES 37 m ITA 36 m MA.17 30 m Up-front After 2-3 y of TAM After 5 y of TAM ATAC 68 m 42% 50% (ns) 46% 50% 0 10 20 30 40 50 60 70 25% ABCSG/ARNO 28 m Jakesz et al. SABCS 2004. Goss et al. JNCI 2005. Mamounas et al. SABCS 2006 Howell et al. SABCS 2004. Coombs et al. SABCS. 2004. Boccardo et al. JCO 2004 AnastrozoleLetrozoleExemestane 42% (ns) Thurlimann et al. ASCO 2005. BIG 1-98 26 m B-33 30 m

Slide 17

Aromatase Inhibitors Remaining Questions Are there significant differences in efficacy and toxicity between different AIs?Are there significant differences in efficacy and toxicity between different AIs? What is the proper time to initiate AIs?What is the proper time to initiate AIs? What is the optimal duration of AIs?What is the optimal duration of AIs? What is the role of AIs in premenopausal women who undergo ovarian function suppression?What is the role of AIs in premenopausal women who undergo ovarian function suppression? What is the role of AIs in patients with DCISWhat is the role of AIs in patients with DCIS

Slide 18

NCIC MA.27 Trial: Anastrozole vs. Exemestane Anastrozole 5 years Celecoxib 3 years Celecoxib 3 years Exemestane 5 years Placebo 3 years Placebo 3 years Postmenopausal ER+ and/or PgR+ Chemo or not Activated: 6/03 Accrual: 6,830

Slide 19

NCIC MA.27 Trial: Anastrozole vs. Exemestane Anastrozole 5 years Celecoxib 3 years Celecoxib 3 years Exemestane 5 years Placebo 3 years Placebo 3 years Postmenopausal ER+ and/or PgR+ Chemo or not Activated: 6/03 Accrual: 6,830

Slide 20

Primary end point:Disease-free survival Secondary end points: Safety, overall survival, time to distant mets, time to CBC, BC- specific survival Early Breast Cancer Postmenopausal ER+ and/or PgR+ Node-positive Anastrozole 1 mg/d RANDOM RRAANNDDOOMMIZEIZERRAANNDDOOMMIZEIZE Letrozole 2.5 mg/d N=4,000 De Boer et al. J Clin Oncol. 2006;24(18S):582s. Abstract 10672. Head-to-Head Adjuvant Phase IIIb Trial: Femara vs Anastrozole Clinical Evaluation (FACE)

Slide 21

RANDOMIZATION BIG 1-98 Trial Design 0 5 years 2 (Following complete tumor resection) Tamoxifen 20 mgn=2,446 Letrozole 2.5 mg Tamoxifen 20 mg n=2,446 Letrozole n=1,530 Tamoxifen n=1,530 Letrozole 2.5 mg

Slide 22

Sequential Treatment Comparisons Median Follow-up 71 months Tam Let vs. LetLet Tam vs. Let Mouridsen HT, et al: SABCS 2008, Abstr. 13

Slide 23

Breast Cancer Events Tam Let vs. Let OverallBy Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen HT, et al: SABCS 2008, Abstr. 13

Slide 24

Breast Cancer Events Let Tam vs. Let OverallBy Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen HT, et al: SABCS 2008, Abstr. 13

Slide 25

TEAM Exemestane vs. Tamoxifen TEAM Trial Amendment: TEAM Exemestane 5 y Tamoxifen 5 y Completed accrual: 5,700 pts (1,600 pts from US) EXE 5 y TAM 2-3 yEXE 2-3 y TEAM

Slide 26

MA.17: Disease-Free Survival Hazard Ratios of Letrozole to Placebo Hazard ratio Months after randomization Upper 95% CL Lower 95% CL Ratio estimate P

Gefitinib in Breast Cancer Previous clinical trials in breast cancer studies showed mainly negative results 1-3 Osborne et al 4 recently reported the first randomized, placebo controlled phase II study of tamoxifen and gefitinib: A modest improved PFS in patients with hormonal-nave disease or who had completed adjuvant tamoxifen >1 year (10.9 vs. 8.8 months, P=0.31) 1 Albain KS, et al SABC 2002 2 Dennison SK, et al Breast Cancer Res Treat 2007 3 Smith IE, et al J Clin Oncol,2007 4 Osborne CK, SABC 2007

Slide 34

Anastrozole +/- Gefitinib Randomized Phase II Trial Cristofanilli et al, ASCO 2008, Abstract 1012 Gefitinib 250 mg / day + Anastrozole 1 mg / day Placebo + Anastrozole 1 mg / day 1:1 randomization Patients Postmenopausal women Age 18 years Newly diagnosed ER and / or PgR positive metastatic breast cancer No prior hormonal therapy, or development of metastatic disease during / after adjuvant tamoxifen Measurable or non- measurable disease (via RECIST) Primary Progression-free survival Secondary Objective response rate Clinical benefit rate Overall survival Safety and tolerability Response variables Trial closed early due to poor accrual 94 patients randomized

Slide 35

Progression-Free Survival 30 Probability of PFS 1.0 0.8 0.6 0.4 0.2 0.0 0369121518212427 50 43 35 40 23 28 13 22 9 13 6 10 56565656 33333333 121212121 Placebo Gefitinib At risk: Months Events Median PFS (months) 22 14.5 32 8.2 Gefitinib + anastrozole (n = 43) Placebo + anastrozole (n = 50) HR (95% CI) = 0.55 (0.32, 0.94) Cristofanilli et al, ASCO 2008, Abstract 1012

Slide 36

Objective Response and Clinical Benefit Rate (RECIST) Objective response rate (CR+PR) Clinical benefit rate (CBR) (CR+PR+SD > 24 weeks) Response rate (%) Gefitinib + anastrozole (n = 43) Placebo + anastrozole (n = 50) 2.3% 12% 48.8% 34% ORR, objective response rate; CBR, clinical benefit rate; CR, complete response; PR, partial response; SD, stable disease Cristofanilli et al, ASCO 2008, Abstract 1012

Slide 37

Neoadjuvant Letrozole +/- RAD001 (Everolimus) Study designStudy design Phase II, randomized double-blind placebo-controlled trial Postmenopausal women with >T2 tumors Tumor samples (surgery) RANDOMIZERANDOMIZE Letrozole 2.5 mg/d Everolimus 10 mg/d Letrozole 2.5 mg/d Placebo n = 138 16 weeks Surgery Tumor biopsies (pretreatment) Tumor biopsies (day 15) SCREENSCREEN n = 132 Baselga et al, ASCO 2008, Abstract 530

Slide 38

Higher response with combinationHigher response with combination PE: 68.1% vs. 59.1%, P = 0.062 US: 58% vs 47%, P = 0.035 Greater decrease in Ki67Greater decrease in Ki67 Increased toxicityIncreased toxicity Hyperglycemia, stomatitis, infections, interstitial lung disease Neoadjuvant Letrozole +/- RAD001 (Everolimus)

Slide 39

ABCSG-12 Trial Design Accrual 1999-2006Accrual 1999-2006 1,803 premenopausal breast cancer patients1,803 premenopausal breast cancer patients Endocrine-responsive (ER and/or PR positive)Endocrine-responsive (ER and/or PR positive) Stage I & II,