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

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

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

Overview Analysis: Benefit from Tamoxifen 2005 Overview Analysis

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

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 Recurrence hazard rate Years ER– (n=1,305) ER+ (n=2,257)

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, Years % 55% TamoxifenControl 15%17% % 64% Years TamoxifenControl 9%18% 91.4 % of patients

NSABP B-14 Tamoxifen Duration Years TRT N Events PLAC TAM p=0.03 Disease-Free Survival 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

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 , % Years % Recurrence Annual Event Rate 3.4% × 5-yr tamoxifen 2.9% × 10-yr tamoxifen Rate Ratio SE (0.048) Breast Cancer Mortality Annual Event Rate 1.5% × 5-yr tamoxifen 1.4% × 10-yr tamoxifen Rate Ratio SE (0.070)

ATLAS Preliminary Results Partial data suggest –About 12% risk reduction in breast cancer recurrence years 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.

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 Recurrence NS Median Follow-up 4.2 Years of 15-Year Analysis

% Recurred Years From Randomization continue stop RR = 0.95 ( ; P = NS) 35% 34% At risk: continue stop Primary Endpoint: Disease Recurrence Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513. No. Patients No. Obs. Events Exp. Continue Stop

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.

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

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

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

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

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

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

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 Head-to-Head Adjuvant Phase IIIb Trial: Femara ® vs Anastrozole Clinical Evaluation (FACE)

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

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

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

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

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

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< for hazard ratio trends based on time dependent Cox model I n gle JN, et al: San Antonio, 2005 # 17

Duration of AIs MA.17 Extended Adjuvant: 5 vs. 10 Yrs 5 y 15 y 10 y 0 y MA.17 Tamoxifen Placebo Letrozole MA.17 Extension (n=900) (n=900) Adapted from Goss. ASCO, Status of Trial 949 patients enrolled as of August 26, 2008

NSABP B-42 Trial Evaluating Adjuvant AI Duration AI X 5 yrs AI X 3-2 yrs TAM X 2-3 yrs Letrozole X 5 yrs Placebo X 5 yrs Primary Endpoint Primary Endpoint Disease-free survival Secondary Endpoints Secondary Endpoints Overall survival Overall survival Time to treatment failure Time to treatment failure Osteoporosis-related fractures Osteoporosis-related fractures Postmenopausal, Disease-free, Stage I, II, or III invasive BC at diagnosis ER-positive and/or PgR-positive Current Accrual: 1,882 / 3,840

*Randomization within a 6-month evaluation period after end of CT, or within 12 weeks after definitive surgery for patients with no CT. SOFT (IBCSG 24-02, BIG 2-02) Premenopausal ER+  10% and/or PgR+  10% Patients with estradiol (E 2 ) in the premenopausal range either after CT or without CT RANDOMIZERANDOMIZE TAM  5 y OFS + TAM  5 y OFS + EXE  5 y Any CT No CT Strata Target sample size: 3,000 patients * Patients who remain premenopausal within 6 months after CT or receive tamoxifen alone as adequate treatment OFS = ovarian function suppression.

NSABP B-35 Postmenopausal women ER- or PgR-positive DCIS Lumpectomy with free margins Anastrozole Tamoxifen XRT Randomization 1/03-6/06 Accrual: 3,104

Recent data with AIs in combination with other agents: EGFR Inhibitors mTOR Inhibitors Bisphosphonates

EGFR Interaction with the ER EGF Growth and survival P E2 P ER CoA ERER ER EGFR MAPK c-Src EGF HBHB nucleus EREs AF1 E2 EGFR HER2 HER3 E2 HBHB MMPs

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-naïve disease or who had completed adjuvant tamoxifen >1 year (10.9 vs. 8.8 months, P=0.31) 1 Albain KS, et al SABC Dennison SK, et al Breast Cancer Res Treat Smith IE, et al J Clin Oncol, Osborne CK, SABC 2007

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

Progression-Free Survival 30 Probability of PFS Placebo Gefitinib At risk: Months Events Median PFS (months) Gefitinib + anastrozole (n = 43) Placebo + anastrozole (n = 50) HR (95% CI) = 0.55 (0.32, 0.94) Cristofanilli et al, ASCO 2008, Abstract 1012

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

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 = weeks Surgery Tumor biopsies (pretreatment) Tumor biopsies (day 15) SCREENSCREEN n = 132 Baselga et al, ASCO 2008, Abstract 530

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

ABCSG-12 Trial Design Accrual Accrual ,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, <10 positive nodesStage I & II, <10 positive nodes No chemotherapy except neoadjuvantNo chemotherapy except neoadjuvant Treatment duration: 3 yearsTreatment duration: 3 years Primary endpoint: DFSPrimary endpoint: DFS Randomize 1:1 : 1:1 Surgery (+RT) Tamoxifen 20 mg/d Goserelin 3.6 mg q28d Anastrozole 1 mg/d + Zoledronic acid 4 mg q6m Anastrozole 1 mg/d Tamoxifen 20 mg/d + Zoledronic acid 4 mg q6m Gnant et al, ASCO 2008, LBA 4 Median follow-up: 60 months

ABCSG-12: Patient Characteristics Tamoxifen n = 452 Tamoxifen + ZA n = 449 Anastrozole n = 450 Anastrozole + ZA n = 449 Median Age (years) T175% 77%76% ≥ T222% 21%22% Node Negative67%66%67% Grade 3 Disease 21%20%22% Neoadjuvant Chemotherapy 5% 6% Breast Conservation 80% Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.

First Efficacy Results Median Follow-up 60 Months N = 1801Hazard RatioP Value Primary Endpoint: Disease-free Survival Tamoxifen vs Anastrozole1.01 ( ).59 Endocrine Therapy + ZA vs Endocrine Therapy Alone 0.64 ( ).01 Secondary Endpoints Relapse-free Survival Endocrine Therapy + ZA vs Endocrine Therapy Alone 0.65 ( ).015 Overall Survival Endocrine Therapy + ZA vs Endocrine Therapy Alone 0.60 ( ).10 Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.

Number at risk TAM ANA ABCSG-12: Primary Endpoint: DFS Anastrozole vs. Tamoxifen Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA No. of events Hazard ratio (95% CI) vsTAM P Value Value ANA72/ ( ).593 TAM65/900 Disease-free Survival Time Since Randomization (months)

Number at risk No ZA ZA ZA Disease-free Survival 0.64 ( ) ABCSG-12: Primary Endpoint: DFS +/- Zoledronic Acid.011 Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4. events Hazard ratio (95% CI) vs No ZA P Value Value No. of ZA54/904 No ZA 83/899

ABCSG-12 ITT Population First Events Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.

ABCSG-12 Clinical Impact Select, premenopausal patient population –Unknown if results can be extrapolated to postmenopausal women or more advanced disease Await data from ongoing clinical trials to confirm and expand findings –AZURE, NSABP B-34, Z-FAST/ZO-FAST, SWOG 0307 –SOFT and TEXT Not yet practice changing

Hormonally Sensitive Early-Stage Breast Cancer Current Considerations and New Directions Concluding Remarks Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer