1. Aromatase inhibitor therapy for early breast cancer. Giorgio Mustacchi Centro Oncologico Università di Trieste

2. Low Intermediate High Node – HER2 – LVI absent Node –, HER2+ or LVI present Node + (1-3) and HER2 - Node + (1-3) and HER2 + Node +  4 G1 T  2 AGE < 35 G2-3 T>2 RISKRISKRISKRISK RISKRISKRISKRISK ST. GALLEN 2005: DEFINITIONS OF RISK

3. 2000 Oxford Overview: ER Status is not a prognostic factor N-N+ EBCTCG, Lancet 2005 No Treatment arm

4. Overall survival ∆: MA-17 N+ (HR: 0.61, p=0.04), IES (HR: 0.83, p=0.05) TrialDesignF/UN∆ in DFS ATAC (Lancet 2005) A vs T vs AT (double-blind) ~ 5 yr9366 2.5%- 3.0% BIG 1-98 (ESMO 2006) T vs Let (double-blind) ~ 4 yr 8028 (4922) ~ 3% ABCSG-8 ARNO95 (Lancet 2005) T  Ana vs T (open label) ~ 3 yr32243% IES (ASCO 2006) T  Exe vs T (double-blind) ~ 5 yr (2-3 post- treat) 47243.5% MA.17 (JNCI 2005) L vs Placebo (double-blind) ~ 3 yr51874.6% Key Aromatase Inhibitors Trials All Favor AI Arm

5. RISKRISKRISKRISK TAM or AI or NIL TAM  AI or ADD CHEMOTHERAPY AI Endocrine- responsiveness Absent UncertainSure ST. GALLEN 2005: GUIDELINES FOR ADJ HT

6. Neoadjuvant IMPACT: Short Term Predictors for ATAC? HR95.2% CI P Value ANAvs TAM0.830.71-0.960.0129 Combvs TAM1.020.88-1.180.7718 Anastrozole Tamoxifen Combination Time to event (mo) Proportion event-free (%) 0 80 85 90 95 100 06121824303642 ATAC n 9366 pts DFS 33 mo A C IMPACT n 330 pts Clinical OR 12 wks Biological Ki67 2 wks T

7. 24% 20% 28% 0 10 20 30 40 50 ATC 39% 36% 37% 0 10 20 30 40 50 ATC Objective Response (%) Overall Population (330 Intent to Treat) OR (%) A v T: OR 1.05 (0.61, 1.81) p=0.87 C v T: OR 1.15 (0.67, 2.00) p=0.61 OR (%) A v T: OR 1.23 (0.65, 2.32) p=0.53 C v T: OR 1.48 (0.79, 2.79) p=0.22 Clinical Ultrasound

8. EARLY BREAST CANCER TREATMENT: LESSONS LEARNED FROM CLINICAL TRIALS An intervention produces, on average, a 50% relative risk reduction in relapse Higher risk women will, on average, derive a greater absolute Higher risk women will, on average, derive a greater absolute benefit 20% 10% 40% 20% Initial risk Final risk N-N+ There is heterogeneity in the magnitude of treatment benefit ! Subset A: 70% relative risk reduction Subset A: 70% relative risk reduction Subset B: <30% risk reduction <30% relative risk reduction Subset B: <30% risk reduction <30% relative risk reduction

9. Molecular Portrait of Breast Cancers HER-2 Basal-like Luminal A Luminal B“Normal” Sorlie, PNAS 2001

10. # Gene profile = # pCR Molecular Type % pCR95% CI Basal-like4524-68 HER2 +4524-68 Luminal A & B61 - 21 Rouzier, Clin Cancer Res. 2005

11. Oncotype DX Recurrence Score REFERENCE Beta-actin GAPDH RPLPO GUS TFRC PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 CD68 16 Cancer and 5 Reference Genes

12. NSABP B14-Results: Benefit from Tamoxifen Paik, NEJM 2005 Tam: High RS DFS = Placebo

13. AROMATASE INHIBITORS AND TAMOXIFEN: HETEROGENEITY IN THE TREATMENT EFFECT A B Subset A : 70 % reduction ? Subset B : 30 % reduction ? On average : 50 % reduction in the odds of relapse molecular signature ? molecular signature ? PGR ?HER-2 ? Other molecular markers ?

14. EGFR HER2 Tam-STam-R Knowlden et al. Endocrinology 144:1032, 2003  10% ‘conversion rate’ to HER2 overexpression in breast cancers that recur (early) on adjuvant tamoxifen (Gutierrez et al. J Clin Oncol 2005; 23:2469) Tamoxifen-resistant breast tumors acquire ErbB receptor overexpression

16. De Laurentiis et al. Clin. Cancer Res. 11:4741, 2005 ER+/HER2+ BC and endocrine therapy N=1,925

17. HER2 + : predictive of resistence to any hormonal treatment ? Ellis, JCO Sep 2001 Dowsett, S. Antonio 03 Neoadjuvant Anastrozole VS Tamoxifen

18. ER+/PR- and hormonal treatment (ATAC trial) From Cui et al. JCO 23:7721, 2005

19. Data are HRs and 95% CIs HR Log Scale Exemestane better Tamoxifen better 0.64 (0.51-0.79) 0.67 (0.39-1.16) 0.58 (0.38-0.90) 0.66 (0.51-0.87) HR (95% CI) 0.40.60.81.01.2 Subgroup (n) All ER+ (3853) ER+/PgR unknown (499) ER+/PgR- (735) ER+/PgR+ (3853) Coombes RC, et al. N Engl J Med. 2004;350:1081-1092. IES 031: DFS According to ER/PgR

20. *Based on local assessment. 1.0 0.5 0.751.332.0 CT given (n = 2024) CT not given (n = 5986) 0.70 0.85 Node (+) (n = 3311) Node (-) (n = 4587) 0.71 0.96 ER+/PgR+ (n = 5055)* ER+/PgR- (n = 1631)* 0.84 0.83 Favors LETFavors TAM HR (LET:TAM) Thürlimann BJ, et al. N Engl J Med. 2005;353:2747-2757. BIG1-98 (Subgroups: DFS)

21. Viale G, et al. SABCS 2005. Abstract 44. Disease-Free Survival Hazard Ratio (95% CI) Letrozole vs Tamoxifen All patients (N = 4399) 0.71 (0.57-0.88) ER+/PgR+ (n = 3330) 0.67 (0.51-0.88) ER+/PgR- (n = 832) 0.88 (0.55-1.41) ER+/HER2- (n = 3971) 0.72 (0.56-0.91) ER+/HER2+ (n = 234) 0.68 (0.33-1.41) The difference is not significant. No tamoxifen resistance observed in ER+/PgR- tumors (??) BIG 1-98: Central Review of ER, PgR, and HER2

22. ER/PgR HER2 & Tamoxifen DFS in tamoxifen- treated patients Arpino, G. et al. J Natl Cancer Inst 2005;97:1254-1261 ER+/PR+ ER+/PR-

23. Need an AI from start Cured without therapy Cured with TAM only TRANSLATIONAL RESEARCH MIGHT SHED LIGHT ON THE HETEROGENEITY OF ER+ BC who needs an early switch ? who does better with a late switch ? Best helped by sequencing... but : ER-ER+

24. AROMATASE INHIBITOR VERSUS TAMOXIFEN WAITING FOR THE FINAL BENEFIT/RISK ASSESSMENT  Osteoporosis risk  Musculo-skeletal events  Cost Neurocognition Sexual function Lipid metabolism Cardiovascular disease  DVT  Stroke  Endometrial Ca  Hot flashes TAMOXIFEN AROMATASE INHIBITOR ?

25. Arguments in favour of the switching strategy First OS advantage demonstration vs tamoxifen –ITT 15% (-2% – 29%) p = 0.08 –ER+/Unknown17% (0% – 31%) p = 0.05 To minimize the adverse risk of both agents To monitoring the menopausal status in patients with chemo-induced amenorrhea

26. HR for recurrence in switched adjuvant trials of AIs vs tamoxifen ABCSG 8 / ARNO 95 1 (anastrozole) ITA 2 (anastrozole) IES 3 (exemestane) 0.60* 0.35* 0.75 † HRFollow-up (months) *all patients; † HR+ve patients 28 36 56 1 Jakesz R et al. Lancet 2005 2 Boccardo F et al. J Clin Oncol 2005 3 Coombes RC et al. Lancet 2007 Trial

27. MA 17: Postunblinding results (Switch vs Placebo)

28. EFS ABCSG 8 Trial (Switch vs Sequence)

29. Arguments in favour of the upfront strategy Contraindication to TAM Previous therapy with SERMs Risk of early relapse (adverse prognostic factors) Biological rationale (PGR-, HER2+) Results based on unselected patients

30. Smoothed event rates for recurrence ( HR*-positive population ) 0123456 Follow-up time (years) Annual hazard rates (%) Anastrozole Tamoxifen 0.5 1.0 1.5 2.0 2.5 3.0 0 *HR=hormone receptor

33. Postmenopausal women Histologically or cytologically confirmed, receptor- positive, adequately excised, primary breast cancer N = 6350* 5 years Exemestane 25 mg/day Anastrozole 1 mg/day Surgery ± RT ± chemo- therapy MA.27: Study Design Randomization *Closed to accrual. Primary endpoint: event-free survival

35. TEAM Phase III, open-label, randomized trial of 5 years’ adjuvant exemestane vs adjuvant tamoxifen followed by exemestane Postmenopausal women with hormone receptor–positive, early-stage breast cancer Sample size = 1240; closed to accrual

36. Oxford 2006 Aromatase Inhibitors vs Tamoxifen Summary RR2p Death Any Cause0.89 (# 0.7%)0.01 BC Deaths0.80 (# 1%)0.0002 Non BC Deaths1.07 (CI very large) 0.4 Fractures1.48 (# 1.4 %)< 0.00001 Much longer Fup is needed

37. Patient on day 0 of adjuvant ET High risk Contra-indication to TAM Doubt about TAM sensitivity (e.g. HER2+ and/or PR-) Anastrozole or Letrozole Other patients Tamoxifen with switch to Ana/Exe at later time Patient on adjuvant TAM Medium to high risk and/or Doubt about TAM sensitivity Switch Switch encouraged Very low risk Discussion with more weight on known / unknown drug side- effects profiles Ana/Exe if early switch (2-3y) Letrozole if late switch (4-6y) Possible Algorithm for Adj Ht in Postmenopausal pts