1. Choosing between different hormonal therapies Rudy Van den Broecke UZ Ghent

2. What is the golden standard in premenopausal hormonal sensitive early breast cancer?

3. CT followed by +/- LHRH-a +/- Tam Ovarian protection with LHRH-a OS + AI Tamoxifen followed by AI Ovarian Suppression alone OS + Tam 5 years Tamoxifen

4. CT followed by +/- LHRH-a +/- Tam Ovarian protection with LHRH-a OS + AI Tamoxifen followed by AI Ovarian Suppression alone OS + Tam 5 years Tamoxifen

5. How to increase survival? EBCTCG Lancet 2005 Vol 365: 1687-1716

6. 15-y follow-up Tamoxifen vs. control Recurrence rates EBCTCG 2000 - The Lancet 2003

7. 15-y follow-up Tamoxifen vs. Control Deaths rates EBCTCG 2000 - The Lancet 2003

8. Ovarian Suppression + AI High risk patients Contra-indications for Tamoxifen Studies: SOFT – TEXT Informed consent Risk for osteoporose 2 to 5 years LHRH-a? When is the patient menopausal?

9. Tamoxifen followed by AI Peri-menopausal woman When is the patient menopausal? What when she starts bleeding again?

10. CT followed by +/- LHRH-a +/- Tam Ovarian protection with LHRH-a OS + AI Tamoxifen followed by AI Ovarian Suppression alone OS + Tam 5 years Tamoxifen Tamoxifen is still the golden standard !!

11. What is the golden standard in Postmenopausal hormonal sensitive early breast cancer?

12. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’s EXTENDEDSUPPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL

13. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’s EXTENDEDSUBPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL

14. Subgroup analysis 2 types of error Attributing an effect to a subgroup when there is no overall effect Claiming a lack of effect in a subgroup when the overall effect is significant * The more subgroups into which a data set is devided, the more likely it is that a statistically significant difference will be found by chance J. Cuzick: The Breast April 2008

15. Overview trials AI’s Randomisation Median follow-up periode Tamoxifen 5y Anastrozole 5y Tam 2-3y Exe 2-3y Tamoxifen 5y Letrozole 5y Letro 3yTam 2y Letro 2yTam 3y ATAC 100 months BIG1-98 50.9 months IES 55.7 months Letrozole 5y Placebo MA.17 2.4 years

16. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’S EXTENDEDSUBPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL

17. P rominent early peak of recurrences 5 10 15 20 25 0.51.52.53.54.55.56.57.58.59.510.5 Time (years) Hazard of recurrence by yearly interval Total Node 0 Node 1-3 Node (4+) Tumour size (<1 cm) Tumour size (1.1-3 cm) Tumour size (>3 cm) ER +ve ER -ve Premenopausal Postmenopausal ER, oestrogen receptor Saphner T et al. J Clin Oncol 1996 Baum M. ASCO 2005, poster 612

18. 05 Time (years) Initial adjuvant trial (ATAC, BIG 1-98) 5 years Tamoxifen 5 years Aromatase Inhibitor Randomisation FUDFS(HR+ patients) TTR(HR+ patients) TTDR(HR+ patients) OS(HR+ patients) ATAC Anastrozole vs Tamoxifen 68 mthsHR=0.83 SS HR=0.74 SS HR=0.84 NS HR=0.97 NS ATAC Anastrozole vs Tamoxifen 100 mthsHR=0.85 SS HR=0.76 SS HR=0.84 SS HR=0.97 NS BIG 1-98 Letrozole vs Tamoxifen 51 mthsHR=0.82 SS HR=0.78 SS HR=0.81 SS HR=0.91 NS ATAC: Lancet Oncology 2008; 9: 45-53 ATAC: Lancet 2005; 365: 60-62 BIG 1-98: Coates AS et al. J Clin Oncol 2007; 25(5) Aromatase inhibitors as initial therapy Patients Newly Diagnosed AI upfront Background Data

19. The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53 Time to recurrence ATAC 100 - HR+ patients Patients (%) 30 25 20 15 10 5 0 0123456789 12.5% 17.0% 21.8% Follow-up time (years) 9.7% 2.8%4.8% Absolute difference HR+ HR 0.76 95% CI (0.67, 0.87) p-value 0.0001 Tamoxifen (T) Anastrozole (A)

20. Recurrence rates continued to be lower with anastrozole after treatment completion¹ There is a statistically significantly difference in TTR (HR=0.75, 95% CI 0.61-0.94, p=0.01)¹, which shows a larger carryover effect for anastrozole ¹The ATAC Trialists’ Group. Lancet Oncol 2008; 9: 45-53 TTR, time to recurrence TTR: Carryover effect in post-treatment period

21. BIG1-98 Treatment arm of 5 years Tamoxifen is unblinded (June 2005) New methode of statistical analysis was proposed on ESMO Sept 2008 and data will be present in San Antonio 2008

22.  [TAM  LET] vs TAM  [TAM  LET] vs TAM [LET  TAM] vs LET  [LET  TAM] vs LET  [TAM  LET] vs LET  [TAM  LET] vs LET [TAM  LET] vs TAM  [TAM  LET] vs TAM [LET  TAM] vs LET  [LET  TAM] vs LET [LET  TAM] vs TAM  [LET  TAM] vs TAM [TAM  LET] vs [LET  TAM]  [TAM  LET] vs [LET  TAM] 5 Prospective Additional Sequence analysis Switching Analysis Ref. BIG 1-98, Poster at ESMO 09/2008

23. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’s EXTENDEDSUBPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL

24. Aromatase Inhibitors: After 2-3 y Tamoxifen 05 Time (years) 2-3 years’ prior Tamoxifen Switch trial (ITA, ARNO/ABCSG 8, IES) 3-2 y Tamoxifen 3-2 y Aromatase Inh Randomisation FUDFSOS ARNO Anastrozole vs Tamoxifen 30.1 mthsHR=0.66 SS HR=0.53 SS ARNO/ABCSG8 Anastrozole vs Tamoxifen 28 mthsHR=0.60 SS ND ARNO/ABCSG8/ITA Anastrozole vs tam 30 mthsHR=0.59 SS HR=0.71 SS IES Exemestane vs tam 55.7 mthsHR=0.76 SS HR=0.85 for ITT pts NS HR=0.83 for ER+/unknown pts SS ARNO: Kaufmann M et al. J Clin Oncol 2007; 25(19) - ARNO/ABCSG 8:Jakesz R et al. Lancet Oncology 2005; 366: 455-62 - ARNO/ABCSG 8/ITA: Jonat W et al. Lancet Oncology 2006; 7: 991-996 - IES: Coombes RC et al. Lancet Feb 2007

25. Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta- analysis. Copyright (2008), with permission from Elsevier. IES-trial: Exemestane After Tamoxifen: DFS

26. Survival in the switch strategy Update on IES: DFS subgroup analysis Coombes R. et al., The Lancet, 2007, vol 369, Issue 9561, 559 - 570 The size of benefit in DFS for switching to exemestane is consistent across subgroups

27. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’S EXTENDEDSUBPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL

28. 05 Time (years) Extended adjuvant trial (MA17, ABCSG 6a, NSABP33) Aromatase Inhibitor No treatment 5 years’ prior tamoxifen Randomisation FUDFSDDFSOS MA 17* Letrozole vs placebo 30 mthsHR=0.58 SS HR=0.61 SS HR=0.82 NS HR=0.61 for Node + SS ABCSG 6a Anastrozole vs no treatment 60.4 mths HR=0.64 SSND NSABP 33** Exemestane vs placebo 30 mthsHR=0.68 NSND *Early unblinded trial **Trial closed prematurely Aromatase Inhibitors: After 5 y Tamoxifen MA 17: Goss PE SABCS 2005 presentation ABCSG 6a: Jakesz R ASCO 2005 Poster 526 NSABP 33: Mamounas E SABCS 2006 Abstr 48

29. DFS Distant DFS OS Node- Negative Patients Node- Positive Patients HR: 0.61* (0.45-0.84) HR: 0.45* (0.27-0.73) HR: 0.63 (0.31-1.27) HR: 0.53* (0.36-0.78) HR: 1.52 (0.76-3.06) HR: 0.61* (0.38-0.98) *Statistically significant benefit of letrozole. Goss PE, et al. J Natl Cancer Inst. 2005;17:1262-1271. Extended Adjuvant Therapy: Letrozole After 5 Years of Tamoxifen MA.17 A similar reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patients Median follow-up 2.4 years

30. Can we identify a superior AI or AI adjuvant strategy? ATAC and BIG1-98 have demonstrated the superiority of AI over TAM in reducing the recurrence risk in the adjuvant setting IES, ABCSG8, ARNO 95 and ITA demonstrated that the switch from TAM to AI after 2-3 years treatment is more effective than continuing TAM for 5 years The different studies can not be directly compared to one another because of the different study groups different definitions of the endpoints

31. Can we identify a superior AI or AI adjuvant strategy? The side effects of the three different AI’s seem to be equivalent There appear to be no difference in side effects whether the AI’s are used in upfront or in a switch strategy In the switch strategy, the patient population is selected for good respons to endocrine therapy

32. Considering the the high rate of early recurrences, especially early distant metastases, the use of the strongest availlable therapy, in order to reduce most effectively the early relapse risk is certainly warranted

33. CONTRA-INDCATIONS FOR TAMOXIFEN More than 5y AI’s EXTENDEDSUBPOPULATIONS UPFRONT UPFRONT CYP2D6 SWITCH ≠ SEQUENTIAL An AI upfront should be at this moment the golden standard

34. Additional information FRAGRANCE trial Genomics could be the key to identify women who are particulary endocrine sensitive and who will benefit most from an AI rather than from tamoxifen l

35. What do we know Take home massages (1) Premenopausal:  Tamoxifen 5 years  LHRH-a as ovarian protection in study or informed consent  Verify the menopausal status carefully before starting an AI  Ovarian suppression is still an option

36. Take home massages (2) Postmenopausal:  Upfront 5y with Anastrozole or letrozole is the only proven treatment strategy for new diagnosed patients that shows an advantages in TTR – DFS – CLBC – TTDR versus 5y Tamoxifen in long follow-up  Patient already on Tamoxifen should be switched at the earliest opportunity to an AI. Here the best option is exemestane  Patient after 5 years Tamoxifen should switch to letrozole if high risk of recurrence

37. What will we probably know: not know in near future Open trial TEAM (San Antonio 2008)Is a sequence therapy of Tamoxifen followed by Exemestane better than 5 years Exemestane? Open trial TEAM (San Antonio 2008) Is a sequence therapy better than 5 year Letrozole? BIG1-98 (modified protocol San Antonio 2008) Are there differences between the AI’s? FACE – MA 27 Is longer therapy with a AI better than 5 years ? Differents trials ongoing