1. Neoadjuvant Endocrine Treatment in Breast Cancer Giorgio Mustacchi Centro Oncologico Università di Trieste

2. Tamoxifen if very effective in Locally Advanced Breast cancer Trieste, 1979; Tam + RT

3. Tamoxifen is very effective in Early Breast Cancer GRETA STUDY PLAN Operable breast cancer, age > 70 years RANDOM Loading dose in order to achieve Tam plasma steady level in 24 hours (Mustacchi Ann Oncol, 2003) N = 474 pts: the biggest trial in the world

4. Local Response with Tamoxifen alone (mx) Mean time to best ever response: 5,2 months (3 - 56) 95 % CI: 3.7 - 6.5 Median duration : 19 months (4 - 118) 95 % CI: 15.4- 30.1 ORR: 41.6 % (Mustacchi Ann Oncol, 2003)

5. Overall Survival Log Rank p = 0.8 At risk1yr 2yrs 5yrs 6yrs 10yrs Surg 236 218 157 124 40 Tam 233 220 153 120 55 (Intent to treat)

6. Breast Cancer Survival Log Rank p = 0.1 At risk1yr 2yrs 5yrs 6yrs 10yrs Surg 230 219 156 120 25 Tam 230 219 147 119 55 (Intent to Treat)

7. Local progression Log Rank p <.00000 (Treatment given) (Mustacchi Ann Oncol, 2003)

8. Endocrine Therapy alone? GRETA (small tumors) –No difference in survival CRC (UK; larger tumors) –Better survival with surgery + tamoxifen Neoadjuvant Endocrine Therapy

9. Treatment and Survival in old women (Bouchardy, JCO Oct 2003)

10. Overall Survival and Type of Surgery Log Rank p = 0.6 (Mustacchi Ann Oncol, 2003)

11. Tamoxifen Neoadjuvant Endocrine Therapy

12. ATAC: Retrospective analysis of FS for ER/PgR subgroups (Howell SABCS 04) At risk: A451435417400390347124 T42941237535332727696 Follow-up time (years) 25 0 5 10 15 20 0123456 Anastrozole (A) Tamoxifen (T) Patients (%) Patient group HR+ ER+PgR+ ER+PgR- Hazard ratio 0.79 0.84 0.43 ER+/PgR-

13. IES DFS (Coombes, SABCS 04)

14. Antiaromatase Neoadjuvant Endocrine Therapy

15. p<0.05 Semiglazov : 83 pts; SABCS 2003, Abs111 Neoadjuvant Exemestane vs Tamoxifen

16. Mustacchi : 19 pts; unpublished Neoadjuvant Exemestane in old women The Italian Study

17. Endocrine Neoadjuvant : take home message The smallest the tumor the highest RR AI are more active than tamoxifen 6 months seems better than 3 months for Tam 3 months seems enough for AI In responders ( 20-50 %) minimal surgery is indicated/possible Response to Neoadjuvant could predict response to adjuvant Early prediction of response is pivotal

18. Neoadjuvant Chemotherapy Clin RR %pCr %BCS % Aberdeen San Antonio 03 623467 GEPARDUO San Antonio 02 6714.876 NSABP B27 JCO 03 9118.768.8

19. pCR and Survival Heys, ASCO 2002; Aberdeen Trial Same findings: Bonadonna (JCO 1998) & NSABP B18 (JCO 1998)

20. Chemo- vs Endocrine Neoadjuvant Therapy BCS 70 – 80 % vs 35-50 % pCR 20 % vs 2 %

21. Neoadjuvant Aromatase Inhibitors followed by minimal surgery are the best choice in older patients (if ER/PGR + responders) 1980 - 2004 : 5.780 New Cases Patients of age > 70 years (23.1 %) % Breast Cancer in Trieste age distribution

22. Neoadjuvant CHT vs HT Doxo+Paclitaxel 60+200 qq21 x 4 Anastrozole X 3 months p value Nr6230 % Clinical OR75.889.8> 0.05 % MX OR62.969.4> 0.5 % BCS20.937.20.054 T2N1-2, T3N0-1,T4N0; ER and/or PgR + (Semiglazov, ASCO 2004, Abs 519, main session)

23. NSABP – B27: response by ER statusAC AC→T % pCR 13.6 22.8 5.7 14.1 31.6 50.8 p=0.0024p<0.001

24. Neoadj Trastuzumab and receptor status Buzdar, ASCO 2004

25. Diagnosis 10-14 days 3 months Responders 8 (4-18) 3 (2-12) 4 (2-11) 38 patients p=0.0015 p=0.0003 Non-responders 9 (6-12) 10.5 (7-15) 14 (8-20) 12 patients 3 months Tamoxifen Median % Proliferating Cells (Interquartile Range) Dixon, Venice 2004

26. ProliferationProliferation + Response or No Response Recurrence17% (5/29) 59% (13/22) No Recurrence83% (24/29) 41% (9/22) Recurrence Rates at 8 years following Neoadjuvant Tamoxifen: 51 Patients Dixon, Venice 2004

27. Neoadjuvant Exemestane in old women The Italian Study Ki67 variations in the first 6 pts (%) -90 - 95 0 -53 +50 -88

28. 024681012 100 80 60 40 20 0 < 90 Days > 90 Days p<0.05 Years % Survival Cameron et al Br J Cancer 1997; 76 : 1099-1105 Survival after neoadjuvant hormone therapy vs time to halve tumour volume

29. 3 Month Ki67 Changes with Letrozole, Anastrozole and Tamoxifen in ER+ Cancers Dixon, Venice 2004

30. IMPACT: Molecular effects of Anastrozole vs Tamoxifen (2 & 12 wks % variation) (Dowsett, ASCO 2004, Abs 537) ANA 2ANA 12TAM 2TAM 12 Ki 67 *- 76- 82- 59- 62 Apoptosis*- 26- 21-15- 3 Growth Index* - 66-77- 51- 61 ER+ 3- 3+ 4- 13 PgR *- 41- 82+ 48+ 3 E2 *- 88 - 70 * : ANA vs TAM significant

31. Endocrine Neoadjuvant Therapy Just for older women Or An alternative to CHT In early HT responders ?

32. 25 % of breast cancers patients are HER2 Positive

33. HER2 IHC 2/3 + : Prediction of adjuvant tamoxifen resistence (+/- Chemo) P =.006 The GUN Study Bianco, ASCO 1998 The SWOG Study Ravdin, ASCO 1998 P =.01

34. HER2 + : predictive of resistence to any hormonal treatments ? Neoadjuvant setting N = 36 Ellis, JCO Sep 2001Dowsett, S. Antonio 03 N = 21 Neoadjuvant Anastrozole VS Tamoxifen

35. HER2 and resistence to endocrine treatments. Take Home message HER2 + is predictive of relative resistence to tamoxifen Resistence to AI could be absent or different between AI Data are conflicting and more informations are needed RE+ HER2 + : endocrine treatment alone ?