1. Department of Surgery, United Christian Hospital Aromatase Inhibitors Current Use in Breast Cancer JHGR 16 Jan 2005 Dr. Sharon Chan Department of Surgery, UCH

2. Estrogen and breast cancer growth Estrogen – main hormone involved in pathogenesis of breast tumors ER & PR status are the most important biomarkers

3. Anti-estrogen in breast cancer

4. Tamoxifen in Breast Cancer Used in treatment of MBC since 70 ’ s Used in treatment of MBC since 70 ’ s Golden standard for adjuvant therapy in 90 ’ s Golden standard for adjuvant therapy in 90 ’ s  Improve 10 yr survival 10.9% in 75000 node +ve  Increase 10 yr survival 5.6% in 2644 node - ve EBCTCG. Systemic treatment of early breast cancer ….Lancet 1992; 339: 71-85 EBCTCG. Systemic treatment of early breast cancer ….Lancet 1992; 339: 71-85

5. Limitation of tamoxifen Partial agonist effect Increase risk of  uterine cancer  Thromboembolism Tumor cell resistance  Eastern Cooperative Oncology Group (J NCI 1996)  Scotish Cancer Trials Breast Group (BJC 1996)  NSABP B14 (J NCI 2001)

6. Aromatase Inhibitors Introduction Introduction  Mechanism of action Current Use Current Use  Advanced breast cancer  Adjuvant therapy  Neo-adjuvant  Chemoprevention

7. Aromatase Inhibitor -Introduction

8. Aromatase - biosynthesis of oestrogen

9. Potency of Aromatase Inhibitors % suppresion total body aromatase % suppresion total body aromatase 1 st generation 2 nd generation 3 rd generation 1x 10-100x 100-2000x 1x 10-100x 100-2000x

10. Types of Aromatase inhibitors

11. Mechanism of action ANDROGENS OESTROGENS P-450 Aromatase + NADPH-cytochrome P-450 reductase (Testosterone, androstenedione, 16-OH-testosterone) (Oestradiol, oestrone) Aromatase Inhibitors tumour growth

12. Postmenopausal Woman peripheral aromatisation Breast tumour MuscleFatLiver

13. Intra-tumoral aromatase activity

14. AI in pre-menopausal woman

15. Aromatase Inhibitor in advanced breast cancer

16. Aromatase inhibitor in advanced disease as second line therapy

17. Aromatase inhibitor in advanced disease as first line therapy

18. Aromatase Inhibitors in adjuvant therapy

19. Major Adjuvant studies of AI Direct comparison Direct comparison  ATAC, TEAM, MA 27 Sequencing therapy Sequencing therapy  IES, ABCSG, ARNO (after 2-3 yrs TAM)  MA 17, NSABP B-33 (after 5 yrs TAM) Combination with ovarian suppression Combination with ovarian suppression  SOFT  TEXT

20. ATAC (Arimidex, Tamoxifen Alone or in Combination)

21. ATAC – result at median 33m FU Disease free survival (3y) Disease free survival (3y)  Ana 89.4% vs Tam 87.4% (HR 0.83, p=0.013)  Combination 87.2% vs Tam 87.4% (HR 1.02, p=0.8) Incidence of contralateral breast cancer Incidence of contralateral breast cancer  Ana vs Tam 0.3% vs 1% (OR 0.42, p=0.007)  Combination 0.7% vs Tam 1% (OR 0.84, p=0.51) ATAC Trialist ’ s Gp. Anastrozole alone or in combination ….Lancet. 359(9324):2131-9, 2002 Jun 22 ATAC Trialist ’ s Gp. Anastrozole alone or in combination ….Lancet. 359(9324):2131-9, 2002 Jun 22

22. ATAC, completed treatment analysis -based on a median FU of 5 years Disease free survival (HR +ve pt) Disease free survival (HR +ve pt) Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

23. ATAC, completed treatment analysis -based on a median FU of 5 years Time to Recurrence (HR +ve pt) Time to Recurrence (HR +ve pt) Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

24. ATAC, completed treatment analysis -based on a median FU of 5 years Incidence of contralateral breast cancer (HR +ve pt) Incidence of contralateral breast cancer (HR +ve pt) Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

25. ATAC, completed treatment analysis -based on a median FU of 5 years Time to distant recurrence (HR +ve pt) Time to distant recurrence (HR +ve pt) Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

26. ATAC, completed treatment analysis -based on a median FU of 5 years Overall survival (HR +ve pt) Overall survival (HR +ve pt) Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

27. ATAC, completed treatment analysis -based on a median FU of 5 years Overview of adverse events Overview of adverse events Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

28. ATAC, completed treatment analysis -based on a median FU of 5 years Pre-specified adverse events % Pre-specified adverse events % Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04 Howell et al, ATAC Trialist Group, presented in San Antonio symposium 04

29. IES – Exem after 2-3 yr Tam 4742 patients 4742 patients Swtiching Tam 2-3y + Exem vs Tam 5y Swtiching Tam 2-3y + Exem vs Tam 5y 183 vs 266 new events 183 vs 266 new events Unadjusted HR 0.68 (0.56-0.82, p<0.001) Unadjusted HR 0.68 (0.56-0.82, p<0.001) R Coombes RCT of exemestane after 2-3 yrs of Tam..NEJM 350(11): Mar 04: 1081-1092 R Coombes RCT of exemestane after 2-3 yrs of Tam..NEJM 350(11): Mar 04: 1081-1092

30. MA 17 – Letrozole after 5yr TAM 5187 patients 5187 patients Let reduced recurrence (42%), Distant disease recurrence (40%) Let reduced recurrence (42%), Distant disease recurrence (40%) Let reduced new contralateral breast cancer (37.5%) Let reduced new contralateral breast cancer (37.5%) Est 4y survival Let 93% vs placebo 87% (p<0.001) Est 4y survival Let 93% vs placebo 87% (p<0.001) SE (hot flushes, osteoporosis) more frequent, but NS SE (hot flushes, osteoporosis) more frequent, but NS Stopped after interim analysis (median FU 2.4 y) Stopped after interim analysis (median FU 2.4 y) Goss E NEJM 349 (19); Nov 03: 1793-1802 Goss E NEJM 349 (19); Nov 03: 1793-1802

31. ASCO Technology Assessment 2005 Optimal adjuvant hormonal therapy for a postmenopausal woman with receptor +ve breast cancer included an AI as initial therapy or after treatment with tamoxifen Optimal adjuvant hormonal therapy for a postmenopausal woman with receptor +ve breast cancer included an AI as initial therapy or after treatment with tamoxifen  Winter E et al J Clin Onc 23; 3 Jan 2005

32. Aromatase Inhibitor Other roles

33. AI – neoadjuvant therapy Higher rate of regression than tamoxifen Higher rate of regression than tamoxifen OR Let 55% vs Tam 36% (p<0.001) OR Let 55% vs Tam 36% (p<0.001) BCT possible Let 45% vs Tam 36% (p=0.022) BCT possible Let 45% vs Tam 36% (p=0.022)   Ellis MJ et alLetrozole is more effective neoadjuvant … Clin Oncol 2001 Sep 15;19(18):3808-16

34. AI - chemoprevention Chemoprevention Chemoprevention  Tamoxifen dec contralateral CA breast by 50%  AI further dec contralateral CA breast by 26%

35. Conclusion AI as first line and second line therapy for advanced CA breast AI as first line and second line therapy for advanced CA breast Included as initial and subsequent therapy in adjuvant setting Included as initial and subsequent therapy in adjuvant setting Potential use in chemoprevention and neo- adjuvant therapy Potential use in chemoprevention and neo- adjuvant therapy

36. Unresolved issue Which is the ideal agent Which is the ideal agent Mono vs sequential vs combination endocrine therapy Mono vs sequential vs combination endocrine therapy What is the optimal duration What is the optimal duration Long term toxicity Long term toxicity Identification of at risk gp of osteoporotic bone loss and prevention of fracture Identification of at risk gp of osteoporotic bone loss and prevention of fracture Cost benefit issue ( 38/tab vs 0.2/tab ) Cost benefit issue ( 38/tab vs 0.2/tab )

37. Department of Surgery, United Christian Hospital Thank You