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Aromatase Inhibitors Current Use in Breast Cancer

Aromatase Inhibitors Current Use in Breast Cancer. JHGR 16 Jan 2005 Dr. Sharon Chan Department of Surgery, UCH. Estrogen – main hormone involved in pathogenesis of breast tumors ER & PR status are the most important biomarkers. Estrogen and breast cancer growth.

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Aromatase Inhibitors Current Use in Breast Cancer

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

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

  3. Anti-estrogen in breast cancer

  4. Tamoxifen in Breast Cancer • Used in treatment of MBC since 70’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

  5. 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) Limitation of tamoxifen

  6. Aromatase Inhibitors • Introduction • Mechanism of action • 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 1st generation 2nd generation 3rd generation 1x 10-100x 100-2000x Anastrozole 93% Letrozole 99% Exemestane 98% Fadrozole 93% Aminoglutethimide

  10. Types of Aromatase inhibitors Steroidal AI -exemestane Nonsteroidal AI -Anastrozole & Letrozole

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

  12. Breast tumour Muscle Fat Liver Postmenopausal Woman peripheral aromatisation

  13. Intra-tumoral aromatase activity 10x

  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 Inhibitorsin adjuvant therapy

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

  20. ATAC (Arimidex, Tamoxifen Alone or in Combination) 9366 3125 3116 3125

  21. ATAC – result at median 33m FU • 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 • 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

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

  29. IES – Exem after 2-3 yr Tam • 4742 patients • Swtiching Tam 2-3y + Exem vs Tam 5y • 183 vs 266 new events • 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

  30. MA 17 –Letrozole after 5yr TAM • 5187 patients • Let reduced recurrence (42%), Distant disease recurrence (40%) • Let reduced new contralateral breast cancer (37.5%) • Est 4y survival Let 93% vs placebo 87% (p<0.001) • SE (hot flushes, osteoporosis) more frequent, but NS • Stopped after interim analysis (median FU 2.4 y) • 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 • Winter E et al J Clin Onc 23; 3 Jan 2005

  32. Aromatase InhibitorOther roles

  33. AI – neoadjuvant therapy • Higher rate of regression than tamoxifen • OR Let 55% vs Tam 36% (p<0.001) • 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 • 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 • Included as initial and subsequent therapy in adjuvant setting • Potential use in chemoprevention and neo-adjuvant therapy

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

  37. Thank You Department of Surgery, United Christian Hospital

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