1. Ashok K Vaid MD,DM Artemis Health Instt National Capital Region Gurgaon Endocrine Therapy in Advanced Breast Cancer Overview (Past to the present)

6. Ovary Pituitary gland LHRH (hypothalamus) Pre-/post- menopausal Premenopausal Gonadotrophins (FSH + LH) ACTH Adrenal glands Oestrogens Progesterone Progesterone Androgens Oestrogens Peripheral conversion ACTH, adrenocorticotrophic hormone; FSH, follicle stimulating hormone; LH, luteinising hormone; LHRH, LH releasing hormone LHRHa Aromatase Inhibitors Hormones affecting the breast Ovary

7. Efficacy of endocrine agents in women with advanced breast cancer Rose C et al. Acta Oncol 1988 Inhibitive Therapy Response data from a comprehensive review Response rate (%) Oophorectomy Adrenalectomy Hypophysectomy Aminoglutethimide + HC Oestrogens Progestins Androgens Glucocorticoids Tamoxifen 33 32 36 31 Competitive Additive Ablative 26 29 21 25 32 HC, hydrocortisone

8. Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens (PREMENOPAUSAL) Aromatase Inhibitors (POSTMENOPAUSAL)

10. The use of hormonal agents in advanced/metastatic disease in pre -menopausal women

12. Goserelin 3.6mg in Pre-/perimenopausal Women with Advanced Breast Cancer: Phase III Trials Reference Objective response rate (%) Median overall survival Taylor CW, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical J Clin Oncol oophorectomy 1998; 16: 994 – 9. ( n =29*) ( n =30*) ( n =69) ( n =67) 31 27 37 months 33 months Boccardo F, et al ‘Zoladex’ 3.6mg Surgical oophorectomy ‘Zoladex’ 3.6mg Surgical Ann Oncol or ovarian irradiation oophorectomy 1994; 5: 337 – 42. or ovarian irradiation ( n =22*) ( n =15*) ( n =24) ( n =18) 27 ( + 19) 47 ( + 25) 36 months 38 months Jonat W, et al ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg ‘Zoladex’ 3.6mg + + tamoxifen tamoxifen Eur J Cancer Part A ( n =159) ( n =159) ( n =159) ( n =159) 1995; 31A: 137 – 42. 31 38 29 months 32 months * evaluable patients

14. Hormonal therapies for postmenopausal women with advanced breast cancer First-line Antioestrogens (eg tamoxifen) Second-line Aromatase inhibitors Third-line Progestins (eg megestrol acetate) Fourth-line Androgens or oestrogens Hortobagyi GN. N Engl J Med 1998

15. The use of aromatase inhibitors in metastatic disease in post -menopausal women

16. Antiestrogen vs Aromatase Inhibitor: Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens PREMENOPAUSAL Aromatase Inhibitors Postmenopausal

18. Development of Aromatase Inhibitors Toxicity Specificity Potency First generation Second generation Third generation Aminoglutethimide Fadrozole 4-OHA Anastrozole Exemestane Letrozole Rash, etc. No adrenal insufficiency, etc. 1,000 to 10,000 100 1

19. Aromatase inhibitors Mechanism of action X Cholesterol Cortisol Progesterone Aldosterone Oestrone Oestradiol Testosterone Aromatase inactivators and aromatase inhibitors X Pregnenolone Androstenedione

20. Inhibition (%) 85 / 92* 91 98.4 / 98.9* 96.7 / 98.1* 97.9 In vivo effect of Aromatase inhibition Lønning P. Acta Oncol 1996 Geisler J et al. Clin Cancer Res 1998 Anti-aromatase agent Formestane (intramuscular) Aminoglutethimide Letrozole Anastrazole Exemestane *Inhibition at different doses

21. Aromatase inhibitors Phase III second-line metastatic breast cancer versus megestrol acetate No. patients CR + PR (%) CR + PR + SD > 24 weeks (%) Median TTP (months) Median survival (months) Letrozole 2.5 mg 174 vs. 189 23.6 vs. 6.4 † 34.5 vs. 31.7 5.6 vs. 5.5 25.3 vs. 21.5 Anastrozole 1 mg (31mo) 263 vs. 253 12.4 vs. 12.2 42.2 vs. 40.3 4.8 vs. 4.6 26.7 vs. 22.5 † Exemestane 25 mg (12 mo) 366 vs. 403 15.0 vs. 12.4 37.4 vs. 34.6 4.7 vs. 3.8 † NR vs. 26.7 † Buzdar A et al. Cancer 1998 Dombernowsky P et al. J Clin Oncol 1998 Kaufmann M et al. J Clin Oncol 2000 *Pooled data; † Statistical significance vs. MA; CR, complete response; MA, megestrol acetate; NR, median not reached; PR, partial response; SD, stable disease; TTP, time to progression

24. TTP in hormone receptor-positive patients Combined analysis of two trials % not progressed Median TTP Anastrozole 10.7 months Tamoxifen 6.4 months p=0.022 TTP (months) 0 20 40 60 80 100 0 6 12 18 24 30 36 42 Anastrozole (n = 305) Tamoxifen (n=306) TTP, time to progression Bonneterre J et al. Cancer 2001

25. Anastrozole versus tamoxifen Tolerability Data (Predefined Adverse Events) Anastrozole Tamoxifen 1 mg 20 mg ( n =506) ( n =511) n % n % Depression 30 5.9 36 7.0 Tumour flare 15 3.0 18 3.5 Thromboembolic disease 27 3.6 46 9.0 Gastrointestinal disturbance 184 36.4 207 40.5 Hot flushes 139 27.5 123 24.1 Vaginal dryness 16 3.2 11 2.2 Lethargy 6 1.2 17 3.3 Vaginal bleeding 5 1.0 13 2.5 Weight gain 12 2.4 8 1.6 Bonneterre J et al. Cancer 2001

26. Phase III trial comparing Anastrazole with tamoxifen in hormone-dependant advanced breast cancer Anastrozole (n=121) Tamoxifen 40 (n=117) CR + PR (%) Median TTP (months) Dead (%) HR for TTP (95% CI) HR for survival (95% CI) 27 (56) 5.3 (7) 92 (0.56-0.91) (0.51-0.89) 34 (CBR 83) 10.6 (18) 61 0.77 0.63 - - - p<0.05 p<0.05 Milla-Santos A et al. Am J Clin Oncol 2003 CI, confidence intervals; CR, complete response; HR; hazard ratio; PR, partial response; TTP, time to progression p-value

28. Randomization Tamoxifen 20 mg od Letrozole 2.5 mg od Tamoxifen 20 mg od Letrozole 2.5 mg od Treatment until progression or discontinuation for any other reason, then cross over to alternative treatment if suitable for further endocrine treatment Treatment until progression Follow-up for survival Mouridsen H et al. J Clin Oncol 2001 Phase III cross-over trial comparing Letrozole with tamoxifen in advanced breast cancer

29. Study 025 - Median TTP Letrozole 9.4 months Tamoxifen 6.0 months p=0.0001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time, months 0 3 6 9 12 15 18 21 24 Progression-free Log-rank P < .0001 Letrozole Tamoxifen Events, Wald N n (%) HR 95% CI P value 453 308 (68) 0.70 0.60 - 0.82 < .0001 454 350 (77)

30. Time to progression of advanced breast cancer for first-line Letrozole or tamoxifen 0.0 0.2 0.4 0.6 0.8 1.0 Start 3 6 9 12 15 18 21 24 Time (months) Proportion of patients progression-free Mouridsen H et al. J Clin Oncol 2001 Median TTP Letrozole 9.4 months Tamoxifen 6.0 months p=0.0001 TTP, time to progression Letrozole (n=453) Tamoxifen (n=454)

31. Exemestane versus tamoxifen as first-line treatment for metastatic breast cancer Randomized Phase II trial Exemestane (n=61) Tamoxifen (n=59) Objective response (%) (CR + PR) Clinical benefit (%) (CR + PR + SD >24 weeks) Median duration of response (months) 95% CI 41 57 16 11-38 17 42 22 12-36 Paridaens R et al. Ann Oncol 2003 CR, complete response; PR, partial response; SD, stable disease; CI, confidence intervals

32. Correlation between TTP and hormone receptor status for non-steroidal AIs and tamoxifen 1 Bonneterre J et al. J Clin Oncol 2000 2 Bonneterre J et al. Cancer 2001 3 Mouridsen H et al. J Clin Oncol 2001 4 Milla-Santos A et al. Am J Clin Oncol 2003 5 Nabholtz JM et al. J Clin Oncol 2000 A 1 A 2 L 3 L 3 A 2 0 20 40 60 80 100 -1 0 1 2 3 4 5 6 % receptor-positive difference in TTP A 4 A 5 % receptor-positive Difference in TTP between AI and tamoxifen (months) A, anastrozole AI, aromatase inhibitor L, letrozole TTP, time to progression

33. Recent Meta analysis AI’s vs. tamoxifen for Survival Mauri D et al. JNCI 2006; 98: 1285 – 91.

34. In postmenopausal patients with HR +ve advanced disease Aromatase Inhibitors as first line hormonal therapy have an overall better therapeutic index than tamoxifen

35. Sequential use of Hormonal Agents in Postmenopausal Women with Metastatic Breast Cancer: Role of the novel anti-estrogen Fulvestrant

37. Fulvestrant vs. Anastrozole: Trial Design Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trial 0020: International, randomised 1:1, open, parallel-group Trial 0021: North American, randomised 1:1, double-blind, double-dummy, parallel-group Anastrozole 1mg daily orally Trial 0020: ( n =229) Trial 0021: ( n =194) Fulvestrant 250mg i.m. once monthly Trial 0020: 1 x 5ml ( n =222) Trial 0021: 2 x 2.5ml ( n =206) Analysis after 340 events (progression or death prior to progression) Trials 0020 and 0021: Recruitment between May 1997 and August 1999 Robertson JFR et al. Cancer 2003; 98: 229–238.

38. Fulvestrant vs. Anastrozole: Time to progression Hazard ratio (95.14% CI): 0.95 (0.82 – 1.10); p=0.48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 6 12 18 24 30 36 Median follow-up 15.1 months Time to progression (months) Median TTP: Fulvestrant = 5.5 months Anastrozole = 4.1 months Fulvestrant 250 mg Anastrozole 1 mg Robertson JFR et al. Cancer 2003; 98: 229–238 Proportion not progressed

39. Duration of response from randomisation to progression (responding patients) Median follow-up 22.1 months 0 6 12 18 24 30 36 42 Fulvestrant 250 mg Anastrozole 1 mg Duration of response (months) 0.0 0.2 0.4 0.6 0.8 1.0 Median DoR: Fulvestrant = 16.7 months Anastrozole = 13.7 months Proportion responding Robertson JFR et al. Cancer 2003; 98: 229–238

40. Duration of response – without or with visceral metastases Duration of objective response (days) 0 200 400 600 800 1000 Fulvestrant 250 mg (n=52) Anastrozole 1 mg (n=45) 0.0 0.2 0.4 0.6 0.8 1.0 Without visceral metastases Proportion with objective response 0 200 400 600 800 1000 0.0 0.2 0.4 0.6 0.8 1.0 Fulvestrant 250 mg (n=30) Anastrozole 1 mg (n=25) With visceral metastases Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233

41. Fulvestrant vs. Anastrozole: Overall survival 0 60 66 0.0 0.2 0.4 0.6 0.8 1.0 Overall survival (months) Proportion alive 54 48 42 36 30 24 18 12 6 Median survival: Fulvestrant = 27.4 months (n=428) Anastrozole = 27.7 months (n=423) Hazard ratio (95% CI): 0.98 (0.84 – 1.15); p=0.81 Median follow-up 27.0 months Fulvestrant 250 mg Anastrozole 1 mg Howell, A et al. Cancer 2005 ; 104: 236–9.

42. Fulvestrant vs. Anastrozole: Tolerability: predefined adverse events Gastrointestinal disturbances Hot flushes Urinary tract infection Joint disorders Thromboembolic disease Vaginitis Weight gain Withdrawn due to adverse event Number of adverse events (%) Anastrozole (n=423) Fulvestrant (n=423) p-value Robertson JFR et al. Cancer 2003; 98: 229–238 0.53 0.91 0.06 0.0036 0.68 0.51 0.35 Robertson JFR et al. Cancer 2003; 98: 229–238 196 89 31 23 15 11 4 12 (46.3) (21.0) (7.3) (5.4) (3.5) (2.6) (0.9) (2.8) 185 87 18 45 17 8 7 8 (43.7) (20.6) (4.3) (10.6) (4.0) (1.9) (1.7) (1.9)

43. Indirect comparison of clinical benefit rates in second-line hormonal treatment trials CB ( CR + PR + SD ≥ 24 weeks) rate (%) Fulvestrant 1 Anastrozole 1 Anastrozole 2 Letrozole 2 Exemestane 3 1 Robertson et al. Cancer 2003; 98: 229–238; 2 Rose et al. Eur J Cancer 2003; 39: 2318-2327 3 Kaufman et al. J Clin Oncol 2000; 18: 1399-1411 ; 4 Buzdar et al. J Clin Oncol 2001; 19: 3357-3366 5 Dombernowsky et al. J Clin Oncol 1998; 16: 453-461 ; 6 Buzdar et al. Cancer 1998; 83: 1142-1152 0 10 20 30 40 50 Megestrol acetate 3 Letrozole 4 Megestrol acetate 4 Letrozole 5 Megestrol acetate 5 Anastrozole 6 Megestrol acetate 6 40% vs 42% 32% vs 35% 30% vs 30% 35% vs 37% 23% vs 27% 41% vs 44%

45. Postmenopausal Patients with ER+ Advanced Breast Cancer and hormonal options after Non-steroidal AI 1st treatment 2nd treatment 4th treatment 3rd treatment Non-steroidal AI Fulvestrant/Tamoxifen? Exemestane? Exemestane Fulvestrant Tamoxifen Tamoxifen Tamoxifen Exemestane or Fulvestrant

49. EFECT: Time to progression (ITT) Proportion of patients progression-free Months At risk: Fulvestrant Exemestane HR = 0.963, 95% CI (0.819, 1.133), p=0.6531 Cox analysis, p=0.7021 Fulvestrant Exemestane 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 351 195 96 50 25 12 4 2 342 190 98 41 21 12 8 6 0 1 0 0 Fulvestrant 3.7 Exemestane 3.7 Median (months) Gradishar W et al. SABCS 2006

50. EFECT: Objective response and clinical benefit rate (evaluable for response population) * Analyses are not adjusted for baseline covariates OR rate (CR + PR) CB rate (OR + SD ≥ 24 wks) Fulvestrant 7.4% (20/270) 32.2% (87/270) Exemestane 6.7% (18/270) 31.5% (85/270) Odds ratio* (95% CI) 1.120 (0.578, 2.186) 1.035 (0.720, 1.487) p-value 0.7364 0.8534 Gradishar W et al. SABCS 2006

51. EFECT: Duration of response (from randomisation) Proportion of patients responding Months At risk: Fulvestrant Exemestane Fulvestrant Exemestane 0 3 6 9 12 15 18 21 24 27 0.0 0.2 0.4 0.6 0.8 1.0 20 20 16 11 8 3 0 0 18 18 15 10 5 4 3 3 0 0 3 3 Fulvestrant 13.5 Exemestane 9.8 Median (months) Gradishar W et al. SABCS 2006

52. EFECT: Adverse events Patient had an AE Drug-related AE Withdrawal due to AE AE of grade 3 or higher Serious AE Drug-related SAE Death due to AE Death due to drug-related AE Fulvestrant n=351 Exemestane n=340 88.9% 45.9% 2.0% 21.7% 11.4% 1.1% 0.9% 0% 88.8% 48.8% 2.6% 22.6% 12.4% 0.6% 0.9% 0% Gradishar W et al. SABCS 2006

54. Recent Evidence with Trastuzumab (Herceptin) plus Anastrozole (Arimidex) in Advanced Breast Cancer in post-menopausal women: TAnDEM Study TrAstuzumab in Dual HER2-positive Metastatic breast cancer ESMO 2006

55. TAnDEM: Study Design HER2-positive, HR-positive MBC (n=208) R Anastrozole 1 mg daily + Trastuzumab 4 mg/kg loading dose  2 mg/kg qw until disease progression Anastrozole 1 mg daily until disease progression ESMO 2006

56. TAnDEM: Progression-Free Survival PFS = time from randomisation to date of progressive disease or death 103 48 31 17 14 13 11 9 4 1 1 0 0 A + H 104 36 22 9 5 4 2 1 0 0 0 0 0 A Probability 1.0 0.8 0.6 0.4 0.2 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 0.0 No. at risk 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 Median PFS 4.8 months 2.4 months Events 87 99

59. Thank You

60. Back-up Slides

61. Many signal pathways target ER EGFR, HER2 Raf MEK1/2 Ras ERK 1/2 p90rsk AKT GRB2 SOS PI3 Kinase Cbl p110 p85 p160 ER CBP Basal Transcription Machinery ERE Target gene P P P Rac1 cdc42 MLK3 MKK3/6 MEKK1 P38 Inflammatory cytokines TNF  ,IL-1 IGFR Cytokines stress

63. The HER Family Adapted from Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25. The epidermal growth factor family of receptors comprises 4 transmembrane proteins, each with different properties but all involved in the regulation of cell proliferation Extracellular Intracellular

65. Trastuzumab Combination (with CT) Pivotal Trial: Time to Progression Slamon et al. N Engl J Med. 2001;344:783. Median TTP was significantly longer for the Herceptin + CT arms (7.4 months) than for the CT arms (4.6 months; p < 0.001). H + CT 235 152 63 15 CT 234 103 25 6 1.0 0.8 0.6 0.4 0.2 0.0 p < 0.001 Median follow-up: 35 mo Herceptin + CT (n = 235) CT alone (n = 234) 0 5 10 15 20 25 30 Progression-free survival Months No. at risk:

66. Treatment paradigm for patients with metastatic breast cancer First-line Second-line Third-line Antioestrogen or non- steroidal AI Non-steroidal AI or anti- oestrogen If response, steroidal AI - exemestane, progestin Fourth-line If response, androgen No response Postmenopausal Premenopausal Antioestrogen or LHRH agonist Chemotherapy Response, ovarian ablation Response, non-steroidal AIs If response, steroidal AI - exemestane If response, progestin If response, androgen AI, aromatase inhibitor LHRH, luteinising hormone-releasing hormone

67. Phase III trials of second- and third- generation aromatase inhibitors versus tamoxifen in the advanced setting Superiority in favour of Endpoint(s) Nabholtz JM et al. J Clin Oncol 2000 Bonneterre J et al. Cancer 2001 Mouridsen H et al. J Clin Oncol 2001 Fadrozole versus tamoxifen Anastrozole versus tamoxifen Letrozole versus tamoxifen Formestane versus tamoxifen Tamoxifen Anastrozole Letrozole Tamoxifen TTP, time to progression; TTF, time to treatment failure TTP / TTF TTF TTP TTP

69. Anastrozole vs letrozole Median TTP (months) Median TTF (months) Median OS (months) Objective response (CR+PR) (%) Letrozole ( n =356) 5.7 5.6 22.0 19.1 Anastrozole ( n =357) 5.7 5.6 20.3 12.3 0.920 0.761 0.624 0.013 Overall population p value OS, overall survival; TTF, time to treatment failure Rose, C et al. Eur J Cancer 2003; 39:2318–27

70. Overall tumour response by hormone receptor status Overall population ER+ve and/or PgR+ve Unknown Letrozole 30/173 (17.3) 38/183 (20.8) Anastrozole 28/167 (16.8) 16/190 (8.4) No. CR+PR/Total no. pts (%) Receptor status Rose, C et al. Eur J Cancer 2003; 39:2318–27

71. FEM-INT-01: summary of adverse events No. patients (%) Adverse event >2% bone pain dyspnoea nausea vomiting abdominal pain Any serious adverse event Discontinuations due to adverse event Letrozole ( n =356) Anastrozole ( n =357) 47 (13) 40 (11) 39 (11) 19 (5) 20 (6) 63 (18) 28 (8) 53 (15) 37 (10) 28 (8) 23 (7) 15 (4) 68 (19) 28 (8) Rose, C et al. Eur J Cancer 2003; 39:2318–27

74. Oestradiol suppression with Goserelin + anastrozole Forward et al 2004; BJC 90; 590-594 0 50 100 150 200 250 Baseline Goserelin + tamoxifen Goserelin + Arimidex Mean serum oestradiol (pmol/L) p<0.0001 p<0.0001