1. CARCINOMA DELLA MAMMELLA

50. UPDATE FROM AROMATASE INHIBITORS STUDIES AT OCTOBER 2006 ANASTROZOLE (A), LETROZOLE (L), EXEMESTANE (E) DFSDDFSOS UPFRONT vs TAMyesno SWITCHyes A yes E no L not mature (2008) EXTENDED ADJUVANTyes (MA.17)

51. What’s really new in endocrine therapy in breast cancer? Jean-Philippe SPANO, MD, PhD GHPS, Paris, France

52. The Aromatase Inhibitor Trials ATAC: Tamoxifen vs Anastrozole vs Combined therapy ATAC: Tamoxifen vs Anastrozole vs Combined therapy MA17 : Letrozole vs placebo after 5yr Tamoxifen MA17 : Letrozole vs placebo after 5yr Tamoxifen IES : Exemestane vs Tamoxifen after 2-3yr Tamoxifen IES : Exemestane vs Tamoxifen after 2-3yr Tamoxifen ITA : Anastrozole vs Tamoxifen after 2-3yr Tamoxifen ITA : Anastrozole vs Tamoxifen after 2-3yr Tamoxifen ABCSG/ARNO : ditto ABCSG/ARNO : ditto BIG 1-98 : Letrozole vs Tamoxifen BIG 1-98 : Letrozole vs Tamoxifen TEAM: exemestane vs Tamoxifen TEAM: exemestane vs Tamoxifen

53. AI Trials in Early Breast Cancer Upfront Extended 0 5 ATAC ARNO/ABCSG8 BIG 1-98 MA-17 IES ABCSG-6ATamoxifenAnastrozoleLetrozolePlaceboAromasin Clemons et al. Cancer Treat Rev. 2004;30:335-332. Switch Years: 2-3 10 combination Upfront Strategy Switch Strategy Extended Strategy Point of Randomization

54. ATAC Recruitment July 1996 – March 2000 Median follow up 68 months (data cut 31 st March 2004 ) 8 % of patients remain on trial therapy Arimidex + Tamoxifen (n=3,125) Tamoxifen (n=3,116) Surgery ± RT ± Chemo (20 %) Anastrozole (n=3,125) 5 years 84 % HR positive 61 % Node negative Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm Reference

55. Disease-free survival Curves shown for HR+ patients DFS includes all deaths as a first event At risk: A261825402448235522682014830 T259825162398230421891932774 Follow-up time (years) 0 5 10 15 20 25 0123456 Absolute difference: 1.6 %2.6 %2.5 %3.3 % Patients (%) Anastrozole (A) Tamoxifen (T) HR 0.83 0.87 HR+ 95 % CI (0.73–0.94) (0.78-0.97) p-value 0.005 0.01 ITT A 424 575 T 497 651 Reference

56. Overall Survival Curves shown for HR+ patients At risk: A261825662505243723772117867 T259825492502243023332080855 Follow-up time (years) 0 5 10 15 20 25 0123456 Includes non breast cancer deaths Patients (%) Anastrozole (A) Tamoxifen (T) HR 0.97 HR+ 95 % CI (0.83–1.14) (0.85-1.12) p-value 0.7 ITT A 296 411 T 301 420 Reference

57. Efficacy Summary * Odds Ratio computed instead of Hazard Ratio Disease-free survival Time to recurrence 0.2 0.4 0.6 0.8 1.0 1.2 1.5 2.0 Time to distant recurrence Overall survival Time to breast cancer death Contralateral breast cancer* ITT population HR+ population Anastrozole better Tamoxifen better Hazard ratio (A : T) and 95 % CI Reference

58. IES: STUDY DESIGN Diagnosis of breast cancer & treatment for primary disease RANDOMISE 2-3 years tamoxifen 2-3 years exemestane years from start of tamoxifen 0 2 3 5 years from randomisation 0 2-3 2 to 3 years tamoxifen Patients followed up Coombes RC et al. N Engl J Med. 2004 ; 350 : 1081-1092.

59. Why This Study ? Patients with ER positive metastatic disease frequently respond to AI’s after tamoxifen Patients with ER positive metastatic disease frequently respond to AI’s after tamoxifen Tamoxifen pre-treatment can increase bone density Tamoxifen pre-treatment can increase bone density Long-term tamoxifen can cause endometrial cancer Long-term tamoxifen can cause endometrial cancer Prior neo-adjuvant tamoxifen studies show that patients frequently relapse after 2-3 years Prior neo-adjuvant tamoxifen studies show that patients frequently relapse after 2-3 years

60. NEJM SABCS 2004 DFS events 449615 Deaths199339 Median Follow-up 30.6 months 37.4 months IES: EFFICACY ANALYSIS Coombes RC et al. N Engl J Med. 2004 ; 350 : 1081-1092.

61. IES : DEMOGRAPHICS 1 ExemestaneTamoxifen Number of patients * 23522372 Median age, n (range) 63.0 (38.0-96.0) 63.0 (31.0-90.0) Nodal Status, n (% known) Negative Negative 1217 (54) 1228 (54) Positive Positive 1048 (46) 1038 (46) Prior Chemotherapy, n (%) Yes 774 (33) 769 (32) No 1578 (67) 1603 (68) * Of the 4742 subjects included in the NEJM analysis, 2 were found to have duplicate PIDs and 16 subjects from one center were excluded from all analyses because data were considered unreliable. Product Labeling Product Labeling

62. IES : DEMOGRAPHICS 2 Exemestane(n=2352)Tamoxifen(n=2372) Receptor Status, n (%) ER & PgR Positive 1331 (56.6) 1319 (55.6) ER Positive & PgR Negative/Unknown 677 (28.8) 692 (29.2) ER and PgR Unknown 288 (12.2) 291 (12.3) ER Negative 54 (2.3) 65 (2.7) Median duration of Tamoxifen treatment (mths) at time of randomisation 28.528.4 US Product Labeling

63. IES : EVENTS CONTRIBUTING TO DFS ExemestaneTamoxifenTotal Local recurrence only † 435699 Distant recurrence 150208358 Contralateral breast primary 122638 Intercurrent deaths (without recurrence) 5763120 Total number of patients experiencing an event 262353615 † Includes 1 ipsilateral breast cancer

64. IES : CAUSES OF DEATH ExemestaneTamoxifenTotal Total number of deaths 152187339 Breast cancer deaths Inc. other COD in patients with recurrence/CLB 95111241221923 Intercurrent (without recurrence/CLB) VascularCardiac Other cancer OtherUnknown5715131311563712221481202225352513

65. IES : DISEASE FREE SURVIVAL Hazard Ratio 95 % CI* P value Disease free survival 0.730.62-0.860.0001 Breast cancer free survival 0.700.58-0.830.00005 Time to contralateral breast cancer 0.500.26-0.970.04 * CI denotes confidence interval

66. Women survivingevent-free (%) Years from randomisation 01234 0 25 50 75 100 No. events/at risk Hazard ratio=0.73 (95% CI: 0.62-0.86) Log-rank test: p=0.0001 Exemestane Tamoxifen 0 / 235257 / 223365 / 208175 / 141341+24 † / 661 0 / 2372 82 / 2243105 / 206296 / 135947+23 † / 650 Tamoxifen Exemestane † events occurring more than 4 years after randomisation IES : DISEASE FREE SURVIVAL (262 events) (353 events)

67. IES : DISEASE FREE SURVIVAL Subgroup Analysis Data are hazard ratios (HR) and 95% confidence intervals (CI)

68. No. events/at risk Women alive (%) Years from randomisation 01234 0 25 50 75 100 Hazard ratio=0.83 (95 % CI : 0.67-1.02) Log-rank test : p = 0.08 Exemestane Tamoxifen 18 / 227041 / 213741 / 146937+15 † / 690 23 / 230053 / 216549 / 146541+21 † / 701 Tamoxifen Exemestane † events occurring more than 4 years after randomisation (152 deaths) (187 deaths) 0 / 2352 0 / 2372 IES : OVERALL SURVIVAL

69. IES : SAFETY PROFILE : Musculoskeletal Incidence Case Analysis Events Events Any Grade Exemestane n (%) Tamoxifen P Treatment emergent P Arthralgia 417 (19.8) 275 (13.1) <0.001+** Myalgia 50 (2.4) 32 (1.5) 0.004+ NS NS Arthritis / osteoarthritis 354 (16.8) 285 (13.5) 0.003 Osteo NS Muscle cramp 64 (3.0) 107 (5.1) 0.001+** FracturesOsteoporosis 80 (3.6) 175(8.3) 60 (2.6) 145(6.9)NSNS* Carpal tunnel 57 (2.7) 8 (0.4) <0.001** Paraesthesiae 69 (3.3) 29 (1.4) <0.001+ **

70. IES SAFETY PROFILE : Cardiovascular / Thrombo-embolic Disease Incidence Case Analysis Events Events Any Grade Exemestane n (%) Tamoxifen P Treatment emergent P Thrombo-embolic disease 41 (1.9) 69 (3.3) <0.001+ * Myocardial Infarction (MI) (Fatal + Non Fatal) All MIs Age (mean) On treatment MIs 20 (0.9) 68.8 14 (0.7) 8 (0.4) 70.9 7 (0.3) NS (0.02) NS (0.13) NS Tamoxifen: association with MI Meta-analysis : Braithwaite et al, 2003 : 52,929 patients. Suggestive of decrease in incidence of MI (HR 0.74 (0.47-1.16)) Decreases death from MI (HR 0.55 (0.36-0.87)) + trend test ; NS = No-significant (p  0.01), * 0.001  p < 0.01, ** p  0.001 Reference All patients with MI had  1 predisposing risk factor

71. IES : SAFETY PROFILE : Gynaecological Incidence Case Analysis Events Events Any Grade Exemestane n (%) Tamoxifen P Treatment emergent P Gynecological symptoms 301 (14.3) 376 (17.8) 0.002 Not done Uterine Hyperplasia 19 (0.9) 39 (1.9) 0.008** Uterine Polyps 12 (0.6) 53 (2.5) <0.001** Reference

72. Preliminary Conclusions The proportion of patients with ET ≥5 mm was significantly reduced in the exemestane arm The proportion of patients with ET ≥5 mm was significantly reduced in the exemestane arm Switching to exemestane allows reversal of subclinical uterine abnormalities associated with tamoxifen Switching to exemestane allows reversal of subclinical uterine abnormalities associated with tamoxifen Post-treatment scans should assess whether effect of exemestane is superior to simple T withdrawal Post-treatment scans should assess whether effect of exemestane is superior to simple T withdrawal

73. IES : SAFETY CONCLUSIONS No excess of intercurrent deaths No excess of intercurrent deaths Endocrine effects similar to tamoxifen Endocrine effects similar to tamoxifen Musculo-skeletal side effects more common Musculo-skeletal side effects more common Cardiovascular - more data required but serious events very rare Cardiovascular - more data required but serious events very rare Exemestane associated with a reduction in gynecological and thrombo-embolic side effects Exemestane associated with a reduction in gynecological and thrombo-embolic side effects

74. IES : EFFICACY CONCLUSIONS Switching to exemestane reduces the risk of: Switching to exemestane reduces the risk of: – breast cancer recurrence or death (p=0.0001) – contralateral breast cancer (p=0.04) Switching to exemestane appears to reduce the chances of dying (p=0.08) but more follow-up is needed Switching to exemestane appears to reduce the chances of dying (p=0.08) but more follow-up is needed

75. The ABCSG/ARNO Trial : Switching at 2-3 years Jakesz et al, 2005

76. BIG 1-98 Design Tamoxifen Letrozole TamoxifenLetrozole Tamoxifen RANDOMIZERANDOMIZE 025 YEARS A B C D 2-Arm Option 3/98 to 3/00 1835 pts 4-Arm Option 9/99-5/03 6193 pts

77. Primary Core Analysis 8028 Randomized 8010 Primary Core Analysis 4007 T4003 L versus 18 withdrew consent (no treatment / FU) 133 (1.66%) ineligible cases included in primary core analysis

78. Follow-Up Time Overall (median FU 35.5 mos.) Primary core (median FU 25.8 mos.)

79. Osservazione STUDIO HERA Qualsiasi CT± RT Tq3sett* x 12 mesi Tq3sett* per 24 mesi Paclitaxel q3sett x 4 o qsett x 12 NSABP B-31 AC x 4 Paclitaxel q3sett x 4 o qsett x 12 + T qsett Paclitaxel qsett x 12 INTERGROUP N9831 AC x 4 Paclitaxel qsett x 12 T qsett Paclitaxel qsett x 12 + T qsett AC x 4 Docetaxel q3sett x 4 BCIRG 006 AC x 4 Docetaxel q3sett x 4 +T qsett Tq3sett* Carboplatino + docetaxel q3sett x 6 + T qsett Tq3sett* *q3sett alla dose di 6 mg/kg STUDI HERCEPTIN ADIUVANTE MAMMELLA – AGGIORNATO MARZO 2006