1. These slides are intended to educate the scientific and medical community and keep them fully informed about continuing progress, as is their right, stipulated by the IFPMA code. However, in some cases, the data may refer to medicines and/or indications which are not currently approved in your country. Under no circumstances should this information be taken as a recommendation for use of the medicine/indication. Always consult relevant local prescribing before use.

2. Fulvestrant (FASLODEX ® ): an emerging story providing an increasing role William Gradishar Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA Breast Cancer Treatment Strategies: Clinical Decisions and Positive Conversations

3. E T ER FULLY ACTIVATED TRANSCRIPTION (increased tumour progression) dimerisation E E AF1 + AF2 active Oestradiol ER PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumour cell division) dimerisation AF1 active AF2 inactive Tamoxifen TT ER AF1 +AF2 inactive F Fulvestrant F F ACCELERATED RECEPTOR DEGRADATION attenuated dimerisation NO TRANSCRIPTION (no tumour cell division) Fulvestrant has a different mode of action

4. Tamoxifen: post-treatment Fulvestrant: pre-treatment Robertson et al. Cancer Res 2001; 61: 6739–6746 Tamoxifen: pre-treatment Fulvestrant reduces cellular ER levels… Fulvestrant: post-treatment

5. 250 300 150 200 50 100 0 Pre-treatment (n=29) 4–6 weeks (n=26) 6 months (n=20) PD (n=8) Time on treatment Mean ER H-score p=0.01 p=0.001 Gutteridge et al. Breast Cancer Res Treat 2004; 86, abs 4086...and this effect is maintained over time

6. Could long-term ER downregulation be beneficial to patients? Breast Cancer Treatment Strategies: Clinical Decisions and Positive Conversations

7. Coactivator AF1 Accelerated tumour growth HER2 EGFR TGF  KK ER AKT MAPK AF2 E E Phosphorylation RNA POL II Cross-talk between GFR and ER is involved in the development of endocrine resistance

8. Coactivator AF1 Accelerated tumour growth HER2 EGFR TGF  KK ER AKT MAPK AF2 E E Phosphorylation X Fulvestrant X RNA POL II Fulvestrant may delay the onset of resistance resulting in a sustained duration of response

9. Median follow-up 22.1 months Proportion of patients responding 1.0 0.8 0.6 0.4 0.2 0.0 0 Time (months) 6121824304236 Fulvestrant 250 mg Anastrozole 1 mg Robertson et al. Cancer 2003; 98: 229–238 Fulvestrant 16.7 Anastrozole 13.7Median (months) Trials 0020 / 0021: prospective combined analysis – duration of response

10. Time (months) At risk: Fulvestrant Exemestane Proportion of patients responding Fulvestrant Exemestane 0369121518212427 0.0 0.2 0.4 0.6 0.8 1.0 20 16118300 18 15105433 00 33 Fulvestrant 13.5 Exemestane 9.8Median (months) EFECT (post-AI): duration of response

11. Predicting which patients may do best on fulvestrant Breast Cancer Treatment Strategies: Clinical Decisions and Positive Conversations

12. A new hypothesis (from 1989!) “It would appear that when considering second- line hormonal therapy the previous effect of first-line hormone therapy is a more direct and accurate means of identifying patients with hormone-sensitive tumours than ER status” Robertson et al. Eur J Cancer Clin Oncol 1989; 25: 469–75

13. Proportion of patients progression- free Time (months) At risk: Fulvestrant Exemestane HR = 0.963, 95% CI (0.819, 1.133), p=0.6531 Cox analysis, p=0.7021 Fulvestrant Exemestane 0369121518212427 0.0 0.2 0.4 0.6 0.8 1.0 3511959650251242 3421909841211286 0 1 0 0 Fulvestrant 3.7 Exemestane 3.7Median (months) EFECT: TTP (overall population) Chia et al. J Clin Oncol 2007; submitted

14. Proportion of patients progression- free 0369121518212427 0.0 0.2 0.4 0.6 0.8 1.0 935431127431 97512372000 Fulvestrant 3.8 Exemestane 3.7Median (months) HR = 0.73, 99.8% CI *(0.45, 1.19) *CI adjusted for multiple subgroup comparisons Chia and Gradishar. The Breast 2007; in preparation EFECT: TTP (subset of 2nd-line and AI-sensitive patients) At risk: Fulvestrant Exemestane Fulvestrant Exemestane Time (months)

15. Potential predictive factors Prognostic factors from Trials 0020 / 0021 WHO PS <1 (p=0.0004) Positive receptor status (p<0.0001) Prior endocrine response (p=0.0272) AstraZeneca, data on file

16. Hormone responsive / resistant definition Hormone responsive –>2 years on adjuvant endocrine therapy –CB (CR / PR / SD  24 weeks) on last endocrine treatment Hormone resistant –<2 years on adjuvant endocrine therapy –PD in first-line setting

17. Proportion of patients progression-free Responsive Resistant Trials 0020 / 0021: TTP responsive vs resistant 2681307042268 160533424127 1 2 At risk: Responsive Resistant 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0369121518243036 33 27 21 279108614023121 1446634201250 0.0 0.2 0.4 0.6 0.8 1.0 Time (months) 0369121518243036 33 27 21 Responsive Resistant FulvestrantAnastrozole

18. Clinical trials in responsive patients Study 004 19 confirmed hormone-responsive patients –69% of patients achieved CB –versus ~ 40% of ER+ population in trials 20 / 21 Study 0-15-22 30 hormone-responsive Japanese patients –60% of patients achieved CB Howell et al. Lancet 1995; 345: 29–30 Watanabe et al. Anticancer Res 2004; 24: 1275–80

19. …and from a clinical experience programme No CB on last therapy (N=99) CB on last therapy (N=293) No CB on fulvestrant 70.7% CB on fulvestrant 29.3% No CB on fulvestrant 61.8% CB on fulvestrant 38.2% Med duration on fulvestrant = 4 months Med duration on fulvestrant = 5 months 392 Belgian patients receiving fulvestrant

20. Faslodex HD 720 postmenopausal women with HR+ advanced breast cancer after failure on one prior endocrine therapy Progression 3 monthly follow-up Endpoints TTP ORR CB Safety Faslodex AD Randomisation 1:1 HD = fulvestrant 500 mg (IM) on Day 0, 500 mg (IM) on Day 14 and 28, and 500 mg/month (IM) thereafter AD = fulvestrant 250 mg (IM) once-monthly COmparisoN of Faslodex In Recurrent or Metastatic breast cancer

21. Potential predictive factors for long-term disease control with fulvestrant Prognostic factors from Trials 0020 / 0021 –WHO PS <1 (p=0.0004) –positive receptor status (p<0.0001) –prior endocrine response (p=0.0272) Line of treatment

22. Fulvestrant: the earlier the better Fulvestrant as line of endocrine therapy in clinical trials 025 1 st -line ABC 0020/0021 2 nd -line 186/428 170/313 CB rate (%) 0 80 70 60 50 40 30 20 10 EFECT 3 rd /2 nd -line 87/270 004 2 nd -line responsive 13/19

23. Clinical experience data: CB by line of endocrine therapy for advanced breast cancer Fulvestrant as line of endocrine therapy in clinical practice 1 st (n=22) 2 nd (n=125) 3 rd (n=105) 4 th (n=58) 5 th (n=22) 6 th (n=5) Steger et al. Can Treat Rev 2005; 31: S10–S16 0 10 20 30 40 50 CB rate (%)

24. Summary Fulvestrant provides an effective and well-tolerated treatment option post-tamoxifen and post-AI for postmenopausal women with advanced breast cancer Fulvestrant offers a durable response, explained in part by a different mode of action Careful consideration of prognostic factors such as prior response, and use of fulvestrant earlier in the treatment sequence, may offer a better chance of achieving improved outcomes and lasting disease control