1. These slides were released by the speaker for internal use by Novartis

2. Risk reduction: why use adjuvant therapy? Antonio Llombart Cussac (Hospital Universitario Arnau de Vilanova, Lérida, Spain)

3. The need for adjuvant therapy In early breast cancer, detectable tumor tissue can be removed by surgical resection BUT –Micrometastatic deposits of disease may remain –Untreated micrometastases can develop into clinical disease recurrence –Metastatic breast cancer is currently incurable Adjuvant therapy protects against recurrence and improves survival

4. Fisher et al. J Natl Cancer Inst Monogr 2001;(30):62–6 Parkin et al. Eur J Cancer. 2001;37(Suppl 8):S4–66 Outcome is related to disease stage at diagnosis 5-year survival rates Stage I disease95% Stage II disease70%–85% Stage III disease50%–52% Stage IV disease 10%–15% Even patients with early-stage breast cancer are at risk of relapse

5. Early breast cancer: common prognostic factors Patient-related –Age –Menopausal status –Race Tumor-related – Lymph node involvement: yes/no and number – Tumor size – Tumor grade – ER/PgR status – Vascular invasion – HER2/neu expression

6. Predictors of early recurrence Update of McArthur et al. Breast Cancer Res Treat 2005;94(Suppl 1):S124(abstract 3001) Moderate/high ER Time (years) p = 0.005 Low-positive ER Rate of relapse N0 N4+ N1–3 Time (years) p < 0.001 Rate of relapse Nodal statusER status Other predictor: grade 3 tumor pathology

7. Decision tools in EBC Clinical trials EBCTCG meta-analysis Consensus: ASCO, NCCN, St Gallen Data-based tools www.adjuvantonline.org

8. Progress in systemic therapy over the last 10 years Chemotherapy – N+ and high-risk N– CAF/CEF > CMF – N+TXN + A/E > AC/CAF Endocrine therapy [ER+ and/or PgR+] – Postmenopausal AI > TAM – Chemotherapy still effective HER2/neu++ –Tamoxifen less effective –Target EGFR CT + trastuzumab > CT

9. Benefits of adjuvant chemotherapy

10. Chemotherapy improves outcomes in postmenopausal women Risk of recurrence Risk of mortality Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

11. Chemotherapy reduces risk of recurrence in ER– and ER+ disease Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

12. Risk reduction with chemotherapy Risk reductions in recurrence and mortality occur irrespective of –Menopausal status –Additional tamoxifen use –ER status –Nodal status –Other tumor characteristics Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

13. Annual odds of recurrence CMF-like = 6.8%/year (risk reduction 24%) Anthracycline = 6.0%/year (risk reduction 12%) Anthracycline & taxanes = 5.0%/year (risk reduction 17–23%) Adapted from EBCTCG 1998, CALGB 9344, BCIRG-001 No treatment = 9.0%/year 01234567 Time (years) Recurrence rate 0 20 40 60 80 100 No treatment CMF-like Anthracycline Anthracyclines + taxanes The future of adjuvant chemotherapy

14. Benefits of adjuvant endocrine therapy: tamoxifen

15. Tamoxifen improves 15-year outcomes in ER+/unknown breast cancer Control Tamoxifen 33.2 34.8 Breast cancer mortality (%) 010 20 0 30 40 60 50 10 515 Years 11.9 25.7 8.3 17.8 25.6 Recurrence (%) 010 20 0 30 40 60 50 10 515 Years 45.0 38.3 24.7 26.5 15.1 Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

16. Tamoxifen reduces recurrence in ER+ but not ER– disease ER statusHazard ratio oflogrank annual events * (SE)2p value ER-poor1.04 (0.07) ER-positive0.59 (0.03) ER-unknown0.69 (0.07) Subtotal0.69 (0.03) < 0.00001 *About 5 years’ tamoxifen vs placebo Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

17. ER statusHazard ratio oflogrank annual death rates * (SE)2p value ER-poor1.04 (0.08) ER+0.66 (0.04) ER-unknown0.80 (0.09) Subtotal0.76 (0.03)< 0.00001 *About 5 years’ tamoxifen vs placebo Tamoxifen reduces breast cancer mortality in ER+ but not ER– disease Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

18. Greater absolute risk reduction with tamoxifen in N+ vs N– disease Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

19. Risk reduction with endocrine therapy Tamoxifen highly effective in ER+ breast cancer Proportional risk reductions for recurrence and mortality are unaffected by –Age –Use of chemotherapy –Other tumor characteristics Tamoxifen has little effect in ER-poor tumors Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

20. Trastuzumab in addition to CT reduces recurrence in HER2+ patients Trial (Median FU ) SchemaTrastuzumab DFS (%) Hazard Ratio p B31 – N9831 (3 years) AC – P AC – PH Simultaneous 75,4 87,1 0,48 < 0.0001 HERA (2 years) CT CT - H Sequential 77,4 85,8 0,54 < 0.0001

21. Trastuzumab in addition to CT also reduces mortality in HER2+ patients TrialSchemaTrastuzumabOS Hazard Ratio p B31 – N9831 (FU 3 years) AC – P AC – PH Simultaneous 91,7 94,3 0,67 0.015 HERA (FU 2 years) CT CT - H Sequential 95,1 96,0 0,76 0.26

22. Survival benefits of adjuvant therapy Postmenopausal woman with ER+ disease –6 months’ chemotherapy (mortality reduction 20%) –5 years’ tamoxifen (mortality reduction 31%) Total mortality reduction 45% Postmenopausal woman ER– disease –6 months’ chemotherapy Total mortality reduction 24% Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;365:1687–717

23. EBCTCG 2005 Summary of adjuvant therapy Adjuvant therapy reduces risk of recurrence in early breast cancer Chemotherapy effective regardless of nodal or tumor status Tamoxifen reduces recurrences and mortality in postmenopausal women with HR+ disease 5 years of tamoxifen reduces risk of recurrence for up to 15 years after surgery Tamoxifen is ineffective in ER– tumors

24. Continuing risk of recurrence Adjuvant chemotherapy and endocrine therapy improve outcomes in patients with early breast cancer However –Not all patients with HR+ tumors respond to endocrine therapy –Up to 40% of patients on adjuvant tamoxifen develop recurrences –In a study of 105 patients on tamoxifen, 29% developed early distant recurrences (median time to recurrence 3.8 years)* Risk of breast cancer recurrence continues indefinitely *Update of Loi et al. J Clin Oncol 2005;23(16S):6s(abstract 509)

25. Considerations for therapy selection St Gallen 2005 Fundamental change in algorithm for selecting adjuvant systemic therapy for early breast cancer –1st consideration = endocrine responsiveness Endocrine responsive Endocrine non-responsive Tumors of uncertain endocrine responsiveness –Divide each category by menopausal status –THEN divide by risk Low, intermediate, high Goldhirsch et al. Ann Oncol 2005;16:1569–83

26. Treatment guidelines for adjuvant therapy for breast cancer Patients should be offered –Chemotherapy for HR– disease –Endocrine therapy for HR+ disease Plus chemotherapy for –some intermediate-risk groups –all high-risk groups –Chemotherapy + endocrine therapy for all patients with tumors with uncertain hormone responsiveness, except in low-risk group (endocrine therapy only) Premenopausal women with HR+ disease may benefit from ovarian ablation/suppression before endocrine therapy Goldhirsch et al. Ann Oncol 2005;16:1569–83

27. Trends in breast cancer mortality Levi et al. Eur J Cancer 2001;37:1409–12 SEER Cancer Statistics Review, 1973-1999. At www.seer.cancer.gov Age-adjusted deaths per 100,000 Years 20 10 0 30 1975-19791980-19841985-19891990-19941995-1997 USA EU Japan

28. The future of adjuvant therapy Need more understanding of resistance mechanisms, particularly for endocrine agents Primary (initial) and secondary (induced) resistance occurs Mechanistic combinations required to target therapies to block the cross-talk pathways –New agents –New combinations/sequences