1. Adjuvant systemic therapy in breast cancer Targeted therapies Update R. Paridaens Belgian Breast Meeting 04-10-2008

2. All our therapies Are (should be) Targeted…. Efficacy Locate target Use specific weapon

3. The oldest targeted molecular therapy is hormonotherapy! When receptors are involved, the principles will remain the same: Interfere with ligand production Or Block the receptor action

8. TARGET EGFR (ErbB) Family (Human Epidermal Growth Factor Receptors) HER1,2,3,4

11. Anti – HER2 therapies having reached the adjuvant level for breast cancer Antibodies targeting HER2: Trastuzumab TKI : Lapatinib

15. The FIN HER Trial Randomized trial comparing : 3x Docetaxel 100mg/m2 q3W followed by 3x FEC Versus 9x Vinorelbine 25mg/m2 weekly followed by 3x FEC The 232 pts with HER2 + tumors were randomized to receive (n=116) or not (n=116) Herceptin weekly during the first nine weeks of treatment DFS was significantly better with Herceptin: 89% vs 78% (HR O.42, P=0.01) OS was also better: 96% vs 90% (HR 0.41, P=0.07)

16. Adjuvant Herceptin FACTS: Efficacy! Cardiotoxicity! Questions: Scheduling with chemo? Duration? HT? Costs? Are chemo regimens Without anthracyclines As efficient and less toxic?

18. TARGET Angiogenesis Pathway

19. Angiogenesis is involved throughout tumour formation, growth and metastasis Stages at which angiogenesis plays a role in tumour progression Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis) Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207 –25

20. Genentech 2007: Beyond the Tumor-Targeting Angiogenesis in Cancer

21. Agents Targeting the VEGF Pathway Podar and Anderson. Blood. 2005;105:1383 P P P P P P P P Endothelial cell Small-molecule VEGFR inhibitors (PTK787, SU11248, ZD6474, BAY 43-9006) Anti-VEGFR antibodies (IMC-1121b) VEGF Anti-VEGF antibodies (bevacizumab) Soluble VEGFRs (VEGF-TRAP) Avastin Sutent Sorafenib

22. Anti – angiogenic therapies having reached the adjuvant level for breast cancer Antibodies targeting VEGF: Bevacizumab (Avastin) ? TKI : Sunitinib (Sutent)? ?Metronomic chemotherapy?

23. Bevacizumab Recombinant humanized monoclonal IgG 1 antibody Recognizes all isoforms of VEGF 1 Estimated half-life approximately 20 days (range, 11-50 days) Presta et al. Cancer Res. 1997;57:4593.

24. Bevacizumab Binds VEGF VEGFR-2 VEGFR-1 P P P P P P P P Endothelial cell VEGF Anti-VEGF antibody (Bevacizumab) Presta et al. Cancer Res. 1997;57:4593.

29. Conclusions Adjuvant setting Targeted therapy 2008

30. Targeting tumor subtypes ER and/or PR + (Tam? AI?) HER2 amplification (TTZ? Other? Chemo?) Triple negative – basal like (Chemo?)

31. Targeting patient geno/phenotypes Metabolic capacity Familial breast cancer DNA repair defects

32. Tamoxifen less efficient when metabolic capacity (SNP of cytochromes) is altered?