Adjuvant systemictherapyin breast cancer Targetedtherapies Update R. Paridaens BelgianBreast Meeting 04-10-2008
All our therapies Are (should be) Targeted…. Efficacy Locate target Use specific weapon
The oldesttargetedmoleculartherapy ishormonotherapy! Whenreceptors are involved, the principleswillremain the same: Interferewith ligand production Or Block the receptor action
TARGETEGFR (ErbB) Family(HumanEpidermalGrowth Factor Receptors)HER1,2,3,4
Anti – HER2 therapies having reached the adjuvant level for breast cancer Antibodies targeting HER2: Trastuzumab TKI : Lapatinib
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)
Adjuvant Herceptin FACTS: Efficacy! Cardiotoxicity! Questions: Scheduling with chemo? Duration? HT? Costs? Are chemo regimens Without anthracyclines As efficient and less toxic?
Angiogenesis is involved throughout tumour formation, growth and metastasis Premalignant stage Malignant tumour Tumourgrowth Vascularinvasion Dormantmicrometastasis Overtmetastasis (Avascular tumour) (Angiogenicswitch) (Vascularisedtumour) (Tumour cellintravasation) (Seeding indistant organs) (Secondary angiogenesis) Stages at which angiogenesis plays a role in tumour progression Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25
Anti-VEGF antibodies (bevacizumab) Soluble VEGFRs (VEGF-TRAP) VEGF Anti-VEGFR antibodies (IMC-1121b) P P P P P P P P Endothelial cell Small-moleculeVEGFR inhibitors (PTK787, SU11248, ZD6474, BAY 43-9006) Agents Targeting the VEGF Pathway Avastin Sutent Sorafenib Podar and Anderson. Blood. 2005;105:1383
Anti – angiogenic therapies having reached the adjuvant level for breast cancer Antibodies targeting VEGF: Bevacizumab (Avastin) ? TKI : Sunitinib (Sutent)? ?Metronomic chemotherapy?
Bevacizumab • Recombinant humanized monoclonal IgG1 antibody • Recognizes all isoforms of VEGF1 • Estimated half-life approximately 20 days (range, 11-50 days) Presta et al. Cancer Res. 1997;57:4593.
Anti-VEGF antibody (Bevacizumab) VEGF P P P P P P P P VEGFR-1 VEGFR-2 Endothelial cell Bevacizumab Binds VEGF Presta et al. Cancer Res. 1997;57:4593.
Conclusions Adjuvant setting Targeted therapy 2008
Targetingtumorsubtypes • ER and/or PR + (Tam? AI?) • HER2 amplification (TTZ? Other? Chemo?) • Triple negative – basal like (Chemo?)
Targeting patient geno/phenotypes • Metabolic capacity • Familial breast cancer • DNA repair defects
Tamoxifen less efficient when metabolic capacity (SNP of cytochromes) is altered?