Post on 31-Dec-2015
description
Adjuvant systemic therapyin breast cancer
Targeted therapies Update
R. Paridaens Belgian Breast Meeting
04-10-2008
All our therapies
Are (should be)
Targeted….
Efficacy
Locate target
Use specific weapon
The oldest targeted molecular therapyis hormonotherapy!
When receptors are involved,
the principles will remain the same:
Interfere with ligand production
Or
Block the receptor action
TARGETEGFR (ErbB) Family
(Human Epidermal Growth 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 TrialRandomized trial comparing :3x Docetaxel 100mg/m2 q3W followed by 3x FEC Versus9x 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 regimensWithout anthracyclinesAs efficient and less toxic?
TARGET
Angiogenesis Pathway
Angiogenesis is involved throughout tumour formation, growth and metastasis
Stages at which angiogenesis plays a role in tumour progression
Premalignantstage
Malignanttumour
Tumourgrowth
Vascularinvasion
Dormantmicrometastasis
Overtmetastasis
(Avasculartumour)
(Angiogenicswitch)
(Vascularisedtumour)
(Tumour cellintravasation)
(Seeding indistant organs)
(Secondaryangiogenesis)
Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25
Genentech 2007: Beyond the Tumor-Targeting Angiogenesis in Cancer
Agents Targeting the VEGF Pathway
Podar and Anderson. Blood. 2005;105:1383
PPP
PPPP
P
Endothelial cell
Small-moleculeVEGFR inhibitors
(PTK787, SU11248, ZD6474, BAY 43-9006)
Anti-VEGFR antibodies(IMC-1121b)
VEGF
Anti-VEGF antibodies(bevacizumab)
Soluble VEGFRs(VEGF-TRAP)Avastin
SutentSorafenib
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.
Bevacizumab Binds VEGF
VEGFR-2VEGFR-1PPP
PPPP
P
Endothelial cell
VEGF
Anti-VEGF antibody
(Bevacizumab)
Presta et al. Cancer Res. 1997;57:4593.
Conclusions
Adjuvant setting
Targeted therapy 2008
Targeting tumor subtypes
• 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?