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)Avasti

n

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?