Rationale for HER2 targeting

1
Rationale for HER2 targeting
2
Characteristics of therapeutic targets in cancer

• Present in many patients with a specific tumour
  type
• Causative link with tumourigenesis
• Essential function in tumour cells
• Not essential for normal cellular function

3
Future perspectives of targeted therapy

• HER1
• Tarceva
• Iressa
• HER2
• 2C4
• Farnesyl-transferase inhibitors
• R115777
• COX-2 inhibitors
• celecoxib
• Proteosome inhibitors
• PS341

4
HER2 terminology

• Human Epidermal growth factor Receptor-2
• Also known as p185HER2
• HER2/neu oncogene encoding production of the
  HER2 receptor
• Also known as
• neu (rat gene)
• c-erbB-2

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Transmembrane structure of HER2 receptor monomer
Extracellular domain (632 amino
acids) Ligand-binding site
Transmembrane domain (22 amino acids)
Plasma membrane
Intracellular domain (580 amino acids) Tyrosine
kinase activity
Cytoplasm
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HER2 receptor dimer transmembrane signal
transduction pathway
Growth factor
Binding site
Plasma membrane
Tyrosine kinase activity
Signal transduction to nucleus
Cytoplasm
Nucleus
CELL DIVISION
Gene activation
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HER2 in breast cancer

• All breast epithelial cells express HER2
• At normal levels, HER2 is involved in the
  regulation of breast growth and development
• HER2 is amplified/overexpressed by 2030 of
  breast cancers (HER2-positive tumours)
• HER2-positive breast cancer is particularly
  aggressive

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Effect of HER2 gene amplificationon human breast
cancer cells
DNA synthesis 5075 Cell growth rate
3050 Growth in soft agar 225 Tumourigenicity
in nude mice Metastatic potential 220in
nude mice
Human breast cancer cells
Transfect with HER2 gene
Transformed phenotype
HER2 negative
HER2 positive
Slamon DJ et al. Unpublished data
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HER2-positive status shortens survival

• Women whose breast cancers are HER2 positive have
  a shorter overall survival

Median survival HER2 positive 3 years HER2
negative 67 years
Slamon DJ et al. Science 198723517782
10
Survival of node-negative breast cancer patients
related to HER2 status
1.00 0.75 0.50 0.25 0
HER2 not amplified
Cumulative probability
HER2 amplified
Amplified gt10 copies/nucleus Not amplified lt3
copies/nucleus Borderline excluded
Log rank plt0.001
0 24 48 72 96 120 144
Time to death (months)
Ross JS, Fletcher JA. Stem Cells 19981641328
11
Disease-free survival of node-positive breast
cancer patients related to HER2 status
100 80 60 40 20 0
HER2 gene lt3 copies/nucleus
Disease-free survival probability
HER2 gene ³3 copies/nucleus
Log rank p0.001
0 12 24 36 48 60 72
Time (months)
Seshadri R et al. J Clin Oncol 199311193642
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Summary role of HER2 in breast cancer

• A HER2-positive status is a predictor of poor
  prognosis
• On multivariate analysis, HER2 was a strong
  independent predictor of
• relapse (p0.001)
• overall survival (p0.02)
• The HER2 receptor provides an extracellular
  target for novel and specific anticancer
  treatment (monoclonal antibodies)

Slamon DJ et al. Science 198723517782