The truth about Herceptin™
The
drug - a genetically engineered version of human antibody
- specifically targets cancer cells.
Trastuzumab
(Herceptin™) is the star in the molecular war in breast
cancer targeted therapy. It is a humanised antibody with a
small murine antigen-binding component, directed against HER2.
Her1,
Her2, Her3 and Her4 are four transmembrane receptors that
belong to the tyrosine kinase (TK) family. The TK family of
receptors, when stimulated by ligand binding, will trigger
multiple intracellular pathways that increase proliferation,
resistance to apoptosis and increase angiogenesis of cancer
cells. The specific target of trastuzumab is Her2 (also called
erbB2). The related Her1 is also known as EGFR (epidermal
growth factor receptor), the site of action for gefitinib
(Iressa™), a new drug in lung cancer. Her2 is over-expressed
in about 25% of breast cancers and is linked to poor clinical
outcomes. The most reliable method of detecting Her2 over-expression
without high false positive rates is by fluorescence in situ
hybridisation (FISH). In preclinical studies, there was loss
of Her2 expression and tumour inhibition in cell lines exposed
to trastuzumab.
After
showing acceptable toxicity profile in phase 1 trials, two
trials confirmed clinical efficacy of trastuzumab. The overall
response rate was 15% when used alone in pre-treated women
with metastatic breast cancer in a phase 2 trial. In phase
3 trials, when immunotherapy was combined with conventional
chemotherapy, a higher response rate (50% vs. 32% p<0.001)
and longer median survival was noted (25.1 months vs. 20.3
months p=0.01). Cardiac dysfunction is the most important
toxicity.
The optimal combination has not yet been found. The optimal
duration of trastuzumab treatment is not clear either. Pre-clinical
studies suggested that chronic administration is required,
as stopping treatment resulted in resumption of Her2 overexpression
and increased cellular proliferation. However, no clinical
study has convincingly shown this to be true.
Studies
on the adjuvant use of trastuzumab are being done to study
how recurrences can be prevented and to prolong life span.
Presently, NCC is participating in one of these trials and
we hope to see trastuzumab make further inroads when it is
combined with other agents administered in an optimal schedule.
Dr Donald Poon
Registrar
Medical Oncology
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