Breast cancer and therapeutic deployment of growth factor receptors

Growth factors and their receptor play a major part in normal growth and differentiation and also in tumour development and progression. Mutations or overexpression of growth factor receptors is associated with aggressive cancers and poor prognosis for patients. Growth factor receptors are transmembrane tyrosine kinase proteins that transduce growth factor signals imparted by their binding to specific receptors leading ultimately to the induction of cell proliferation. HER2 is a human epidermal growth factor receptor. Approximately 25% of breast cancers show HER2 gene amplification and this correlates with aggressive behaviour and poor prognosis. The deployment of Herceptin (Trastuzumab), a humanised chimeric antibody against HER2, to treat HER2+ patients, has emerged as a successful approach to the treatment of breast cancers that over-express HER2 and are resistant to tamoxifen. These patients could benefit from anti-oestrogen therapy combined with blockade of HER2 signalling. Post-menopausal patients with advanced breast cancer appear to benefit significantly from this combination therapy. Combination of Herceptin with chemotherapy might yield considerable benefits in terms of reduction of recurrence and mortality. The efficacy of conjugates of anti-HER2 antibodies with cytotoxic drugs to achieve targeted delivery of the cytotoxic agents is being evaluated. The toxicity associated with the administration of monoclonal antibodies has been recognised. Cardiotoxicity, pulmonary toxicity and infusion-related problems such as anaphylaxis occur, albeit infrequently, with monoclonal antibody therapies. The EGFr (epidermal growth factor receptor) inhibitor Lapatinib (Tykerb) is a protein kinase inhibitor (a 4-anilinoquinazoline derivative), which inhibits growth factor signalling by binding to the ATP-binding pocket of both EGFr and HER2 receptor proteins. Lapatinib has shown much promise in clinical trials in patients with advanced metastatic breast cancer and is believed to have little cardiac toxicity. A strategy similar to that adopted with EGF family growth factor receptors has been used to target the vascular endothelial growth factor receptor (VEGFr) and inhibit signalling by VEGF. Avastin (Bevacizumab) is a humanised monoclonal anti-VEGFr antibody. Avastin combined with Paclitaxel improves progression-free survival and response rate in patients with advanced breast cancer. However, on account of possible side effects, Avastin has not received general approval.