Breast surgery

TL;DR: Breast surgery involves the targeting of molecular mechanisms of cancer for the development of designer drugs. Successful drugs include inhibitors of RTK and their downstream signalling molecules, monoclonal antibodies targeting T cell surface molecules, and drugs regulating apoptotic pathways.

Abstract: The careful dissection of the molecular mechanisms of cancer provides a rational basis for designer drugs that is already delivering dramatic clinical benefits. Those most successful so far in the clinic are inhibitors of the receptor tyrosine kinase (RTK) group of growth factor receptors and their downstream signalling molecules, like BRAF and mTOR. These include monoclonal antibodies, like trastuzumab and cetuximab, and small molecules, like imatinib, gefitinib, erlotinib, lapatinib and sorafenib. ‘Cross-talk’ between the RTK signalling pathways and the oestrogen receptor signalling pathway provides a rational basis for overcoming resistance to hormone therapy. RTK ligands, like Vascular Endothelial Growth Factor (VEGF) have also been effectively targeted with drugs like bevacizumab. Other clinically relevant molecular targets include farnesyltransferases, cyclin-dependent kinases, proteosomes, histone deacetylases, and transcription factors. Clinical trials of new monoclonal antibodies to T cell surface molecules like CTLA4, (ticilimumab, ipilimumab), offer new hope of profoundly enhancing anti-tumour immunity in cancer therapy. The regulation of apoptotic pathways provides clinically useful targets for therapeutic manipulation, exemplified by the use of drugs like oblimersen that inhibit the bcl-2 family of apoptosis inhibitor proteins. The standard testing ground of heavily pre-treated patients may be inappropriate for these new drugs. Short-term testing in the neoadjuvant setting has many advantages, using biomarker responses to select active agents for more extensive clinical trial.