Modulation of the biologic behaviour of breast cancer; in vitro models and clinical correlates

Abstract

Breast cancer is a common, devastating disease with an enormous impact on society. It has a complex biology, perhaps more complex than other tumour types, at least in part due to its hormonal control. While this complex biology poses an enormous challenge to researchers investigating breast cancer, it conversely offers the hope o f additional interventions, not feasible with other tumours that may have a beneficial impact on outcomes. Important in choosing patients for such interventions are the definition o f prognostic indicators that allow the tailoring of therapy to patients, limiting toxic treatments to those patients in whom they may be beneficial. Another potential approach is the modulation o f tumoir biology to circumvent drug resistance, either constitutional or acquired. The studies included in this thesis have attempted to translate preclinical hypotheses into clinical investigations and ultimately new management. Hormone receptors, growth factors (TGF-P, PDGF) and markers o f growth (Ki67) and oestrogen action (P24) have been demonstrated to have prognostic relevance in the clinic. Proof o f principle o f the modulation o f breast cancer behaviour both in the preclinical and clinical setting has been attempted. These studies include an examination o f the effects o f oestrogen, g m n 'irior to cytotoxic chemotherapy. Biologic effects have been demonstrated although m ih: ..unic a beneficial effect on survival was not seen. In addition, the studies demonstrate tha* interferon (IFN), given prior to tamoxifen treatment modulates cell behaviour and r e c e p ;v r expression, potentially improving clinical outcomes. Interferon also modulates multidrug resistance, at least in an in-vitro model and may have clinical relevance. The real clinical import o f these observations however awaits definitive clinical study, and the development of more effective modulators o f drug resistance.