Ah-See, M-L.W.; (2007) Evaluation of the vascular response to neoadjuvant chemotherapy in primary breast cancer. Doctoral thesis , University of London.

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Abstract

Neoadjuvant chemotherapy (NAC) is being increasingly used in the treatment of primary breast cancer (PBC). With the primary tumour in situ, the neoadjuvant treatment setting allows an in vivo assessment of tumour chemo-responsiveness and permits an evaluation of the possible underlying biological mechanisms of response. Angiogenesis is critical for the growth and metastases of breast cancer and with the development of novel agents targeting this process, an understanding of the vascular effects of conventional chemotherapy will enable the rational design of future drug combinations. Functional magnetic resonance imaging (MRI) provides a non-invasive method for assessing tumour microvasculature. Using this technique, pre-treatment tumour vascularity and changes following two cycles of anthracycline-based NAC were measured in a series of patients with PBC. This demonstrated a significant reduction in the permeability and perfusion-related MRI parameters in tumours responding to treatment. The degree of change in K* was able to predict for pathological non-response with a positive predictive value of 84%. Further, an evaluation of the pathophysiological correlates of functional MRI demonstrated an association between the permability/perfusion-related parameters and aggressive tumour features. An evaluation of the effect of anthracycline-based NAC on immunohistochemically-derived measures of tumour angiogenesis was performed on a series of patients treated for PBC. A quantitative and a qualitative measure of tumour angiogenesis was performed (microvessel density MVD and pericyte coverage index PCI respectively), together with an assessment of VEGF expression. This demonstrated no change in MVD following treatment but a significant increase in PCI reflecting a reduction in the proportion of immature proliferating blood vessels. This was accompanied by a reduction in VEGF expression, which may be mediating this effect. These observations may have clinical importance as they may help identify patients who could benefit from alternative therapies early in their treatment course and they may assist in the rational design of combination cytotoxic and antiangiogenic treatment regimens.

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