Epidermal growth factor receptor overexpression as a target for imaging and radiotherapy of breast cancer

The overexpression of the epidermal growth factor receptor in 30--60% of human breast cancers was investigated as a target for radiopharmaceuticals specifically directed against the receptor for diagnostic imaging and radiotherapy of the disease. Using phantoms (models) of breast cancer lesions targeted in vitro with indium-111 labelled human epidermal growth factor ( 111In-hEGF), it was demonstrated that diagnostic imaging through targeting EGFR overexpression in breast cancer could be a very sensitive technique able to detect as few as 5 x 104 to 105 cancer cells under ideal conditions. The sensitivity was reduced up to 300-fold however by receptor heterogeneity or a low proportion of tumour cell targeting combined with tissue attenuation. A comparison of the tumour imaging properties of 111In-hEGF and 111In-labelled anti-EGFR monoclonal antibody 528 (111In-mAb 528) in athymic mice with human breast cancer xenografts showed that macromolecules are more effective tumour targeting agents than peptide growth factors due to higher absolute tumour uptake at only slightly lower tumour/blood ratios. The 10-fold higher tumour uptake of 111In-mAb 528 compared to 111In-hEGF was likely due to its prolonged residence time in the blood. The internalization and nuclear translocation of 111In-hEGF after binding to its receptor was exploited to selectively deliver 111In into the cytoplasm and nucleus of breast cancer cells overexpressing the EGFR. Internalized 111In-hEGF was radiotoxic in vitro to the breast cancer cells with <5% survival at <130 mBq/cell. The radiotoxicity was probably due to the emission of Auger electrons by 111In at close proximity to the chromosomal DNA. There was no evidence of radiotoxicity in vivo in mice administered high doses of the 111In-hEGF to normal tissues such as the liver and kidneys which express moderate amounts of EGFR. These results are encouraging for the application of radiopharmaceuticals specifically targeted to the EGFR for diagnostic imaging or radiotherapy of advanced forms of breast cancer in humans.