HER2neu imaging

HER2, the human epidermal growth factor receptor, is encoded for by the HER2 proto-oncogene (HER2/neu or c-erbB-2), and has growth stimulating activity. Overexpression of HER2 as a result of HER2 amplification has been shown in 25-30% of breast cancer patients, and is associated with a worse prognosis and more aggressive clinical behaviour. The anti-HER2 monoclonal antibody trastuzumab (Herceptin®) binds specifically to HER2. The addition of trastuzumab to chemotherapy is effective in the treatment of patients with HER2-overexpressing breast cancer, both in the metastatic and in the adjuvant setting (28).

However, HER2 expression in breast cancer is a dynamic entity that can vary within one patient. Discordance of HER2 expression between primary breast cancers and corresponding metastases was found in 14% of the patients (8). In patients with HER2 negative primary tumours, HER2 positive cells have been detected in bone marrow (9) and in the circulation (29). Also, patients with HER2 positive primary tumours can have metastases with different HER2 expression levels, or they can convert during therapy to a HER2 negative tumour or a tumour with less HER2 expression in about 25% (30). Variation in time of HER2 expression was also shown by Rasbridge et al. (31). Neo-adjuvant anthracycline containing chemotherapy as well as hormonal therapy may induce HER2 expression (9). During cancer progression, nearly 40% of breast cancer patients whose primary tumour was HER2 negative acquired HER2 gene amplification (32). Heterogeneity of tumour tissue can also lead to over or underestimation of HER2 expression, as a result of sampling error (33).

In vivo testing of HER2 expression in a non-invasive fashion may circumvent these problems. Various approaches have been described to image HER2, including intact monoclonal antibodies and more recently: antibody fragments. The anti-HER2 antibody trastuzumab has been radiolabelled with various isotopes, both with diagnostic and therapeutic objectives. Immunolocalisation studies with 124I- and 99mTc-ICR12 (a rat anti-HER2 antibody) in athymic mice bearing HER2 overexpressing human breast carcinoma xenografts showed specific tracer uptake (34), which was strongly correlated with HER2 expression level (35). In humans however, data are limited. In a recent study, immuno-SPECT (single photon emission computed tomography) has been performed using radiolabelled trastuzumab (mIndium-trastuzumab) in 17 patients with HER2 positive metatastatic breast cancer (36). With this technique, 45% of single tumour lesions, detected with conventional imaging, could be shown (Figure 2). However, new tumour lesions were discovered in 13 of 15 patients. Although the number of patients in this study was small, these results may indicate a role for tumour-specific detection by means of radiolabelled trastuzumab. Further studies, including histological samples of the detected lesions, are needed to confirm this. Currently, researchers are optimising the HER2 imaging technique by developing PET tracers based on trastuzumab or Fab fragments - either by labelling of intact antibodies or antibody fragments with PET isotopes (e.g., 68Ga, 18F, 89Zr) (37). Smaller size fragments may improve sensitivity of HER2 imaging. Although preclinical data are promising, this requires further study in humans.

Figure 2. HER2 SPECT performed 5 days after radiolabelled trastuzumab (111Indium), showing bone, supraclavicular and possibly intrapulmonary lesions (arrows).
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