PET imaging of HER-2-positive tumours

Abstract

Human epidermal growth factor receptor 2 (HER-2; neu, cerb-B2) is a transmembrane protein and a member of the erbB family of receptor tyrosine kinase proteins that amplifies the signal provided by other members of the HER family (HER-1, HER-3, and HER-4) by forming heterodimers with them. Overexpression of HER-2 increases tumorigenicity, production of vascular endothelial growth factor, angiogenesis and metastatic potential, and it also confers a survival advantage on cancer cells by making them resistant to apoptosis induced by certain proapoptotic stimuli. HER-2 is amplified and overexpressed in 20–30% of breast cancers, and is also overexpressed in other tumours, including ovarian, lung, gastric and oral cancers. Several studies have found that breast cancers that overexpress HER-2 have a more aggressive course and are associated with a higher relapse rate and mortality rate [1]. Therefore HER-2 has great value as a prognostic indicator of patient survival, as a molecular target for therapeutic intervention and as a predictive marker of response to antineoplastic drugs. Indeed, previous studies have shown that agents that target HER-2 are remarkably effective both in the metastatic and adjuvant settings in breast cancer. Trastuzumab, a humanized monoclonal antibody, improves response rates, time to progression and even survival when used alone or added to chemotherapy in patients with stage IV disease. Moreover, in recent years several targeted agents have become available including lapatinib, a selective, reversible dual inhibitor of the epidermal growth factor receptor (EGFR; HER-1) and HER-2 [2]. However, HER-2 tumour expression can vary during treatment and can differ across metastatic lesions, and also between primary tumour and distant localization within a patient. This is well documented in breast cancer, where a change in HER-2 status has been reported in up to 38% of patients, raising questions about the validity of making decisions concerning the use of trastuzumab based on the HER-2 status of the primary tumour alone [3–5]. Furthermore, the assessment of HER-2 status is still plagued by a high rate of false-positive and false-negative results, leading to the administration of unnecessary therapies (that could be associated with side effects, such as serious cardiac toxicity), and to the termination of effective treatments, respectively [6, 7]. Therefore there is the need for methods that are able to assess the HER-2 status repeatedly, preferably in all lesions and noninvasively. HER-2 imaging through radioisotopelabelled trastuzumab-like molecules could be very useful in this setting. Currently available HER-2 targeted ligands include full-length monoclonal antibodies, Fab fragments, F(ab’)2 fragments, diabodies, minibodies, Affibodies and peptides. When radiolabelling these HER-2-targeted molecules, the physical half-life of the radioisotope ideally should suit the biological half-life of the HER-2-targeting molecules to allow imaging at the optimal time-point. Thus fulllength monoclonal antibodies are mostly radiolabelled with long-lived isotopes, while the smaller HER-2-targeting molecules, which have a more rapid clearance, are radiolabelledwith shorter-lived isotopes. In, I and Tc have been used to label full-length HER-2 monoclonal antibodies and smaller HER-2-targeting antibody fragments, proteins and peptides for SPECT/gamma camera imaging. Moreover, full-length monoclonal antibodies have been labelled with This Editorial Commentary refers to the articles http://dx.doi.org/10.1007/ s00259-011-1810-4 and http://dx.doi.org/10.1007/s00259-011-1879-9