The development of brain metastases marks a serious downturn in the course of disease for cancer patients, marked by high morbidity and virtually 100% mortality. Brain metastases are becoming more frequent in line with population ageing and improving treatment of systemic disease, and the incidence now outweighs that of any individual malignancy. The societal burden is further increased by expensive multimodal treatments and hospitalisations. Diagnosis is normally based on magnetic resonance imaging (MRI) of symptomatic patients – that is, once tumours are sufficiently advanced to produce neurological symptoms through localised disruption of brain tissue architecture. Furthermore, obtaining diagnostic information on potential therapeutic targets is difficult, with histopathologic assessment limited to surgical candidates (patients with suitable performance status and operable disease).
We propose that clinical management could be improved by the development of theranostic approaches, providing precise and sensitive diagnostic information on the extent of disease, expression of targetable markers and ancillary parameters impacting on drug uptake (e.g. perfusion dynamics and interstitial pressure). We and others have shown that the HER2-3 dimer is overexpressed and activated in BM from multiple primary cancer types. Here, we present new data demonstrating efficacy of HER2-3 combination therapy (trastuzumab+pertuzumab) in intracranial SKBr3 and MDA-MB-361 breast cancer xenografts. On the imaging side, we have developed a pertuzumab-based PET tracer (Ptz-89Zr) with favourable in vitro stability, HER2-binding affinity, and in vivo biodistribution properties. The next phase is a pilot clinical PET-MRI study in brain metastatic HER2+ breast cancer patients using the Ptz-89Zr tracer, where we aim to delineate relationships between the administered dose, uptake and retention over time, tumour size and perfusion.
We anticipate this work will provide important information about factors affecting the uptake of monoclonal antibody-based therapies in these unique tumours, and on the feasibility of applying theranostics for brain metastasis management in the future.