Title A Feasibility PET Study of HER2 Receptors in Breast Cancer Using 89Zr-Trastuzumab Project Summary The use of monoclonal antibodies (MAbs) for treatment of oncologic patients is rapidly expanding while the imaging tools for evaluation of the specific tumor antigens targeted by these therapies lagged behind. Breast cancer remains the leading cause of cancer mortality among women in Western countries. HER2-amplified breast cancers, which consist of 20-30% of breast cancers, are associated with a more aggressive growth rate, increased risk of metastasis and worse overall survival compared with HER2-negative breast cancers. The identification of HER2 amplification as the driver mutation in these cancers and the subsequent development of trastuzumab, a MAb directed against the extracellular domain of the HER2 receptor, have dramatically improved the prognosis in these patients. However, only half of HER2-positive patients receiving first-line trastuzumab and chemotherapy for metastatic disease have objective responses. This suggests that the presence of HER2 positivity by current in vitro assays is not an accurate predictor of response to therapy, possibly related to within-patient tumor heterogeneity. PET using radiolabeled antibodies (Immuno-PET) is a novel option for non-invasive identification of the presence of specific targets throughout the body, tracing and quantification of monoclonal antibodies binding to the target and ultimately helping in better understanding of in vivo behavior and effectiveness of treatment with MAbs in individual patients. In this application, we are proposing a feasibility study using Zirconium-89 (89Zr) labeled trastuzumab in breast cancer. Because of its longer physical half-life that matches the biological half-life of a MAb (i.e., the mean half-life of trastuzumab is 5.8 days), 89Zr is preferred to 68Ga- (t1/2 = 1.13 h) and 64Cu- (t1/2 = 12.7 h) for radiolabeling of MAbs. In studies with tumor xenografts, significantly greater 89Zr-trastuzumab uptake has been detected in HER2- positive than in HER2-negative tumor sites. In a small study of patients with HER2-positive breast cancer, high image quality with optimal biodistribution and excellent tumor uptake have been demonstrated with 89Zr- trastuzumab-PET. We are proposing to perform a pilot study with goals of demonstrating the feasibility of imaging breast cancer patients with 89Zr-trastuzumab-PET, evaluating the relationship between tumor 89Zr- trastuzumab uptake and in vitro status of HER2, assessing the safety of 89Zr-trastuzumab and determining the human dosimetry of this radiopharmaceutical.
Developing a noninvasive means, 89Zr-trastuzumab-PET, which can address the intrinsic heterogeneity of HER2 expression, for predicting responsiveness to trastuzumab therapy would significantly change treatment paradigms in HER2-positive breast cancer and ultimately save costs and avoid the morbidity associated with unnecessary therapy with trastuzumab based therapies in patients who are not going to respond to such therapy.