MICA: Molecular imaging of HER2 receptor expression using PET: mechanistic study of the novel [18F]-HER2-Affibody tracer in metastatic breast cancer

1 in 8 women in the UK will develop breast cancer, 20% of whom will have cancer which is her2 positive - meaning that the tumours have a protein receptor on the surface of the cancer cells. The presence of the her2 receptor has been found to make cancers more aggressive, and generally their outcomes are worse than those tumours that are her2 negative. Her2 positive breast cancer can be treated with drugs such as trastuzumab (otherwise known as Herceptin) which is used in the early stages to reduce the risk of relapse, or in the metastatic stage when the cancer has spread to distant organs to try and control the disease.
This study aims to develop a new type of scan for imaging patients with her2 positive breast cancer. The test involves a very small amount of a radioactive chemical (called a tracer), which can bind to the her2 receptor. This tracer can be detected in a PET scanner and used to localise the areas that are her2 positive. At present doctors rely on biopsies of tumours to detect her2, the biopsies can be painful and are not always possible from certain areas of the body for example the biopsy might cause bleeding if the tumour is near a blood vessel. In patients with advanced cancer (meaning that the tumour has spread to distant parts of the body) new drugs have been developed which target the her2 receptor.
Compared to standard treatments the newer drugs have significantly higher response rates and have been hailed as breakthroughs in the treatment of her2 positive cancer. However the prognosis for this disease remains poor, and the clinical studies show that between 20 and 50% of patients with metastatic her2 positive cancer will not respond to some of these newer agents. Resistance only becomes apparent after several treatments have been given, and is generally found in CT scans which show either new lesions or that the existing tumour lesions have enlarged in size. The newer drugs do have a significant risk of side effects including low platelets (which help the blood to clot in 12%), and heart toxicity (1%).
However for individual patients we cannot predict before the start of treatment if their metastatic tumours will respond to treatment, and it is not possible to biopsy every single lesion.
This study will be divided into two phases, in the first phase we will assess whether the tracer is taken up more in her2 positive tumours than her2 negative tumours, this will involve detailed PET scans lasting approximately 90 minutes in 16 patients in total, as the tracer (also known as GE-226) has not been used in this specific form before, we will also study safety by monitoring patients carefully before and after the scans, this phase will all be done in one centre in London (Imperial College) which has particular expertise in this type of study, if this phase is successful and there is no significant toxicity we will proceed to the second phase which will involve 25 patients with her2 positive patients who will have a PET scan with GE-226 in one of four centres (whichever is closest), the PET scan will be done at the start of a course of therapy and compared to standard CT scans which are done before treatment and after 3 cycles of treatment (63 days) to measure if the findings from the PET scan can predict which patients will respond to treatment. We will have regulatory approval from all the relevant committees in place (ethics, radiation, MHRA) before the study can start.
The outcomes for this project we hope for are to demonstrate that GE-226 has higher uptake in her2 positive disease, that it is safe and well tolerated, and that it can predict response to treatment. If this is successful then larger studies could be done in the future to confirm this, and eventually this could become a routine test in this group of patients which would help oncologists select the best treatments, and also reduce drug costs for the NHS. The study will be led by leading oncologists and imaging scientists from the UK.

1 in 8 women will develop breast cancer in the UK. In 25% of cases over-expression of the human epidermal growth factor receptor-2 (Her2) is found, which is an adverse prognostic factor and used to guide therapy selection. Tumour biopsies are unreliable and painful. There is an urgent need now for a non-invasive test which can measure her2 expression reliably.
Aims:To evaluate the clinical utility of the novel PET probe GE-226 Affibody ([18F]FBA-ZHER2:2891) in patients with breast cancer.
Methodology: An initial method development phase will include 8 patients with her2 positive and 8 patients with her2 negative metastatic breast cancer who will dynamic PET imaging over 90 minutes post-injection of GE-226. Radial arterial sampling will be performed to obtain a kinetic input function. Scans will be reconstructed by iterative and filtered back projection algorithms. Mathematical modelling techniques will determine GE-226 binding, delivery, and retention in tumour and non-tumour tissue. Metabolism of GE-226 will be quantified by HPLC. A tissue specimen will be obtained for immunohistochemistry and silver in situ hybridisation testing to quantify her2 expression and amplification. Safety data will be collected and patients will be monitored for any adverse effects as this is a first in patient study. This study will determine the optimum time-point for imaging for the second phase of the study.
The second phase will include a baseline static PET imaging study to be performed in 25 her2 positive patients with metastatic breast cancer who are to be treated with trastuzumab- emtamsine (TDM-1) (standard for this group). Tumour uptake will be quantified by SUV, response will be measured using standard CT imaging and RECIST criteria after 3 cycles of treatment.
The study will be performed at 4 of the largest breast cancer units in the UK by leading oncologists and imaging physicians. The results could redefine management of patients with her2 positive cancer.

Who will benefit from this research?
The NHS and patients will benefit from this research as this test could redefine the manner in which patients with her2 positive breast cancer are managed.
The UK would benefit by demonstrating that we can lead the field in first in man imaging studies
How will they benefit from this research?
There is a lot of interest in the cost of non-curative treatments in health economics. As the pharmacokinetic profile of therapies improve, less systemic toxicity is seen together with enhanced anti-tumour effects, however the newer therapies have high costs. This study should provide the initial data for a larger international study which will harness the use of predictive imaging as a biomarker for response to her2 targeted therapies. Professor Steve Morris (Professor of Health Economics, UCL) is a collaborator for this application.