Periodic Reporting for period 4 - HYPMED (Digital Hybrid Breast PET/MRI for Enhanced Diagnosis of Breast Cancer) Reporting period: 2020-01-01 to 2021-02-28 Summary of the context and overall objectives of the project HYPMED will develop and evaluate a novel medical device that is used to improve diagnosis of breast cancer. Aim of the project is to build a positron emission tomography–magnetic resonance (PET–RF) insert for breast PET–MRI hybrid imaging. This means that the two most powerful imaging methods that are currently available for early diagnosis of cancer, PET and MRI, are fused to yield a novel device that offers maximum diagnostic accuracy. The project will integrate an innovative, fully digital MRI-transparent PET detector directly into a novel, fully PET-transparent breast MRI surface coil. The PET-RF insert will allow precision imaging of breast cancer by combining high-resolution and ultra-low dose breast PET with highest level structural and multi-parametric functional MR imaging. HYPMED’s novel PET–RF insert will identify imaging correlates of molecular processes that are specific for carcinogenesis, i.e. tissue mechanisms that stimulate cancer growth, cancer metabolic homeostasis, and metastatic potential of cancers. The specific project objectives are:• Technical development of a dedicated ultra-low-dose, ultra-high-sensitivity, PET–RF insert with integrated vacuum biopsy capability as the ultimate tool for breast cancer diagnosis• Development and evaluation of quantitative PET-MRI acquisition, image reconstruction, post-processing and visualization methods for the targeted application of breast cancer• Establish the technical capabilities and demonstrate diagnostic utility of the novel PET–RF insert• Establish novel functional and molecular imaging-based biomarkers from whole-body PET–MR datasets for future comparison with data from the HYPMED device Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The mechanical design of structural parts of the PET–RF insert, several subsystems of the PET–RF insert and the PET detector mounting system was finalised. The RF coil prototype was developed and tested, and safety measurements were performed. In terms of the PET detector the electronics prototypes were developed and tested (coincidence testing) and performance testing of prototype PET detector electronics inside the MRI environment was performed. The device was finalised at TUD in Nov. 2020 and preparations were made to gain legal clearance for shipping and hold an integration meeting between the teams at TUD and UKA. Due to COVID-19 restrictions, shipment was only achieved in March 2021 (period 5). Since COVID-19 restrictions have not permitted the integration meeting, a video tutorial was conducted instead. Clinical testing may be achievable by October 2021 at the earliest.In terms of required software implementations to operate the device, MR-fingerprinting for different patients was investigated, and two papers published. Attenuation maps for MR-Dixon-based images showing the operation of the segmentation and the assignment of linear attenuation coefficient values were generated. For the clinical study ethical approval for several tracers among them [18F]FGD, [18F]FMISO and [18F]choline mpPET–MRI was obtained. A total 200 patients for whole-body [18F]FGD mpPET–MRI and 40 patients for whole-body [18F]choline mpPET–MRI were included. In addition, a protocol entitled multiparametric whole-body [18F]fluoroestradiol PET–MRI coupled with radiomics analysis and machine learning for prediction and assessment of response to neoadjuvant endocrine therapy in patients with hormone receptor+/HER2− invasive breast cancer was also approved. First results indicate that due to the complementary information of different parameters whole-body [18F]FDG mpPET–MRI has the potential to improve diagnostic accuracy by lowering false positives. In addition, it was demonstrated that whole-body [18F]FDG mpPET–MRI allows accurate evaluation of the axillary status in breast cancer patients.For tissue biomarkers over 40 cases were examined by conventional immunohistochemistry. In parallel, the Opal system is now established to allow parallel immunofluorescent stainings on the same slide with up to six fluorescent markers to study relations between the different cellular component between each other and their interplay with the tumour cells. A tissue collection of pre-invasive breast lesions with sufficient pathological and clinical data has been selected from a stock of 146 DCIS cases. Pure tumour cells were captured using laser microdissection from 19 DCIS stages. Extracted DNA quantity ranges between 2.2 ng and 78.8 ng. Reduced Representation Bisulfit Sequencing (RRBS), a large-scale high-resolution DNA methylation analysis, has been established for investigation of epigenetic aberrations. The RRBS technology has been set up on DNA samples from invasive ductal carcinoma. Dissemination activities continued and online presence was maintained through the project website and appearance in social media. HYPMED was promoted on major congress events in the field (via online formats due to Covid-19). Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) HYPMED develops a breast PET-RF insert with a more than twofold increase in sensitivity and resolution and the capability to perform PET- and MRI-guided biopsy. Due to the high sensitivity and low radiation dose involved, it will be indicated for many more clinical applications than PET imaging before. The concept of HYPMED will greatly increase the availability of this technique and, thus, patients’ access to high-level molecular and functional breast imaging. HYPMED introduces a novel approach: It gives up the whole-body approach, in favor of a local, targeted, focused PET–MR imaging method that provides maximum-sensitivity functional as well as structural imaging of cancers. It allows PET to become an “only” localized, but high-resolution, high-sensitivity, organ/sub-organ-wise imaging method.This will significantly improve the accuracy and reliability with which we will be able to detect and characterize invasive as well as non-invasive breast cancer, or to delineate its extent. Beyond the mere diagnosis of presence or absence of breast cancer, we will improve the non-invasive biological classification of breast cancers, to improve appropriate treatment selection.The expected improved response predication and assessment and prognostication in patients undergoing therapy will allow an earlier adaption in case of treatment failure. Based on the innovative PET-RF insert, HYPMED will enable a more accurate and early diagnosis of breast cancer and will provide new imaging biomarkers that are needed to guide local and systemic treatment of breast cancer. As a side effect, the HYPMED device can be plugged into every all-purpose MR system, transferring it into a high-performance focused MR–PET hybrid system. This will substantially promote the availability of and demand for PET–MR hybrid imaging.The introduction the breast PET–RF insert will reduce the overall economic costs associated with breast cancer and pave the way for similar developments in prostate cancer, cardiac, brain and abdominal imaging among others, bolstering the sustainability of the European healthcare system. The successful completion of HYPMED will unlock a new market that is estimated to amount to €100 million per year. In the beginning, this market will be exclusively served by the industry partners participating in the project. Extending the concept will to cardiac and prostate imaging will enlarge the market size to an estimated €300 million per year. HYPMED Logo
