Advancing research on metastatic breast cancer: the UPTIDER post-mortem tissue donation program

Abstract Background. Research in metastatic breast cancer is hampered by limited sample availability. Post-mortem tissue donation programs can help to overcome this problem but are logistically challenging and have thus far mainly focused on histopathological and genomic research. We here present the UPTIDER program (NCT04531696), aimed at the multilevel characterization of advanced breast cancer and generation of tumour models. Patients and Methods. Patients with stage IV breast cancer receiving their last line(s) of treatment are eligible for participation. Blood, urine and saliva samples are collected upon inclusion. Upon death, a post-mortem MRI (when possible) followed by a rapid autopsy is performed. Liquid biopsies from all body fluids and tissue samples from all macroscopically identified metastatic sites are collected. Samples are processed as mirrored biopsies in different conditions, such as fresh frozen for omics analyses, formalin fixed paraffin-embedded for histopathology, and slowly frozen in freezing medium or fresh for generation of xenograft and organoid models. Results. Since approval by the local Ethical Committee in November 2020, 22 patients have been enrolled and 15 autopsies have been performed. Mean interval between death and start of autopsy was 3h (range 2-6h), mean duration of the autopsies was 6h (4-9h). A post-mortem MRI was performed in 6 patients. Peripheral blood, central blood and bone marrow were collected from all patients; urine, ascites, cerebrospinal, pericardial and pleural fluid all in more than 2/3 of patients. On average, 232 (range 90-406) tissue samples of which 164 (45-303) pathological from 42 (15 – 79) metastases were collected for each patient. Most often sampled metastatic sites were lymph nodes, liver, bones, pleura and peritoneum. Samples from the primary tumour could be retrieved from all patients, either during the autopsy (n=6) or from historical archives. In total, 133 tumour samples were sent to collaborating partners for patient-derived xenograft creation. Already some have been successfully established and stored, including models derived from a patient with invasive lobular carcinoma (ILC) and one with metaplastic squamous cell carcinoma. When correlating microscopic and macroscopic findings, patients could largely be divided into three main categories. Eleven patients presented with overt and extensive disease burden, often characterized by diffuse visceral, pleural, peritoneal, bone and lymph node involvement. Two patients, both with ILC, presented with underestimated yet extensive disease burden. While gross examination and cross sectioning of organs did not reveal clear involvement, microscopical invasion of stomach and liver, amongst others, was found. Lastly, limited disease burden was seen in two patients, both with leptomeningeal involvement. In those patients, massive tumoral infiltration in the subarachnoid space and along the blood-brain barrier was seen microscopically, with no grey matter invasion. Conclusion. We successfully launched a new and comprehensive post-mortem tissue donation program for patients with metastatic breast cancer, enrolling ~ 1 patient per month. Post-mortem tumour samples already resulted in successful establishment of some patient-derived xenografts. From a clinical point of view, vast underestimation of the disease extent on imaging during life as well as macroscopically during the autopsy was observed in some patients with metastatic ILC. For patients with leptomeningeal metastasis, we showed that the highly aggressive nature of their disease might be explained by extensive meningeal infiltration disrupting the blood-brain barrier. Further insights into disease progression and heterogeneity will be generated by the ongoing multi-omics analyses. Citation Format: Tatjana Geukens, Maxim De Schepper, Karen Van Baelen, François Richard, Marion Maetens, Amena Mahdami, Ha-Linh Nguyen, Edoardo Isnaldi, Anirudh Pabba, Sophia Leduc, Imane Bachir, Maysam Hajipirloo, Emily Vanden Berghe, Sigrid Hatse, Eleonora Leucci, Maria Francesca Baietti, Georgios Sflomos, Cathrin Brisken, Patrick Derksen, Colinda Scheele, Vincent Vandecaveye, Ann Smeets, Ines Nevelsteen, Kevin Punie, Patrick Neven, Elia Biganzoli, Hans Wildiers, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Advancing research on metastatic breast cancer: the UPTIDER post-mortem tissue donation program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-14.