2022-RA-1529-ESGO Endometrial Cancer patient-derived explants detect drug-responses to standard-of-care chemotherapies and immunotherapy ex-vivo

Introduction/BackgroundA novel Endometrial Cancer Patient-Derived-Explant (EC-PDE) preclinical model system was developed that is capable of detecting patient-specific drug-responses to standard-of-care chemotherapies and immunotherapy ex vivo.MethodologyEndometrial tumour was obtained from 21 patients with endometrial cancer and processed into explants. EC-PDEs were then cultured at the air-liquid interface for up to 24 h followed by a further 24 h treatment with Carboplatin and Paclitaxel (CP) or Pembrolizumab and then processed into histology slides. Multiplexed immunofluorescence for Ki67 (proliferation marker), cPARP (apoptosis marker) and CAM 5.2 (tumour mask) was performed for viability studies. Images were then analysed with quantitation of biomarker expression and necrosis area.ResultsEC-PDEs maintained the histological architecture of the tumour and surrounding TME and remained viable for up to 48 h. Differential drug-responses were detected to single- and dual-agent chemotherapy with positive correlations identified between cell-death and advanced stage (r2=0.21, p=0.04), grade (r2=0.28, p=0.01) and ESGO risk-categorisation of disease (r2=0.49, p<0.01). Cell-death-responses were identified in 61.9% of EC-PDEs following Pembrolizumab-treatment. A third (33.3%) of EC-PDEs responded to both chemotherapy and immunotherapy, 28.5% responded to Pembrolizumab but were resistant to CP, 19% responded to CP but were resistant to Pembrolizumab and 19% of EC-PDEs were resistant to both CP and Pembrolizumab.ConclusionEC-PDEs are a rapid, low-cost pre-clinical model which offers the potential for rapid, personalised pre-clinical drug-response testing. Drug-resistance can be identified in EC-PDEs and EC-PDEs could be used in future to explore the biological effects of immunotherapy and to evaluate predictors of drug response and mechanisms of drug-resistance.