Introduction/Background Endometrial cancer (EC) is the second most frequent gynaecological cancer worldwide. Mortality in patients with high-risk and recurrent EC is high since treatment options are limited, and tumours are highly chemoresistant. In the recent years, EC has been depicted as a highly heterogeneous tumour, however, the role of intra-tumour heterogeneity (ITH) in treatment response needs to be further investigated. In this study, our goal is to understand the impact of molecular ITH in treatment response for EC patients.

Methodology Preclinical mouse models were generated from 28 different tumour areas of 12 EC patients. Those areas were analyzed by genome sequencing to investigate pathogenic genes and oncogenic alterations that might drive the tumour formation. A bioinformatic pipeline was developed to find the best candidate’s drugs targeting the specific mutated genes or altered pathways of each tumor area. Viability assays were performed to assess the efficacy of the selected drugs in 3D in vitro models (organoids) which also represents the ITH of patients.

Results All EC models presented molecular ITH as tumour drivers and pathogenic genes were altered between the areas. Drugs targeting specific genes per area were also founded. Organoids from 2 EC patients were used for testing such targeted drugs and standard chemotherapy revealing changes in the drug sensitivity between the areas. Specifically, a relevant variance in the cell viability of the different organoids from one patient was encountered when assessing the efficacy of Geldanamycin, an HSP90 inhibitor.

Conclusion We have established a workflow for the identification of specific drugs according to the mutational profile of EC patients. Our preliminary results indicate that ITH might have an important role in treatment response. The need to incorporate the molecular profiling of different areas of the tumor to define a precision medicine approach should be further investigated.

Disclosures Authors do not have any conflict of interest.