Introduction/Background Given their genotypic and phenotypic correlation with in vivo tumour, patient-derived organoids (PDOs) are in increasing use as pre-clinical models for High Grade Serous Ovarian Cancer (HGSOC) and other malignancies, including as putative predictive biomarkers. We sought to demonstrate inter- and intra-patient heterogeneity in PDOs from disseminated HGSOC tumours.

Methodology Multi-site tumour samples were obtained from patients undergoing primary cytoreductive surgery, tumour cells were extracted and PDOs propagated using different media conditions (± R-spondin supplementation). Once established, PDOs were assessed against conventional and targeted therapeutics using IC50 and AUC for comparison. RNA sequencing was also performed to characterise transcriptomic differences between PDOs.

Results Multi-site PDOs were grown from 14 patients with a mean of 5 sites cultured per patient, successfully established (≥5 passages) in 8/14 cases (57%) and immortalised in 5/14 cases (36%). Large variation was observed in IC50 and AUC values for platinum compounds and PARP inhibitors between patients, and between different tumour PDOs from the same patient. Interpatient heterogeneity was observed with cisplatin sensitivity varying up to 20-fold across 8 different PDO lines (p<0.0001). Intra-patient heterogeneity was observed with variations in carboplatin sensitivity by almost 10-fold between anatomical sites in one case (p<0.0001). Heterogeneity in rucaparib sensitivity was also demonstrated between cases and between sites from the same case (p<0.001). Dependence on R-spondin for growth was variable and influenced treatment sensitivity. Resistance was induced in 2 PDO lines through growth in low-dose conditions, with increments in AUC observed for cisplatin (p<0.01) and rucaparib (p<0.05) compared to controls.

Conclusion HGSOC PDOs are a reliable model for drug screening and enable characterisation of inter and intra-patient heterogeneity ex vivo. The extent of intra-patient heterogeneity is a likely contributory factor to the high rates of treatment resistance and relapse observed with HGSOC.

Disclosures JC received honoraria from Novartis and Pfizer, outside of the submitted work. CF received honoraria from Ethicon, GSK, Astra Zeneca/MSD, Tesaro, Clovis, Sequana and Roche, outside of the submitted work.