Predicting Chemosensitivity in Epithelial Ovarian Cancer Using Patient Derived Tissue Organoids

PUBLICATIONS

March 29, 2020

SGO Annual Meeting 2020, Tempus-acknowledged —

Objective: The aims of this study were to develop patient-derived tissue organoids from epithelial ovarian cancer tissue obtained at the time of debulking surgery; to perform chemosensitivity profiling with standard-of-care agents and correlate to clinical outcome; and to determine the integrated genetic homology of tumor organoids with associated primary tumor tissue.

Method: Tumor tissue was obtained from patients at the time of debulking surgery, dissociated, and established in vitro using factor-defined media. Representative micrographs were H&E stained and compared with primary tumor. Eleven anticancer compounds were tested as monotherapy, as well as a 4:1 carboplatin/paclitaxel combination. Cytotoxicity was measured using high content imaging for Caspase 3/7 fluorometry as well as cellular viability via MTS assay. EC50 results of each tested agent were compared against each patient’s response to chemotherapy. Molecular profiling was accomplished using a next-generation sequencing (NGS) panel and whole transcriptome RNA-sequencing. Mutational concordance was performed by comparison of sequencing results between the primary tumor specimen and the resultant tumor organoids.

Results: So far, 11-patient derived tissue organoids cell lines have been established, and 6 have been fully characterized. Three samples demonstrate inherent sensitivity to carboplatin, and 3 samples demonstrate resistance (Table 1). Ninety-eight percent of called somatic variants and 96% of total variants (all somatic, germline, and VUS) identified in the primary tumor are also present in the tissue organoid sequence. Five more samples are currently proliferating and will soon achieve biomass necessary for full characterization.

Conclusion: Ovarian epithelial tissue organoids can be successfully established from patients at the time of debulking surgery in the chemo-naïve and neoadjuvant settings. Tissue organoids demonstrate a high degree of genetic homology to primary tumor tissue. Interestingly, altered variant allelic fractions in some canonical pathogenic genes, such as TP53, are indicative of potential clonal selection events. Chemosensitivity profiles appear to recapitulate clinical response, but correlation with advanced-stage patients is ongoing.

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Authors: J.W. Gorski, J.R. McCorkle, J. DeJohn, B.T. Burgess, A.B. McDowell Jr, M.B. Riggs, R.W. Miller, C.S. Dietrich III, L.A. Baldwin, C.P. Desimone, H.H. Gallion, F.R. Ueland, J. Kolesar