Conversion Therapy of Intrahepatic Cholangiocarcinoma Is Associated with Improved Prognosis and Verified by a Case of Patient-Derived Organoid

Abstract

This study was performed to determine the efficacy of conversion therapy in intrahepatic cholangiocarcinoma (IHCC) and explore the feasibility of cancer organoid to direct the conversion therapy of IHCC. Patient data were retrospectively reviewed in this study and cancer organoids were established using tissues obtained from two patients. A total of 42 patients with IHCC received conversion therapy, 9 of whom were downstaged successfully, and another 157 patients were initially resectable. Kaplan-Meier curves showed that the successfully downstaged patients had a significantly improved overall survival compared to those in whom downstaging was unsuccessful (p = 0.017), and had a similar overall survival to that of initially resectable patients (p = 0.965). The IHCC organoid was successfully established from one of two obtained tissues. Routine hematoxylin and eosin staining and immunohistological staining found the organoid retained the histopathological characteristics of the original tissues. Whole exome sequencing results indicated the IHCC organoid retained appropriately 87% of the variants in the original tissue. Gemcitabine and paclitaxel exhibited the strongest inhibitory effects on the cancer organoid as determined using drug screening tests, consistent with the levels of efficacy observed in the patient from whom it was derived. This study indicates that conversion therapy could improve the survival of patients with IHCC despite its low success rate, and it may be directed by cancer organoids though this is merely a proof of feasibility.

Keywords: conversion therapy; drug screening; genetic profiles; intrahepatic cholangiocarcinoma; organoid; overall survival.

Figure 1

Flow chart of this study.

Figure 2

Kaplan–Meier curves comparing overall survival of successfully downstaged patients, unsuccessfully downstaged patients, and initially resectable patients based on the log-rank test. p1: successfully downstaged patients versus unsuccessfully downstaged patients; p2: successfully downstaged patients versus initially resectable patients; p3: unsuccessfully downstaged patients versus initially resectable patients.

Figure 3

Histopathological characterization of cancer organoid. (A) Gross specimen and (B) H&E staining of intrahepatic cholangiocarcinoma (IHCC) tissue, and (C) bright-field image and (D) H&E staining of the cancer organoid. Scale bar, 50 μM.

Figure 4

Immunohistological staining of IHCC tissue and cancer organoid, including CK7 and EpCAM. Scale bar, 50 μM.

Figure 5

Whole exome sequencing of original tissue and the cancer organoid. (A,B) Circos plots of the original tissue and cancer organoid. (C) The distribution of base substitutions in the organoid and original tissue. (D) Venn diagram demonstrating 89% overlap of single nucleotide variants between the original tissue and cancer organoid. (E) Representative variants in the original tissue and cancer organoid.

Figure 6

Drug screening of cancer organoid and validation of clinical case. (A,B) Magnetic resonance images of patient 8 at admission (A) and after receiving treatment of gemcitabine plus albumin-bound paclitaxel for three months (B). (C–F) Dose-response curves and half-maximal inhibitory concentrations (IC50) of the derived IHCC organoid treated with conventional chemotherapeutic drugs (C,D) and targeted drugs (E,F). Screening of each drug was performed in triplicate.