Patient-derived tumor organoids-guided adjuvant chemotherapy after surgical resection of intrahepatic cholangiocarcinoma: A multicenter and retrospective study

Abstract

This multicenter retrospective study investigated the clinical utility of patient-derived tumor organoids (PDOs) in guiding adjuvant chemotherapy for intrahepatic cholangiocarcinoma (ICC) patients. A total of 82 ICC patients at the Shanghai Eastern Hepatobiliary Surgery Hospital and the Shanghai Tenth People’s Hospital between 2021 and 2022 were included in the study. All of these patients underwent surgical resection and were pathologically confirmed to have high-risk factors for recurrence. Therefore, they received adjuvant chemotherapy post-surgery. Sixty-one PDOs were successfully established from resected tumor tissues and tested against four common regimens: Gemcitabine + cisplatin, gemcitabine + oxaliplatin, capecitabine, and S-1. A novel fluorescence-based method was developed for drug sensitivity testing, showing significant concordance with conventional half-maximal inhibitory concentration quantification. Patients were stratified into matched (n=26) and unmatched (n=35) groups based on alignment between PDOs-based drug sensitivity results and actual chemotherapy received. The matched group demonstrated significantly improved recurrence-free survival (RFS) (hazard ratio = 2.52, p=0.007), with 63% versus 17% experiencing recurrence events. Through eXtreme Gradient Boosting machine learning and Cox regression analyses, we identified PDOs-based drug sensitivity, tumor multiplicity, and vascular invasion as key predictors of 2-year recurrence. A clinical nomogram incorporating these factors showed that patients with matched PDO-guided therapy had 46% 12-month RFS probability versus 28% in unmatched cases. This study provides a clinically translatable platform to guide adjuvant chemotherapy decisions and predict the prognosis of ICC patients with a high recurrence risk after surgery.

Keywords

Intrahepatic cholangiocarcinoma / Patient-derived tumor organoids / Drug sensitivity testing / Recurrence-free survival / Adjuvant therapy

References

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.Global cancer statistics Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. doi: 10.3322/caac.21492

[2] Brindley PJ, Bachini M, Ilyas SI, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021; 7(1):65. doi: 10.1038/s41572-021-00300-2

[3] Wang K, Zhang H, Xia Y, Liu J, Shen F.Surgical options for intrahepatic cholangiocarcinoma. Hepatobiliary Surg Nutr. 2017; 6(2):79-90. doi: 10.21037/hbsn.2017.01.06

[4] Moris D, Palta M, Kim C, Allen PJ, Morse MA, Lidsky ME. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin. 2023; 73(2):198-222. doi: 10.3322/caac.21759

[5] Benson AB, D’Angelica MI, Abrams T, et al. NCCN Guidelines® insights: Biliary tract cancers, Version 2.2023. J Natl Compr Canc Netw. 2023; 21(7):694-704. doi: 10.6004/jnccn.2023.0035

[6] Nakachi K, Ikeda M, Konishi M, et al. Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2023; 401(10372):195-203. doi: 10.1016/s0140-6736(22)02038-4

[7] O’Rourke CJ, Salati M, Rae C, et al. Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy. Gut. 2024; 73(3):496-508. doi: 10.1136/gutjnl-2023-330748

[8] Xu H, Jiao D, Liu A, Wu K. Tumor organoids: Applications in cancer modeling and potentials in precision medicine. J Hematol Oncol. 2022; 15(1):58. doi: 10.1186/s13045-022-01278-4

[9] Tang XY, Wu S, Wang D, et al. Human organoids in basic research and clinical applications. Signal Transduct Target Ther. 2022; 7(1):168. doi: 10.1038/s41392-022-01024-9

[10] Spolverato G, Yakoob MY, Kim Y, et al. The impact of surgical margin status on long-term outcome after resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015; 22(12):4020-4028. doi: 10.1245/s10434-015-4472-9

[11] De Witte CJ, et al.Espejo Valle-Inclan J, Hami N, Patient-derived ovarian cancer organoids mimic clinical response and exhibit heterogeneous inter-and intrapatient drug responses. Cell Rep. 2020; 31(11):107762. doi: 10.1016/j.celrep.2020.107762

[12] Yao Y, Xu X, Yang L, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell. 2020; 26(1):17-26.e6. doi: 10.1016/j.stem.2019.10.010

[13] Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010; 362(14):1273-1281. doi: 10.1056/NEJMoa0908721

[14] Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): A randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20(5):663-673. doi: 10.1016/s1470-2045(18)30915-x

[15] Wang Y, Li J, Xia Y, et al. Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol. 2013; 31(9):1188-1195. doi: 10.1200/jco.2012.41.5984

[16] Ma X, Wang Q, Li G, Li H, Xu S, Pang D. Cancer organoids: A platform in basic and translational research. Genes Dis. 2024; 11(2):614-632. doi: 10.1016/j.gendis.2023.02.052

[17] Seppälä TT, Zimmerman JW, Suri R, et al. Precision medicine in pancreatic cancer: Patient-derived organoid pharmacotyping is a predictive biomarker of clinical treatment response. Clin Cancer Res. 2022; 28(15):3296-3307. doi: 10.1158/1078-0432.Ccr-21-4165

[18] Liang C, Shan D, Wei Z. PDO-based drug screening in advanced pancreatic cancer. Gastroenterology. 2024; 168:627-628. doi: 10.1053/j.gastro.2024.10.045

[19] Boilève A, Cartry J, Goudarzi N, et al. Organoids for functional precision medicine in advanced pancreatic cancer. Gastroenterology. 2024; 167(5):961-976.e13. doi: 10.1053/j.gastro.2024.05.032