Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment.
chemotherapy
pancreatic cancer
patient-derived organoids
personalized medicine
treatment response
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
11
03
2022
received:
13
09
2021
accepted:
30
03
2022
pubmed:
5
4
2022
medline:
2
8
2022
entrez:
4
4
2022
Statut:
ppublish
Résumé
Drug combination therapies for cancer treatment show high efficacy but often induce severe side effects, resulting in dose or cycle number reduction. We investigated the impact of neoadjuvant chemotherapy (neoCTx) adaptions on treatment outcome in 59 patients with pancreatic ductal adenocarcinoma (PDAC). Resections with tumor-free margins were significantly more frequent when full-dose neoCTx was applied. We determined if patient-derived organoids (PDOs) can be used to personalize poly-chemotherapy regimens by pharmacotyping of treatment-naïve and post-neoCTx PDAC PDOs. Five out of ten CTx-naïve PDO lines exhibited a differential response to either the FOLFIRINOX or the Gem/Pac regimen. NeoCTx PDOs showed a poor response to the neoadjuvant regimen that had been administered to the respective patient in 30% of cases. No significant difference in PDO response was noted when comparing modified treatments in which the least effective single drug was removed from the complete regimen. Drug testing of CTx-naïve PDAC PDOs and neoCTx PDOs may be useful to guide neoadjuvant and adjuvant regimen selection, respectively. Personalizing poly-chemotherapy regimens by omitting substances with low efficacy could potentially result in less severe side effects, thereby increasing the fraction of patients receiving a full course of neoadjuvant treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
607-619Informations de copyright
© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Références
GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2019; 4: 934-947.
Müller PC, Frey MC, Ruzza CM, et al. Neoadjuvant chemotherapy in pancreatic cancer: an appraisal of the current high-level evidence. Pharmacology 2021; 106: 143-153.
Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet 2011; 378: 607-620.
Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403-2413.
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817-1825.
Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703.
Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). J Clin Oncol 2020; 38: 4504.
Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26: v56-v68.
Balaban EP, Mangu PB, Yee NS. Locally advanced unresectable pancreatic cancer: American Society of Clinical Oncology clinical practice guideline summary. J Oncol Pract 2017; 13: 265-269.
Okusaka T, Ikeda M, Fukutomi A, et al. Phase II study of FOLFIRINOX for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. Cancer Sci 2014; 105: 1321-1326.
Liutkauskiene S, Grizas S, Jureniene K, et al. Retrospective analysis of the impact of anthracycline dose reduction and chemotherapy delays on the outcomes of early breast cancer molecular subtypes. BMC Cancer 2018; 18: 453.
Crawford J, Denduluri N, Patt D, et al. Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer. Support Care Cancer 2020; 28: 925-932.
Blazevic I, Vaillant W, Basso M, et al. Survival and relative dose intensity of 5-fluorouracil, oxaliplatin and irinotecan in real-life treatment of metastatic colorectal cancer. Contemp Oncol (Pozn) 2020; 24: 150-156.
Frappart PO, Walter K, Gout J, et al. Pancreatic cancer-derived organoids - a disease modeling tool to predict drug response. United European Gastroenterol J 2020; 8: 594-606.
Flaum N, Hubner RA, Valle JW, et al. Adjuvant chemotherapy and outcomes in patients with nodal and resection margin-negative pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. J Surg Oncol 2019; 119: 932-940.
DePeralta DK, Ogami T, Zhou JM, et al. Completion of adjuvant therapy in patients with resected pancreatic cancer. HPB (Oxford) 2020; 22: 241-248.
Hennig A, Wolf L, Jahnke B, et al. CFTR expression analysis for subtyping of human pancreatic cancer organoids. Stem Cells Int 2019; 2019: 1024614.
Tiriac H, Belleau P, Engle DD, et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov 2018; 8: 1112-1129.
Seino T, Kawasaki S, Shimokawa M, et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 2018; 22: 454-467.e6.
Driehuis E, van Hoeck A, Moore K, et al. Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Proc Natl Acad Sci U S A 2019; 116: 26580-26590.
Dantes Z, Yen HY, Pfarr N, et al. Implementing cell-free DNA of pancreatic cancer patient-derived organoids for personalized oncology. JCI Insight 2020; 5: e137809.
Huang L, Bockorny B, Paul I, et al. PDX-derived organoids model in vivo drug response and secrete biomarkers. JCI Insight 2020; 5: e135544.
Hirt CK, Booij TH, Grob L, et al. Drug screening and genome editing in human pancreatic cancer organoids identifies drug-gene interactions and candidates for off-label treatment. Cell Genom 2022; 2: 100095.
Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 2018; 359: 920-926.
Wensink GE, Elias SG, Mullenders J, et al. Patient-derived organoids as a predictive biomarker for treatment response in cancer patients. NPJ Precis Oncol 2021; 5: 30.
Le Scodan R, Mornex F, Partensky C, et al. Histopathological response to preoperative chemoradiation for resectable pancreatic adenocarcinoma: the French Phase II FFCD 9704-SFRO trial. Am J Clin Oncol 2008; 31: 545-552.
Hruban RH, Boffetta P, Hiraoka N, et al. Ductal adenocarcinoma of the pancreas. In WHO Classification of Tumours of the Digestive System, WHO Classification of Tumours (4th edn), Bosman FTJ, Lakhani SR, Ohgaki H (eds). International Agency for Research on Cancer: Lyon, 2010; 281-291.
Karczewski KJ, Francioli LC, Tiao G, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581: 434-443.
Tate JG, Bamford S, Jubb HC, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res 2019; 47: D941-D947.
Cingolani P, Patel VM, Coon M, et al. Using Drosophila melanogaster as a model for genotoxic chemical mutational studies with a new program, SnpSift. Front Genet 2012; 3: 35.
Cingolani P, Platts A, Wang LL, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 2012; 6: 80-92.
Crowdis J, He MX, Reardon B, et al. CoMut: visualizing integrated molecular information with comutation plots. Bioinformatics 2020; 36: 4348-4349.
Suker M, Beumer BR, Sadot E, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 2016; 17: 801-810.
Janssen QP, O'Reilly EM, van Eijck CHJ, et al. Neoadjuvant treatment in patients with resectable and borderline resectable pancreatic cancer. Front Oncol 2020; 10: 41.
Bayat Mokhtari B, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget 2017; 8: 38022-38043.
Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019; 393: 1948-1957.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938-2947.
Palmer AC, Sorger PK. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 2017; 171: 1678-1691.e13.
Qi W, Wang X, Gan L, et al. The effect of reduced RDI of chemotherapy on the outcome of breast cancer patients. Sci Rep 2020; 10: 13241.
Kirino S, Tsuchiya K, Kurosaki M, et al. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PLoS One 2020; 15: e0231828.
Kobayashi S, Ueno M, Omae K, et al. Influence of initial dose intensity on efficacy of FOLFIRINOX in patients with advanced pancreatic cancer. Oncotarget 2019; 10: 1775-1784.
Ooft SN, Weeber F, Dijkstra KK, et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci Transl Med 2019; 11: eaay2574.
Yao Y, Xu X, Yang L, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 2020; 26: 17-26.e6.