Correlation between tumor engraftment in patient-derived xenograft models and clinical outcomes in colorectal cancer patients

Abstract

Despite numerous studies involving patient-derived xenograft (PDX) models, few studies have investigated the relationship between the ability of the tumor to engraft (tumorigenicity) and the clinical features of colorectal cancer (CRC). The aim of this study was to determine whether tumorigenicity correlates with clinical outcomes of CRC patients. We included 241 CRC patients who underwent radical surgery from 2010 to 2013. PDX models were established by implanting tumor fragments obtained from these patients into the subcutaneous layer of immunodeficient mice. Xenografts were successfully established from 62.2%. Successful engraftment was associated with advanced stage (p < 0.001) and moderate/poor differentiation (p = 0.029). Three-year disease-free survival (DFS) rates were lower for patients with tumorigenicity (p = 0.011). In stage III patients, tumorigenicity was an independent predictor of poor DFS (p = 0.034). In addition, mutation of TP53 was most frequently detected in stage III patients with tumorigenicity. Two models of stage IV disease without KRAS mutations showed high sensitivity to EGFR-targeted agents, while none of the models with KRAS mutations showed high sensitivity. In conclusion, PDX models may provide an effective preclinical tool for predicting cancer progression and could be used to further genomic and pharmacologic research on personalized treatments.

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…The engraftment rate of PDX tumors is associated with overall survival (OS), recurrence‐free survival (RFS), disease‐free survival, stage, tumor subtype and other clinical features of the patient. Previous studies have also linked the engraftment rate of PDX tumors to the clinical prognosis of patients . The OS and RFS of donor patients with successful PDX tumor engraftment appear to be significantly shorter than those of donor patients whose tumors fail to generate PDXs.…”

“…Additionally, multivariable‐adjusted survival analyses identified tumor engraftment as an independent prognostic marker of poor RFS . Patient tumor samples at a more advanced stage or with more aggressive clinical characteristics showed higher engraftment rates . In a breast cancer study, Kanya et al .…”

Capturing colorectal cancer inter‐tumor heterogeneity in patient‐derived xenograft (PDX) models

“…2f ). As PDX establishment has been linked to patient outcome, 14 we investigated whether this observation is clinically relevant and can be exploited to stratify patients. We found that low Ki67 gene expression was prognostic for recurrences when analyzing 741 stage II CRC patients (HR = 1.76, p < 0.006; Fig.…”

Bringing 3D tumor models to the clinic – predictive value for personalized medicine

“…The results were mixed, with two trials reporting a significant correlation with clinical response and survival [170,171], while the trial using mesothelioma reported no such association [172] Application of the PDX mouse model in regard to clinical outcome has recently been studied in three studies using various, colorectal, and pancreatic cancer tissue. In the studies using pancreatic and colorectal tumor tissue studies a significant correlation between successful tumor engraftment and patient outcome was found, no comparison in regard to drug efficacy was included as primary or secondary study endpoint [173,174] . In a pilot study by Hidalgo et al from 2011, patients were treated according to impact of selected drugs on tumor volume in a PDX mouse model.…”