The Ability to Form Primary Tumor Xenografts Is Predictive of Increased Risk of Disease Recurrence in Early-Stage Non–Small Cell Lung Cancer

Abstract

Purpose: Primary tumor xenografts (PTXG) established directly from patients' primary tumors in immunosuppressed animals might represent the spectrum of histologic complexity of lung cancers better than xenografts derived from established cell lines. These models are important in the study of aberrant biological pathways in cancers and as preclinical models for testing new therapeutic agents. However, not all primary tumors engraft when implanted into immunosuppressed mice. We have investigated factors that may influence the ability of primary non-small cell lung cancer (NSCLC) to form xenografts and their association with clinical outcome.Experimental Design: Tumor fragments from patients undergoing curative surgery were implanted into NOD-SCID (nonobese diabetic-severely combined immunodeficient) mice within 24 hours of surgery. Patient characteristics for tumors that engrafted (XG) and did not engraft (no-XG) were compared. Patient tumor DNA was profiled for the presence of 238 known mutations in 19 cancer-associated genes by using the MassARRAY platform.Results: Xenografts were established and passaged successfully from 63 of 157 (40%) implanted NSCLCs. Tumor factors associated with engraftment included squamous histology, poor differentiation, and larger tumor size. Significantly fewer EGFR (epidermal growth factor receptor)-mutated tumors engrafted (P ¼ 0.03); conversely, more K-RAS-mutated tumors engrafted (P ¼ 0.05). In multivariate analysis including age, sex, stage, and mutation, patients with XG tumors had significantly shorter diseasefree survival compared with no-XG patients (hazard ratio : 7.0, 95% CI: 3.1-15.81; P < 0.000003).Conclusion: PTXGs closely mirror the histology and molecular profiles of primary tumors and therefore may serve as important preclinical models. Tumors that engraft are biologically more aggressive and may be more representative of cancers with a higher propensity to relapse after surgery. Clin Cancer Res; 17(1); 134-41. Ó2010 AACR.

Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment

“…Consistent with other studies, 9,20 we have also seen the formation of lymphoid proliferations/lymphomas in four implantations. Three cases (one adenosquamous and two adenocarcinomas) were replaced by tumor-forming lymphoid proliferations in P1.…”

“…Poorly differentiated tumors have higher engraftment rates in other xenograft models such as early stage lung, 9 head and neck, 21 and breast cancer. 10 All of these models also showed a lower overall patient survival for engrafted specimens when compared with their non-engrafted counterparts, suggesting a bias towards engraftment of more aggressive tumors.…”

“…9 Time to second passage was compared with many potential predictors, including histological differentiation, stage and neoadjuvant chemo-radiation status. Poor differentiation was the only factor that showed a univariate trend towards shorter time to second passage (P ¼ 0.07); no associations were significant.…”

“…PTXGs are created by implanting tumor fragments from a patient into immunocompromised mice and using the resultant tumor for tissue expansion and subsequent experimentation. Similar models of lung, 9 breast, 10 pancreatic, 11 colon, 12 head and neck 13 and various other gastrointestinal and female genital cancers 14 have been shown to recapitulate the original tumor by having similar histology and cell morphology to the patient tumor. Though few studies have focused on the genomic similarities of patient tissue and primary xenografts, those published suggest that mutations are generally conserved.…”

Preclinical and clinical implications of TERT promoter mutation in glioblastoma multiforme

“…As preclinical models may summarize the clinicopathological features of patient with GBMs (9,(21)(22)(23), the preclinical models may be utilized to predict the treatment effects of TERT-targeting therapies for TERT promoter mutation-positive GBMs, compared with those for TERT promoter mutation-negative GBMs. In the present study, the majority of GBMs with in vitro sphere formation capacity exhibited TERT promoter mutations (92.3%).…”