Cancer Therapy: Preclinical Patient-Derived First Generation Xenografts of Non–Small Cell Lung Cancers: Promising Tools for Predicting Drug Responses for Personalized Chemotherapy Xin Dong 1,3 , Jun Guan 1 , John C. English 5 , Julia Flint 5 , John Yee 6 , Kenneth Evans 6 , Nevin Murray 2 , Calum MacAulay 3 , Raymond T. Ng 7 , Peter W. Gout 1 , Wan L. Lam 4 , Janessa Laskin 2 , Victor Ling 4 , Stephen Lam 3 , and Yuzhuo Wang 1,8,9 Abstract Purpose: Current chemotherapeutic regimens have only modest benefit for non–small cell lung cancer (NSCLC) patients. Cumulative toxicities/drug resistance limit chemotherapy given after the first-line reg- imen. For personalized chemotherapy, clinically relevant NSCLC models are needed for quickly predict- ing the most effective regimens for therapy with curative intent. In this study, first generation subrenal capsule xenografts of primary NSCLCs were examined for (a) determining responses to conventional che- motherapeutic regimens and (b) selecting regimens most effective for individual patients. Experimental Design: Pieces (1×3×3 mm 3 ) of 32 nontreated, completely resected patients' NSCLCs were grafted under renal capsules of nonobese diabetic/severe combined immunodeficient mice and trea- ted with (A) cisplatin+vinorelbine, (B) cisplatin+docetaxel, (C) cisplatin+gemcitabine, and positive re- sponses (treated tumor area ≤50% of control, P < 0.05) were determined. Clinical outcomes of treated patients were acquired. Results: Xenografts from all NSCLCs were established (engraftment rate, 90%) with the retention of major biological characteristics of the original cancers. The entire process of drug assessment took 8 weeks. Response rates to regimens A, B, and C were 28% (9 of 32), 42% (8 of 19), and 44% (7 of 16), respec- tively. Certain cancers that were resistant to a particular regimen were sensitive to others. The majority of responsive tumors contained foci of nonresponding cancer cells, indicative of tumor heterogeneity and potential drug resistance. Xenografts from six of seven patients who developed recurrence/metastasis were nonresponsive. Conclusions: Models based on first generation NSCLC subrenal capsule xenografts have been devel- oped, which are suitable for quick assessment (6-8 weeks) of the chemosensitivity of patients' cancers and selection of the most effective regimens. They hold promise for application in personalized chemotherapy of NSCLC patients. Clin Cancer Res; 16(5); 1442–51. ©2010 AACR. Lung cancer is the leading cause of cancer-related mor- tality worldwide (1). Non–small cell lung cancer (NSCLC) represents over 80% of lung cancer deaths (2, 3). Chemo- therapy has been shown to improve the survival of pa- tients with advanced, inoperable NSCLCs or, as adjuvant therapy, to reduce the rate of relapse of patients following resection of early-stage cancers (2, 3). Generally, two-drug combinations of cytotoxic drugs such as gemcitabine, vinorelbine, and docetaxel with cisplatin or carboplatin are used. A recent meta-analysis study showed that plat- inum-based, adjuvant chemotherapy of patients with re- sected NSCLCs was associated with a 5% greater 5-year survival rate, revealing marginal effectiveness of current chemotherapeutic regimens (4). Moreover, only a portion of patients who receive first-line treatment can receive fur- ther chemotherapy because of rapid disease progression and intolerance to side effects. Additional chemotherapy is particularly limited for patients who have experienced severe toxicity with previous chemotherapy and especially for older individuals who may suffer comorbidity from ef- fects of smoking. Clearly, optimal selection of the initial chemotherapy regimen is crucial whether it be in an ad- vanced disease or adjuvant situation. There is an urgent need for tools to reliably and quickly predict responses of patients' cancers to particular chemotherapeutic regi- mens to provide more effective personalized treatment or to spare nonresponders from futile chemotherapy. Authors' Affiliations: Departments of 1 Cancer Endocrinology, 2 Medical Oncology, 3 Cancer Imaging, and 4 Cancer Genetics and Developmental Biology, BC Cancer Agency; Departments of 5 Pathology, 6 Surgery, 7 Computer Science, and 8 Urologic Sciences, University of British Columbia; and 9 The Living Tumor Laboratory at the Vancouver Prostate Centre, Vancouver, British Columbia, Canada Corresponding Author: Yuzhuo Wang, Department of Cancer Endocri- nology, BC Cancer Agency-Research Centre, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. Phone: 604-675-8013; Fax: 604-675-8019; E-mail: ywang@bccrc.ca. doi: 10.1158/1078-0432.CCR-09-2878 ©2010 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 16(5) March 1, 2010 1442 Research. on June 8, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst February 23, 2010; DOI: 10.1158/1078-0432.CCR-09-2878