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Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.

ABSTRACT: The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of the SMAD4 gene and content of tumor-generating cells were determined by immunohistochemistry. Gene expression was carried out by using a U133 Plus 2.0 array. Patients were followed for progression and survival.A total of 94 patients with PDA were resected, 69 tumors implanted in nude mice, and 42 (61%) engrafted. Engrafted carcinomas were more often SMAD4 mutant, and had a metastatic gene expression signature and worse prognosis. Tumors from patients resistant to gemcitabine were enriched in stroma-related gene pathways. Tumors sensitive to gemcitabine were enriched in cell cycle and pyrimidine gene pathways. The time to progression for patients who received treatment with gemcitabine for metastatic disease (n = 7) was double in patients with xenografts sensitive to gemcitabine.A successful xenograft was generated in 61% of patients attempted, generating a pool of 42 PDA xenografts with significant biological information and annotated clinical data. Patients with PDA and SMAD4 inactivation have a better engraftment rate. Engraftment is a poor prognosis factor, and engrafted tumors have a metastatic gene expression signature. Tumors from gemcitabine-resistant patients were enriched in stromal pathways.

SUBMITTER: Garrido-Laguna I

PROVIDER: S-EPMC3210576 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.

Garrido-Laguna Ignacio I Uson Maria M Rajeshkumar N V NV Tan Aik Choon AC de Oliveira Elizabeth E Karikari Collins C Villaroel Maria C MC Salomon Ana A Taylor Gretchen G Sharma Rajni R Hruban Ralph H RH Maitra Anirban A Laheru Daniel D Rubio-Viqueira Belén B Jimeno Antonio A Hidalgo Manuel M

Clinical cancer research : an official journal of the American Association for Cancer Research 20110708 17

<h4>Purpose</h4>The goal of this study was to evaluate prospectively the engraftment rate, factors influencing engraftment, and predictability of clinical outcome of low-passage xenografts from patients with resectable pancreatic ductal adenocarcinoma (PDA) and to establish a bank of PDA xenografts.<h4>Experimental design</h4>Patients with resectable PDA scheduled for resection at the Johns Hopkins Hospital were eligible. Representative pieces of tumor were implanted in nude mice. The status of ...[more]

PMID: 21742805

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Project description:Although gemcitabine monotherapy is the standard treatment for advanced pancreatic cancer, patient outcome varies significantly, and a considerable number do not benefit adequately. We therefore searched for new biomarkers predictive of overall patient survival. Using LC-MS, we compared the base-line plasma proteome between 29 representative patients with advanced pancreatic cancer who died within 100 days and 31 patients who survived for more than 400 days after receiving at least two cycles of the same gemcitabine monotherapy. Identified biomarker candidates were then challenged in a larger cohort of 304 patients treated with the same protocol using reverse-phase protein microarray. Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities differed significantly between the two groups (p < 0.001, Welch's t test). Two MS peaks with the highest statistical significance (p = 2.6 x 10(-4) and p = 5.0 x 10(-4)) were revealed to be derived from alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, respectively. The levels of alpha(1)-antitrypsin (p = 8.9 x 10(-8)) and alpha(1)-antichymotrypsin (p = 0.001) were significantly correlated with the overall survival of the 304 patients. We selected alpha(1)-antitrypsin (p = 0.0001), leukocyte count (p = 0.066), alkaline phosphatase (p = 8.3 x 10(-8)), and performance status (p = 0.003) using multivariate Cox regression analysis and constructed a scoring system (nomogram) that was able to identify a group of high risk patients having a short median survival time of 150 days (95% confidence interval, 123-187 days; p = 2.0 x 10(-15), log rank test). The accuracy of this model for prognostication was internally validated and showed good calibration and discrimination with a bootstrap-corrected concordance index of 0.672. In conclusion, an increased level of alpha(1)-antitrypsin is a biomarker that predicts short overall survival of patients with advanced pancreatic cancer receiving gemcitabine monotherapy. Although an external validation study will be necessary, the current model may be useful for identifying patients unsuitable for the standardized therapy.

Project description:BackgroundIn a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer.MethodsWe randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate.ResultsA total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days.ConclusionsIn patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

Dataset Information

Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.

Publications

Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer.

Similar Datasets

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