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Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.

ABSTRACT: PURPOSE:The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis. EXPERIMENTAL DESIGN:Two hundred fifty FHWT of all stages enriched for relapses treated on National Wilms Tumor Study-5 passed quality variables and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification used support vector machine; 2- and 10-fold cross-validations were applied. RESULTS:The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT treated with chemotherapy, and no further analyses were done. This number was greater than expected by chance for 76 local stage III patients. Cross-validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) showed that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47% and specificity of 70%. CONCLUSIONS:This study shows the feasibility and modest accuracy of stratifying local stage III FHWT using a classifier of <50 genes. Validation using an independent patient population is needed. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40.

SUBMITTER: Huang CC

PROVIDER: S-EPMC2847352 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.

Huang Chiang-Ching CC Gadd Samantha S Breslow Norman N Cutcliffe Colleen C Sredni Simone T ST Helenowski Irene B IB Dome Jeffrey S JS Grundy Paul E PE Green Daniel M DM Fritsch Michael K MK Perlman Elizabeth J EJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20090210 5

<h4>Purpose</h4>The past two decades has seen significant improvement in the overall survival of patients with favorable histology Wilms tumor (FHWT); however, this progress has reached a plateau. Further improvements may rely on the ability to better stratify patients by risk of relapse. This study determines the feasibility and potential clinical utility of classifiers of relapse based on global gene expression analysis.<h4>Experimental design</h4>Two hundred fifty FHWT of all stages enriched ...[more]

PMID: 19208794

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Project description:Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

Project description:Background The National Wilms Tumor Study (NWTS) approach to treating stage III favorable-histology Wilms tumor (FHWT) is Regimen DD4A (vincristine, dactinomycin, and doxorubicin) and radiation therapy. Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.

Project description:The gene expression patterns of favorable histology Wilms tumors (FHWT) that relapsed were compared with those that did not relapse using oligonucleotide arrays; Description: 250 FHWT of all stages enriched for relapses treated on National Wilms Tumor Study 5 passed quality parameters and were suitable for analysis using oligonucleotide arrays. Relapse risk stratification utilized Support Vector Machine; two and ten fold cross-validation was applied. The number of genes associated with relapse was less than that predicted by chance alone for 106 patients (32 relapses) with stages I and II FHWT and no further analyses were performed. This number was greater than expected by chance for 76 local stage III patients. Cross validation including an additional 68 local stage III patients (total 144 patients, 53 relapses) demonstrated that classifiers for relapse composed of 50 genes were associated with a median sensitivity of 47%, specificity 70%, and total error rate of 38%. Analysis of genes differentially expressed in relapse patients revealed apoptosis, Wnt signaling, IGF pathway, and epigenetic modification to be mechanisms important in relapse. Potential therapeutic targets include FRAP/MTOR and CD40. Experiment Overall Design: 144 stage 3 FHWT, with fifty-three relapses (cases) and ninety-one non-relapses (controls) with a minimum of three years follow-up, included all relapses and a 30% random selection of non-relapses for which frozen tumor tissue was available who passed all quality control parameters. The NWTS-5 protocol was approved by the review boards of institutions that registered patients. Histological diagnosis and local stage were confirmed by central review. Experiment Overall Design: Quality control steps taken: Experiment Overall Design: 1. Samples were snap frozen immediately following surgery and were mailed on dry ice to the Tumor Bank and retained at -80C. Experiment Overall Design: 2. Frozen sections were evaluated histologically and tumors with less than 80% viable tumor cellularity were excluded. Experiment Overall Design: 3. Array images were assessed by eye to confirm scanner alignment and the absence of significant bubbles or scratches. Experiment Overall Design: 4. Samples for which the 3'/5' ratios for GAPDH were greater than 3.2 were excluded. Experiment Overall Design: 5. The BioB spike controls were confirmed as present; BioC, BioD and cre were confirmed as increasing intensity. Experiment Overall Design: 6. When scaled to a target intensity of 2500, scaling factors were between 12 and 53; background levels were 34 â 115: Q values were 1.3 â 3.7 and mean intensities were within acceptable limits. Experiment Overall Design: 7. The range of percent present calls was from 38% to 52%. Experiment Overall Design: 8. Verification of gene expression was performed utilizing quantitative RT-PCR for five genes. Â Â Experiment Overall Design: Statistical Analysis: Positional-dependent-nearest-neighbor model (PDNN) software was used to translate the scanned images into expression analysis files and to normalize the data across all arrays (http://odin.mdacc.tmc.edu/~zhangli/PerfectMatch/). Genes with maximum expression less than a log scale of 6 across all tumors and Affymetrix control genes were excluded, resulting in 20,931 probe sets for analysis. Support Vector Machine (SVM) as developed by Chang and Lin (http://www.csie.ntu.edu.tw/~cjlin/libsvm) and implemented in an R software package, e1071 was chosen for relapse risk stratification using the p-value of the t-test comparison between case and control to select the genes. Using all 144 tumors, 109 genes were identified with p-value <0.001 and are provided in the data table labelled "t-test comparison between case and control" (ie, Supplemental table 2, in related publication)." Two and ten fold cross validations were utilized to investigate the ability of classifiers established in randomly selected training set to predict relapse in an independent test set comprised of the remaining tumors. For two-fold cross validation, the dataset was randomly divided 500 times into training and corresponding test sets of equal size, each including half the patients who relapsed. A classifier for relapse was identified for each training set and used to assign tumors in the corresponding test set to low and high risk categories. The training and test sets were then swapped. The number of top K genes in each classifier evaluated ranged from 1-150. Therefore, a total of 150,000 different classifiers were developed, one for each value of K from 1-150, for each of the 1,000 (500*2) training sets. For ten-fold cross validation the dataset was randomly divided 500 times into ten groups of approximately equal size. Each group included approximately the same number of relapses. For each such group, a classifier was built with the remaining 9/10 of the samples and then used to categorize tumors in the group as low or high risk; the process was repeated until all tumor samples were categorized as low or high risk. For all the cross validation procedures, to avoid gene-selection bias, classifiers were completely rebuilt in each cross validation iteration.

Project description:PurposeIn National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.MethodsPatients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.ResultsLOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).ConclusionAugmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Dataset Information

Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.

Publications

Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.

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