Genetic changes associated with relapse in favorable histology Wilms tumor: A Children's Oncology Group AREN03B2 study.
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SUBMITTER: Gadd S
PROVIDER: S-EPMC9244995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeThe 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 designTwo 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.ResultsThe 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%.ConclusionsThis 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.
| S-EPMC2847352 | biostudies-literature
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.
| S-EPMC6075846 | biostudies-literature
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.
| S-EPMC5773840 | biostudies-literature
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. Keywords: Classification by microarray analysis
2009-01-30 | GSE10320 | GEO
Project description:PurposeThe use of computed tomography (CT) for routine surveillance to detect recurrence in patients with Wilms tumor (WT) has increased in recent years. The utility of CT, despite increased risk and cost, to improve outcome for these patients is unknown. We conducted a retrospective analysis with patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) to determine if surveillance with CT correlates with improved overall survival (OS) after recurrence compared with chest x-ray (CXR) and abdominal ultrasound (US).Patients and methodsOverall, 281 patients with recurrent unilateral favorable-histology WT were reviewed to assess how WT recurrence was detected: sign/symptoms (SS), surveillance imaging (SI) with CT scan, or SI with CXR/US.ResultsThe estimated 5-year OS rate after relapse was 67% (95% CI, 61% to 72%). Twenty-five percent of recurrences were detected with SS; 48.5%, with CXR/US; and 26.5%, with CT. Patients with SS had a 5-year OS rate of 59% (95% CI, 46% to 72%) compared with 70% (95% CI, 63% to 77%; P = .23) for those detected by SI. Recurrences detected by CT had a shorter median time from diagnosis to recurrence (0.60 years) compared with SS (0.91 years) or CXR/US (0.86 years; P = .003). For recurrences detected by SI, more tumor foci at relapse ( P < .001) and size of the largest focus greater than 2 cm ( P = .02) were associated with inferior OS. However, there was no difference in OS after relapse when recurrence was detected by CT versus CXR/US (5-year OS rate, 65% v 73%; P = .20).ConclusionIn patients with favorable-histology WT, elimination of CT scans from surveillance programs is unlikely to compromise survival but would result in substantial reduction in radiation exposure and health care costs.
| S-EPMC6269130 | biostudies-literature
Project description:BackgroundStage I epithelial-predominant favorable-histology Wilms tumors (EFHWTs) have long been suspected to have an excellent outcome. This study investigates the clinical and pathologic features of patients with stage I EFHWTs to better evaluate the potential for a reduction of chemotherapy and its associated toxicity.MethodsAll patients registered in the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 with stage I EFHWTs were identified. EFHWTs were defined as tumors with at least 66% epithelial differentiation, regardless of the degree of differentiation. Clinical information was abstracted from COG records. Event-free survival (EFS) and overall survival (OS) were calculated and compared between groups based on age and therapy.ResultsThe 4-year EFS rate was 96.2% (95% confidence interval, 92%-100%), and the OS rate was 100%; EFS and OS did not statistically significantly differ with the age at diagnosis (<48 vs ≥48 months; P = .37) or treatment (EE4A vs observation only; P = .55). Six events were reported. Three patients developed contralateral tumors and did not otherwise relapse; none of these had nephrogenic rests or a recognized predisposition syndrome. Three patients developed metastatic recurrence; all 3 had received EE4A as their primary therapy after nephrectomy.ConclusionsThese findings demonstrate an excellent outcome for stage I EFHWTs with >95% EFS and OS. These data support the utility of investigating the treatment of stage I EFHWTs with observation alone after nephrectomy.
| S-EPMC7717680 | biostudies-literature
Project description:Introduction and objectivesWilms' tumor (WT) relapse occurs in 15% of patients. We aim to investigate the association between the expression of several genetic markers and WT relapse risk.Materials and methodsThe study included 51 children treated for WT at a tertiary center between 2001 and 2019: 23 patients had disease relapse (group A) and 28 remained relapse-free after at least 2 years of follow-up (group B). Patients with syndromic, bilateral synchronous or anaplastic WT were excluded. Autologous renal tissue from 20 patients served as control. Total RNA was isolated from tumor tissue and control. Gene expression levels of WT1, HIF1α, b-FGF, c-MYC and SLC22A18 were assessed using quantitative RT-PCR and normalized to GAPDH. Immunohistochemical staining for WT1 and gene expression levels were compared between the study groups.ResultsMedian patient age was 3 (IQR = 2-5) years and 36 (70.6%) had stage I disease. Baseline characteristics were similar between study groups. Relapse occurred at a median of 6.8 (2.8-24.7) months, predominantly in the lungs (11/23, 47.8%). Tumors that relapsed expressed significantly higher levels of WT1, HIF1α, b-FGF and c-MYC and lower levels of SLC22A18 (p < 0.001). Strong immunohistochemical staining for WT1 was seen in 73.9% of group A and 14.29% of group B (p < 0.001). These associations retained statistical significance irrespective of patient and tumor characteristics.ConclusionsHigher expression levels of WT1, HIF1 α, b-FGF and c-MYC and lower level of SLC22A18 are associated with increased risk of WT relapse. These genetic markers can serve as future prognostic predictors and help stratify patients for treatment.
| S-EPMC9930804 | biostudies-literature
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.
| S-EPMC7001789 | biostudies-literature
Project description:PurposeStage III designation in NWTS-5 (National Wilms Tumor Study-5) was determined by four pathologic criteria: positive lymph nodes (LNs), peritoneal implants, residual disease, and tumor rupture. The objective of this study was to determine the prognostic significance of each of the stage III criteria.Patients and methodsChildren with stage III Wilms tumor (WT) treated in NWTS-5 were assessed for event-free (EFS) and overall survival (OS). Sites of relapse and molecular status of tumors are reported. EFS and OS are reported 8 years after diagnosis.ResultsThere were 569 patients with local stage III favorable-histology (FH) WT in this analysis, of whom 109 had overall stage IV disease. LN involvement alone was the most frequent criterion for stage III designation (38%), followed by microscopic residual disease alone (20%), microscopic residual disease and LN involvement (14%), and spill or soilage alone (9%). The 8-year EFS and OS estimates for all patients with local stage III FHWT were 82% and 91%, respectively. Multivariate analysis demonstrated that both LN involvement (relative risk, 1.89; P = .005) and microscopic residual disease (relative risk, 1.87; P = .007) were predictive of EFS, and OS results were similar. There was no apparent difference in pattern of relapse according to stage III subtype. The rate of loss of heterozygosity was higher (6%) for those with positive LNs than for those without (2%; P = .05).ConclusionLN involvement and microscopic residual are the stage III criteria highly predictive of EFS and OS for patients with stage III FHWT. It is possible that in future studies, patients with different stage III criteria may receive different therapies.
| S-EPMC3595426 | biostudies-literature
Project description:We performed genome-wide sequencing and analyzed mRNA and miRNA expression, DNA copy number, and DNA methylation in 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), we identified mutations in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and MIRLET7A loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.
| S-EPMC5712232 | biostudies-literature