Favorable Histology Wilms Tumor Research Articles

Loss of Heterozygosity at Chromosome 16q Is a Negative Prognostic Factor in Korean Pediatric Patients with Favorable Histology Wilms Tumor: A Report of the Korean Pediatric Hematology Oncology Group (K-PHOG).

PurposeLoss of heterozygosity (LOH) at chromosomes 1p and 16q is a poor prognostic factor in favorable histology Wilms tumor (FHWT). This study investigated the prevalence of LOH at 1p and 16q and evaluated its prognostic value in Korean children with FHWT.Materials and MethodsWe analyzed 101 FHWT patients who were diagnosed between 1996 and 2016 in Korean Society of Pediatric Hematology Oncology Group hospitals. Using paraffin-embedded kidney tissue samples sent from each center, we reviewed LOH at 1p and 16q in each patient and assessed the prognostic value of LOH status for clinical parameters affecting event-free survival (EFS).ResultsOf the 101 patients, 12 (11.9%) experienced recurrence; the 3-year EFS was 87.6%. LOH at 1p or 16q was detected in 19 patients (18.8%), with five having LOH at both 1q and 16q. The frequency of LOH at 1p was higher among younger patients (p=0.049), but there was no difference in LOH prevalence according to tumor stage. In the multivariate analysis, LOH at 16q was a significant negative prognostic factor affecting EFS (3-year EFS, 73.7% vs. 91.1%; hazard ratio, 3.95; p=0.037), whereas LOH at 1p was not (p=0.786).ConclusionLOH at 16q was a significant negative prognostic factor affecting outcome in Korean pediatric FHWT patients. Due to the small sample size of this study, large-scale multicenter trials are warranted to investigate the prognostic value of LOH at 1p and 16q in Korean children with FHWT.

Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report.

In 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. Patients 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. LOH1p/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%). Augmentation 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.

Simulation-selection-extrapolation: Estimation in high-dimensional errors-in-variables models.

Errors-in-variables models in high-dimensional settings pose two challenges in application. First, the number of observed covariates is larger than the sample size, while only a small number of covariates are true predictors under an assumption of model sparsity. Second, the presence of measurement error can result in severely biased parameter estimates, and also affects the ability of penalized methods such as the lasso to recover the true sparsity pattern. A new estimation procedure called SIMulation-SELection-EXtrapolation (SIMSELEX) is proposed. This procedure makes double use of lasso methodology. First, the lasso is used to estimate sparse solutions in the simulation step, after which a group lasso is implemented to do variable selection. The SIMSELEX estimator is shown to perform well in variable selection, and has significantly lower estimation error than naive estimators that ignore measurement error. SIMSELEX can be applied in a variety of errors-in-variables settings, including linear models, generalized linear models, and Cox survival models. It is furthermore shown in the Supporting Information how SIMSELEX can be applied to spline-based regression models. A simulation study is conducted to compare the SIMSELEX estimators to existing methods in the linear and logistic model settings, and to evaluate performance compared to naive methods in the Cox and spline models. Finally, the method is used to analyze a microarray dataset that contains gene expression measurements of favorable histology Wilms tumors.

How many lymph nodes are enough? Assessing the adequacy of lymph node yield for staging in favorable histology wilms tumor

PurposeCurrent investigational priorities in the treatment of favorable histology Wilms tumor (FHWT) center on accurate staging and risk-stratification. The extent of lymph node (LN) sampling has not been clearly defined; its importance cannot be overstated as it guides adjuvant therapy. The identification of a minimum LN yield to minimize the risk of harboring occult metastatic disease could help development of surgical guidelines. This study focuses on using the beta-binomial distribution to estimate the risk of occult metastatic disease in patients with FHWT. Materials & methodsThe National Cancer Database was queried for patients with unilateral FHWT from 2004 to 2013. Data were used to characterize nodal positivity for patients who underwent surgery and had ≥1 positive LN and ≥2 LNs examined. The probability of missing a positive LN (i.e., false negative) for a given LN yield was calculated using an empirical estimation and the beta-binomial model. Patients were then stratified by tumor size. Results422 patients met study criteria. To limit the chance of missing a positive LN to ≤10%, the empirical estimation and beta-binomial model estimated that 6 and 10 LNs needed to be sampled, respectively. Tumor size did not influence the result. Internal validation showed little variation to maintain a false negative rate ≤ 10%. ConclusionsUsing mathematical modeling, it appears that the desired LN yield in FHWT to reduce the risk of false-negative LN sampling to ≤10% is between 6 and 10. The current analysis represents an objective attempt to determine the desired surgical approach to LN sampling to accurately stage patients with FHWT. Level of evidenceII

Efficacy and tolerability of stereotactic body radiotherapy for lung metastases in three patients with pediatric malignancies.

Purpose: To report a case series of 3 pediatric patients treated with Stereotactic Body Radiation Therapy (SBRT) for lung metastases.Patients and methods: Three patients (ages 9, 11, and 21) received SBRT for rhabdoid tumor, Ewing sarcoma, and Wilms tumor histologies, respectively. SBRT doses were 37.5–50 Gy in 3–5 fractions treating twelve lesions.Results: Three patients (ages 9, 11, and 21) received photon SBRT for pulmonary metastases. The patients were as follows: 1) 21-year-old male with favorable histology Wilms tumor and 1 lesion treated, 2) 11-year-old female with Ewing sarcoma and 1 lesion treated for relapse after previous whole lung radiation (15 Gy), and 3) 9-year-old female with rhabdoid tumor of the left thigh with 10 lesions treated over a two-year period. Median dose delivered was 40 Gy (range, 37.5–50 Gy), delivered in a median of 4 fractions (range, 4–5) of a median of 10 Gy per fraction (range, 9.4–10 Gy). Within a minimum follow-up of 1.9 years (range 1.9–4 years), local control for all 13 treated metastases is 100% without any observed acute toxicities. One possible late toxicity (grade 2 rib fracture) developed 1.3 years following SBRT for treatment of a peripheral lesion (rhabdoid tumor) in an area of disease progression and was managed conservatively. Two patients are surviving 2.9 years (Wilms tumor) and 1.9 years (Ewing sarcoma) after SBRT, and one (rhabdoid tumor) expired 2 years after her final course (4 years after initial SBRT). Two patients (rhabdoid tumor and Ewing sarcoma) suffered disease progression outside of the treated lesions and one patient (Wilms tumor) is without evidence of disease and has not required whole lung irradiation or further systemic therapy.Conclusion: SBRT appears effective and well tolerated for pediatric lung metastases, however further studies are warranted.

A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: A Children's Oncology Group study.

This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT), tumors that have been characterized by their expression of post-induction renal developmental genes (Subset 1 WT). We demonstrate copy neutral loss of heterozygosity involving 19q13.32-q13.43, unaccompanied by evidence for imprinting by DNA methylation. We further identified loss-of-function somatic mutations in TRIM28 (also known as KAP1), located at 19q13, in 8/9 Subset 1 tumors analyzed. An additional germline TRIM28 mutation was identified in one patient. Retrospective evaluation of previously analyzed WT outside of Subset 1 identified an additional tumor with anaplasia and both TRIM28 and TP53 mutations. A major function of TRIM28 is the repression of endogenous retroviruses early in development. We depleted TRIM28 in HEK293 cells, which resulted in increased expression of endogenous retroviruses, a finding also demonstrated in TRIM28-mutant WT. TRIM28 has been shown by others to be active during early renal development, and to interact with WTX, another gene recurrently mutated in WT. Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive.

Impact of Radiation Therapy on Patterns of Relapse and Survival in Children with Stage III Favorable Histology Wilms Tumor

Impact of Radiation Therapy on Patterns of Relapse and Survival in Children with Stage III Favorable Histology Wilms Tumor

Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients With Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group.

The 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). Overall, 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. The 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). In 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.

Abstract PR14: Mutations in microRNA processing genes dysregulate a miR-16/34-PLAG1-IGF2 axis in Wilms tumors

Abstract Mutations in microRNA processing genes arise in ~20% of Wilms tumors, the most common pediatric kidney cancer. These mutations block microRNA production, yet the key microRNA target genes that drive tumorigenesis in this setting are unknown. To address this question, we performed whole-transcriptome and small RNA sequencing in Wilms tumors. In tumors with microRNA processing mutations, the most significantly overexpressed gene was Pleomorphic adenoma gene 1 (PLAG1). PLAG1 has known oncogenic activity in other cancers but has never been studied in Wilms tumor. This transcription factor is normally expressed only in the developing kidney and liver, where it transactivates insulin-like growth factor 2 (IGF2). Because IGF2 overexpression plays a major role in Wilms tumor pathogenesis, we hypothesized that microRNA pathway mutations contribute to Wilms tumor formation by de-repressing PLAG1, thus overexpressing IGF2. To determine the effect of ectopic PLAG1 expression in vivo, we generated mice that overexpress PLAG1 throughout the developing kidney (Wt1-Cre; LSL-PLAG1). These mice develop grossly enlarged kidneys and die by 4 weeks of age. Prenatally, nephron production is impaired, resulting in fewer glomeruli and dilated tubules. Importantly, PLAG1-overexpressing kidneys progressively acquire several neoplastic characteristics. The kidney parenchyma becomes replaced by cysts that develop polyps and dysplastic thickening. As these dysplastic cells continue to proliferate and fill the cyst lumen, they form nodules that appear precancerous and exhibit markers of active proliferation (Ki-67) and Igf2 signaling (phospho-Erk1/2, phospho-S6). Thus, ectopic PLAG1 expression in the developing kidney recapitulates the two key features of Wilms tumor: blocked differentiation and neoplastic proliferation. We next confirmed that PLAG1 is a microRNA target gene that promotes proliferation of Wilms tumor cells in vitro. Luciferase reporter assays demonstrated that highly conserved sequences in the PLAG1 3’UTR can be targeted by miR-16 and miR-34a. These two miRNAs are strongly downregulated in Wilms tumors with microRNA processing mutations. In addition, mimics and inhibitors of miR-16 and miR-34a modulate endogenous PLAG1 and IGF2 expression in the Wilms tumor cell line WiT49. Finally, PLAG1 overexpression in WiT49 produced increased IGF2 expression, increased activating phosphorylation of its receptor, and increased proliferation. Lastly, we interrogated PLAG1 levels in publicly available data from the TARGET consortium. In 75 relapsed favorable-histology Wilms tumors, microRNA pathway mutations were seen in 14 cases. However, other genomic aberrations were also associated with high PLAG1 expression. For instance, chromosome 8p12, containing the PLAG1 locus, is amplified in 15 cases. Additionally, nine cases show loss of chromosome 1p, which includes the miR-34a locus. These copy number changes rarely overlap with each other or with microRNA pathway mutations. Together, however, these three changes account for 35 of the 75 tumors, and all 35 display high PLAG1 expression. Regardless of mechanism, high levels of PLAG1 correlated with earlier relapse, implying that high PLAG1 expression drives more aggressive tumors. In sum, Wilms tumors can produce high levels of the oncogenic transcription factor PLAG1 through 1p loss, 8p12 gain, or microRNA processing blockade. PLAG1 activates IGF2 transcription and enhances proliferation of Wilms tumor cells in vitro. Overexpression of PLAG1 in developing mouse kidneys produces impaired differentiation and neoplastic growth. These data establish PLAG1 as a novel mediator of Wilms tumor formation and a potential therapeutic target. Citation Format: Kenneth S. Chen, Emily K. Stroup, Albert Budhipramono, Joshua T. Mendell, James F. Amatruda. Mutations in microRNA processing genes dysregulate a miR-16/34-PLAG1-IGF2 axis in Wilms tumors [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr PR14.

Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases.

Treatment of Stage IV Favorable Histology Wilms Tumor With Lung Metastases.

High‐dose chemotherapy without whole lung radiation for refractory pulmonary metastases in an infant with stage IV favorable histology Wilms tumor

High‐dose chemotherapy without whole lung radiation for refractory pulmonary metastases in an infant with stage IV favorable histology Wilms tumor

Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group Study AREN0532.

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.

Patterns of lymph node sampling and the impact of lymph node density in favorable histology Wilms tumor: An analysis of the national cancer database

There is controversy about the role of lymph node (LN) sampling or dissection in the management of favorable histology (FH) Wilms tumor (WT), specifically how it performed and how it may impact survival. The objective of this study was to analyze factors affecting LN sampling patterns and the impact of LN yield and density (number of positive LNs/LNs examined) on overall survival (OS) in patients with advanced-stage favorable histology Wilms tumor (FHWT). The National Cancer Database (NCDB) was queried for patients with FHWT during 2004-2013. Demographic, clinical and OS data were abstracted for those who underwent surgical resection. Poisson regression was performed to analyze how factors influenced LN yield. Patients with positive LNs had LN density calculated and were further analyzed. A total of 2340 patients met criteria, with a median age at diagnosis of 3 years (range 0-78 years). The median number of LNs examined was three (range 0-87). Lymph node yield was affected by age, race, insurance, tumor size, laterality, advanced stage, LN positivity, and institutional volume. A total of 390 (16.6%) patients had LN-positive disease. Median LN density for these LN-positive patients was 0.38 (range 0.02-1) (Summary Figure). Estimated 5-year OS was significantly improved for those with LN density ≤0.38 vs. >0.38 (94% vs. 84.6%, P=0.012). In this population, on multivariate analysis, age and LN density were significant predictors of OS. It is difficult to compile large numbers of cases in rare diseases like WT, and fortunately a large administrative database such as the NCDB can serve as a great resource. However, administrative data come with inherent limitations such as missing data and inability to account for a variety of factors that may influence LN yield and/or OS (specimen designation, pathologist experience, surgeon experience/volume, institutional Children's Oncology Group (COG) association, etc.). In this specific disease, the American Joint Committee on Cancer staging (captured by the NCDB) is different than the COG WT staging system that is used clinically, and the NCDB does not capture oncologic outcomes beyond OS. In a review of the NCDB, various factors associated with LN yield and observed LN density were identified to be significantly associated with OS in patients with LN-positive FHWT. This reinforces the need for adequate LN sampling at the time of WT surgery, to maximize surgical disease control. It was proposed that LN density as a metric may allow for improved risk-stratification, and possibly allow for therapeutic reduction in a sub-set of patients with low LN density.

A long-term follow-up report of pediatric relapsed Wilms tumor after retreatment

Objective: To investigate the long-term efficacy and prognostic factors of pediatric relapsed Wilms tumor (WT) after retreatment. Method: Sixteen children in Shanghai Children's Medical Center with relapsed Wilms tumor were enrolled consecutively in this study between April 2006 and June 2016. All patients were diagnosed according to pathology, imaging and medical and surgical oncologist's assistance. Relapse treatment included surgical excision, chemotherapy and selective radiation therapy. The clinical features, long-term outcomes and prognostic factors of patients were analyzed retrospectively.Survival data were analyzed by Kaplan-Meier.Log-Rank analysis was used for univariate analysis. Result: One case was excluded because of giving up the therapy even though no disease progress was identified. A total of 15 cases (5 males and 10 females) were included in this study. The median age at diagnosis was 3.8 years (range 0.5-9.1 years). The tumor staging at diagnosis included one case of stageⅠ, 7 cases of stageⅡand 7 cases of stage Ⅲ. Among cases of stage Ⅲ, 6 cases had radiation therapy history. The pathology of all patients' recurrent tumor was favorable histology (FH). The median follow-up time was 34.6 months (range 12.5-132.7 months) until March 21, 2017. The time from initial diagnosis to relapse was 7.9 months (range 3.1-17.9 months). Four cases experienced local recurrence, 9 cases relapsed with metastases (6 cases in lungs, 2 in livers, 1 in mediastinum) and 2 cases relapsed in both local site and with metastases. Except to 2 cases received irregular retreatment, 13 cases received regimen I (doxorubicin, vincristine, epoposide and cyclophosphamide for 25 weeks) as relapsed chemotherapy. Five cases received autologous bone marrow transplantation (ABMT). Until the last follow-up, 8 cases achieved continuous complete remission (range 6.7-104.3 months), 3 cases had relapse again or progressing and 4 cases died. The estimated 5-year overall survival (OS) rate and event free survival (EFS) rate were (70±15)% and (52±15)%. According to whether received ABMT or not, the 5-year EFS rate were 51% and 53%. According to whether relapsed within 6 months after diagnosis or not, the 5-year EFS rate were 38% and 56% respectively. Conclusion: The 5-year EFS rate of pediatric relapsed FH WT have reached above 50% by multi-disciplinary treatment in our experience and we encourage patients and doctors to receive retreatment.

Loss of heterozygosity on chromosome 16q increases relapse risk in Wilms' tumor: a meta-analysis.

Wilms’ tumor (WT) is the most frequent malignant renal tumor in children. The survival rate is lower in patients with recurrence, and the factors that influence relapse in WT are not fully understood. Loss of heterozygosity on chromosome 16q (LOH 16q) has been reported to be associated with the relapse in WT, but this remains controversial. We performed a meta-analysis to clarify this. PUBMED, EMBASE, and the Cochrane Library were searched up to March 17, 2017. Ten studies involving 3385 patients were ultimately included in the meta-analysis. The meta-analysis showed that LOH 16q was significantly associated with the relapse in WT (relative risk [RR] = 1.74, 95% confidence interval [CI] = 1.43–2.13, P < 0.00001; hazard ratio [HR] = 1.76, 95% CI = 1.38–2.24, P < 0.00001). No significant heterogeneity among studies or publication bias was found. Sensitivity analysis showed omitting one study in each turn could not change the results. Subgroup analysis based on two studies indicated LOH 16q was more effective on elevated replase risk in patients with favorable-histology WT (RR = 2.52, 95% CI = 1.68–3.78, P < 0.00001; HR = 2.99, 95% CI = 1.84–4.88, P < 0.0001) but further work are needed to confirm this. These findings confirm that LOH 16q increased the relapse risk in WT, but more studies are required to further assess the association between LOH 16q and WT relapse among different subgroups.

Outcome of patients with intracranial relapse enrolled on national Wilms Tumor Study Group clinical trials.

The occurrence of brain metastases (at diagnosis or at relapse) in patients with Wilms tumor is very rare. We retrospectively reviewed the clinical characteristics of patients with Wilms tumor and relapse to the brain enrolled on the National Wilms Tumor Studies (NWTSs) 1-5. Intracranial relapse was documented in 47 patients (0.5%). Of the 45 patients with adequate data, 26 (58%) patients were male. Thirty-eight (84%) patients had favorable histology Wilms tumor. In 30 patients (67%), the appearance of intracranial disease was preceded by relapse at another site. Ten patients did not have any disease-directed therapy. Surgical resection was attempted in 15 patients; gross total resection was achieved in 11 patients. Twenty-nine patients received brain irradiation; the median dose was 3,000 cGy (range 1,080-4,000 cGy). Twenty-seven patients received chemotherapy. The 5-year overall survival from the time of intracranial relapse was 28.7% (95% confidence interval: 14.4-43.1%). Nine patients (all favorable histology Wilms tumor) were alive with a median follow-up from brain relapse of 140 months (range 35-381 months). All nine survivors received radiation therapy, eight received chemotherapy, and four underwent surgery (two gross total resection, two partial resection). The overall survival after brain metastases of the NWTS-5 patients was significantly higher than the overall survival of the NWTS 1-4 patients (P value = 0.029, log-rank test). Patients with Wilms tumor recurrence involving the brain may have durable survival, particularly those treated in recent years. Multimodality therapy including radiation and chemotherapy should be considered for these patients.

Abstract LB-180: The genetic landscape of Wilms tumor

Abstract Introduction: The National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative seeks to characterize the genomes of high-risk pediatric tumors to identify therapeutic targets. The High-Risk Renal Tumor TARGET initiative includes the analysis of pre-therapy favorable histology Wilms Tumors (FHWT) that relapsed and tumors with diffuse anaplasia (unfavorable histology; DAWT). These two tumor subsets have survival rates of approximately 50% and 60%, respectively. Experimental procedures: Genomic sequencing (whole genome [WGS] or exome [WXS]), global copy number analysis, and global gene expression analysis were performed on a discovery set of 117 (78 FHWT, 39 DAWT) pre-therapy high-risk WTs treated on National Wilms Tumor Study-5 (NWTS-5). To determine the frequency of recurrent variants, targeted sequencing (Illumina HiSeq2500) was performed on a validation set of pre-therapy tumor DNA from a case-cohort of all FHWT treated on NWTS-5 (531 FHWT) and all available 118 DAWT treated on NWTS-5 (these groups include tumors from the discovery set). Results: WGS and WXS revealed an average of 21.74 ± 22.6 high-quality variants per DAWT (range, 3-131) and 13.8 ± 10.9 per FHWT (range 2-58). Genes previously reported to be recurrently mutated in WT were mutated at the following frequencies in the validation set: WTX (6%), CTNNB1 (15%), WT1 (7.5%), DROSHA (11%), DGCR8 (4.5%), XPO5 (2%), SIX1/2 (7%), and MLLT1 (3%). In addition, mutations were identified in three genes that impact the NMYC pathway, which is known to be involved in renal development. These include MYCN P44L/H (4%), MAX R60Q (2%), and novel mutations in NONO (2%); these mutations were mutually exclusive. Novel mutations in BCOR, a transcriptional corepressor that regulates both gene expression during development and chromatin modification, were found in 3% of validation set tumors. Analysis of global gene expression revealed significant up-regulation of genes associated with kidney development, extracellular matrix organization, and epithelial tube development in BCOR-mutant tumors compared with precursor lesions (5 hyperplastic perilobar nephrogenic rests). TP53 mutations were identified in 48% of DAWTs and 1% of FHWTs. The above data do not include copy number changes, which were recurrently detected in WT1, WTX, NMYC, and TP53. Conclusions: Through the TARGET initiative, we have identified several novel, potential driver mutations that occur in WT and have not been reported in other pediatric tumors. The majority of these genes are known to function in processes critical to early development and/or specifically in renal development. Many of these mutations are accompanied by Wnt activating mutations or 11p15 biallelic expression. However, approximately 50% of WTs lack clear driver mutations. Future studies will need to focus on elucidating epigenetic alterations in these tumors as well as genetic changes outside of protein-coding regions. Citation Format: Samantha L. Gadd, Amy L. Walz, Ariadne HAG Ooms, Vicki Huff, Daniela S. Gerhard, Malcolm A. Smith, Jaime M. Guidry Auvil, Leandro Hermida, Tanja Davidsen, Patee Gesuwan, Daoud Meerzaman, Yussanne Ma, Marco A. Marra, Jeffrey S. Dome, Charles G. Mullighan, David A. Wheeler, Oliver A. Hampton, Julie M. Gastier-Foster, Nicole Ross, Elizabeth J. Perlman. The genetic landscape of Wilms tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-180.

Association of Chromosome 1q Gain With Inferior Survival in Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group.

The goal of this study was to analyze the association of copy number gain of 1q in favorable-histology Wilms tumors (FHWTs) with event-free survival (EFS) and overall survival (OS) within each tumor stage and with 1p and 16q copy number loss and/or loss of heterozygosity. Unilateral FHWTs from 1,114 patients enrolled in National Wilms Tumor Study-5 that were informative for 1p and 16q microsatellite markers (previously determined) and informative for 1q gain, 1p loss, and 16q loss using multiplex ligation-dependent probe amplification were analyzed. Eight-year EFS was 86% (95% CI, 84% to 88%) for the entire cohort. Of 1,114 patients, 317 tumors (28%) displayed 1q gain. Eight-year EFS was 77% for those with 1q gain and 90% for those lacking 1q gain (P < .001). Eight-year OS was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS (stage I, 85% v 95%; P = .0052; stage II, 81% v 87%; P = .0775; stage III, 79% v 89%; P = .01; stage IV, 64% v 91%; P = .001). OS was significantly inferior in patients with stage I (P < .0015) and stage IV disease (P = .011). With multivariable analysis, 1q gain was associated with an increased relative risk of relapse of 2.4 (P < .001), whereas 1p loss was not, despite significance on univariable analysis. Gain of 1q is associated with inferior survival in unilateral FHWTs and may be used to guide risk stratification in future studies.

Considerations in the Diagnosis and Management of Pediatric Patients With Favorable Histology Wilms Tumor Who Present With Only Pulmonary Nodules.

More than 70% of children with stage IV, favorable histology (FH) Wilms tumor will be relapse-free survivors 16 years after diagnosis. Successful treatment generally includes whole lung radiation therapy and doxorubicin. Such therapy is associated with adverse, long-term effects, including impaired pulmonary function, congestive heart failure, and second malignant neoplasms, especially breast cancer. Cooperative groups have adopted a risk-based approach to the treatment of these patients. It is important to recall the good overall prognosis for this group before recommendations for intensification are made based on preliminary data and in the absence of histological confirmation of persistent malignant disease.

Omission of lung radiation in patients with stage IV favorable histology Wilms Tumor (FHWT) showing complete lung nodule response after chemotherapy: A report from Children’s Oncology Group study AREN0533.

10011 Background: In National Wilms Tumor Study-5, patients with stage IV FHWT with metastases limited to the lung had 5-year EFS of 74% in the setting of incomplete lung nodule response by Day 70 ...