Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration.

Project description:PAPER 1:"Identification of novel subgroups of high-risk pediatric precursor B acute lymphoblastic leukemia (B-ALL) by unsupervised microarray analysis: clinical correlates and therapeutic implications. A Children's Oncology Group (COG) study." ABSTRACT We examined gene expression profiles of pre-treatment specimens from 207 patients from the COG P9906 study to identify signatures of children with high risk B-precursor acute lymphoblastic leukemia (ALL) and to determine whether the resulting clusters are associated with either specific clinical features or treatment response characteristics. Four unsupervised clustering methods were utilized to classify patients into similar groups. The different clustering algorithms showed significant overlap in cluster membership. Two clusters contained all cases with either t(1;19)(q23;p13) translocations or MLL rearrangements. The other six clusters were novel and had no recurring chromosomal abnormalities or distinctive clinical features. Members of two of these novel clusters had significant survival differences when compared to the overall 4-year relapse-free survival (RFS) of 61%. These included clusters of patients with either significantly better (94.7%) or worse (21.0%) RFS at 4 years. Children of Hispanic/Latino ethnicity were disproportionately present in the poor outcome cluster. The poor outcome cluster represents a novel biologically distinctive subset of B-precursor ALL that may occur at least as frequently as BCR/ABL. Further molecular characterization of this cluster may lead to the discovery of genomic abnormalities that can be targeted to improve the currently dismal outcome for children with this gene signature. The Sample data have also been used in another study: PAPER 2: "Gene expression classifiers for minimal residual disease and relapse free survival improve outcome prediction and risk classification in children with high risk acute lymphoblastic leukemia. A Children's Oncology Group study". ABSTRACT Background. Nearly 25% of children with B-precursor ALL present with "high-risk" disease (HR-ALL) that is resistant to current therapies. Gene expression profiling may yield molecular classifiers for outcome prediction that can be used to improve risk classification and therapeutic targeting. Methods. Expression profiles were obtained in pre-treatment leukemic samples from 207 uniformly treated children with HR-ALL. Relapse free survival (RFS) was 61% at 4 years and flow cytometric measures of minimal residual disease (MRD) at the end of induction (day 29) were predictive of outcome (P<0.001). Molecular classifiers predictive of RFS and MRD were developed using extensive cross-validation procedures. Results. A 38 gene molecular risk classifier predictive of RFS (MRC-RFS) distinguished two groups in HR-ALL with different relapse risks: low (4 yr RFS: 81%, n=109) vs. high (4 yr RFS: 50%, n=98) (P<0.0001). In multivariate analysis, the best predictor combined MRC-RFS and day 29 flow MRD data, classifying children into low (87% RFS), intermediate (62% RFS), or high risk (29% RFS) groups (P<0.0001). A 21 gene molecular classifier predictive of MRD could effectively substitute for day 29 flow MRD, yielding a combined classifier that similarly distinguished three risk groups at pre-treatment (low: 82% RFS; intermediate: 63% RFS; and high risk: 45% RFS) (P<0.0001). This combined molecular classifier was further validated on an independent cohort of 84 children with HR-ALL (P = 0.006). Conclusions. Molecular classifiers predictive of RFS and MRD can be used to distinguish distinct prognostic groups within HR-ALL, significantly improving risk classification schemes and the ability to prospectively identify children at diagnosis who will respond to or fail current treatment regimens. NOTE: Due to Children's Oncology Group (COG) restrictions, outcome and MRD data cannot be provided as part of the covariate data for this dataset at the present time. If you would like to arrange individual access to this data, please contact COG or the PI of this study, Dr. Cheryl Willman, at the University of New Mexico Cancer Center (cwillman@unm.edu) to arrange a collaboration. Unsupervised clustering and supervised risk classification analyses of 207 diagnostic samples and associated clinical covariate data. See the Summary for greater details. The data were analyzed using Microarray Suite version 5.0 (MAS 5.0) in the Affymetrix Gene Chip Operating Software Version 1.4. Probe masking was used (see 9906_TT207_Affymetrix_probe_mask.msk, linked below as a supplementary file). Otherwise all Affymetrix default parameter settings were used. Global scaling as the normalization method, with the default target intensity of 500, was used.

Project description:BackgroundVarious human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.MethodsIn this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m(2) per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770.Findings79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10.1 years (range 1.1-21.4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m(2) twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC).InterpretationThe findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted.FundingPfizer and National Cancer Institute grant to the Children's Oncology Group.

Project description:BACKGROUND:Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases. METHODS:The authors used array genotyping data from a Children's Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth-19 years). Using Fisher's exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS-GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1-year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases. RESULTS:Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS-GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7-30.0). CONCLUSIONS:Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one-third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.

Project description:PURPOSE:Stratum 1 of ACNS1123 (ClinicalTrials.gov identifier: NCT01602666), a Children's Oncology Group phase II trial, evaluated efficacy of reduced-dose and volume of radiotherapy (RT) in children and adolescents with localized nongerminomatous germ cell tumors (NGGCTs). The primary objective was to evaluate the impact of reduced RT on progression-free survival (PFS) with a goal of preserving neurocognitive function. PATIENTS AND METHODS:Patients received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide, as used in the Children's Oncology Group predecessor study (ACNS0122; ClinicalTrials.gov identifier: NCT00047320). Patients who achieved a complete response (CR) or partial response (PR) with or without second-look surgery were eligible for reduced RT, defined as 30.6 Gy whole ventricular field and 54 Gy tumor-bed boost, compared with 36 Gy craniospinal irradiation plus 54 Gy tumor-bed boost used in ACNS0122. RESULTS:A total of 107 eligible patients were enrolled. Median age was 10.98 years (range, 3.68 to 21.63) and 75% were male. Sixty-six of 107 (61.7%) achieved a CR or PR and proceeded to reduced RT. The 3-year PFS and overall survival and standard error values were 87.8% ± 4.04% and 92.4% ± 3.3% compared with 92% and 94.1%, respectively, in ACNS0122. There were 10 recurrences, prompting early study closure; however, after a retrospective central review, only disease in eight of 66 (12.1%) patients eligible for reduced RT subsequently progressed; six patients had distant spinal relapse alone and two had disease with combined local plus distant relapse. Serum and CSF α-fetoprotein and β-human chorionic gonadotropin levels were not associated with PFS. CONCLUSION:Patients with localized NGGCT who achieved a CR or PR to chemotherapy and received reduced RT had encouraging PFS similar to patients in ACNS0122 who received full-dose craniospinal irradiation. However, the patterns of failure were distinct, with all patients having treatment failure in the spine.

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Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study.

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