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© 2000 American Society for Clinical Oncology Loss of Heterozygosity at 1p36 Independently Predicts for Disease Progression But Not Decreased Overall Survival Probability in Neuroblastoma Patients: A Children’s Cancer Group StudyFrom the Department of Pediatrics, University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; Departments of Pediatrics and Preventive Medicine, University of Southern California School of Medicine, Los Angeles; Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco; and Children’s Cancer Group, Arcadia, CA. Address reprint requests to John M. Maris, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email brodeur@ email.chop.edu.
PURPOSE: To determine the independent prognostic significance of 1p36 loss of heterozygosity (LOH) in a representative group of neuroblastoma patients. PATIENTS AND METHODS: Diagnostic tumor specimens from 238 patients registered onto the most recent Children’s Cancer Group phase III clinical trials were assayed for LOH with 13 microsatellite polymorphic markers spanning chromosome band 1p36. Allelic status at 1p36 was correlated with other prognostic variables and disease outcome. RESULTS: LOH at 1p36 was detected in 83 (35%) of 238 neuroblastomas. There was a correlation of 1p36 LOH with age at diagnosis greater than 1 year (P = .026), metastatic disease (P < .001), elevated serum ferritin level (P < .001), unfavorable histopathology (P < .001), and MYCN oncogene amplification (P < .001). LOH at 1p36 was associated with decreased event-free survival (EFS) and overall survival (OS) probabilities (P < .0001). For the 180 cases with single-copy MYCN, 1p36 LOH status was highly correlated with decreased EFS (P = .0002) but not OS (P = .1212). Entering 1p36 LOH into a multivariate regression model suggested a trend toward an independent association with decreased EFS (P = .0558) but not with decreased OS (P = .3687). Furthermore, allelic status at 1p36 was the only prognostic variable that was significantly associated with decreased EFS in low-risk neuroblastoma patients (P = .0148). CONCLUSION: LOH at 1p36 is independently associated with decreased EFS, but not OS, in neuroblastoma patients. Determination of 1p36 allelic status may be useful for predicting which neuroblastoma patients with otherwise favorable clinical and biologic features are more likely to have disease progression.
NEUROBLASTOMA IS a common embryonal malignancy of childhood. Overall survival (OS) rates have improved modestly over the last decade, and currently nearly two thirds of patients can be expected to achieve cure.1 An important component of the trend toward improved survival has been the identification of reliable clinical and biologic prognostic variables. Analyses of these prognostic markers have resulted in an evolving risk stratification system that is used within the Children’s Cancer Group (CCG) to assign therapy. Clinical variables associated with a poor disease outcome include age older than 1 year at diagnosis, metastatic disease at diagnosis, and unfavorable histopathology according to the system of Shimada et al.2-4 There are also a large number of tumor-specific biologic variables that have been associated with an aggressive clinical phenotype and, therefore, have been postulated to be of prognostic utility.5 Amplification of the MYCN proto-oncogene is reliably associated with rapid disease progression and a poor outcome6,7 and has been incorporated into treatment stratification systems for more than a decade. In addition, DNA index (ploidy) also seems to be independently prognostic within the subset of patients younger than 1 year at diagnosis.8,9 Thus, analysis of age, stage, histopathology, MYCN gene status, and, for infants, DNA index is currently used by CCG and the Pediatric Oncology Group (POG) to stratify therapy for all newly diagnosed neuroblastoma patients. Several studies have documented that loss of heterozygosity (LOH) at the distal short arm of chromosome 1 (1p36) is strongly correlated with high-risk clinical and biologic features, which indicates that allelic loss of 1p36 occurs frequently in the more malignant subset of neuroblastomas.10-13 However, there have been conflicting reports concerning the independent prognostic power of 1p36 LOH.14-20 Discrepancies in these study findings may be a result of relatively small sample sizes, heterogeneously assessed and treated patient populations, and differing statistical methods. In particular, some studies used only event-free survival (EFS) as the primary outcome measure,16 whereas others used only OS.14,15,19,20 Because the majority of low-risk patients who relapse are ultimately cured21-23 but disease progressions in high-risk patients are usually fatal, analysis of both EFS and OS may be necessary to unequivocally determine the prognostic significance of 1p36 LOH. In this study, we identified a large and representative series of neuroblastoma patients from the most recent and concurrent CCG phase III trials for all neuroblastoma patients to test the hypothesis that 1p36 LOH is independently prognostic for adverse disease outcome. The primary aim of this study was to retrospectively determine if analysis of 1p36 allelic status would add prognostic information to that gained from the current panel of clinical and biologic variables used to assign treatment for neuroblastoma patients.
Patients, Treatment Assignment, and Risk Groups All patients were newly diagnosed with neuroblastoma between July 1985 and March 1996 and registered onto a CCG phase III trial (CCG-321P, CCG-3881, or CCG-3891). Disease was staged according to Evans et al2 and the International Neuroblastoma Staging System (INSS).24 Treatment was stratified according to risk group assignment based on evaluation of patient age at diagnosis, Evans stage, Shimada histopathology, MYCN gene status, and serum ferritin level. Patients with low-risk (stages I, II, or IVS) and intermediate-risk (biologically favorable stage III, infants with stage IV, and single-copy MYCN) disease features were assigned to CCG-3881.25 Low-risk patients were treated with surgery alone, and intermediate-risk patients were treated with surgery and adjuvant chemotherapy. High-risk patients (biologically unfavorable stage III, infants with stage IV and amplified MYCN, and all patients  1 year of age with stage IV and any biology) were treated on CCG-3891 or the preceding pilot study, CCG-321P.25,26 Each of the high-risk patients received intensive induction and consolidation chemotherapy. Patients enrolled onto CCG-3891 were randomized to receive either myeloablative consolidation chemotherapy with autologous, purged bone marrow rescue or intensive continuation chemotherapy. In addition, there was a second randomization for patients enrolled onto CCG-3891 after consolidation therapy to receive either 6 months of 13-cis-retinoic acid or no further treatment.
For the purposes of this study, we modified the risk assignments using the INSS staging system to more closely match the current CCG and POG definitions (Fig 1). Thus, low-risk patients were defined as children with INSS stage 1, 2, or 4S disease and not meeting CCG-3881 criteria for adjuvant chemotherapy. Intermediate-risk patients were defined as all other patients who were registered onto CCG-3881, treated with adjuvant chemotherapy, and not meeting current criteria for high-risk disease. High-risk patients were defined as the following: all patients
Tissue Samples Tumor, blood, and bone marrow specimens from each patient were initially sent at diagnosis to the CCG Neuroblastoma Resource Laboratory at the Children’s Hospital of Los Angeles as part of CCG biology study B973. Tumor specimens were snap frozen at the individual CCG institutions and maintained frozen at Children’s Hospital of Los Angeles in the Neuroblastoma Resource Laboratory Tumor Bank. The only criteria for inclusion in this retrospective CCG biology study (CCG-B974) were the availability of diagnostic tumor tissue and either a matched blood or bone marrow specimen that was negative for tumor contamination by immunohistochemistry.27 Patients on the therapeutic protocols were required to have multiple blood and bone marrow mononuclear cell pellets reviewed centrally, with excess material being banked. Thus, the paired specimens available were not biased against patients with initial marrow involvement by metastatic tumor. Tissue samples were selected in an attempt to match the INSS stage distribution observed for a large cohort of newly diagnosed neuroblastoma patients registered over a 4-year period (August 1, 1991, to August 1, 1995), during which time both CCG-3881 and CCG-3891 were open. Specimens were shipped to the Children’s Hospital of Philadelphia for analysis of 1p allelic status. The Children’s Hospital of Philadelphia Institutional Review Board approved this study.
Shimada Histopathology, MYCN, and Serum Ferritin
1p36 LOH Detection
Statistical Analyses
Patient Characteristics and Disease Outcome The 238 neuroblastoma patients identified for this study were compared with all patients registered onto CCG-3881 and CCG-3891 between August 1, 1991, and August 1, 1995, a period of time when the CCG had phase III trials open for all newly diagnosed neuroblastoma patients (Table 1). There was an equivalent distribution of the characteristics of sex, age, stage, serum ferritin status, and MYCN amplification status among patient cohorts. There was a slight overrepresentation of patients 1 year of age at diagnosis, and there was a higher proportion of unfavorable Shimada histopathology cases in the study cohort with 238 patients. However, there was no difference in either EFS or OS between subject populations.
Median length of follow-up was 60.0 months. There were 107 events, including 101 disease progressions and six toxic deaths. Each of the toxic deaths was in the high-risk group of patients. Thus, all events in the low- and intermediate-risk groups were disease progressions.
Based on retrospective analysis of the variables listed in Table 1, patients were assigned to risk groups (Fig 1). Sixty patients with INSS stage 1, 2, or 4S disease who were treated with surgery alone were assigned to the low-risk group. This group included two patients with stage 2B disease and MYCN amplification, but both were younger than 1 year at diagnosis. The intermediate risk group of 38 patients consisted mainly of patients with INSS stage 3 disease and infants with INSS stage 4 and single-copy MYCN. This subset also included one patient with INSS stage 1, who was originally staged as Evans III and who received adjuvant chemotherapy on CCG-3881. In addition, two patients with stage 4S disease were included in this group because both required treatment for symptomatic progression of disease. There were 140 patients assigned to the high-risk group, and each of the patients with INSS stage 3 in this subset had tumors with MYCN amplification (N = 16) and/or were
Prevalence of 1p36 LOH and Clinicobiologic Correlations
LOH at 1p36 was significantly correlated with age
1p36 LOH and Univariate Measures of Disease Outcome Stratification of the entire patient cohort by 1p36 LOH status showed an EFS and OS disadvantage for patients whose tumors had 1p36 LOH (Fig 2 and Table 3). Subset analyses confirmed that 1p36 LOH was predictive for decreased EFS in all groups analyzed except for the 57 cases with MYCN amplification (Table 3; log-rank P value was marginal for the infant subgroup). However, LOH at 1p36 was not associated with decreased OS in several subsets, most notably the 180 cases with single-copy MYCN (Fig 3).
Additional stratified univariate analyses were performed to determine the prognostic significance within risk groups. However, there were only two disease progressions and no deaths among the 38 patients in the intermediate-risk group, so this subset was not analyzed further. When the 140 high-risk patients were stratified by 1p36 allelic status, there was a significant decrease in both EFS and OS for those patients with 1p36 LOH (Fig 4A and 4B). In the low-risk subset of patients, there was significant EFS disadvantage for the 12 patients with 1p36 LOH (Fig 5A). Seven of 12 low-risk patients with 1p36 LOH had disease progression, but all were salvaged with second surgeries and/or chemotherapy (Fig 5B).
Multivariate Analyses Several multivariate analysis models were used to determine the independent prognostic significance of 1p36 LOH. Because complete data on age, stage, and MYCN status were available for all but one patient, we first constructed a Cox proportional hazards model that included these variables and 1p36 LOH. Table 4 shows that each prognostic factor except MYCN status was an independent predictor for EFS probability. In contrast, 1p36 LOH was the only factor analyzed not independently prognostic for OS. Next, 202 patients with complete data on age, stage, MYCN status, and Shimada histopathology were analyzed (Table 5). In this model, unfavorable Shimada pathology was the only prognostic factor significantly associated with decreased EFS probability. Allelic status at 1p36 was only marginally predictive for EFS and was, again, the only variable analyzed not associated with a decreased OS probability.
Lastly, we constructed multivariate models that examined the influence of 1p36 LOH within risk groups. There was no evidence for an independent prognostic impact of 1p36 LOH for either EFS (RR, 1.363; 95% CI, 0.764 to 2.433; P = .2942) or OS (RR, 1.580; 95% CI, 0.866 to 2.833; P = .1359) in the high-risk group of patients in a model that included age, stage, MYCN status, and Shimada pathology. However, for the low-risk subset of patients, 1p36 LOH was the only prognostic marker analyzed that was predictive for EFS (Table 6). OS was not analyzed because there were only four deaths in the low-risk group of patients, and each of these occurred after disease progression in cases with no 1p36 LOH.
Despite a growing number of clinical and biologic variables postulated to be of prognostic importance for neuroblastoma patients, age at diagnosis and disease stage remain among the most powerful and reliable predictors of disease course and outcome.2,4 In addition, amplification of the MYCN proto-oncogene is strongly correlated with a highly malignant clinical phenotype and is also a powerful independent prognostic marker that adds information to that gained from analysis of age at diagnosis and disease stage.6,7 As originally proposed by Shimada et al,3 combined assessment of tumor histopathology and patient age is an independent prognostic marker, even when controlling for MYCN.36 DNA index also seems to be independently prognostic in the subset of patients younger than 1 year at diagnosis.8,9 Taken together, these prognostic variables are remarkably efficient at properly assigning patients to the appropriate intensity of therapy.25,37 However, treatment failures in all patient subgroups occur, which suggests that additional prognostic markers may be available to further refine treatment stratification. Deletion of distal 1p is the most common structural rearrangement noted in neuroblastoma karyotypes.38,39 PCR-based analyses of chromosome 1p36 status in primary neuroblastomas have shown LOH in 19% to 36% of cases.11,13-17,19,20 The present study included the largest series of newly diagnosed neuroblastoma cases analyzed for 1p36 allelic status reported to date. In addition, the patient population was generally representative of the known natural distribution of the major clinical and biologic variables typically present at diagnosis. There was a slight overrepresentation of cases diagnosed at an older age and with unfavorable Shimada histopathology, compared with a cohort of CCG cases accrued over a 4-year period when phase III clinical trials were concurrently available for all newly diagnosed CCG neuroblastoma patients. However, the distribution within stages, frequency of MYCN amplification, and disease outcomes were similar between groups. Thus, the 35% prevalence of 1p36 LOH detected in this study is a valid approximation of the true frequency of this somatically acquired genetic event. A common region of deletion has been mapped to the most telomeric subband of 1p36 (1p36.3),13,32 and our current data are consistent with these observations. Thus, the subtelomeric region of the short arm of chromosome 1 is likely to contain a neuroblastoma suppressor gene, but more proximal 1p suppressor gene loci may also exist.19,40-42 Whether 1p36 LOH is a surrogate marker for inactivation of a single 1p36 tumor suppressor gene or an indicator of hemizygous deletion of multiple genes critical to neuroblastoma tumorigenesis has not yet been clearly defined. There were no tumors identified with a region of LOH distinct from 1p36.3. However, the study was designed to unequivocally determine 1p36 allelic status by saturating this region with highly informative markers and was not designed to thoroughly analyze for noncontiguous regions of deletion proximal to 1p36. Additional studies will be required to address the prevalence and relative prognostic significance of LOH at regions proximal to 1p36. Several previous studies clearly documented an association of 1p36 LOH with adverse prognostic markers.11,14-17 This study serves to both confirm and extend these observations. Allelic loss of 1p36 was highly correlated with each of the adverse prognostic variables analyzed, especially MYCN amplification. However, we found 52 cases that were discordant for 1p36 and MYCN amplification status, including 39 cases with 1p36 LOH and single-copy MYCN. In addition, 1p36 LOH was identified in 12 (20.0%) of 60 cases that were classified as low-risk and, thus, had otherwise favorable clinical and biologic features. Therefore, the study cohort was large enough to allow for subset analyses, especially within the currently used risk grouping system. There have been seven prior investigations of the clinical significance of 1p36 LOH for neuroblastoma patients.14-20 Each of these studies was limited by the size of the subject population, with the largest series including 156 patients14 and the others including between 51 and 89 cases. In addition, the patients were often derived from heterogeneously assessed and treated populations and were sometimes biased toward certain clinical or biologic features. Lastly, some studies analyzed EFS,16 whereas others measured OS14,15,19,20 as the primary outcome. This is relevant because the majority of patients with low-risk neuroblastoma that have disease progression are ultimately cured.21-23 Thus, consideration of both EFS and OS seems warranted to most thoroughly analyze the prognostic utility of 1p36 LOH. In this study, allelic loss of 1p36 was significantly associated with decreased EFS in univariate analysis and within most prognostic variable subsets in stratified analyses. The major exception was within the group of 57 patients with MYCN-amplified neuroblastomas, in whom the dismal 3-year EFS for patients with amplification was not made significantly worse with the addition of 1p36 LOH status. There was also a significant OS disadvantage for cases with 1p36 LOH in univariate analyses. However, there was only a marginal decrease in OS probability within each of the more favorable subsets for each factor. For example, within the 180 cases with single-copy MYCN, in whom a clear EFS difference was detected, there was no significant difference when OS was analyzed (there were 42 deaths in this cohort). However, several deaths occurred at 4 to 6 years from diagnosis in the 1p36 LOH subset of patients. Therefore, additional follow-up will be necessary to determine if 1p36 LOH ultimately predicts for a decreased OS within this patient cohort. Multivariate analyses showed that 1p36 LOH was independently associated with decreased EFS but not with decreased OS probability. The first multivariate analysis was performed on the entire patient cohort and is comparable to models presented in previous publications that investigated the prognostic significance of genetic variables, none of which included evaluation of pathology.14-17,19,43 These data emphasize that 1p36 LOH has as much or more impact on EFS probability as MYCN amplification. This is consistent with the data of Caron et al,16 which suggested that 1p36 LOH is a more powerful prognostic factor than MYCN amplification when EFS is measured as the primary outcome variable. However, in this study, MYCN amplification but not 1p36 LOH was independently prognostic for decreased OS probability. This apparent discrepancy may be a result of the fact that there were seven of 12 cases with 1p36 LOH and low-risk features (by definition, MYCN single-copy) that had disease progression, but all were salvaged with additional therapy. The prognostic importance of Shimada histopathology was highlighted by the second multivariate analysis. Indeed, Shimada pathology was the only factor analyzed in this model that was significantly associated with decreased EFS. Allelic status at 1p36 LOH was marginally predictive for decreased EFS but was the only factor not significantly associated with decreased OS probability. CCG and POG currently use the Shimada system for treatment stratification, and it is being adapted for use worldwide.44 Thus, our data further demonstrate the importance of including evaluation of histopathology when analyzing the impact of potentially new predictive factors for neuroblastoma patients. It has been postulated that neuroblastoma may represent a spectrum of diseases and that low-risk patients have tumors that are biologically and genetically distinct from those derived from patients with high-risk features.5,45,46 Subset analyses based on risk groups may therefore be necessary to determine the clinical utility of proposed prognostic markers. Although univariate analyses showed a significant EFS and OS survival disadvantage for cases with high-risk features and 1p36 LOH, multivariate analyses showed that this variable did not override the effects of age, stage, MYCN status, and Shimada pathology. Thus, evaluation of 1p36 allelic status currently has no prognostic utility in patients classified as high-risk. This will need to be reevaluated as survival probabilities improve in the future. On the other hand, 1p36 allelic status was the only variable independently prognostic for disease progression in the low-risk subset of patients. These data are consistent with a preliminary report from Rubie et al on 91 localized neuroblastomas (four cases identified with 1p36 LOH and single-copy MYCN), which also suggested an EFS disadvantage for cases with 1p36 LOH.18 Although the number of patients included in this study is relatively large, there were only 12 cases in the low-risk subset that had 1p36 LOH. Nonetheless, the data support the hypothesis that 1p36 LOH has significant power to predict disease progression in this patient cohort and that this marker might have prognostic utility when present in a tumor with otherwise favorable biologic features. Although the data clearly indicate that 1p36 LOH has more influence on EFS than OS, it is important to emphasize that there were fewer deaths (N = 77) compared with total events (N = 107), and therefore, the statistical power to detect a difference in OS is less than that for EFS. Thus, it is possible that future analyses that include more cases will show that 1p36 is independently prognostic for OS probability. It also emphasizes the fact that unequivocal demonstration of the utility of any prognostic marker for neuroblastoma patients will require large numbers of patients and cooperation among the major pediatric clinical trials groups, especially if analyses within risk groups are desired. Analysis of DNA content by flow cytometry was not routinely assessed as part of tumor evaluation in the CCG trials represented here. Therefore, we were unable to analyze the prognostic significance of 1p36 LOH with DNA index in this retrospective study. This may be especially relevant for the low-risk cohort, as 33 of 60 patients were infants at diagnosis, the age range in which DNA index is postulated to be especially discriminatory.8,47 In addition, these tumors were not analyzed for unbalanced gain of distal 17q material. A recent report suggested that this variable is a powerful prognostic marker, but multivariate analyses did not include histopathology or DNA index.43 Thus, prospective evaluation of 1p36 allelic status with these, and perhaps other, genetic variables will be necessary to determine the relevant prognostic value of each as treatment strategies evolve. In summary, 1p36 LOH was identified in 35% of a large and representative cohort of neuroblastoma patients. Our data confirmed the association of 1p36 LOH with high-risk disease features but also showed that 1p36 allelic loss occurred in a substantial number of neuroblastomas that were localized and had otherwise favorable biologic features. Our data also indicate that 1p36 LOH is independently associated with decreased EFS in neuroblastoma patients but not with decreased OS probability. This may be especially relevant to the subset of patients otherwise judged to be at low risk. In this study, all of the events in the low-risk subset were disease progressions, and each patient whose tumor had 1p36 LOH survived after additional therapy. Thus, these data do not justify upstaging of low-risk patients based on 1p36 allelic status but may support a need for closer surveillance after surgery for disease progression. A prospective evaluation of the prognostic significance of 1p36 allelic status with DNA index and 17q copy number is planned within the combined pediatric oncology cooperative groups.
Supported in part by grants no. CA78545 (J.M.M.), CA78966 (J.M.M.), CA02649 (R.C.S.), CA60104 (R.C.S.), CA39771 (G.M.B.), and CA13539 (Children’s Cancer Group) from the National Institutes of Health, by Career Development Awards from the American Society of Clinical Oncology (J.M.M.) and the American Cancer Society (J.M.M.), and by the Audrey E. Evans Endowed Chair (G.M.B.).
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.5 or 
2 test. Disease progression was defined according to the International Neuroblastoma Response Criteria as the presence of any new lesion, including a previously negative marrow becoming positive for tumor, or an increase in any measurable lesion of greater than 25%.
