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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 913-918 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.9493 Clinical Significance of MYCN Amplification and Ploidy in Favorable-Stage Neuroblastoma: A Report From the Children's Oncology Group
From the Children's Memorial Hospital and the Department of Pediatrics, Northwestern University, Feinberg School of Medicine; Department of Pediatrics, The University of Chicago and Comer Children's Hospital, Chicago, IL; University of Florida, Children's Oncology Group Statistics and Data Center, Gainesville, FL; The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL; and Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, MA Corresponding author: Susan L. Cohn, MD, Section of Pediatric Hematology/Oncology, University of Chicago, 5841 Maryland Ave, MC 4060, Rm N114, Chicago, IL 60637; e-mail: scohn{at}peds.bsd.uchicago.edu
Purpose MYCN amplification is rarely detected in patients with favorable-stage neuroblastoma (NB). To determine the clinical significance of MYCN amplification in children with favorable-stage NB, we performed a retrospective review of data from the Pediatric Oncology Group (POG) biology study 9047. Patients and Methods MYCN status, tumor cell ploidy, treatment, and outcome of patients with stage A, B, or Ds NB, enrolled on POG 9047 between 1990 and 1999 were analyzed. Event-free survival (EFS) and overall (OS) survival rates were analyzed using the Kaplan-Meier method. Results Of the 1,667 patients enrolled on POG 9047, 643 had favorable-stage disease. Of these, follow-up data were available on 568 (34%) with stage A, B, or Ds disease and normal MYCN copy number, and 32 (1.9%) patients with MYCN-amplified, stage A, B, or Ds tumors. Within the cohort lacking MYCN amplification, the 7-year EFS and OS rates (± SE) were 91% ± 1% and 96% ± 1%, respectively. Patients with MYCN amplification had significantly worse EFS and OS (50% ± 9% and 59% ± 9%, respectively, P < .0001). Within the cohort of children with MYCN amplification, the 7-year EFS and OS rates were 80% ± 10% and 87% ± 9%, respectively for patients with hyperdiploid tumors and 25% ± 11% and 38% ± 12% for patients with diploid/hypodiploid NBs (P = .0063 and P = .0074, respectively). Conclusion Tumor cell ploidy may be a clinically useful factor for prognostication and treatment stratification in children with MYCN-amplified, favorable-stage NB tumors.
Neuroblastoma (NB) is remarkable for its clinical heterogeneity, with the likelihood of tumor progression varying widely according to age at diagnosis, extent of disease, and tumor biology.1,2 A subset of tumors will undergo spontaneous regression while others show relentless progression. Modern treatment strategies are risk based and are stratified according to clinical and biologic classifiers. Using this approach, substantial progress has been made in the treatment of children with low- and intermediate-risk NB. However, cure rates remain at less than 40% for patients classified as high risk. MYCN amplification, which occurs in approximately 22% of primary NBs, is one of the most powerful prognostic factors identified to date.3,4 It is significantly associated with advanced-stage disease, rapid tumor progression, and poor prognosis. Amplification of this oncogene is also strongly associated with other unfavorable prognostic factors, including unfavorable histology, 1p deletion, and diploidy. However, rare cases of MYCN amplification in favorable-stage disease have been reported. Although the majority of studies have demonstrated significantly worse outcome for patients with localized or stage 4s tumors with MYCN amplification compared with those lacking amplification,3,5,6 some patients have been successfully treated with surgery alone, and spontaneous regression has been reported in a subset of infants with MYCN-amplified stage 4s disease.7-9 Thus, the clinical significance and optimal treatment for children with MYCN-amplified, favorable-stage NB remains unclear. Additional markers are clearly needed to distinguish those children with favorable-stage tumors with MYCN amplification who will be successfully treated with minimal therapy or observation alone from those who will require more intensive treatment approaches. To determine whether tumor cell ploidy and/or histology have prognostic value in this rare cohort of patients, we performed a retrospective analysis of patients with MYCN-amplified localized tumors (Pediatric Oncology Group [POG] stages A and B) and infants with stage Ds (analogous to International Neuroblastoma Staging System [INSS] 4s) enrolled on the POG biology study 9047 between 1990 and 1999. We found that children with MYCN-amplified, hyperdiploid, favorable-stage tumors had significantly better survival than those with diploid tumors. Our results suggest that tumor cell ploidy is a strong prognostic factor in this rare cohort of patients, and it may prove to be an important criterion to consider for treatment stratification.
Patient Characteristics A retrospective review of all patients with localized NB (POG stage A or B) or stage Ds disease (analogous to INSS 4s) enrolled in POG 9047 from 1990 to 1999 was performed. The eligibility requirements of this biology study were diagnosis of neuroblastoma confirmed by central pathology review, age  21 years, and written informed consent. The POG 9047 study was approved by the institutional review boards of all participating centers. Data for age, stage, and outcome were collected on all enrolled patients, and submission of tumor tissue to the reference laboratory for biologic studies was strongly encouraged. POG staging was defined as follows: A –complete gross resection of the primary tumor, nonadherent nodes must be free of tumor, and liver must be free of tumor; B –incomplete gross resection of primary tumor, nodes and liver must be free of tumor; C –complete or incomplete gross resection of primary tumor, nonadherent nodes positive for tumor, liver without tumor; D –any disseminated disease beyond lymph nodes except as described in Ds; Ds –infants under 1 year of age with a localized primary tumor with additional disease confined to the liver, skin, or bone marrow (bone scan negative).10 A questionnaire was sent to those participating institutions to clarify clinical presentation, chemotherapy, radiation therapy, and follow-up for patients with favorable-stage disease and MYCN amplification when necessary.
MYCN, Ploidy and Tumor Histology
Statistical Analysis
Clinical and Biologic Characteristics Table 1 lists the characteristics of the patients with favorable-stage NB and MYCN amplification. Of the 1,667 patients enrolled on POG 9047, 643 had favorable-stage tumors. Within this cohort, 600 patients had available follow-up data. MYCN amplification was detected in tumors from 32 (5%) of these patients; 568 patients had tumors that were not amplified; and 43 had unknown MYCN status. Twelve patients with MYCN amplification had stage A disease, 12 had stage B, and eight presented with stage Ds disease. Within the cohort of patients with MYCN amplification, age ranged from 0.25 to 77 months (mean, 16 months; median, 10 months) at the time of diagnosis. Fifteen patients had hyperdiploid tumors, 16 had diploid, and in one child, ploidy was unknown. Tumor histology was available in only a subset of the patients. Six children had tumors that were classified as favorable histology; eight had unfavorable histology; and in 18 cases, tumors histology was unknown. Median follow-up time among the 15 who did not have an event was 9.8 years, with a minimum of 8.1 years and a maximum of 14.2 years.
Initial Therapy Initial therapy included surgery alone, followed by observation for all stage A patients (n = 12). Stage B patients received various regimens of conventional-dose chemotherapy (n = 12). Five received chemotherapy according to the regimen in the POG 8743 which consisted of cyclophosphamide plus doxorubicin or cisplatin plus teniposide after an initial course of cyclophosphamide and doxorubicin, depending on ploidy at the time of diagnosis.14 Two were treated with chemotherapy according to the POG 9243 protocol that compared oral cyclophosphamide plus doxorubicin (arm A) to carboplatin and etoposide alternating with etoposide and ifosfamide (arm B) depending on the tumor's MYCN status and ploidy.15 Four patients received carboplatin, etoposide, and ifosfamide, and the initial therapy is unknown for one patient. Three of the 12 stage B patients subsequently underwent myeloablative therapy with autologous stem-cell rescue (auto-SCT) while in first best response. One of the eight children with MYCN-amplified stage Ds tumors was initially observed, and the remaining seven initially received conventional-dose chemotherapy. Four were treated according to the POG 9243 regimen.15 Three patients were treated with cyclophosphamide, adriamycin, and etoposide, or with ifosfamide, carboplatin, and etoposide. One of the seven infants with stage Ds NB underwent high-dose chemotherapy plus auto-SCT after the initial chemotherapy regimen (Table 2).
Salvage Therapy Salvage therapy varied significantly by treating institution. Eight stage A patients had an event: seven had progressive disease, and one had death as a first event. Four of the seven stage A patients with progressive disease were treated with chemotherapy, whereas salvage therapy for the other three patients included chemotherapy plus myeloablative therapy followed by auto-SCT. Three of the seven stage A patients remain alive and disease-free; two after treatment with chemotherapy, and one after chemotherapy plus myeloablative therapy and stem-cell rescue. Five stage B patients had an event: four had relapse, and one had death as a first event. Of the four stage B children who relapsed, two were treated with chemotherapy, one underwent chemotherapy plus myeloablative therapy with autologous stem-cell rescue, and one received "alternative" therapy. Three of these four patients died of progressive disease. Four stage Ds patients had an event: two had relapses, and two had death as a first event. Of those who relapsed, one patient was treated with myeloablative therapy and auto-SCT when he was first diagnosed, and did not receive further therapy at the time of relapse, while the other child received chemotherapy. Both died of disease.
Patient Outcome According to MYCN Status and Ploidy
Interestingly, tumor cell ploidy was associated with significant differences in outcome in this cohort of patients with MYCN amplification. Patients with hyperdiploid tumors (n = 15) had 7-year (mean ± SE) EFS and OS rates of 80% ± 10% and 87% ± 9%, respectively, whereas patients with diploid tumors (n = 16) had EFS and OS of 25% ± 11% and 38% ± 12% (EFS: P = .0063, OS: P = .0074; Figs 2A and 2B). Tumor histology was known in only 14 of the 32 children with MYCN-amplified, favorable-stage tumors. Five of six patients with favorable histology remain alive, and three of eight with unfavorable histology have survived. No differences in outcome for children younger versus older than 12 months of age were seen (EFS: 53% ± 12% v 47% ± 13%, P = .8580 and OS: 58.8% ± 12% v 60% ± 13%, respectively P = .9180).
Stage is a well established prognostic factor for NB, and more than 95% of patients with localized disease can be cured with surgery with or without adjuvant chemotherapy.6,16,17 Similarly, patients with stage 4s disease have excellent outcome with an overall survival probability of 85% to 92%.18-20 Although most favorable-stage tumors lack unfavorable biologic markers, small numbers of localized and stage 4s NB tumors have MYCN amplification. Because of the rare incidence of these tumors, the clinical significance and optimal treatment for these children remain unclear. In this study, we analyzed the largest cohort of children with favorable-stage NB and MYCN amplification ever reported. Of the 1,667 patients enrolled on the POG biology study 9047, MYCN amplification was detected in tumor samples from 32 patients. As expected, outcome was significantly worse for the patients with MYCN amplified stage A, B, or Ds tumors compared with those with tumors with normal MYCN copy numbers. No difference in survival was seen in the 32 children with MYCN-amplified tumors who were less than 12 v  12 months. Interestingly, we did find that tumor cell ploidy was strongly associated with outcome. Patients with hyperdiploid tumors had significantly better EFS and OS rates compared to those with diploid tumors, demonstrating that clinical and biologic heterogeneity exists even within this rare subset of NB tumors. Thus, ploidy may be a useful factor to consider when decisions regarding treatment strategies are made in this rare cohort of patients. Histology was not routinely evaluated on POG 9047 and was available in only a subset of these tumors. We were, therefore, not able to evaluate the prognostic impact of tumor histology. Other genetic features such as 1p or 11q deletion, which are known to be of prognostic value in NB, were not analyzed in this cohort of tumors. Seeger et al3 first reported the association of MYCN amplification with rapid progression of NB more than 20 years ago. In that series of 89 patients, tumors from two of 24 children with localized disease were MYCN-amplified, and both children developed progressive disease. None of the five stage 4s tumors were MYCN-amplified. Subsequently, larger series have been reported which have confirmed that the incidence of MYCN amplification is rare in localized NB tumors and stage 4s disease. Alvarado et al16 reported that 11 of 329 patients with stage A NB had MYCN-amplified tumors. In that study, 5-year EFS and OS rates for this cohort were (mean ± SE) 36% ± 29% and 64% ± 27, respectively. Similarly, MYCN amplification was detected in tumors from seven of 374 children with stages I and II disease in a Children's Cancer Group study, with 4-year OS of 50% ± 35.17 Tonini et al9 reported the Italian experience and showed that MYCN amplification was associated with a worse prognosis in all stages of disease, except in infants with stage 4s. In the Italian series, three children with MYCN-amplified, stage 4s NB were long-term survivors. Six patients in the Tonini study had stage 1 or 2 disease and MYCN amplification, and 5-year OS was 53%. Taken together, these studies along with our results confirm the clinical heterogeneity of favorable-stage NB tumors with MYCN amplification. The challenge for treating physicians is to distinguish those patients for whom minimal treatment will be curative from those who are destined to fail with this approach. DNA index is another strong prognostic marker for children with NB, particularly for those younger than 2 years who have disseminated disease.12,21 The DNA content of NBs fall into two broad categories: diploid or hyperdiploid (often near triploid). Significantly improved long-term outcome is seen in children with hyperdiploid tumors compared to those with diploid NBs.12,22 Other investigators have found that in locoregional disease, diploidy is associated with an increased risk of local and distant relapse.23 Although MYCN amplification is strongly associated with diploid DNA content, diploidy remains a prognostically significant factor in MYCN-nonamplified, stage 4 tumors in children younger than 24 months.21 Favorable biologic and clinical features are only rarely seen in MYCN-amplified tumors. In our cohort of children with favorable stage and MYCN amplification, approximately 60% achieved long-term survival. Although survival was significantly worse for these children than for those with MYCN-nonamplified, favorable-stage tumors, outcome was better than that reported for children with advanced-stage disease and MYCN amplification.24 Furthermore, a subset of the survivors were successfully treated with minimal therapy, indicating that the biology of some MYCN-amplified, favorable-stage tumors differs from that of advanced stage tumors with MYCN amplification. In the COG, patients with INSS stage 1 tumors with MYCN amplification are currently classified as low risk, whereas those with MYCN-amplified stage 2 and 4s tumors are classified as high risk. Our data suggest that it may be possible to utilize ploidy to refine risk-group classification in this rare cohort of patients. If our findings are confirmed in a prospective study, it may be possible to reduce therapy for patients with hyperdiploid, stage 2 and 4s MYCN-amplified tumors without compromising survival. Conversely, more intensive treatment strategies may be needed to improve the outcome of patients with diploid, MYCN-amplified stage 1 tumors. As we learn more about the biology of NB tumors, additional markers are likely to be identified that will further distinguish children with MYCN-amplified, favorable-stage tumors who will be successfully treated with minimal therapy or observation alone from those who will require more intensive treatment approaches. Tumor histology is currently being evaluated in the COG NB biology study ANBL00B1, and future analyses of these data will determine if histology will provide additional prognostic information. The results of ongoing genetic studies and profiling studies using microarrays should further enhance our ability to accurately classify patient risk in the face of conflicting biologic information. A further refinement in risk stratification will ensure that treatment strategies are optimized, particularly for children with diploid, favorable-stage NB tumors and MYCN amplification.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jennifer Schneiderman, Susan L. Cohn Provision of study materials or patients: Robert P. Castleberry Collection and assembly of data: Jennifer Schneiderman, Wendy B. London, A. Thomas Look Data analysis and interpretation: Jennifer Schneiderman, Wendy B. London, Susan L. Cohn Manuscript writing: Jennifer Schneiderman, Wendy B. London, Robert P. Castleberry, Susan L. Cohn Final approval of manuscript: Wendy B. London, Garrett M. Brodeur, Robert P. Castleberry, A. Thomas Look, Susan L. Cohn
Supported by the Children's Oncology Group Statistics and Data Center Grants No. U10CA29139, CA25408, CA 98543, and CA 30969; the Neuroblastoma Children's Cancer Society; Friends for Steven Pediatric Cancer Research Fund; the Elise Anderson Neuroblastoma Research Fund, Neuroblastoma Kids; and National Institutes of Health Grants No. R01 NS049814 and R01 CA039771. Presented in part at the Advances in Neuroblastoma (ANR) Meeting in Los Angeles, CA, May 17-20, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
