Navin Pinto

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

Racial and Ethnic Disparities in Risk and Survival in Children With Neuroblastoma: A Children's Oncology Group Study

PURPOSE Although health disparities are well-described for many cancers, little is known about racial and ethnic disparities in neuroblastoma. To evaluate differences in disease presentation and survival by race and ethnicity, data from the Childrens Oncology Group (COG) were analyzed. PATIENTS AND METHODS The racial/ethnic differences in clinical and biologic risk factors, and outcome of patients with neuroblastoma enrolled on COG ANBL00B1 between 2001 and 2009 were investigated. RESULTS A total of 3,539 patients (white, 72%; black, 12%; Hispanic, 12%; Asian, 4%; and Native American, < 1%) with neuroblastoma were included. The 5-year event-free survival (EFS) rates were 67% for whites (95% CI, 65% to 69%), 69% for Hispanics (95% CI, 63% to 74%), 62% for Asians (95% CI, 51% to 71%), 56% for blacks (95% CI, 50% to 62%), and 37% for Native American (95% CI, 17% to 58%). Blacks (P < .001) and Native Americans (P = .04) had a higher prevalence of high-risk disease than whites, and significantly worse EFS (P = .01 and P = .002, respectively). Adjustment for risk group abrogated these differences. However, closer examination of the EFS among high-risk patients who remained event free for 2 years or longer, revealed a higher prevalence of late-occurring events among blacks compared with whites (hazard ratio, 1.5; 95% CI, 1.0 to 2.3; P = .04). CONCLUSION Black and Native American patients with neuroblastoma have a higher prevalence of high-risk disease, accounting for their worse EFS when compared with whites. The higher prevalence of late-occurring events among blacks with high-risk disease suggests that this population may be more resistant to chemotherapy. Studies focused on delineating the genetic basis for the racial disparities observed in this study are planned.

Drug Focus: Pharmacogenetic studies related to cyclophosphamide-based therapy

Cyclophosphamide is a cornerstone in the treatment of many pediatric and adult malignancies, as well as in the treatment of refractory autoimmune conditions. Genetic factors are thought to play a role in the interindividual variation in both response and toxicities associated with cyclophosphamide-based therapies. This drug focus reviews the most compelling studies conducted on the pharmacogenetics of cyclophosphamide-based therapies. Broader pharmacogenomic studies are needed and may reveal additional factors important in susceptibility to toxicity and/or response to therapy.

Clinically relevant genetic variations in drug metabolizing enzymes.

In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patients genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.

Second malignancies in patients with neuroblastoma: the effects of risk-based therapy.

To investigate the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma, we analyzed patients from the SEER database according to three treatment eras (Era 1: 1973–1989, Era 2: 1990–1996, and Era 3: 1997–2006) corresponding to the introduction of multi‐agent chemotherapy, risk‐based treatment, and stem cell transplant.

Trans-population Analysis of Genetic Mechanisms of Ethnic Disparities in Neuroblastoma Survival

BACKGROUND Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma. METHODS The analytic cohort was composed of 2709 patients. Principal components were used to assign patients to genomic ethnic clusters for survival analyses. Locus-specific ancestry was calculated for use in association analysis. The shorter spans of linkage disequilibrium in African populations may facilitate the fine mapping of causal variants in regions previously implicated by genome-wide association studies conducted primarily in patients of European descent. Thus, we evaluated 13 single nucleotide polymorphisms known to be associated with susceptibility to high-risk neuroblastoma from genome-wide association studies and all variants with highly divergent allele frequencies in reference African and European populations near the known susceptibility loci. All statistical tests were two-sided. RESULTS African genomic ancestry was associated with high-risk neuroblastoma (P = .007) and lower event-free survival (P = .04, hazard ratio = 1.4, 95% confidence interval = 1.05 to 1.80). rs1033069 within SPAG16 (sperm associated antigen 16) was determined to have higher risk allele frequency in the African reference population and statistically significant association with high-risk disease in patients of European and African ancestry (P = 6.42 × 10(-5), false discovery rate < 0.0015) in the overall cohort. Multivariable analysis using an additive model demonstrated that the SPAG16 single nucleotide polymorphism contributes to the observed ethnic disparities in high-risk disease and survival. CONCLUSIONS Our study demonstrates that common genetic variation influences neuroblastoma phenotype and contributes to the ethnic disparities in survival observed and illustrates the value of trans-population mapping.

Using Germline Genomics to Individualize Pediatric Cancer Treatments

The amazing successes in cure rates for children with cancer over the last century have come in large part from identifying clinical, genetic, and molecular variables associated with response to therapy in large cooperative clinical trials and stratifying therapies according to the predicted risk of relapse. There is an expanding interest in identifying germline genomic variants, as opposed to genetic variants within the tumor, that are associated with susceptibility to toxicity and for risk of relapse. This review highlights the most important germline pharmacogenetic and pharmacogenomic studies in pediatric oncology. Incorporating germline genomics into risk-adapted therapies will likely lead to safer and more effective treatments for children with cancer. Clin Cancer Res; 18(10); 2791–800. ©2012 AACR.

Patterns of PD‐1, PD‐L1, and PD‐L2 expression in pediatric solid tumors

Significant antitumor effects have been observed in a variety of malignancies via blockade of immune checkpoints. Interaction of programmed death 1 (PD‐1) with its ligands PD‐L1 and PD‐L2 suppresses T‐cell function and restricts immune‐mediated tumor killing. We examined expression of these proteins in children with solid tumors, as expression may serve as biomarkers of response to this class of drugs.

Treatment of two cases with refractory, metastatic intermediate-risk neuroblastoma with isotretenoin alone or observation

Patients <12 months with favorable biology, metastatic neuroblastoma have >90% overall survival following treatment with chemotherapy and surgery. We report two infants with favorable biology, stage 4 neuroblastoma with refractory disease after standard intermediate‐risk chemotherapy and additional retrieval chemotherapy. One patient was treated with six additional cycles of isotretinoin and the other observed. Both remain clinically well with persistent disease but no evidence of tumor progression for 28 and 13 months following completion of cytotoxic treatment. Similar to residual tumor in primary sites, refractory metastatic disease may not portend a poor outcome in patients with favorable biology, intermediate‐risk neuroblastoma. Pediatr Blood Cancer 2014;61:1104–1106.

Second Malignant Neoplasms in Rhabdomyosarcoma: Victims of Our Own Success or an Underlying Genetic Predisposition Syndrome?

M children survive a diagnosis of cancer, and as a result, there is an increasing prevalence of late effects associated with exposure to chemotherapy and radiotherapy. The second leading cause of death among 5-year survivors of childhood cancer is the development of second malignant neoplasms (SMNs).[1] Nearly 20% of deaths 5 years after the treatment of childhood cancer are attributable to an SMN, and 20 years after the treatment, SMNs become the leading cause of death.[2] In this issue of Pediatric Blood and Cancer, we have two articles focused on SMNs in survivors of rhabdomyosarcoma (RMS). RMS is the most common pediatric soft tissue tumor with an incidence of 4.5 cases per 1 million children and 50% of cases occurring in the first decade of life.[3] Most cases of RMS are sporadic, but they can be associated with several cancer risk syndromes. First-degree relatives of children with RMS have a 1.4-fold increase in developing cancer, and individuals diagnosed with cancer before the age of 30 are 2.4 times more likely to have a first-degree relative with RMS.[4] Li and Fraumeni original description of a familial cancer syndrome with high risk of developing breast, soft tissue, hematologic, and adrenal malignancies (now named Li–Fraumeni syndrome, mostly attributable to germline TP53 mutations) came from a review of 648 children with RMS.[5] Increased risks of developing RMS are also seen in children with the pleuropulmonary blastoma (from germline DICER1 mutations) [6] and Beckwith–Weidemann syndrome.[7] Germline aberrations in the RAS pathway seen in neurofibromatosis type 1 (NF1 mutations), Costello syndrome (HRAS mutations), and Noonan syndrome (PTPN11 mutations) are also associated with the development of RMS, not surprising since the RAS pathway is frequently perturbed in RMS without FOXO1 fusions.[8] In addition to genetic factors that influence cancer risk, patients with RMS have an increased risk of developing SMN after the treatment with radiotherapy and chemotherapy, both of which significantly influence development of SMN.[2] Patients with soft tissue sarcomas represent 20% of patients with SMNs,[2] and this disproportionate representation is likely due to the interaction between underlying genetic cancer susceptibility and DNA-damaging chemotherapy and radiotherapy used to treat the majority of patients with these malignancies. Bradee et al. describe a case of a 12-year-old child with stage IV embryonal RMS treated with intensive multiagent chemotherapy, surgery, and pelvic radiotherapy who developed an isolated, minimally invasive lung adenocarcinoma 4.25 years after the end of therapy.[9] Interestingly, this SMN developed outside of the patient’s radiation field and with a relatively short latency from diagnosis, suggesting that an underlying genetic cancer predisposition may be contributing. The occurrence of minimally invasive adenocarcinoma of the lung in a young patient with metastatic RMS has only been previously described once in the literature.[10] In contrast to the case presented by Bradee et al., the adenocarcinoma in this patient was likely present at diagnosis of pulmonary metastatic RMS, as two nodules that failed to resolvewithRMS-directed therapywere found to both be minimally invasive adenocarcinoma. Both cases were successfully treated with wide surgical excision, which appears to be adequate therapy. Archer et al. used the Surveillance, Epidemiology and End Results (SEER) database to determine the risk of SMNdevelopment among 1,151 children aged 0–19 with RMS and found that children with embyronal and pleomorphic variants had a 5.6fold and 15.8-fold increase in developing SMNs, respectively.[11] In a subset analysis, the risk of SMN development was greatest in children with pleomorphic RMS exposed to radiation with a 300-fold increase and a 15-fold increase in children under the age of 2 with embryonal RMS. Interestingly, the authors did not find that patients with alveolar RMS were not at increased risk of developing SMN. Exposure to radiation therapy also did not appear to influence the development of SMN in the overall cohort. The SEER database is limited in terms of granular data regarding treatment exposures, so the role of cumulative chemotherapy exposure on SMN development is unable to be ascertained from this analysis. It is also unclear what the authors used as their control cohort in this analysis, one must assume that the “general population” referred to in Archer et al.’s analysis is aged-matched children diagnosed with malignancies other than RMS. Taken together, these articles should underscore a need for heightened awareness of subsequent neoplasms in patients with RMS. Children with RMS should have careful family histories to determine if other family members have been affected by cancer. Families with strong cancer histories and patients with the pleomorphic and anaplastic variants (in a recent analysis, 11 of