Risk-stratified treatment strategies have led to improvements in the outcome of children with neuroblastoma, and efforts to further refine risk classification using molecular signatures and global genomic patterns are ongoing.10,11
However, despite more than four decades of research investigating classifiers for neuroblastoma, little is known about the prognostic significance of race and ethnicity, factors that contribute to health disparities in many diseases including cancer.12
Here, we examined survival based on race and ethnicity in more than 3,500 patients with neuroblastoma. To our knowledge, this is the largest neuroblastoma cohort ever analyzed for outcome disparities, and the first to show that black, Asian, and Native American children have a significantly worse outcome than white children.
Interestingly, a significantly higher proportion of patients with high-risk disease was seen in the black and Native American populations compared with the white population. In contrast, the prevalence of high-risk disease among Hispanics and Asians did not differ significantly from whites. In concordance with the higher prevalence of high-risk disease, black and Native American children had significantly worse OS and EFS. Asian children were also found to have significantly poorer OS than white children, but no statistically significant difference in EFS was seen. No significant differences in OS or EFS were seen in the Hispanic children compared to white children. When the EFS data were analyzed controlling for risk group, the outcome disparities were abrogated. However, examination of the EFS of the subgroup of patients who remained event-free for 2 years or longer revealed that blacks had significantly more late-occurring events than white children. This was confirmed in a multivariable analysis restricted to high-risk patients who remained event-free 2 years or longer from diagnosis, where blacks had significantly worse EFS compared to white children. Taken together, these observations suggest that black children are more likely than white children to have chemotherapy-resistant residual disease that progresses or relapses 2 or more years from diagnosis.
Our results contrast those recently reported by Linabery and Ross using Surveillance, Epidemiology and End Results (SEER) data collected between 1975 to 1999.12
In the SEER cohort of 757 patients, no difference in survival of non-Hispanic white versus non-Hispanic black and Hispanic patients was observed. In the most recent SEER cohort, diagnosed between 1995 and 1999, the 5-year survival rate for non-Hispanic whites was 67.0% (95% CI, 60.7% to 73.2%) compared to 68.1% (95% CI, 53.5% to 82.8%) for non-Hispanic blacks and 69% (95% CI, 58.3% to 79.6%) for Hispanics. The children analyzed in our study were diagnosed between 2001 and 2009, and treatment strategies have been significantly modified in the past decade.13,14
The disparities in outcome observed in our cohort suggest that modern treatment strategies may be more effective in the non-Hispanic whites and Hispanic children than in the black cohort. Linabery and Ross12
did find that black children and adolescents with other cancers had worse outcome than whites. Using SEER data, others have reported that blacks, Native Americans, and Hispanic children with acute lymphocytic leukemia have worse survival than white and Asian children.15
Similarly, a COG acute lymphocytic leukemia study demonstrated worse survival among black and Hispanic children compared to white children, whereas outcome was better for Asian children.16
Studies of acute myelogenic leukemia outcomes have also shown that black patients have poorer outcomes than white counterparts.17,18
Multiple factors contribute to the racial and ethnic differences in survival observed in pediatric and adult cancers. Outcome disparities have been shown in some cases to reflect differences in access to health care.19
This may result in delayed detection of illness or differences in treatment adherence. In our cohort of children with neuroblastoma, a higher prevalence of high-risk disease was observed in the blacks compared to whites, and a number of studies have indicated that it is unusual for favorable biology tumors to progress to high-risk tumors over time. A watch and wait approach has been followed in a subset of infants detected by mass screening, and none of the patients with tumor growth necessitating surgical removal were found to have unfavorable tumor biology.20
Other studies have shown that MYCN
status and ploidy do not change over time.21–23
Taken together, these studies indicate that a delay in diagnosis is not likely to account for the higher percentage high-risk disease observed in the black cohort. Nonadherence is also a less common problem in neuroblastoma, since patients with high-risk disease receive almost all of their therapy in the hospital.
Genetic factors have also been shown to contribute to outcome disparities. Specific polymorphisms have been shown to play a critical role in the racial and ethnic diversity in drug effectiveness and/or toxicity.24–26
In addition, genomewide association studies conducted in white children with neuroblastoma have shown that variability of genes located at common 6p22 single nucleotide polymorphism alleles and less-common single nucleotide polymorphisms at 2p35 within BARD1
contribute to the etiology of clinically aggressive disease.27,28
Studies are planned to determine if these or other at-risk alleles are contributing to the higher prevalence of high-risk disease and poor outcome we observed in our cohort of black children with neuroblastoma.
Despite the large size of this modern cohort of neuroblastoma patients, there are some notable limitations to this study. It is possible that patients for whom complete biologic information was not available may have introduced bias if the reasons for not having these assays performed were associated with prognosis and race/ethnicity. However, a good-faith effort to submit tumor tissue for MYCN
analysis was a requirement for enrollment on ANLB00B1. Although we excluded 261 patients with unknown race/ethnicity in our analysis, these patients were found to have a similar distribution of risk to that of the entire cohort. Thus, elimination of this cohort most likely did not impact our study results. In addition, patients missing from the ANBL00B1 cohort we analyzed may have introduced bias. For example, our study cohort did not capture rare infants with stage 4S disease who were too sick to biopsy and small numbers of infants with localized neuroblastomas in which a watch and wait strategy was taken because they were not eligible for enrollment on ANBL00B1. Furthermore, children diagnosed at institutions that do not participate in COG neuroblastoma studies were not enrolled. Nevertheless, since the inception of ANBL00B1, approximately 75% (average yearly enrollment; n = 486) of the 650 children diagnosed in the United States with neuroblastoma each year29
were enrolled. The significantly older age at diagnosis of the black children in our cohort is consistent with SEER data that show that white infants have a higher incidence of neuroblastoma than black infants, whereas little difference by race was observed among older children.30
We also found that the proportion of blacks and Hispanics in our cohort is consistent with 2000 US census data,31
further indicating that our cohort is representative.
We did not have access to patient treatment data, and as such could not control for the different chemotherapeutic agents and doses patients received. It is also important to note that race/ethnicity is not a mutually exclusive variable, and some patients may have mixed racial and ethnic ancestry. Reflecting the general population in North America, the vast majority of patients in our cohort were white, with significantly fewer numbers of black and Hispanic patients, and very small numbers of Native American and Asian patients. Because of the small numbers of Native American and Asian patients in the cohort, the survival results for these populations must be interpreted with caution.
In conclusion, we show for the first time that blacks and Native American neuroblastoma patients are statistically significantly more likely to present with high-risk disease than whites, and that, overall, this likely accounts for the inferior EFS observed in these populations. However, we report a higher prevalence of late-occurring events among blacks compared to white patients after controlling for clinical and biologic features of disease, suggesting that blacks may be more resistant to chemotherapy. Future research must focus on understanding the reasons for these disparities, including racial and ethnic differences in drug metabolism and bioavailability of commonly used agents, and genetic differences that may contribute to the etiology of clinically aggressive disease. A better understanding of the genetic basis of the outcome disparities observed in children with neuroblastoma will further refine risk classification, and may also direct us to more effective, individualized treatment strategies.