Combined analysis of PHOX2B at two time points and its value for further risk stratification in high-risk neuroblastoma.

Abstract

Risk stratification of high-risk neuroblastoma (NB) is crucial for exploring treatments. This study aimed to explore the value of minimal residual disease (MRD) based on PHOX2B levels for further risk stratification in high-risk NB. The expression of PHOX2B was monitored at two time points (after two and six cycles of induction chemotherapy, TP1 and TP2, respectively) by real-time polymerase chain reaction (RT-PCR). The clinical characteristics between groups and survival rates were analyzed. The study included 151 high-risk patients. Positive expression of PHOX2B at diagnosis was seen in 129 cases. PHOX2B was mainly expressed in patients with high lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) levels (p<.001), bone marrow metastasis (p<.001), more than three metastatic organs (p<.001), 11q23 loss of heterozygosity (LOH) (p=.007), and when more events occurred (p=.012). The 4-year EFS rate was significantly lower in patients with positive PHOX2B expression compared to thenegative group at diagnosis (32.9%±6.2% vs. 74.5%±10.1%, p=.005). We stratified the 151 patients into three MRD risk groups: low high-risk (low-HR), with TP1 less than 10-4 and TP2 less than 10-4 ; ultra-HR, with TP1 greater than or equal to 10-2 or TP2 greater than or equal to 10-4 , and others classified as intermediate-HR. Patients in ultra-HR had the worst survival rate compared with other two groups (p=.02). In a multivariate model, MRD risk stratification based on PHOX2B levels at TP1 and TP2 was an independent prognostic factor for high-risk patients (p=.001). Patients in ultra-HR were associated with 11q23 LOH (p<.001), more than three organs of metastasis (p=.005), bone marrow metastasis (p<.001), and occurrenceofmore events (p=.009). MRD risk stratification based on PHOX2B levels at two time points (after two and six cycles of induction chemotherapy) provideda stratification system for high-risk NB, which successfully predicted treatment outcomes. Our results present an effective method for further stratification of high-risk NB.