International integrated analysis to identify markers of poor survival in high-risk neuroblastoma
Solving Kids' Cancer
Vall d'Hebron Hospital Universitari
The outcome for patients with high-risk neuroblastoma is currently inadequate despite intensive multimodal therapy and despite continued treatment intensification (such as the addition of immunotherapy or tandem high-dose chemotherapy). To date, most patients with high-risk are treated in a broadly similar manner.  Many researchers have looked at biomarkers (biological characteristics) that could identify those patients with the poorest outcome right from the time of diagnosis, so that these patients could be offered novel therapies very early in their disease course. So far, despite hundreds of studies evaluating factors routinely used in the clinic (such as age or number of metastasis) or more advanced technologies including complex genomic analyses, none of these biomarkers has been validated nor is available for clinical-decision making.  The novelty of our approach is that we aim to integrate all (or as many as possible) biomarkers that have been described to date, pull together all the data, and analyse and compare all biomarkers head to head in the same dataset.  We will do this in three phases: First, we will look at all published literature about neuroblastoma biomarkers from 1995 onwards and conduct a thorough analysis (this is called a systematic review and meta-analysis) to select the best biomarkers reported to date. Second, we will gain access to patient databases for each of the biomarkers (at the moment, each biomarker has been evaluated in a separate study/dataset) and create an enlarged INRG database including as many datasets, variables and biomarkers as possible; to then conduct an analysis integrating all the data together, which is called multivariate analysis. Thirdly, in order to confirm which biomarker(s) found on the first two phases are definitely the best one(s), we will analyse the best performing biomarkers in a homogeneous cohort of patients treated within a contemporaneous clinical trial, i.e. repeating all biomarkers in the same patients (which has never been done), to confirm which one(s) perform better and is taken forward to make treatment decisions in real clinical practice.  With this ambitious approach, our proposal aims to identify patients with high-risk neuroblastoma with the poorest outcome at the time of diagnosis, with the final aim of giving these patients access to early therapies upfront, without waiting for them to relapse or become refractory to treatment.
4.1 Discovery and preclinical testing of markers and technologies