Research explainer: How do ALK gene alterations affect the clinical outcome for patients with high-risk neuroblastoma?

Study Summary 

Recently researchers from a range of institutions across Europe published a paper looking at the frequency and impact of ALK gene amplifications and mutations in the group of patients enrolled in the SIOPEN High-Risk Neuroblastoma Trial (HRNLB1). Here in the UK the work was led by Professor Deb Tweddle at the Newcastle University Centre for Cancer. Tumour samples from 1092 patients were analysed to look for the presence of alterations to the ALK gene, including amplification and mutation. The occurrence of these genetic features were as below: 

  • ALK gene amplification was found in 4.5% of patients 
  • ALK gene mutation at a clonal level was seen in 10% of patients 
  • ALK gene mutation at a subclonal level in 3.9% of patients 

Mutations are described as either clonal or subclonal, depending on what proportion of the cells display genetic changes. 

The survival of these groups of patients was then tracked and the data was analysed to look for any link between these genetic alterations and prognosis for children with high-risk neuroblastoma. The team of researchers found that ALK amplification and ALK clonal mutations were both associated with a poorer outcome for children with high-risk neuroblastoma. The overall survival for those with amplification was found to be 26% and for those with clonal mutation, 33%, compared to 51% for patients with neither ALK amplification or mutation.

Though this research establishes for the first time a definitive link between patients having ALK amplifications or mutations and a worse overall outcome, we must always remember that when it comes to each child they are an individual and such statistics are not important.

What is the significance of these findings? 

With neuroblastoma being such a heterogeneous disease- meaning it can vary greatly between case to case, finding out which patients have the poorest prognosis and the factors that cause this is incredibly important. Not only does this help to unravel the complications of treating the disease, but it also has a vital role in steering clinical research so that it targets the areas that are most urgent, for the children who are collectively most in need of better and more effective therapy options. 

The results of this particular study are a perfect example of this, as they have confirmed the clinical significance of ALK gene alterations, which is a strong argument to progress research into treatments which target the ALK gene. Inhibitors to target ALK gene abnormalities have been developed to help treat a range of adult cancers, but they have mostly been ineffective against neuroblastoma due to the uniqueness of the disease. Recently however a drug called lorlatinib, which is a third-generation ALK inhibitor, has been produced and is showing early promise in children with relapsed or refractory high-risk neuroblastoma. This means that there is now a potentially more effective drug to target ALK alterations as well as a strong scientific backing that this type of treatment could make a real difference in the survival of children with high-risk neuroblastoma which shows these genetic features. Potentially this could lead to a breakthrough in the process of bringing better, more effective, and targeted treatments into frontline therapy for these children. 

How does this affect patients right now? 

As with any research, whilst it is important to gain more knowledge and understanding of the disease, what matters most is that this is translated to make real impact for children facing neuroblastoma now. Although this publication was released very recently, the research itself took place alongside the SIOPEN High-Risk Neuroblastoma Trial which began in 2002, meaning that there have already been a number of advances in this area since the work was started- such as the development of lorlatinib for use in childhood cancers. 

One of the biggest potential advancements for children is the rapid initiation by researchers of the TITAN study, which was driven and partially funded by Solving Kid’s Cancer. This is an amendment to current Phase III trials which will see the ALK inhibitor lorlatinib introduced into frontline treatment for children with newly diagnosed high-risk neuroblastoma where their disease shows ALK alterations. Not only is this exactly in line with the recommendation of the recent publication, it also represents the first time that the SIOPEN research network in Europe and the Children’s Oncology Group in North America have worked together to design and implement a clinical trial. 

This links to the other achievement of this research which will benefit patients for years to come- and that is the international collaboration that has been integral to producing such substantial findings about a disease which is statistically so rare. This applies not only to the research institutions, but the multiple charities that have come together to sustain this work. We know that this interconnected approach to research is our best chance to making the discoveries necessary to beat neuroblastoma and solidifying this through these types of studies will bring the best outcomes for children fighting this disease. 


Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)Angela Bellini, Ulrike Pötschger, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F. Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R. Betts, Jaydutt Bhalshankar, Nick Bown, Katleen de Preter, Nathalie Clément, Valérie Combaret, Jaime Font de Mora, Sally L. George, Irene Jiménez, Marta Jeison, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Martina Morini, Annick Mühlethaler-Mottet, Rosa Noguera, Gaelle Pierron, Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner, Geneviève Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck, Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A. Tweddle, Ruth Ladenstein, and Gudrun Schleiermacher, 10.1200/JCO.21.00086 Journal of Clinical Oncology (2021).