New high-resolution DNA technology opens the door to treatment of aggressive childhood cancer

Neuroblastoma affects young children, and arises in the autonomous nervous system. The treatment of the disease is adapted according to the genetic nature of the cancer cells, which is analysed when the disease is diagnosed. If the child experiences relapse into cancer after treatment, the prognosis is often very poor. The scientists explain in the new study how relapse arises, and this opens new opportunities for tailored treatment in certain cases.

“One of the greatest challenges is to identify young patients at a high risk of relapse, and then to equip such patients with adapted treatment,” says Tommy Martinsson, professor at the Sahlgrenska Academy at the University of Gothenburg, and expert in the genetic background of neuroblastoma.

Half of patients relapse

Approximately half of the children with the severe neuroblastoma known as “high-risk neuroblastoma” experience relapse, even though they appear initially to have been cured by the treatment. The reason is that a few individual tumor cells remain in the body despite the intense treatment, mainly in the bloodstream and bone marrow. A small number of the tumor cells develop new genetic mutations that enable them to survive better, or that make then resistant to treatment. This leads to relapse into disease. There are too few cells present to be detected by clinical tests, but as time passes these cells grow and lead to relapse.

Previous research has shown that mutations in a gene known as the “ALK” gene, which controls the rate at which cancer cells divide, affects the risk for relapsing into neuroblastoma. The scientists have now managed to identify specific genetic changes that affect the risk of relapse, with the aid of a significantly improved method based on extremely sensitive DNA sequencing technology.

Opens for new treatment

“We have analysed mutations in the ALK gene in 54 tumors. Specimens have been taken at the time of diagnosis and when relapse occurred. The frequency of ALK mutations was significantly higher in tumors from patients who relapse, and this suggests that the mutations contribute to tumor development and relapse,” says Tommy Martinsson.

These discoveries may lead to new treatments for children who are affected, since pharmaceutical companies have recently developed cancer drugs, known as “ALK inhibitors”, that target the mutated ALK gene.
Nine patients in the high-risk group that was followed had ALK mutations in the tumor when first analysed, and this number rose to 14 for tumors at relapse. There were very few cases with ALK mutation in patients who had had neuroblastoma and who had not relapsed.

Specimens at diagnosis and relapse

“The results show that we must change the way we take specimens and analyse them, and the way we treat children with neuroblastoma,” says Per Kogner, professor at Karolinska Institutet and pediatric oncologist at the Astrid Lindgren Children’s Hospital.

Per Kogner states that one conclusion is that the medical care system should take samples of tumors both when the diagnosis is made and when relapse occurs, in order to determine whether ALK mutations are present. The samples should be analysed using the high-resolution DNA sequencing technology, and the patients should be given the opportunity to participate in clinical studies and be given treatment with ALK inhibitors.

“The ALK treatment has already been tested in several Swedish children with neuroblastoma, and the initial results are promising,” says Per Kogner.

This brings new hope to families with a child affected by neuroblastoma, where previously available treatments have not always been able to prevent relapse.

The research is now to be published in the Journal of Clinical Oncology, and has been supported by the Swedish Cancer Society, The Swedish Childhood Cancer Foundation and BioCARE/Statens strategiska satsningar.

In Sweden, the study has been carried out by research groups under the leadership of Professor Tommy Martinsson, Sahlgrenska Academy at the University of Gothenburg, and Professor Per Kogner, Karolinska Institutet in Stockholm. In France, the study has been led by professor Gudrun Schleiermacher and professor Olivier Delattre, at the Institut Curie, Paris.

The ALK gene:
The ALK gene codes for a protein, tyrosine kinase, that is present at the cell surface as a receptor, and that acts as a switch for cell signals. When permanently set to “On” in tumor cells, it sends orders to the cells to divide, by interacting with other genes and gene products, one of which is known as “MYCN”. Several pharmaceutical companies have recently developed new cancer drugs, known as “ALK inhibitors”, that inhibit the action of ALK. Several cancer forms in adult patients, such as certain variants of lymphoma and certain variants of lung cancer, also have mutations in the ALK gene. Clinical treatment trials have been carried out, and others are in progress, in order to assess the effect of the new treatment in children who have neuroblastoma with an ALK mutation. The study shows that treatment may be successful in patients with neuroblastoma where relapse is caused by mutation in the ALK gene.

Neuroblastoma – key facts:

• Between 15 and 20 new cases in Sweden every year
• Affects mainly young children – 50 percent of children with neuroblastoma are younger than 1½ years
• It is the most common form of cancer in children under the age of 1 year, and 90 percent of cases occur before school age.
• 60 percent of cases of neuroblastoma are diagnosed when the tumor has already metastasised.
• Approximately 40 percent of patients have a local form of tumor and can be cured with relatively mild treatments.
• Survival rates range from 50 percent to nearly 100 precent, depending on whether the tumor has spread (metastasised) and the genetic nature of the tumor when diagnosed.

For more information, contact:
Tommy Martinsson, Professor of Cancer Genetics at the University of Gothenburg, phone.: +46 31 343 4803, e-mail: tommy.martinsson@gu.se
Per Kogner, Professor of Pediatric Oncology at Karolinska Institutet, phone +46 70 571 3907, e-mail: per.kogner@ki.se

Article:
Journal of Clinical Oncology, "Emergence of new ALK mutations at relapse of neuroblastoma":
Schleiermacher G, Javanmardi N, Bernard V, Leroy Q, Cappo, Frio TR, Pierron G, Lapouble E, Combaret V, Speleman F, de Wilde B, Djos A, Øra I, Hedborg F, Träger C, Holmqvist BM, Abrahamsson J, Peuchmaur M, Michon J, Janoueix-Lerosey I, Kogner P, Delattre O, Martinsson T.