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Precision medicines for children with cancer hit the mark

New, targeted drugs can extend the lives of children with cancer who have particular DNA changes in their tumor, a new study shows. The results offer evidence for the value of treating children based on the biology of their tumor, says co-lead researcher Jan Molenaar.

In a large, international study, scientists tested genetic and molecular changes in just over a thousand children with various cancers from the Netherlands, Germany, and six other European countries. Some 330 children from the Princess Máxima Center took part. The study looked at children whose cancer had already come back for the second or third time, and for whom standard treatment was no longer successful.

Treatment based on biology

Prof. dr. Jan Molenaar was co-lead of the Dutch part of the study at the Princess Máxima Center. ‘The precision medicine program we have here, iTHER, looks purely at the biology of the tumor,’ he explains. That is fundamentally different from looking at drugs that have already been tested in the clinic. Such studies are difficult to set up in childhood cancer, because all forms of childhood cancer are rare. Molenaar: ‘An important question that we asked ourselves in this study was: does it make sense to shape treatment based on tumor biology? Our results offer strong evidence in favor of that approach.’

Abnormalities in the tumor

The researchers analyzed a tumor sample from each child to see if there were any changes in the DNA or RNA – or the genes and their activity. They then looked for existing precision medicines that target one of these faults. The final disease outcome of 519 children was also known to the researchers. This allowed them to see how effective the precision approach is.

A change in the DNA or RNA was found in the majority, 85%, of children. The scientists had classified the abnormalities by how ‘clinically relevant’ they are, meaning how likely a matching targeted drug is to be effective. A third of the children with a tumor fault – 147 out of 446 – were actually treated with a precision medicine.

Longer survival

A ‘clinically very relevant’ DNA or RNA fault was found in 42 children. The 20 children treated with the matching drug lived on average for just over six months without their tumor continuing to grow. They lived more than one and a half times longer than children with a tumor fault who could not be treated with a precision medicine – their disease remained stable for an average of just under four months. In total, the lives of children were extended by an appropriate targeted drug by an average of 2.5 months: from 9.5 months to a year.

Appropriate clinical trials

Molenaar: ‘These are very sick children who have already undergone many treatments. It is then quite difficult for doctors and parents to decide whether a child would benefit from joining a clinical trial. This new research shows that it is – and that we simply have to ensure that a child can take part in an appropriate trial.’

This study started before the Princess Máxima Center was opened. Since then, tumor DNA in all children with cancer treated at the Máxima has been extensively studied for diagnosis and research. During a so-called molecular tumor board meeting, doctors, pathologists and researchers discuss the changes in the biology of the tumor and any matching clinical trials. The final treatment decision is made by a child’s attending physician in consultation with the family.

Collaborative effort

The Dutch part of this study was a close collaboration between research (prof. dr. Jan Molenaar) and clinic (prof. dr. Michel Zwaan), and was coordinated by pediatric oncologist Karin Langenberg. The responsible trial manager at the Trial and Data Center was Miriam Stumpf.

The study was a collaboration with the Hopp-KiTZ pediatric cancer center in Heidelberg, Germany, with which the Princess Máxima Center announced a ‘Twinning Program’ this summer. The study was published last week in the November issue of the journal Cancer Discovery, alongside a commentary on the study co-authored by Lex Eggermont. The research was funded by, among others, Deutsche Krebshilfe, Deutsche Kinderkrebsstiftung and the German government.