Personalized medicine for children with cancer

In a joint project involving Rigshospitalet and DTU, parents of all Danish children with cancer will be given the offer to have the genetic characteristics of their children mapped.

This may help identify the cause of the cancer, so that the children can receive more precise treatment in the long term and avoid unnecessary side effects.

Personalized medicine is now a reality for Danish children with cancer. If children can be prevented from dying from the disease, receive a better treatment effect, and avoid serious side effects from treatment, this adds to both quality of life and a longer life.

But this is only part of the reason why this particular group of patients has been selected.

“When elderly people develop cancer, there are usually many different gene defects and environmental factors involved at the same time, and the gene damage has built up over many years. But when children develop cancer, there is a greater chance of finding a specific genetic defect that is the dominant cause. That is why it has particularly high value to perform a complete genome mapping for children with cancer,” explains Professor Kjeld Schmiegelow, Senior Hospital Physician at Rigshospitalet .

According to the Danish Cancer Society, approx. 170 children under 15 years of age are diagnosed with cancer each year in Denmark, and cancer causes 20 per cent of all deaths among children aged 1 or older.

Under the project, all families are being given the offer to have their child’s complete genome mapped. Around 85 per cent are accepting this offer. The mapping is being done jointly by Rigshospitalet and DTU Health Technology.

DTU researchers are responsible for sequencing the children’s genomes. The data is being processed on DTU’s Computerome supercomputer.

Since the project began two years ago, the cancers have been linked to a genetic disposition in approx. one in seven of the children investigated.

Five out of six survive

The children and their families who are found to have a genetic disposition to cancer are offered regular check-ups, such as an annual MRI scan. This allows new outbreaks of the disease to be discovered at an early stage, improving the chances of recovery.

“Parents who are told their child has cancer want answers to three questions in particular: Will I lose my child? Why has my child developed cancer? Can the same thing happen to the child’s siblings?,” says Professor Schmiegelow.

He adds that even for the children who are found to have no hereditary disposition to cancer, it is of great benefit to know this:

“It’s good for the family to be assured that the other children and the parents themselves do not have an elevated risk. It also becomes important to the child later in life, when they become an adult and consider having children of their own. It gives peace of mind to know that you are not carrying a hereditary cancer risk.”

Improved survival rates

There has been a marked improvement in survival rates for Danish children who develop cancer over the last few decades. Five out of six patients survive today. Paradoxically, however, this success story actually increases the need for genome mapping.

“Throughout human evolution there has been a harsh selection process. Genetic defects that gave children cancer have simply not been passed on, because the children died before reaching child-bearing age. Many of the genetic dispositions to cancer that children carry are therefore new mutations. Fortunately we are able to save the majority of children today, but one of the side effects is that they can pass on their genetic defects,” says Kjeld Schmiegelow.

When the drug is toxic

The project revolves around more than just finding genetic defects that directly cause cancer. Genes that affect how the body metabolises the drugs used in treatment are also in focus.

“For example, we have considerable knowledge about which enzymes are involved in the metabolism of the 13-15 drugs used for the treatment of leukaemia. Patients with a hereditary disposition to producing enzymes with lower or higher activity will have different dosage needs, in order to get the effect of the treatment or avoid side effects,” explains Professor Schmiegelow.

In medical jargon we talk about the ‘therapeutic window’. This refers to when the dose of a medication is large enough to have an effect, yet small enough to avoid serious damage to normal tissue. Penicillin is an example of a medication with a very large therapeutic window. Doctors have the freedom to prescribe a large enough dose to ensure that it is effective in all patients. Patients who are given an unnecessarily high dose will not be harmed by it. But the situation is quite different for cancer drugs.

“Most types of cancer drugs have a very small therapeutic window. Some products have no window at all—they are toxic at even the lowest effective dose. So it is of great value to be able to determine how small a dose is sufficient for a given patient.”

The project flowed out of dialogue between Kjeld Schmiegelow and Ramneek Gupta, Associate Professor at DTU Health Technology.

Turned the problem upside down

“Researchers usually start by finding a genetic defect they believe can be linked to a particular cancer or a specific side effect. They can then spend the next 10-20 years mapping out the underlying mechanism. If they succeed, they can then try to develop a medication that addresses this mechanism. Ramneek Gupta and I had the idea of turning the problem upside down,” says Kjeld Schmiegelow.

“Instead of looking for new mechanisms, we would start with the vast knowledge we already have about many of the cell toxins we use in leukaemia treatment. We therefore identified more than 30,000 known variants in genetic make-up that we know to play a role in the metabolism of cell toxins. In a study involving almost 1,000 children with leukaemia from Denmark and Germany, we were able to identify combinations of changes in the genetic material that could predict with a very high degree of certainty which patients would suffer relapse, and which would be cured. Now we have moved on to mapping the patient’s entire genome.”

As the project advances, researchers expect to be able to find correlations between cancer and genetic defects in more than every seventh child, as is the case today.

“There are a number of children for whom we suspect there is a hereditary link, but are unable to determine what it is. My best estimate is that we will eventually be able to demonstrate a hereditary link for about one in three children,” says Kjeld Schmiegelow.

For the other children, it will not be possible to demonstrate a hereditary link simply because no link exists. A large number of cancer cases are caused by mutations that arise due to environmental factors, or spontaneously, without a genetic cause. In addition to the medical aspects of the project, the research team is also interested in ethical and psychological factors.

“It might be controversial in itself that the decision to do the mapping is left to the parents. In principle, one could imagine that when some children become adults, they might wish that their genome had never been mapped. Some people do not want to know if they have an elevated risk of, say, cancer, but would rather live without this knowledge. It is, of course, not possible to undo the mapping—the family will have already received the results. It is our assessment that the great advantages in terms of better survival rates, fewer side effects and higher quality of life more than outweigh the fact that the child is denied the possibility of not being made aware of their risk level. But this is something we are monitoring closely. And this is why there are anthropologists linked to the project,” says the professor.

For the same reason, mapping is only being offered on a voluntary basis. Around 15 per cent of the parents say no initially.

“Some come back later once they have had time to get over the initial diagnosis, and want their child to be involved in the study. And of course they are allowed to join.”

Other projects on the way

The project is receiving funding from several Danish foundations. It is the first in which all patients in the country with a particular disease are offered full genome sequencing, and where the project not only has research value, but actually aims to improve treatment.

Benefits in relation to other diseases

“Our project is the first of its kind, but many others will follow. There are several other types of cancers where hereditary factors also play a significant role,” says Kjeld Schmiegelow.

“Generally speaking, such mapping will be particularly valuable for diseases where the treatment dose is continuously adjusted. Unfortunately, at present, the dose often has to set low for the sake of perhaps 5-10 per cent of patients, who are at risk of unacceptable side effects. This is not good for all the others, who thereby receive an unnecessarily low dose. Some of them would be able to tolerate a much higher dose, increasing their chances of recovery. For other patients, a lower dose can reduce the risk of serious side effects.”

Source: DTU