Fundamental research formed the basis for the personalised treatment of cancer patients. Thanks to whole gene sequencing, doctors can now treat their patients based on their genetic makeup. That is not only good news for the patient but also medical science, says Edwin Cuppen, director of the Hartwig Medical Foundation. ‘Knowledge about cancer is increasing, and much of that is entering the clinic to improve the treatment of patients’.

‘Every letter from you r DNA mutates at least once every three years somewhere in your body’, says Edwin Cuppen, Professor of Human Genetics at the University Medical Center Utrecht and principal investigator at the Oncode Institute. Cuppen is also director of the Hartwig Medical Foundation, a non-profit organisation that through a systematic, data-driven approach is trying to understand the development of cancer and in so doing aims to improve the treatment of patients.

Recipe book

DNA, our molecular recipe book, can be found in every cell of the body. It contains all the recipes for the proteins that give each cell its function: the genome. The information in the genome is written in four types of letters: the bases cytosine, guanine, adenine and thymine. But just like during the repeated copying of a recipe, during the copying of the DNA, errors can occur between the letters, and mistakes can happen due to external factors such as ultraviolet light and smoking. These mutations can cause cancer by undermining the self-correcting capacity of the genome.

Sequencing

Thanks to fundamental research into the function of DNA, scientists have been able to read the letters of the molecular recipe book since the 1970s. They read the DNA by chemically unravelling it to make the sequence of the base visible so that recipes can be read. Initially, researchers could decipher 100 to 1000 letters of the genome per day using manual sequencing techniques. Due to the automation of this process that increased to hundreds of thousands in the 1990s. This led to the development of the Human Genome Project, an international collaboration of researchers that managed to read out the entire human genome in 15 years.

Comparing

Thanks to improvements in and the scaling up of that sequencing process, the genome of a single person can now be processed within a single day (whole genome sequencing). That technology enables researchers and treating physicians to examine the DNA of cancer patients and to offer a personalised treatment based on the patient's genetic makeup. Cuppen: ‘We compare the DNA of the tumour with the normal DNA of the patient. This allows us to make statements about the characteristics of the cancer, such as heritability, and how drugs will respond to it.’

Precision drugs

The fundamental research underlying Cuppen's work makes it possible to develop drugs that are more precise than traditional chemotherapy, which inhibits the division of all cells in the body. Newer drugs specifically target one or more processes that underlie the onset of cancer. However, these drugs are often so specific, or the processes they are aimed at so complex, that they do not work for all cancer patients. More specific administration of these drugs is therefore desperately needed, says Cuppen. ‘We still do not know enough to find an effective, personalised treatment of cancer for every patient. Currently, we feel that a treatment is effective when we have done scientific studies that prove that the drug has a better result than the one we obtained previously. Nevertheless, this still often means that the drug only works for 30% of the patients and that 70% of the patients are overtreated.

Side effects and costs

This overtreatment often causes serious side effects, whereas doctors want to treat their patients as safely as possible. Moreover, if the treating physician prescribes a drug that does not work, then the patient only experiences the side effects. Furthermore, these drugs are expensive and unnecessary prescribing creates cost pressures. Cuppen: ‘It is in the interest of pharmaceutical companies that their drugs are prescribed to as many patients as possible. At the same time, they therefore put pressure on our healthcare system. I support effective drugs entering the market on time, but we subsequently do nothing to reduce overtreatment and to investigate which patients benefit from these drugs, and which not. I find that unacceptable.'

Project TANGO

In the project TANGO, a national collaboration of researchers is seeking a solution for these problems. The whole genome sequencing realised by the Hartwig Medical Foundation lies at the basis of this. It collects relevant information from the DNA of individual patients and is building a database that includes patients' clinical details. Thus, researchers and treating physicians can look for correlations and explain the effectiveness of drugs. The aim is to be able to predict whether or not somebody will respond to a particular type of immunotherapy. That will prevent side effects and the unnecessary prescription of expensive drugs. In addition, TANGO will explore how making systematic use of whole genome sequencing for this patient group will influence the costs for our healthcare system.

Alternative

The database of the Hartwig Medical Foundation contains information from more than 400,000 cancer patients and is therefore a unique source for research worldwide. Furthermore, the genetic information enables doctors to offer an alternative treatment possibility to some patients who have exhausted other treatment options, as it often provides leads for medication registered for other indications. But this comes too late for many of the patients whose DNA information can be found in the database. They have since died from the consequences of their illness. And that is distressing, says Cuppen. ‘A broader diagnostics and another therapy might have been able to help them. Although fundamental knowledge about cancer has increased considerably, much of that knowledge is still waiting for the development of appropriate drugs.’

For the generation of the sequencing data, researchers from the Hartwig Medical Foundation are working on this project together with the Antoni van Leeuwenhoek Hospital, Netherlands Cancer Institute, University Medical Center Utrecht, Maastricht University Medical Centre, Erasmus Medical Center, University Medical Center Groningen, Amsterdam University Medical Center, University of Twente and CPCT.

TANGO is one of the projects awarded funding from the ZonMw research programme Personalised Medicine with a focus on Rare Diseases and Oncology. The initiators of this programme, the Dutch Cancer Foundation, health insurer Zilveren Kruis and ZonMw, are jointly investigating how developments in the area of gene sequencing can reach the patients faster.

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