Circulating tumor DNA: New Tumor Screening

Small quantities of DNA from our cells is circulating in our blood. In the event of cancer, tumor DNA is also present. This is known as circulating tumor DNA or ctDNA. Detecting and analyzing ctDNA is now possible using recent sequencing techniques. Tools still need to be developed to use these techniques medically. Decoding this ctDNA could:

• enable cancer to be detected preventatively before the first symptoms;
• after the diagnosis, enable a tumor to be characterized more accurately to determine the disease’s prognosis and make the right treatment choices;
• during treatment, enable the effectiveness of treatments to be monitored: if the circulating tumor DNA is less abundant, the tumor is regressing.

And above all, these data could be obtained simply and less invasively: a simple blood test instead of biopsies or other heavy examinations (MRI, bone scan, etc.).

Marc-Henri Stern presents a new technique for analyzing ctDNA to characterize cancers. It aims at detecting “microsatellite instability”, a DNA anomaly found in some cancers. The strange term ‘microsatellites’ denotes sequences of a few repeated “letters” of the DNA alphabet (AAAAAAA or ATATATATAT for example). They are found almost everywhere in our DNA. The role of these sequences is unknown, but they are known to be the seat of numerous replication errors (the DNA copy that precedes any cell division). In a normal cell, these anomalies are identified by natural controls. When this fails, it is known as microsatellite instability, which is associated with some cancers. Today, we know methods for identifying these instabilities in tumor cells, from a sample of the tumor (biopsy); however, these anomalies could not be detected using ctDNA, in insufficient quantity in the blood. Marc-Henri Stern and his colleagues have developed a technique which appears one hundred times more sensitive than current methods, and which is also fast and inexpensive. Their patented invention is eagerly awaited in the medical sphere, as these cancers can benefit from personalized treatments; immunotherapies which enable a patient’s natural defenses to recognize cancer cells and attack them specifically.

Dr Gudrun Schleiermacher, head pediatricians and head of a research team at Institut Curie, has also been looking into circulating tumor DNA (ctDNA). "Today, we cure 80% of pediatric cancers, but in 20% of cases, we have no way of treating these children and cannot do so using traditional methods: we cannot increase the doses currently used in chemo and radiotherapies. So, we need to develop new approaches and in particular, find molecular alterations that could be the target for innovative treatments", she explains. The first challenge is that childhood cancers only have very few recurring DNA alterations. A multitude of potential anomalies therefore need to be sought in all of the genes. Another challenge which is common to all cancers is that tumor DNA alterations change over time. Monitoring is necessary during the disease for the appearance of new anomalies that could lead to treatment resistances, so that the therapeutic strategy can be changed. Hence the advantage of detecting these tumor DNA anomalies in a simple blood test for ctDNA. Dr Schleiermacher and her team have succeeded in doing this. “When we started the project two years ago, nobody had managed to sequence all the genes (called the exome) using ctDNA from a child’s blood sample. We developed our own technique and did it for 30 young patients as part of a clinical trial. We found tumor DNA in all the samples and were able to monitor the change in the quantity of DNA and thus see the disease regress during treatment, simply from the blood samples. Finally, we also discovered new mutations which appeared in the children in the event of a relapse. Now we will be better able to characterize them”, explains Dr Schleiermacher. This study to be presented at the AACR congress has already been used in a program called MICCHADO, initiated and coordinated by Dr Schleiermacher. It will consist of extending the initial trial to enable the analysis to be done in all pediatric or adolescent patients treated at a specialist center in France and suffering from a high-risk pediatric cancer. “In this way, we will be able to monitor genetic anomalies that occur during the disease and better characterize these cancers on a molecular and immunological level to be able to develop new therapeutic strategies for these children, including more suitable targeted treatments and immunotherapies, possibly from the onset”, concludes Dr Schleiermacher.

Copyright: Alexandre Lescure et Christophe Hargoues / Institut Curie

De l’intérêt de l’ADNtc en pédiatrie

Le Dr Gudrun Schleiermacher, pédiatre et chef d’une équipe de recherche à l’Institut Curie, s’est elle aussi intéressée à l’ADN tumoral circulant (ADNtc). « On guérit aujourd’hui 80 % des cancers pédiatriques mais dans 20 % des cas, on n’a pas les moyens de soigner ces enfants : on ne peut pas augmenter les doses aujourd’hui utilisées en chimiothérapie et radiothérapie. Il faut donc développer les nouvelles approches et notamment trouver des altérations moléculaires qui peuvent être la cible de traitements innovants », explique-t-elle. Premier défi : les cancers de l’enfant ne possèdent que très peu d’altérations de l’ADN récurrentes. Il faut donc chercher dans l’ensemble des gènes une multitude d’anomalies potentielles. Autre défi commun à tous les cancers : les altérations de l’ADN tumoral se modifient au cours du temps. Il faudrait donc pouvoir suivre pendant la maladie l’apparition de nouvelles anomalies susceptibles d’entraîner des résistances aux traitements, pour changer alors de stratégie thérapeutique. D’où l’intérêt, donc, de détecter ces anomalies de l’ADN tumoral dans une simple prise de sang, à partir de l’ADNtc. C’est ce que le Dr Schleiermacher et son équipe sont parvenus à faire. "Quand nous avons lancé le projet, il y a deux ans, personne n’était parvenu à séquencer l’ensemble des gènes à partir de l’ADNtc extrait d’un échantillon sanguin chez l’enfant. Nous avons développé notre propre technique pour le faire et l’avons fait pour 30 jeunes patients dans le cadre d’une étude clinique. Nous avons retrouvé de l’ADN tumoral dans l’ensemble des échantillons et nous avons pu suivre l’évolution de la quantité d’ADN et donc voir le recul de la maladie au cours des traitements à partir de simples prises de sang. Enfin, nous avons aussi mis en évidence de nouvelles mutations apparues chez les enfants en cas de rechute. Nous allons pouvoir maintenant mieux les caractériser", détaille encore le Dr Schleiermacher. Cette étude a déjà servi de base à un programme appelé MICCHADO, initié et coordonné par le Dr Schleiermacher. Il consiste à étendre cette première étude pour permettre cette analyse chez tous les patients pédiatriques ou adolescents pris en charge dans un centre spécialisé en France et atteints d’un cancer pédiatrique de haut risque. "Ainsi nous pourrons suivre des anomalies génétiques au cours de la maladie et mieux caractériser ces cancers sur le plan moléculaire et immunologique afin de pouvoir développer pour ces enfants des nouvelles stratégies thérapeutiques y compris traitements ciblées, et immunothérapies, éventuellement dès la première ligne, et les mieux adaptés", conclut le Dr Schleiermacher.

Crédit photos : Alexandre Lescure et Christophe Hargoues / Institut Curie