Questions to Dr Jean-Marc Extra
Breast cancers are at the heart of this new personalized medicine that mobilizes researchers, clinicians and industry.
What is the impact of this "new medicine" in the diagnosis and treatment of breast cancer?
Today personalized medicine is no longer an utopia, but we are just entering into this new era. Indeed, in recent years we have many more targeted treatments. The antibody Trastuzumab/Herceptin® allows us to combat certain tumor cells by blocking a surface molecule (called HER2) implicated in the disease but also to spare the healthy cells (which do not express this molecule or express it only at low levels on their surface). Surgery and radiotherapy have also made considerable progress. By using a technique called sentinel node, now we avoid the large axillary dissections that often lead to lymphatic edema. Irradiation techniques are also much more focused: conformal radiotherapy at the site of the intervention.
Mammary tumorigenesis is a complex process that remains poorly understood
However, mammary tumorigenesis is a complex process that remains poorly understood. Progressive resistance to these targeted therapies emerges, which requires in turn the development of new treatments (actually, at some point all metastatic breast cancer continue to progress under Trastuzumab). Other tumors, such as triple negative breast cancer, still lack effective targeted therapies (these express neither hormone receptors nor HER2 molecule that would make them susceptible to hormone therapy or trastuzumab).
Breast tumors are also extremely heterogeneous, not only among themselves but also within the same tumor. So we must still improve our understanding of biology to find biomarkers that can improve the classification of these cancers and provide new diagnostic and therapeutic targets.
How is the team organized to meet these new challenges?
Clinically, it includes four medical oncologists, three surgeons, a radiology unit specializing in breast imaging, two radiotherapists and two biopathologists expert in breast pathology. Scientifically, Pr. Emmanuelle Charafe-Jauffret, Pr François Bertucci and Dr. Antony Goncalves make connections with researchers from CRCM including molecular oncology team of Dr Daniel Birnbaum, the immunology group of Dr Daniel Olive and the teams of Dr Robert Fuchs and Dr Vincent Géli that explore the mechanisms of DNA repair.
Finally, we benefit from common platforms to work on tumor samples (Biobank), validate the therapeutic potential of a discovery (TrGET®), conducting early clinical studies (ETOH), follow the immune response of our patients (with the immunomonitoring platform), design, manage and exploit our clinical trials (with the DRCI).
What are your priorities for translational research?
We have three priorities:
- The first is to improve the classification of breast cancers and discover new theranostic markers (markers for diagnosis and therapy, such as the HER2/Trastuzumab duo). For this, we characterize each tumor of our Biobank to identify genetic defects responsible for the disease and the cells primarily affected by these alterations. Dr Daniel Birnbaum and Pr Bertucci are in charge of these researches.
- The second is to launch innovative preclinical and clinical trials based on new therapeutic targets discovered by researchers from the CRCM.
- Finally, our third objective is to develop new combination therapies to improve treatment of breast tumors with poor prognosis: HER2+ cancer, inflammatory cancer, tumors associated with a BRCA mutation and triple negative cancers (which like cancers called "basal like" have common molecular features with BRCA1-mutated tumors). More rational, these combinations aim to simultaneously target multiple cell types (including stem cells) and different biological mechanisms: DNA repair, signaling pathways, reaction of the tumor microenvironment, androgen receptors...
At IPC, we are very interested in cancer stem cells. The source of all tumor cells, they determine the clinical prognosis because they are the direct cause of relapse and metastasis. If the treatments most often succeed in eliminating tumor, cells are indeed still unable to kill these immature cells they may at any point give birth to a new tumor. Their molecular profile, very different from that of more differentiated tumor cells, makes them insensitive to most treatments.
Design treatments that specifically target cancer stem cells
In the laboratory of Molecular Oncology Dr. Daniel Birnbaum, Professor Emmanuelle Charafe-Jauffret and Dr. Christophe Ginestier lead a research group dedicated to the study of breast cancer stem cells. Through them, we are now able to isolate these cells using biomarkers (CD44, CD24, Notch, P53 ...) or functional tests but also to follow their evolution in patients (with a biomarker called ALDH1).
In parallel we are trying to develop new therapeutic approaches that specifically target these populations (the "family" stem cells are in fact composed of several members, some of which remain to be identified). In this context we are a sponsor of a clinical trial referred to proof of concept that evaluates the effect on these cells of combined treatment with an anti-angiogenic chemotherapeutic Bevacizumab/Avastin® (a drug that prevents the manufacture of blood vessels that supply the tumor).
More generally, what types of clinical trials you conducting?
We are exploring all clinical situations (neodjuvant, adjuvant, first line, relapse ...) and all types of trials (studies testing early post-marketing). From an organizational perspective, I supervise clinical studies Phase IIb and III concerning the early stages of the disease (adjuvant or neoaduvant) while Dr Anthony Goncalves is more focused on the metastatic and early clinical trials.
What proportion of new targeted therapies are in these early trials?
These medicines are part of many of our early clinical trials. In the world today, nearly 500 drug candidates are in Phase I clinical studies, over 200 are targeted therapies (PI3K/AKT pathway, Notch, Hedgehog ...). While few of these compounds demonstrate efficacy and safety in the clinic, tomorrow some of them will permit us to have better and more efficient results. Our mission is therefore to select the best of these innovations but also to identify good combinations because experience shows us that none of these drugs alone will bring the solution.
This assessment is the result of teamwork: clinicians and methodologists design testing in the smartest possible manner, work with the biopathologists, with researchers analyzing the biological effects of these new treatments in close relationship with the scientists and physicians of the biopharmaceutical industry that developed them...
Through this chain of expertise, IPC is one of several European institutes that can carry out this type of project.
L’équipe de médecine translationnelle sur le cancer du sein
Sur le plan clinique, l’équipe comprend des oncologues médicaux, des chirurgiens, une unité de radiologie spécialisée en sénologie, des radiothérapeutes référents et des biopathologistes experts de la pathologie mammaire. Une équipe d’Oncogénétique (Pr. Hagay Sobol, Dr. Cornel Popovici) et de Médecine Anticipatoire (Dr. François Eisinger et Dr. Jessica Moretta) est également présente. Sur le plan scientifique, le Pr. Emmanuelle Charafe-Jauffret, le Pr. François Bertucci et le Pr. Anthony Goncalves font le lien avec les chercheurs du CRCM, notamment l’équipe d’oncologie moléculaire du Dr. Daniel Birnbaum, les immunologistes du groupe de Dr. Daniel Olive et les équipes des Dr. Robert Fuchs et Vincent Géli qui explorent les mécanismes de réparation de l’ADN.
Par ailleurs, l’équipe bénéficie de plateformes communes pour retravailler sur les échantillons de tumeurs, valider le potentiel thérapeutique d’une découverte (TrGET®), conduire des études cliniques précoces (ETOH), suivre la réponse immunitaire de nos patients (plateforme d'immunomonitoring), concevoir, gérer et exploiter nos essais cliniques (DRCI).
Doctors and researchers in this team
- Marie BANNIER (Doctor)
- François BERTUCCI (Professor)
- Lise-Marie BILLARD/DAUFRESNE
- Daniel BIRNBAUM
- Cécile BRATICEVIC (Doctor)
- Serge BRUNELLE (Doctor)
- Max BUTTARELLI (Doctor)
- Jacques CAMERLO (Doctor)
- Christian CHABANNON (Professor)
- Emmanuelle CHARAFE-JAUFFRET (Professor)
- Monique COHEN (Doctor)
- Yves COLLETTE
- Béatrice DELARBRE (Doctor)
- François EISINGER (Professor)
- Jean-Marc EXTRA (Doctor)
- Robert FUCHS (Doctor)
- Vincent GELI (Doctor)
- Anthony GONÇALVES (Professor)
- Gilles HOUVENAEGHEL (Professor)
- Aurélie JALAGUIER-COUDRAY (Doctor)
- Eric LAMBAUDIE (Doctor)
- Marc LOPEZ
- Virginia MICHEL
- Jessica MORETTA-SERRA (Doctor)
- Jacques NUNES
- Daniel OLIVE
- Rodica POPOVICI (Doctor)
- Renaud SABATIER (Doctor)
- Hagay SOBOL (Professor)
- Carole TARPIN (Doctor)