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SHORT ACCOUNTS OF ADVANCES ALREADY IN PRACTICE
AND THOSE WE HAVE STILL TO SEE!

PERSONALISED PREVENTION FOR AT-RISK INDIVIDUALS

Advances in the technology of imaging and very powerful laboratory testing mean that we can now envisage what it was impossible to imagine only ten years ago. This includes the identification of specific risks, even earlier screening and targeted prevention for certain cancers. This is the main objective of the Personalised Prevention of Cancer Unit, a pilot unit for targeted prevention which is being developed by Gustave Roussy. It will rely on the Institute’s major resources in the fields of laboratory medicine, precision medicine and immunotherapy and will be open to access from throughout the Gustave Roussy health catchment area. Taking personalised medicine into the field of cancer prevention is one of the major developments in oncology.

MOLECULAR MEDICINE

Molecular medicine – or personalised medicine, still called precision medicine – is based on detailed molecular diagnosis on the individual patient, leading to a better knowledge of the individual tumour’s genetic information. Depending on this diagnosis, targeted drugs tailored to the identified genetic profile are tried. Up to the present, tumours have been characterised by the organ where they arise and their stage of development. With molecular medicine, they are also defined by alterations in their genes. The objective is to be able to offer each patient drugs which are specifically targeted at the tumour’s genetic profile. This therapeutic strategy requires the identification of one or several key molecular abnormalities exhibited by the individual tumour in the individual patient. A “targeted therapy” can then be offered which focuses on a specific molecular abnormality. And finally, the efficacy of these targeted therapies has to be assessed rapidly. At Gustave Roussy the laboratory and pathology services are carrying out and developing tests for known molecular defects. The laboratory service, approved by the National Cancer Institute, is concentrating on the molecular diagnosis of very specific mutations; while the functional genomic unit performs genomic analysis to identify new molecular abnormalities. The Drug Development Department (DITEP) – the leading European department performing phase 1 and 2 clinical trials in oncology – gives patients access to many novel targeted therapy agents. The imaging department, armed, in particular, with an especially innovative contrast ultrasound technique can rapidly assess the efficacy of a new anti-tumour therapy. The construction in 2013 of a new dedicated research wing for the molecular medicine programme is a powerful reflection of our commitment to personalised treatment of cancer.

IMMUNOTHERAPY

Immunotherapy is currently one of the most promising areas of research in oncology. It seeks to use various treatments to stimulate the immune system, enabling the latter to attack tumour cells. Thus, it alerts the immune system to the cancer. A variety of novel therapies are effective, notably in conditions where standard treatment (chemotherapy, surgery, etc.) has been ineffective in terms of remission and quality of life. Gustave Roussy, through its translational, clinical and fundamental research programmes, is actively participating in the elaboration of novel drugs which are already proving to be effective.


DNA REPAIR

Gustave Roussy has incorporated DNA repair – another promising area of research in oncology – into its principal research programmes. The DNA repair system helps maintain the integrity of the genome. When it malfunctions, there is an increased risk of development of a cancer.

Within the Institute, several research teams, basic scientific and clinical alike, are collaborating in this field. They are studying genetic predisposition to disease linked to failure in DNA repair mechanisms, in order to find suitable treatments. Using targeted therapies aimed at the DNA repair proteins it is possible to increase the effectiveness of a chemotherapeutic agent or to induce tumour cell death.

GENOMICS

Since 2010, patients included in molecular medicine research studies have had their therapy directed according to the results of sequencing of tens of thousands of tumour genes looking for tumour markers.
In the spring of 2014, in partnership with the Integragen Company, the first department devoted to large scale high-throughput sequencing was established. Testing provides information on the sequence and expression of all the coding genes in the tumour. Results are available within a short time scale which is compatible with making therapeutic decisions. This thorough analysis of patients’ tumours without preconceptions is subject to strict quality control up to the standards required for clinical research, and yields results quickly enough to facilitate a prompt therapeutic response. It represents a major advance in molecular diagnosis. In the longer term this molecular portrait will serve to predict responses to drugs and help avoid the use of ineffective or even contraindicated agents. Treatment will be better directed and individualised.

TARGETED THERAPY

Targeted therapies are used to improve the effectiveness of cancer drugs and the term refers to drugs used to block certain specific mechanisms in cancer cells. These therapies are based on study and detailed knowledge of molecular mutations involved in the development of a cancer. Once the molecular portrait of the tumour has been established, the doctors decide on the best therapy to target the abnormalities directly. Targeted therapy means that patient treatment becomes truly personalised. After an initial stage of clinical trials to prove the concept of “personalised medicine”, the Gustave Roussy research groups are embarking on a new phase. This carries strong hopes of progress in cancer treatment.

ROBOTIC HIGH-THROUGHPUT CELL SCREENING

High-throughput cell screening principally consists in identifying anti-cancer agents that work by inducing an immune response, thereby increasing the efficacy of treatment. In 2013, Gustave Roussy invested in an industrial scale, high-throughput cell screening apparatus. This places us in the vanguard of genomic and pharmacological screening. Using this machine, the research teams at Gustave Roussy screen collections of chemical agents, some of which come from foreign centres and from DNA banks. Screening is carried out on human cell line models for all types of cancer. The high-throughput device is also used in clinical trials to identify the mode of action of therapeutic agents. It is available for collaborative ventures with commercial partners interested in screening and characterisation of their own collections. It is capable of analysing up to 20,000 samples per day. A 5-person team runs it.

PRECLINICAL

The development of genomics requires the development of numerous animal models and also of alternatives to such models. The introduction of new drugs in man necessitates 2-way journeys along the pathway running from models to preclinical studies and to clinical studies involving patients. Gustave Roussy, in partnership with the Institut Curie, the Xentech Company and the CNRS (National Centre for Scientific Research), has established a pre-clinical research and development unit in oncology. The building has a surface area of 5,000 m2. Its role will be to develop the design of model systems and experiments on them; training, in collaboration with the University of Paris-Saclay; and to make technological progress in imaging and radiotherapy. This large establishment will welcome academic and commercial research collaboration. The biotechnology companies that the Grand Paris project will be bringing to the Gustave Roussy campus, will also be able to benefit from such a provision, which is essential for advances in cancer research.

TRANSLATIONAL RESEARCH

Translational research – or research on transfer – sits at the interface between fundamental, laboratory-based scientific research and clinical research involving patients. Its goal is to improve the treatment of patients with cancer by swiftly transferring knowledge resulting from basic research to patient treatment and vice-versa. At Gustave Roussy, the translational research laboratory implements collaborative projects between clinical and basic science teams. A large part of its work is focused on therapeutic trials and the personalised medicine programme. In addition, the laboratory teams participate in fundamental research projects and in projects devoted to technological innovation. The first priority of the translational research laboratory is to use its skills to ensure that the continuum between basic and clinical research is maintained, aiming to transfer the most recently acquired knowledge as rapidly as possible for the benefit of patients.

CLINICAL TRIALS

A clinical trial – or study – is a scientific study performed to assess the efficacy and safety of a diagnostic technique or of a treatment. The establishment of clinical trials helps patients to get access to the most relevant treatment. In oncology, patients in whom therapy has become ineffective may be asked to participate in a clinical trial. They are looked after according to the rules of good clinical practice which ensure that clinical research is carried out in conformity with the ethical principles laid out in the Declaration of Helsinki. In particular, these define the role and responsibilities of each of those involved (sponsor, investigator, etc.). To initiate a clinical trial, the sponsoring body must first have obtained a favourable response from a Research Ethics Committee and authorisation from the National Agency for Safety of Drugs and Health Products. Clinical trials may concern new agents or combinations of agents, new ways of administering them or new treatment techniques (surgery, radiotherapy). Drug research is divided into two complementary areas: early trials, known as phase I and II, and advanced trials, phase II randomised or phase III. All the medical research units in the world, in oncology as in other specialties, support clinical trials or develop them. At Gustave Roussy, 26% of patients are recruited to clinical trials and 369 studies are currently ongoing.

BIG DATA, RESEARCH AND TREATMENT

The analysis of the genome of cancer cells, with results now available within a few days of obtaining a tumour biopsy, is a technological breakthrough. It supplies doctors with great quantities of information. This "big data", the analysis of which profoundly changes the management of cancer, also poses a number of challenges. The first of these is the need for new pathways of data handling and communication. The surgeon or radiologist biopsies the tumour, the pathologist validates it, the laboratory scientist extracts the nucleic acids. That is the traditional approach. The analysis of the genome of the cells in the sample, however, requires new skills because relevant information has to be extracted from these data. Our cellular DNA codes for more than 20,000 genes… A new profession, that of the bioinformatician, has the role of identifying defects in these genes in sick cells – the number of alterations in a given tumour can vary from a few to several thousand. The bioinformatician converts this mass of information into a report which is validated by the laboratory scientist before it is sent to the clinician. The next challenge consists in choosing from the defects in the genome those which will orientate treatment. Not all of the changes are of equal importance: some play a role in the appearance or the progression of the tumour while others do not.
The data provided by analysis of the genome of the normal cells, used as controls, also contains useful information. They may reveal a specific susceptibility to the toxic effects of a drug, leading to a decision to avoid it or modify the dose. They may also uncover genetic predispositions to other diseases. In practice, these are not looked for but this subject does raise ethical questions which are still not resolved.
All the data obtained should then be stored under the best conditions of safety and confidentiality. This does not exclude their being shared anonymously, because holding this information in common at an international level is a key to making rapid advances in effective patient care .

E-HOSPITAL

To make progress in research, it is essential to share clinical and laboratory data: the consolidation of a vast body of information is indispensable if one is to detect phenomena which frequently only concern a small number of patients. This is especially so in the current context of the development of personalised medicine, where great variations in tumour genetic profiles need to be taken into account.
Cancer Core Europe was created in July 2014. It brings together six European centres: Gustave Roussy, the Cambridge Cancer Centre (United Kingdom), the Karolinska Institute (Sweden), the Netherlands Cancer Institute (Holland), the Vall d’Hebron Institute of Oncology (Spain) and the German Cancer Research Centre-National Centre for Tumour Diseases (Germany). Cancer Core Europe is a network. But more than that, it is a virtual hospital where a critical mass of data is combined and shared. Oncology is by its nature a specialty where work across disciplines is very extensive. It is, therefore, essential to coordinate the complementary nature of programmes and expertise. With 60,000 new cases, 300,000 courses of treatment, 1.2 million outpatient consultations and more than 1,500 clinical trials, the scale of annual activity within Cancer Care Europe is such as to constitute a strike-force to lead the battle against cancer at the highest level.

ROBOTIC SURGERY

Less invasive and less traumatising surgery for a maximum number of cancer patients? This is possible thanks to robotic surgery. The benefits for the patient include a shorter hospital stay, reduced post-operative pain, a lesser risk of infection, a smaller chance of requiring a blood transfusion and a much shorter time to recover with faster return to the home and to normal activity.
The da Vinci Xi latest generation surgical robot arrived in the Gustave Roussy theatre suite in 2014. This equipment is offering patients a better quality of life and maximising their comfort during treatment.
Robotic surgery is being developed at the Institute in several disciplines: gynaecological, digestive tract, ENT and face and neck surgery and reconstructive surgery (breast among others but also in surgery of sarcomas). In total, there are some 450 operations performed annually at Gustave Roussy which are eligible for robotic surgery techniques.

OUTPATIENT RADIOSURGERY

Radiosurgery is defined as very high precision targeted radiotherapy, delivered in one or more sessions, which minimises exposure of healthy tissues to ionising radiation even when that tissue is juxtaposed to the radiation field. It means that tumours which are not accessible to standard surgery or which lie too close to sensitive organs can be treated or retreated in a radical way. The Gustave Roussy Novalis Tx was commissioned in April 2012. It incorporates a 3D imaging facility enabling visualisation of the tumour and its differentiation from adjacent healthy tissues and organs. It can also allow for the patient’s respiratory and other body movements. As it does not require positioning of a frame screwed to the cranium, patients are never admitted for their treatment, which takes only 20 to 25 minutes on average. The first patients treated at Gustave Roussy had primary cerebral tumours (benign or malignant) or cerebral metastases. Indications have now been widened and patients with tumours of lung, liver, spinal cord and prostate are also being treated.

IMPROVING PALLIATIVE CARE

One of the anxieties for people in relation to the end of life is of not being able to have palliative care. To make personalised medicine into medicine for the person and improving treatment in every way at every stage of the disease also involves treatment at the end of life. For that reason an acute palliative care unit is going to be established at Gustave Roussy to complement the mobile team provision which already operates. This unit will deploy all the skills of support care teams and of the technical facilities of the Institute to stabilise the patient’s clinical and psychological state. A structure for end-of-life support is in the process of being set up on Gustave Roussy’s second campus, the Chevilly-Larue Hospital, where convalescent beds are already used for long stay admissions.

COORDINATED, INTERACTIVE AND PERSONALISED PATIENT PATHWAYS

With advances in treatment, cancer has become in many instances a chronic disease. This tendency will become more prominent with the advent of targeted and outpatient therapies, leading to a part of treatment being administered near to or within patients’ homes and involving larger numbers of care staff.
Patient management will require increasing coordination between the various professional staff involved (hospital doctors and nurses, family doctors, pharmacists outside hospitals and private nurses) and will be personalised and interactive.
Information technology will be a key element in development of the pathways. Digitised patient files, dedicated internet access, management of patient data, apps to aid follow-up and coordination… Access to information technology should help generate sharing of information in real time between health professionals and with patients. At Gustave Roussy, the experimental Capri project plans to develop two internet portals, one for patients and the other for private professional staff. These should aid the monitoring of patients at a distance and increase the relevance of hospital visits. A new profession is emerging at the heart of this coordination, that of the clinical nurse. These nurses will be able to help anticipate patient needs; improve management before admission to hospital and at discharge; create connections between professionals; and reinforce programmes of education of patients and those close to them, thus facilitating coordination of the care pathway.

INTEGRATED RESEARCH

Given the rationale underpinning the coordination of different types of research with treatment, should research itself not rely on a combined strategy involving exchanges and interdisciplinary coordination? Would this not increase transparency and encourage international research exchanges? At Gustave Roussy, a fundamental revolution is in train with consideration of the idea of a completely integrated research centre housing the various types of research: from basic scientific to clinical, from epidemiology to human and social sciences, from biostatistics to bioinformatics and systems biology and from biophysics to technology! A centre bringing together all the research teams with a permanent link to the hospital and patients, interacting with its environment and the economic development of its local authority. That would really represent the creation of a unique ecosystem based on research in cancer and the innovative therapies we have described here… Towards the 2020 horizon.