Lung Cancer PNES Programme

This programme has set up and co-ordinated a national expert lung cancer research network organised around five main lines of research.

Introduction to the lung cancer PNES programme and its lines of research

Background information on lung cancer
Lung cancer is the leading cause of death due to cancer in the developed world, with a 5-year survival rate estimated at 15%. In France, this cancer is responsible for around 28,000 deaths a year and its incidence is constantly on the rise, particularly among women. In recent years, identification of molecular biomarkers has led to significant strides forward in our understanding of the aetiology and the histopathological and molecular diversity of this complex disease.

One spectacular development in this regard is the application of small molecule tyrosine kinase inhibitors (TKIs) to treat patients with adenocarcinoma of the lung exhibiting activating mutations of the Epidermal Growth Factor Receptor gene (EGFR).
The emergence of more affordable, reliable technologies for molecular biomarker analysis has enabled the development of large-scale studies to further our understanding of the disease's molecular mechanisms and to translate our new molecular knowledge into new clinical and public health approaches, with the aim of reducing the burden of lung cancer and its mortality.

Accomplishing these goals will require the collection, dissemination, analysis and integration of complex data on human tissue samples representing the full range of lung cancers. The main requirement is that these samples must be taken under conditions meeting the highest standards in terms of ethics, biological quality and rigour and organisation of individual, pathological and clinical data.

Lung cancer PNES programme

Founded in 2006 at INCa’s initiative by funding a call for proposals for lung cancer projects, the Specialised National Excellence Programme in lung cancer (Lung cancer PNES) brings together 24 research teams, 6 tumour banks and a clinical research data processing and management centre.

The primary objective of the lung cancer PNES programme was to validate and exploit new methods, particularly molecular methods, firstly to discover the mechanisms of the disease and secondly to speed up the conversion of our knowledge of the mechanisms that cause lung cancer into clinical applications.

The main research lines of the lung cancer PNES programme

This programme has set up and co-ordinated a national expert lung cancer research network organised around five main lines of research:

1. Molecular epidemiology for lung cancers with occupational origins
2. Definition of diagnostic and prognostic molecular markers in the early stages of lung cancer (T1N0)
3. A study of molecular and pathological mechanisms in basaloid and neuroendocrine lung carcinomas
4. A study of genes involved in adenocarcinoma and its molecular mechanisms, in association with tobacco use
5. A study of biomarkers indicating a response to chemotherapy and targeted therapies in non-small cell bronchopulmonary cancers (NSCBPC).

This programme has also provided support for three clinical trials and furthered the organisation of national translational lung cancer research.

Organisation and co-ordination

The lung cancer PNES programme is based on a Co-ordinating Committee and a Scientific Committee.

The Co-ordination Committee*:

• P. Hainaut, (IARC, LYON), Scientific Co-ordinator, This e-mail address is being protected from spambots. You need JavaScript enabled to view it This email address is protected against bots and spammers. Please enable JavaScript to view it.   

• J.C. Soria (IGR, Villejuif), Programme Representative for INCa, This e-mail address is being protected from spambots. You need JavaScript enabled to view it This email address is protected against bots and spammers.  Please enable JavaScript to view it.  

• F. Morin (IFCT, Paris), Co-ordination of the tumour bank and clinical trial network, data management support, This e-mail address is being protected from spambots. You need JavaScript enabled to view it

The Scientific Committee:
The members
The Scientific Committee is made up of the scientists responsible for the programme’s lines of research plus the members of the co-ordination committee.

• Christian Brambilia, Inserm U823, Grenoble
• Elisabeth Brambilia, Inserm U823, Grenoble
• Pierre Fouret, IGR, Villejuif
• Pierre Hainaut, IARC, Lyon
• Christophe Paris, Inserm ERI11, Vandoeuvres-lès-Nancy
• Jean-Charles Soria, IGR, Villejuif
• Bernard Milleron, IFCT, Paris

Role of the Scientific Committee

The role of the scientific committee is to determine research priorities in the programme’s lines of research, evaluate the progress of the work, optimise the pooling of resources and access to platforms, develop scientific and technical monitoring to identify and take advantage of opportunities and co-ordinate the production of activity reports and publication policy. The Scientific Committee is “open”, which means that, depending on developments and opportunities, it can invite outside people on a temporary or permanent basis who are likely to contribute to the programme and diversify its impact.

*This co-ordination is carried out with the support of two organisations:

1. The IARC (International Agency for Research on Cancer, Lyons): co-ordination of tumour registers, conducting multicentre studies on genetic propensities to lung cancer, identification and classification of exposure factors
2. Francophone Thoracic Oncology Intergroup (IFCT): A multidisciplinary, interdisciplinary organisation that co-ordinates the development of phase III trials in thoracic cancer and epidemiological studies (11 studies have been launched over the last 6 years encompassing 2500 patients).

Biological resources

A common reference manual has been adopted by all tumour banks, which defines:

1. Guidelines for tissue sample collection, processing, annotation and preservation conditions
2. The quality control mechanisms 
3. DNA and RNA extraction and quality control protocols (at least 10% of the samples are tested by nucleic acid extraction and quality control, the quality threshold for RNA is a score of RIN ≥ 7.) 
4. Mechanisms and guidelines for sample shipment and traceability 

These shared protocols are compatible with international standards and recommendations (ISBER, NCI, IARC).

Description of biological resources collected
The biological resource classification criteria give special attention to histopathological variables (pTNM, histological subtypes according to the WHO’s ICD-O classification, the percentage of tumour cells and tumour necrosis).
For each patient, and as frequently as possible, the healthy tissue matched with the tumorous lesion is systematically collected and cryopreserved.
Analysis of the 3,897 samples registered in the National Virtual Tumour Bank (TVN) as of January 2010 shows that:

1. 85% were obtained during a surgical resection and 13% in biopsies during fibre optic endoscopies.
2. 80% are non-small cell lung carcinomas (32.9% ADC, 46.3% CCN and 2% LCC). 
3. 65% of non-small cell lung carcinomas are not at a very advanced stage (pT 0, 1 and 2). 
4. 40% of the tumours collected meet the inclusion criteria for the lung cancer PNES protocols. 

The six tumour banks in the network have a collection capacity of around 2,000 new specimens a year.

Projects, developments and prospects

Based on the current state of our knowledge and on the PNES organisation and the tumour bank network, four areas of research have been prioritised:

A- Genome and biomarker research
The genome research partnership between IARC and the Centre for the Study of Human Polymorphisms (CEPH) has identified multiple genes likely to cause a predisposition to lung cancers. Additional studies have been started to understand the predisposition mechanisms in these genes and to understand the genomic processes behind cancer genomics. Current work is focusing on genes CHRNA3, CHRN5 and CHRNB4, which encode for sub-units of nicotinic acetylcholine receptors.

B- Translational research and biomarkers
Detection of biomarkers for lung cancer diagnosis and prognosis and to predict their therapeutic response was made possible by the discovery of new drugs such as tyrosine kinase inhibitors. Additional studies need to be conducted on biomarker combinations in order to devise better diagnostic and predisposition algorithms. This kind of research should be structured as phase III clinical trials.

C- Molecular causes for interactions between genetic and epigenetic alterations
Teams in the ‘Lung Cancer PNES’ and their French collaborators gathered information on three main pathways of molecular interaction: the Tyrosine Kinase/AKT line, the RASSF1/Hippo pathway and the p14arf/p53 link. Additional studies on these mechanisms will be conducted using different approaches:

• In vitro characterisation, by means of transformed and untransformed cellular models

• Use of RNA interference for systematic screening for elements of these pathways and their impact on cell proliferation, survival, migration and response to drugs

• Development of animal models

• Isolation and molecular characterisation of cancerous cells with some properties of stem cells

• In-depth study of histopathologically rare cancers and mesotheliomas. These are two domains in which France is recognised as an international leader.

D- Early detection and risk prediction
A new approach must be organised around joint epidemiological, genetic predisposition and metabolomic studies.Metabolomic techniques have now come of age and are reliable for studying a large number of metabolites of physiological products and environmental contaminants which can be detected by such methods as NMR and mass spectrometry urinalysis. Studies on these factors should be possible using prospective cohorts from whom biological material of interest has been collected.

Partnership conditions

In principle, the programme is open to any partnership proposal based on:

• A mutual scientific interest

• A collaborative approach integrated into the programme

The Programme does not aim to act as a provider of biological services or supplier of biological resources outside scientific projects of mutual interest.

Contact: Pierre Hainaut, (IARC, LYONS), Scientific Co-ordinator, This e-mail address is being protected from spambots. You need JavaScript enabled to view it