At the forefront of a new era of clinical research
The International Association for the Study of Lung Cancer is at the beginning of a creative period of bottom-up research activity. Dr. Giorgio Scagliotti, President Elect, IASLC, makes an assessment of the challenges within respiratory oncological research and notes that the right amount of coordination and encouragement from all healthcare players is required to facilitate better clinical developments
Lung cancer is the most frequent cause of cancer death in the world. Annually, 1.8 million people are diagnosed with this disease and 1.6 million die of it, making this disease a relevant social problem. The 5-year survival rates vary from 4–17%, depending on stage and regional differences.
Tobacco smoking remains the main risk factor for lung cancer, though a rising incidence of the disease in smokers has been observed only in the last two decades, and the vast majority of the clinically diagnosed lung cancers are in an advanced stage, both locally or internationally.
In the last 15 years, a series of studies indicated a potential role of low-dose CT scan as a potential effective tool for early diagnosis. Cancer screening is a process chain and each link in the chain needs to be performed correctly in order to maintain its significant but fragile benefit. While the primary goal in cancer screening is to achieve an objective reduction in cancer-related mortality, the utility of a screening approach is also defined by the extent of resultant harms, such as latrogenic injury and psychological stress, from the delivery of that process. At a time of profound financial stress on healthcare systems, if screening is to be delivered then it is essential to ensure that it is of high quality and includes optimal intensity cessation services so that harms and costs are minimised.
Nowadays physicians are often making diagnoses using symptoms-based disease archetypes as opposed to underlying molecular patho-physiology. The growing concept of “precision medicine” addresses this challenge by recognising the vast yet fractured state of biomedical data, and calls for a patient-centred view of data in which molecular, clinical, and environmental measurements are stored in large shareable databases. Such efforts have already enabled large-scale knowledge advancement, but they also risk enabling large-scale misuse.
With the completion of the human genome we understood that life is based on dynamic molecular networks rather than on a direct connection between genotype and phenotype.
The genomic revolution is still “work in progress” and represents an unprecedented opportunity with regard to emerging cancer diagnosis and therapies. Advances in genomic technologies have made it possible to sequence candidate oncogenes in cancers, quickly and affordably, and gene expression profiling, and/or full genome sequencing will hopefully characterize a reasonably wide collection of tumours. These data provide critical information about the spectrum and frequencies of mutations in cancers and will facilitate the development of drugs against targets that are most frequently mutated.
Despite the early successes of targeted therapies, it is also becoming evident that primary and acquired resistance will be major limitations. Most solid and liquid tumours will not be overcome by single-agent targeted therapies. Even in those cases in which a single agent dissolves the tumour, the victory is short lived and the tumours re-emerge. More often, single-agent trials involving targeted therapies administered to solid tumours result in modest effects, or no responses, even when confined to patients who have mutations in the target oncogene.
Clearly, there is much yet to understand about in vivo tumour biology and exploring resistance mechanisms is essential to decide what combination of drugs will treat resistant tumours, or even to prevent the emergence of resistance.
However, the genomic revolution impasses only a portion of the emerging hallmarks of cancer, which include enabling characteristics and a better understanding of the tumor microenvironment. In this context an understanding of the immune landscape of the tumours, including immune-evasion strategies, have led to breakthrough therapeutic advances for patients with non-small cell lung cancer and made a platform for future therapeutic developments.
We are at the beginning of a creative period of bottom-up research activity, organised through pilot projects of increasing scope and scale, from which best practices would progressively emerge. Particularly given the size and diversity of the healthcare enterprise, a single approach to data gathering that will populate the space is probably not appropriate for all contributors. As in any initiative of this complexity, what will be needed is the right level of coordination and encouragement of the many players who will need to cooperate to create a higher level of biomedical knowledge.
Patient-centric advocates are and will be more critical, from one side, in promoting the right social pressure for the systematic implementation of the results of preclinical and clinical research and, from the other, in developing a work in progress and continuous discussion with the regulatory bodies and national health care systems in the attempt to guarantee to every patient drug accessibility but also in helping national authorities in maintaining the long term financial sustainability of the health care systems.