Lung Cancer in the Context of a Precision Medicine Approach

Posted: April 2017

By Giorgio Vittorio Scagliotti, MD, PhD

The ambition to personalize medicine is intrinsic to the mission of every individual physician with the twin goals of reducing drug-related toxic effects and improving treatment efficacy. Hippocrates first proposed a combined assessment of the 4 humors—blood, phlegm, yellow bile, and black bile—to determine the best course of treatment for each patient. Today, exploiting gene sequencing enables more accurate medical predictions for almost every disease. Personalized predictions include whether an individual is currently developing an illness or will develop it many years ahead, whether a patient will respond positively to treatment or will suffer a serious adverse reaction to a drug. Modern medicine—and the reason why the word “personalized” has been added for emphasis—offers technology that has brought us much closer to exquisite precision in disease diagnosis and treatment.

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 global social problem. The 5-year survival rate for all stages combined varies from 4% to 17%, depending on regional differences.

Tobacco smoking remains the main risk factor for lung cancer, even if a rising incidence of the disease in never-smokers has been observed in the last two decades, and the vast majority of newly diagnosed lung cancers are metastatic or locally advanced.

In the last 15 years, a series of studies documented a potential role of low-dose computed tomography (CT) scan as an effective tool for early diagnosis. Cancer screening is a process chain, and each link in the chain needs to be performed correctly 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 iatrogenic injury and psychological stress, from the execution of that process. At a time of profound financial stress on healthcare systems worldwide, if screening is to be delivered, then it is essential to ensure that it is of high quality and includes smoking cessation services so that harms and costs are minimized.

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 recognizing the vast, yet fractured, state of biomedical data, and calls for a patient-centered 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.

The genomic revolution encompasses only a portion of the emerging hallmarks of cancer, which include delineating tumor characteristics and enabling better understanding of the tumor microenvironment.

With the completion of the human genome, we understand now that life is based on dynamic molecular networks rather than on a direct connection between genotype and phenotype.

The genomic revolution is still a “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; gene expression profiling and/ or full genome sequencing will hopefully characterize a reasonably wide collection of tumors. 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 becoming evident that primary and acquired resistance will be major limitations. Most solid and liquid tumors will not be overcome by single-agent targeted therapies. Even in those cases in which a single agent dissolves the tumor, the victory is short-lived and the tumors re-emerge. More often, single-agent trials involving targeted therapies administered to solid tumors result in modest effects, or no responses, even when confined to patients who have mutations in the target oncogene. Clearly, there is much to learn about in vivo tumor biology, and exploring resistance mechanisms is essential to identify which combination of drugs will treat resistant tumors or prevent the emergence of resistance.

However, the genomic revolution encompasses only a portion of the emerging hallmarks of cancer, which include delineating tumor characteristics and enabling better understanding of the tumor microenvironment. In this context, an understanding of the immune landscape of cancers, including immune-evasion strategies, have led to breakthrough therapeutic advances for patients with non-small cell lung cancer and have created a platform for future therapeutic developments.

We are at the beginning of a creative period of bottom-up research activity, organized through pilot projects of increasing scope and scale, from which best practices will progressively emerge. In particular, 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, we will need the right level of coordination and encouragement of the many players who must cooperate to create a higher level of biomedical knowledge.

In this patient-centered context, patients and their advocates are and will be more critical, each and every day: first, to promote the right social pressure for the systematic implementation of the results of preclinical and clinical research and, second, to develop a work in progress and continuous discussion with the regulatory bodies and national healthcare systems in an attempt to guarantee drug accessibility to every patient as well as to help national authorities maintain the long-term financial sustainability of healthcare systems.✦