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Imprecision in the Era of Precision Medicine in Non-Small Cell Lung Cancer

View Article: PubMed Central - PubMed

ABSTRACT

Over the past decade, major advances have been made in the management of advanced non-small cell lung cancer (NSCLC). There has been a particular focus on the identification and targeting of putative driver aberrations, which has propelled NSCLC to the forefront of precision medicine. Several novel molecularly targeted agents have now achieved regulatory approval, while many others are currently in late-phase clinical trial testing. These antitumor therapies have significantly impacted the clinical outcomes of advanced NSCLC and provided patients with much hope for the future. Despite this, multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in NSCLC and the impact of precision medicine in this disease. We also discuss the areas of “imprecision” that still exist in NSCLC and the modern hypothesis-testing studies being conducted to address these key challenges.

No MeSH data available.


Related in: MedlinePlus

Relative frequency of genetic abnormalities in non-small cell lung cancer lung cancer. Note: some aberrations can occur concomitantly (not displayed in figure).
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Figure 2: Relative frequency of genetic abnormalities in non-small cell lung cancer lung cancer. Note: some aberrations can occur concomitantly (not displayed in figure).

Mentions: One of the main issues to address in NSCLC is that many driver aberrations only constitute a small percentage of the entire NSCLC population (Figure 2). Traditional registration trial strategies involving randomized, placebo-controlled, double-blind phase III clinical trials are, therefore, not optimal approaches and may even be considered unethical in view of the placebo control arms. Technical issues also arise as the detection of the multiple driver mutations are performed on different platforms. For example, EGFR mutations are usually detected by real-time polymerase chain reaction, while ALK rearrangements are detected by IHC and/or fluorescent in situ hybridization. Currently, a large number of driver aberrations in NSCLC can be assessed using large multiplexed next-generation sequencing (NGS) platforms. These are now increasingly being incorporated into clinical trials and daily clinical practice (106). Such an approach involving multiple NGS platforms abrogates issues associated with screening patients for “low frequency” genetic aberrations, especially if they are directly linked to a master protocol adaptive clinical trial. Umbrella trials assess multiple pre-specified genetic aberrations using NGS or other platforms and are matched to targeted agents, usually involving specific tumor types. Basket trials involve patients with a single or family of genetic abnormalities and are matched to targeted therapies, regardless of tumor origin (Table 1).


Imprecision in the Era of Precision Medicine in Non-Small Cell Lung Cancer
Relative frequency of genetic abnormalities in non-small cell lung cancer lung cancer. Note: some aberrations can occur concomitantly (not displayed in figure).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5385461&req=5

Figure 2: Relative frequency of genetic abnormalities in non-small cell lung cancer lung cancer. Note: some aberrations can occur concomitantly (not displayed in figure).
Mentions: One of the main issues to address in NSCLC is that many driver aberrations only constitute a small percentage of the entire NSCLC population (Figure 2). Traditional registration trial strategies involving randomized, placebo-controlled, double-blind phase III clinical trials are, therefore, not optimal approaches and may even be considered unethical in view of the placebo control arms. Technical issues also arise as the detection of the multiple driver mutations are performed on different platforms. For example, EGFR mutations are usually detected by real-time polymerase chain reaction, while ALK rearrangements are detected by IHC and/or fluorescent in situ hybridization. Currently, a large number of driver aberrations in NSCLC can be assessed using large multiplexed next-generation sequencing (NGS) platforms. These are now increasingly being incorporated into clinical trials and daily clinical practice (106). Such an approach involving multiple NGS platforms abrogates issues associated with screening patients for “low frequency” genetic aberrations, especially if they are directly linked to a master protocol adaptive clinical trial. Umbrella trials assess multiple pre-specified genetic aberrations using NGS or other platforms and are matched to targeted agents, usually involving specific tumor types. Basket trials involve patients with a single or family of genetic abnormalities and are matched to targeted therapies, regardless of tumor origin (Table 1).

View Article: PubMed Central - PubMed

ABSTRACT

Over the past decade, major advances have been made in the management of advanced non-small cell lung cancer (NSCLC). There has been a particular focus on the identification and targeting of putative driver aberrations, which has propelled NSCLC to the forefront of precision medicine. Several novel molecularly targeted agents have now achieved regulatory approval, while many others are currently in late-phase clinical trial testing. These antitumor therapies have significantly impacted the clinical outcomes of advanced NSCLC and provided patients with much hope for the future. Despite this, multiple deficiencies still exist in our knowledge of this complex disease, and further research is urgently required to overcome these critical issues. This review traces the path undertaken by the different therapeutics assessed in NSCLC and the impact of precision medicine in this disease. We also discuss the areas of “imprecision” that still exist in NSCLC and the modern hypothesis-testing studies being conducted to address these key challenges.

No MeSH data available.


Related in: MedlinePlus