Emerging uses of circulating tumor DNA in advanced stage non-small cell lung cancer
Melina Marmarelis1, Jeffrey C Thompson1, Charu Aggarwal1
1Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
Targeted therapies have dramatically changed the treatment paradigm for a select group of patients with non-small cell lung cancer (NSCLC) whose tumors harbor targetable genetic aberrations. Patients with such genetic changes enjoy excellent responses to tyrosine kinase inhibitors (TKIs), but resistance is nearly inevitable. Resistance to first line TKIs is heterogeneous and multifactorial-multiple resistance mechanisms have been reported, and different metastatic foci in the same patient may have distinct resistance mechanisms. The recent approval of next-generation TKIs specific to particular resistance mechanisms, and the likely future approval of others, necessitates the acquisition of repeat molecular analysis at time of progression. Tumor tissue has traditionally been the preferred source to detect oncogenic driver and resistance mutations, but tissue biopsies are invasive and often difficult to obtain. The use of circulating tumor DNA (ctDNA), so-called "liquid biopsies", has emerged as a promising technique to molecularly profile tumors non-invasively and is becoming increasingly utilized in the routine management of lung cancer. This review will describe the current role of ctDNA in the management of lung cancer, and explore emerging data that point towards its increasingly important role in clinical care.
Insights
Targeted therapies offer excellent responses in non-small cell lung cancer (NSCLC) but resistance develops. Liquid biopsies using circulating tumor DNA (ctDNA) provide a non-invasive method for molecular profiling at progression.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genetics
Background:
- Targeted therapies, including tyrosine kinase inhibitors (TKIs), have transformed non-small cell lung cancer (NSCLC) treatment for patients with specific genetic aberrations.
- Tumor resistance to TKIs is common, heterogeneous, and can involve distinct mechanisms across different metastatic sites within the same patient.
Purpose of the Study:
- To review the current clinical utility of circulating tumor DNA (ctDNA) in managing NSCLC.
- To explore the emerging role of ctDNA in guiding treatment decisions following TKI resistance.
Main Methods:
- Review of current literature on targeted therapies, TKI resistance mechanisms, and liquid biopsy applications in NSCLC.
- Analysis of data supporting the use of ctDNA for molecular profiling at disease progression.
Main Results:
- Resistance to first-line TKIs is multifactorial, necessitating repeat molecular analysis.
- Circulating tumor DNA (ctDNA) analysis, or liquid biopsies, offers a non-invasive alternative to traditional tissue biopsies for detecting resistance mutations.
- Liquid biopsies are increasingly integrated into routine NSCLC management.
Conclusions:
- Repeat molecular profiling using ctDNA is crucial for identifying resistance mechanisms and guiding subsequent treatment strategies in NSCLC.
- The non-invasive nature and growing utility of ctDNA position it as a key tool in the evolving landscape of lung cancer care.
