A recent review, published in Cancers, has summarised the current landscape of ctDNA analysis in clinical practice as well as the challenges and opportunities of its use in non-small cell lung cancer (NSCLC).
Genotyping to ctDNA analysis
Understanding the specific genomic alterations driving NSCLC development has been critical in developing therapeutics and impacting patient outcome. Molecular profiling is also valuable at the time of acquired resistance to optimise subsequent treatments. While tissue-based molecular analysis is still the gold standard for precision medicine, liquid biopsy in recent years has gained a lot of traction. Several studies have shown that ctDNA analysis is feasible to evaluate tumour mutational burden. Tumour mutational burden acts as a predictive biomarker of response to therapies. Researchers can also use ctDNA analysis in other settings, such as lung cancer screening. While the data is still scarce, this option is attractive to avoid risks related to radiological assessments. Additionally, monitoring minimal residual disease (MRD) after surgical treatment may also help patient selection in the adjuvant setting. Finally, liquid biopsy could also provide insight into response to systemic therapies.
Technical issues and benefits
While both cfDNA and ctDNA are measurable in blood samples, detection of ctDNA is clinically more relevant. Several factors can influence ctDNA content. These include the nature of the primary tumour, tumour grade and vascularity. Therefore, consideration of these factors when interpreting liquid biopsy results in clinical practice is essential.
The main challenge using liquid biopsy is the detection of minor allelic fractions of mutant DNA on fragment cfDNA. This requires optimisation of pre-analytical, analytical and post-analytical aspects, which still need to be standardised. Each step has to be well controlled to ensure reliable results and optimise clinical decisions.
The most obvious benefit of liquid biopsy is the limited invasiveness and reduced procedural risks for patients compared with the collection of tumour specimens. Solid tumour biopsies provide a snapshot of the specific region of origin. Whereas, liquid biopsy may offer a more inclusive representation of the whole tumour burden, including intra- and inter-tumour heterogeneity. However, liquid biopsy information cannot be directly correlated with the histological characteristics of the tumour.
Detecting mutational burden
Studies have shown that adding ctDNA analysis at the time of diagnosis improves the detection of molecular alterations in a significant proportion of patients. For example, in the NILE trial, the addition of ctDNA tumour tissue characterisation improved the number of patients who benefited from targeted therapies by 48%. Additionally, ctDNA appears to be a clinically relevant tool in patients with progressive disease. However, the authors noted that ctDNA analysis at the time of disease progression may be challenging as ctDNA quantity in plasma is lower, resulting in decreased sensitivity. Despite these limitations, the feasibility and value of ctDNA molecular profiling at the time of progression has been established.
Lung cancer screening
Lung cancer remains the leading cause of cancer-related death worldwide. Unfortunately, lung cancer is more often diagnosed at an advanced stage. Moreover, no early detection approaches for non-smokers have been proposed. Therefore, this increase in non-smoking related NSCLC represents a key unmet need.
In this setting, liquid biopsy could help avoid the risk of second radiation-related cancers and allow non-invasive longitudinal surveillance. However, the costs and low sensitivity of these technologies currently limit their development in this setting. An alternative could be to increase the number of target mutations contained in the gene-sequencing panel to increase sensitivity, yet this also increases cost-effectiveness issues. Another strategy the authors suggested is to look at aberrant methylation of certain regions of ctDNA as a biomarker for early diagnosis. Some studies, have suggested the possibility of combining the detection of multiple methylation markers to increase sensitivity.
Adjuvant chemotherapy for patients with early-stage NSCLC improves overall 5-year survival. However, to date, there are no biomarkers that can identify high-risk patients. In this setting, ctDNA may be useful by identifying MRD still present after initial treatment and potentially disease relapse or recurrence. The detection of this biomarker could be useful to tailor therapies. Furthermore, sampling patients longitudinally could allow for early detection of changes in the amount of ctDNA that could be translated into therapeutic anticipation.
Response to therapies
Targeted therapies typically result in higher response rates and durable responses. However, some patients experience disease progression early. This is likely due to primary or acquired resistance mechanisms. In this case, researchers can use ctDNA as a predictive biomarker to identify these individuals. Plasma monitoring could be useful for early identification of early-progressive patients in the oncogenic-driven NSCLC setting. Experts could also use it to evaluate which patients may better benefit from combination strategies versus targeted monotherapies.
Immune checkpoint inhibitors have changed the treatment of metastatic and locally advanced NSCLC. However, it is clear that only some patients achieve long-term benefit from this strategy. In addition, there are currently no sufficiently reliable biomarkers for patient selection. The FDA recently approved tumour mutational burden for the prescription of immunotherapy in lung cancer patients. High tumour mutational burden is associated with the presence of more neoantigens and therefore an increased chance of immunotherapy working. Here, experts can use ctDNA-based assays to help guide immune checkpoint inhibitor treatment planning. They could also use it to evaluate response to immunotherapy and identify long-responders.
Experts are already using ctDNA in cases where tissue availability is scarce and genomic analysis is not possible. It is likely that in the next decade liquid biopsy will progressive further into routine care. ctDNA has multiple applications, from treatment response monitoring to screening. While the use of liquid biopsies and ctDNA analysis is still not approved, studies are continually demonstrating their clinical relevance. In the near future, it will be important to work on standardised assays and translate those observations into clinically useful tests.
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