|Year : 2020 | Volume
| Issue : 3 | Page : 577-579
Circulating tumor DNA in non-small-cell lung cancer: A step beyond blood
Alfredo Addeo, Alex Friedlaender
Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
|Date of Submission||13-Aug-2020|
|Date of Decision||14-Aug-2020|
|Date of Acceptance||14-Aug-2020|
|Date of Web Publication||19-Sep-2020|
Rue Perret Gentil 4, 1211 Geneva (CH)
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Addeo A, Friedlaender A. Circulating tumor DNA in non-small-cell lung cancer: A step beyond blood. Cancer Res Stat Treat 2020;3:577-9
Lung cancer remains the leading cause of cancer-related deaths, with an incidence that continues to increase in both the sexes and across all ages. Over the past few decades, a better understanding of cancer biology has led to the development of new and more effective treatments.
In particular, the advent of personalized therapy targeting molecular alterations in the tumor DNA has led to improved outcomes with a concomitant reduction in the toxicity. Among the various activating mutations, those in the epidermal growth factor receptor (EGFR) gene have been most widely studied. Several studies have proven that EGFR tyrosine kinase inhibitors (TKIs) are more effective than standard chemotherapy. As a consequence, first- and second-generation TKIs have been approved for use in the first-line setting in patients with metastatic non-smal-cell lung cancer (NSCLC) harboring specific EGFR mutations., Unfortunately, despite the use of targeted therapy, all patients experience disease progression at some point due to the resistance mechanisms developed by the cancer cells. Different types of molecular mechanisms are responsible for the development of acquired resistance; however, T790M, which is a secondary point mutation in the exon 20 of the EGFR gene, is the most predominant one. This mutation has been observed in approximately 50%–60% of the tumors post-treatment with TKIs and is therefore considered the leading cause of disease progression in patients with NSCLC. Several clinical trials have assessed the potential of various drugs to overcome this acquired resistance. A new molecule, osimertinib, showed great efficacy in the AURA 3 study, which was a randomized phase III trial. Osimertinib is a third-generation oral EGFR TKI that can not only target EGFR-activating mutations but also the T790M resistance mutation. Osimertinib has been clinically approved as the new standard of care in patients with NSCLC harboring the T790M mutation, who have received prior lines of therapy with other EGFR TKIs. Therefore, it is essential to perform a re-biopsy at disease progression to determine the status of the T790M mutation. While the gold standard for mutation detection is a tumor tissue biopsy, it is not always feasible. Therefore, an alternative non-invasive approach has emerged that involves ctDNA-based detection of EGFR mutations. Many studies have shown that ctDNA-based mutation detection is highly concordant with the gold standard tissue-based mutation detection,, with a sensitivity and specificity of about 70% when compared to the tissue-based approach.
In this issue of the Journal, Chougule et al. have published their data from 11 patients with metastatic NSCLC harboring an EGFR mutation. Analysis of the 11 baseline formalin-fixed paraffin-embedded (FFPE) tumor tissues revealed that seven patients (63.6%) had an EGFR exon 19 deletion and four (36.4%) had the exon 21 L858R point mutation. At disease progression, ctDNA was obtained from the plasma and other bodily fluids of these patients such as the cerebrospinal fluid (CSF), pleural effusion, ascites, and pericardial effusion, and the presence of EGFR mutations in these bodily fluids was determined. Interestingly, of 11 patients, an EGFR-sensitizing mutation (exon 21 L858R mutation or exon 19 deletion) could be detected in the CSF for 6 (54.5%) patients, pleural effusion for 3 (27.3%) patients, ascites for 1 (9.1%), and pericardial effusion for 1 patient (9.1%). On the other hand, sensitizing mutations at progression could be detected in the plasma for only 7 of 11 patients (63.6%). Therefore, the authors concluded that the concordance for mutation detection between FFPE tissue samples and plasma was 64% and that between FFPE tissue samples and other bodily fluids was 100%. Furthermore, the exon 20 T790M resistance mutation could be detected in the plasma for 3 (27.3%) and in other bodily fluids for 9 of the 11 patients (81.8%) at progression. These findings highlight the importance of collecting bodily fluids other than blood, whenever feasible, in particular from the site of progression, as this might overcome the limitations of plasma ctDNA for mutation detection.
Similar findings were reported by Zhang et al., who pointed out the differences pertaining to tumor cell sediments among the different types of bodily fluids. They identified that the cell-free DNA obtained from the bodily fluid supernatants allowed for higher detection rates and greater sensitivity for tumor-specific mutations when compared to plasma or sedimented cells.
Although these are single-cohort studies with a small number of patients, they highlight the increasing relevance of integrating “liquid biopsy” approaches into our standard care treatment pathways, especially for patients harboring sensitizing EGFR mutations. Several methods based on polymerase chain reaction (PCR) have been utilized to determine the presence of specific molecular alterations in ctDNA. These methods usually require a small amount of DNA for testing and have a good signal-to-noise ratio. However, except for droplet digital PCR, these methods are more suitable for qualitative rather than quantitative analyses. The method used for ctDNA-based analysis depends on the type of information required such as the detection of minimal residual disease (MRD) or certain specific mutations. Cost is another important parameter to bear in mind. Several affordable approaches have been used to sequence specific genes in a targeted manner, and at times, the entire human exome such as those based on oligonucleotide DNA capture. Does the type of fluid used influence the ability of detection of ctDNA? Different factors impact the sensitivity of the tests. In plasma, the extent of ctDNA shedding affects the sensitivity of the analysis. The shedding depends on tumor size and spread, vascularization, as well as the necrosis and apoptosis of cells. Those that release lower amounts of ctDNA will clearly have higher rates of false-negative results in the plasma.
Bearing this in mind, it is reasonable to expect higher concentrations of ctDNA in bodily fluids at the sites of progression (central nervous system, ascites, etc.) than in the plasma. This difference could be particularly prominent in non-shedding tumors.
Liquid biopsy has rapidly become an effective and non-invasive strategy. Based on this article and other recent works,, we should not limit this term to plasma alone but extend it to any fluid that has a clear correlation with cancer progression.
In the future, prospective clinical trials assessing the utility of liquid biopsy in monitoring disease progression and thereby leading to practice-changing protocols are warranted. Therefore, it is essential to standardize the laboratory procedures to obtain highly reproducible results, and this remains a hurdle yet to be overcome.
We have no doubt that ctDNA analyses in patients with NSCLC harboring an oncogenic driver mutation represent the present and no longer the future. It's possible applications are limitless and not restricted to EGFR mutations or to patients with metastatic disease. Many ongoing studies are assessing further roles for ctDNA. For instance, it could act as a possible biomarker for MRD in the case of radical surgery or radical chemotherapy and radiotherapy. This could guide us in treatment intensification and the selection of patients for whom adjuvant therapy should be considered.
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