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Liquid biopsy genotyping in lung cancer: ready for clinical utility?

View Article: PubMed Central - PubMed

ABSTRACT

Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy.

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A. The suggested paradigm for using plasma genotyping in clinical utility. For NSCLC patients when tumor samples are not eligible for EGFR mutation assay or the result of EGFR genotyping is inclusive at initial diagnosis, ctDNA can be used to complement tissue biopsy guiding EGFR-TKI treatment. B. Among patients who developed resistance to first-line EGFR-TKI, liquid biopsies can compensate tumor biopsies because tumor biopsies themselves provide an incomplete window into the heterogeneous nature of acquired drug resistance.
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Figure 2: A. The suggested paradigm for using plasma genotyping in clinical utility. For NSCLC patients when tumor samples are not eligible for EGFR mutation assay or the result of EGFR genotyping is inclusive at initial diagnosis, ctDNA can be used to complement tissue biopsy guiding EGFR-TKI treatment. B. Among patients who developed resistance to first-line EGFR-TKI, liquid biopsies can compensate tumor biopsies because tumor biopsies themselves provide an incomplete window into the heterogeneous nature of acquired drug resistance.

Mentions: Among patients who developed resistance to first line EGFR-TKI, many are too weak for re-biopsy, and a wide heterogeneity in resistance mechanisms may require its own therapeutic strategy [85, 106]. Therefore, liquid biopsies may compensate for the limitations of tissue biopsies. Liquid biopsies use less invasive techniques and are capable of capturing tumor heterogeneity. Although Oxnard et al [93] proposed a paradigm where plasma genotyping is used as a screening test for T790M, before performing an EGFR resistance biopsy, the high false-positive rate (30%) in plasma DNA and the outcomes of these patients depended on tumor genotyping. This dependence caused clinicians to become concerned about whether positive plasma DNA can be used to guide third-generation TKI use for patient developing drug resistance. In a recent update, the consensus statement on optimizing the management of EGFR mutation-positive NSCLC is that tissue-based molecular analysis remains the gold standard for establishing the initial diagnosis, as well as for evaluation of TKI resistance [107]. Recently, Sundaresan et al [108] compared the T790M genotype from tumor biopsies with an analysis of simultaneously collected CTCs and ctDNA. T790M genotypes were successfully obtained in 30 tumor biopsies (75%), 28 CTC samples (70%), and 32 ctDNA samples (80%). Although CTC-based and ctDNA-based genotyping failed to detect T790M in 20% to 30% of all cases, both assays together enabled genotyping in all patients with available blood samples and identified the T790M mutation in 14 patients (35%) in whom the concurrent tumor biopsy was negative or indeterminate. The finding was compatible with that of Oxnard et al [93, 109], wherein cases that were T790M negative in the tumor but were T790M positive in the plasma were further studied by use of orthogonal plasma genotyping assays such as ddPCR or Cobas®, and 78% of these cases could be confirmed as positive. Therefore, liquid biopsies can compensate for tumor biopsies because individual tumor biopsies alone provide an incomplete window into the heterogeneous nature of acquired drug resistance. Only their correlation with the clinical response to third-generation EGFR inhibitors may ultimately provide a true “gold standard” for T790M genotyping. The suggested paradigm for the use of plasma genotyping to complement tissue genotyping is summarized in Figure 2.


Liquid biopsy genotyping in lung cancer: ready for clinical utility?
A. The suggested paradigm for using plasma genotyping in clinical utility. For NSCLC patients when tumor samples are not eligible for EGFR mutation assay or the result of EGFR genotyping is inclusive at initial diagnosis, ctDNA can be used to complement tissue biopsy guiding EGFR-TKI treatment. B. Among patients who developed resistance to first-line EGFR-TKI, liquid biopsies can compensate tumor biopsies because tumor biopsies themselves provide an incomplete window into the heterogeneous nature of acquired drug resistance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392351&req=5

Figure 2: A. The suggested paradigm for using plasma genotyping in clinical utility. For NSCLC patients when tumor samples are not eligible for EGFR mutation assay or the result of EGFR genotyping is inclusive at initial diagnosis, ctDNA can be used to complement tissue biopsy guiding EGFR-TKI treatment. B. Among patients who developed resistance to first-line EGFR-TKI, liquid biopsies can compensate tumor biopsies because tumor biopsies themselves provide an incomplete window into the heterogeneous nature of acquired drug resistance.
Mentions: Among patients who developed resistance to first line EGFR-TKI, many are too weak for re-biopsy, and a wide heterogeneity in resistance mechanisms may require its own therapeutic strategy [85, 106]. Therefore, liquid biopsies may compensate for the limitations of tissue biopsies. Liquid biopsies use less invasive techniques and are capable of capturing tumor heterogeneity. Although Oxnard et al [93] proposed a paradigm where plasma genotyping is used as a screening test for T790M, before performing an EGFR resistance biopsy, the high false-positive rate (30%) in plasma DNA and the outcomes of these patients depended on tumor genotyping. This dependence caused clinicians to become concerned about whether positive plasma DNA can be used to guide third-generation TKI use for patient developing drug resistance. In a recent update, the consensus statement on optimizing the management of EGFR mutation-positive NSCLC is that tissue-based molecular analysis remains the gold standard for establishing the initial diagnosis, as well as for evaluation of TKI resistance [107]. Recently, Sundaresan et al [108] compared the T790M genotype from tumor biopsies with an analysis of simultaneously collected CTCs and ctDNA. T790M genotypes were successfully obtained in 30 tumor biopsies (75%), 28 CTC samples (70%), and 32 ctDNA samples (80%). Although CTC-based and ctDNA-based genotyping failed to detect T790M in 20% to 30% of all cases, both assays together enabled genotyping in all patients with available blood samples and identified the T790M mutation in 14 patients (35%) in whom the concurrent tumor biopsy was negative or indeterminate. The finding was compatible with that of Oxnard et al [93, 109], wherein cases that were T790M negative in the tumor but were T790M positive in the plasma were further studied by use of orthogonal plasma genotyping assays such as ddPCR or Cobas®, and 78% of these cases could be confirmed as positive. Therefore, liquid biopsies can compensate for tumor biopsies because individual tumor biopsies alone provide an incomplete window into the heterogeneous nature of acquired drug resistance. Only their correlation with the clinical response to third-generation EGFR inhibitors may ultimately provide a true “gold standard” for T790M genotyping. The suggested paradigm for the use of plasma genotyping to complement tissue genotyping is summarized in Figure 2.

View Article: PubMed Central - PubMed

ABSTRACT

Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy.

No MeSH data available.


Related in: MedlinePlus