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In the era of precision medicine, molecular typing is crucial to guide targeted therapy of non-small cell lung cancer (NSCLC). However, there are still certain challenges in how to accurately and quickly perform molecular typing. In recent years, liquid biopsy technology has developed rapidly, and clinical practical evidence has increased, and its application in the treatment of NSCLC has become increasingly widespread. So what are the advantages and disadvantages of liquid biopsy compared with tissue biopsy? What is the value of liquid biopsy in the detection of rare targets of NSCLC? This article will explain this.
How much do I know about liquid biopsy?
Liquid biopsy detection mainly includes circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, microRNAs (miRNA), peripheral blood circulating RNA, tumor-induced platelets (TEPs) and circulating tumor vascular endothelial cells (CTECs). The application of liquid biopsy in the field of lung cancer includes early diagnosis, guidance on treatment and prognosis prediction, etc. [1].
ctDNA, as the most commonly used liquid biomarker, has been recommended by many authoritative guidelines at home and abroad. So what is ctDNA? In the plasma of normal people, there is cell free DNA (cfDNA) from normal cells, but the levels are low. However, under stress conditions, including exercise, inflammation, surgery or tissue damage, cfDNA levels will increase. ctDNA is a type of cfDNA, which is a small nucleic acid released by apoptotic or necrotic tumor cells and encodes the genes of tumor cells. The amount of ctDNA entering the blood is affected by a variety of factors, such as tumor location, size, metastasis, vascular infiltration, tumor status and staging. Therefore, the proportion of ctDNA varies greatly, ranging from 0.1% to 90% [1].
At present, ctDNA detection technology mainly includes ARMS, digital PCR and second-generation sequencing (NGS). They can all perform qualitative and quantitative analysis of ctDNA and accurately detect ctDNA[1] through DNA amplification. However, according to the consensus on liquid biopsy of advanced NSCLC issued by the International Association for Lung Cancer Research (IASLC), ctDNA detection should be preferred for NGS[2]. The consensus points out that, as the guidelines recommend more oncogene targets evaluated in advanced NSCLC, plasma ctDNA testing should be performed through a clinically validated NG platform rather than a single-gene, PCR-based approach. If due to technical and economic constraints, single gene or multiple approaches may be a suitable alternative in the case where plasma NGS detection is not accessible. However, single gene detection is incomplete and if the result is negative, additional biomarker detection must be performed [2].
How to choose tissue detection and liquid biopsy?
tissue detection has high sensitivity and high specificity, and was previously considered the "gold standard" of molecular typing [2]. However, tissue biopsy has many limitations. Studies have shown that only 18% of NSCLC patients have sufficient tumor samples to guide the complete tissue genotyping of 8 genomic biomarkers (EGFR mutation, ALK fusion, ROS1 fusion, BRAF V600E mutation, RET fusion, MET amplification, MET14 exon jump mutation, HER2 mutation) recommended by [3]. Moreover, compared with liquid biopsy, the turnover time for tissue biopsy is longer, especially when secondary biopsy is required.
Liquid biopsy has the advantages of short turnover time, low trauma, and easy to repeat detection, which can compensate for the limitations of tissue biopsy to a certain extent. Furthermore, liquid biopsy can overcome tumor heterogeneity after previous treatments, so it may be a preferred method for monitoring the efficacy of targeted therapy and can be used to evaluate micro-residual lesions (MRD) and drug resistance mechanisms [2]. However, liquid biopsy also has its limitations, especially false negatives (variances that actually exist in the tumor but are not detected) are an important issue in ctDNA detection, which may be due to low plasma ctDNA levels, insufficient detection sensitivity or "non-falling" tumors (i.e., the tumor itself does not release ctDNA).
IASLC advanced NSCLC liquid biopsy consensus states that plasma ctDNA can now be considered an effective tool for genotyping of newly diagnosed advanced NSCLC patients, and the results are often complementary to tissue analysis results.In oncogene-driven NSCLC, ctDNA is preferred to evaluate the mechanism of resistance (plasma priority) when acquired resistance occurs after treatment with tyrosine kinase inhibitors (TKI); if plasma ctDNA does not provide information, tissue biopsy is repeated. Due to its ease of continuous sampling and high patient acceptance, ctDNA has gradually become the preferred method for real-time monitoring [2]. In addition, the consensus points out that for NSCLC patients carrying oncogenes, liquid biopsy can not only be used as a supplement to tissue analysis, but also as an initial method for evaluating and monitoring the efficacy of targeted therapy in biomarker at diagnosis (plasma priority). Plasma-first approaches are suitable for identifying drug-resistant mechanisms for targeted therapy in a variety of clinical settings [2]. What are the detection of rare NSCLC targets that
ctDNA can be used for?
In addition, this year, the European Society of Oncology (ESMO) Precision Medicine Working Group released a report on the application of ctDNA in the clinical practice of tumors, which recommended ctDNA detection in advanced NSCLC [4]. In addition to common EGFR mutations, the expert group also recommends ctDNA for detection of rare NSCLC targets such as ALK fusion, MET14 exon jump mutation, MET amplification, and RET fusion. The specific indications and recommendations are shown in the following table:
Table 1 NSCLC ctDNA detection recommendation
targets different rare target mutations NSCLC. Several studies have confirmed the value of ctDNA liquid biopsy. VISION and GEOMETRY mono-1 studies show that ctDNA can be used to detect exon jump mutations in MET14, but when the test result is negative, tissue sample retest [5,6] should be considered. The BFAST trial is the first clinical study to prospectively identify NSCLC patients with driver gene mutations using plasma-based NGS. Of the 2219 patients who were screened, 98.6% obtained plasma-based NGS results. Among them, 5.4% of the patients tested positive for ALK, which was consistent with the results reported in previous literature; the median follow-up time was 12.6 months, the confirmed objective response rate (ORR) evaluated by the investigator was 87.4%, and the confirmed ORR evaluated by the independent review agency (IRF) was 92.0%, which was close to the results reported by the ALEX study [7]. In addition, the ROS1 cohort results of the BFAST study published at the 2022 American Society of Clinical Oncology (ASCO) also support the use of plasma-based NGS for detection of ROS1 gene fusion status and guide the treatment of [8].
In short, although tissue testing is still the "gold standard" for NSCLC gene detection, the role of liquid biopsy cannot be ignored. Especially when tissue specimens are out of reach or insufficient, liquid biopsy will provide more NSCLC with opportunities for accurate diagnosis, improve the detection rate of rare targets such as ALK, MET, and ROS1, and then guide subsequent precise treatment, so that patients can benefit more. In the future, we hope that with the development of detection technology, liquid biopsy will play a greater value in the entire NSCLC management.
References
[1]Li W, et al. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring. Mol Cancer. 2022;21(1):25.
[2]Rolfo C, et al. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-1662.
[3]Leighl NB, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res. 2019;25(15):4691-4700.
[4]Pascual J, et al. ESMO recommendations on the use of circulation tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022;33(8):750-768.
[5]Xiuning Le, et al. Liquid biopsy to detect MET exon 14 skipping (METex14) and MET amplification in patients with advanced NSCLC: Biomarker analysis from VISION study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3385.
[6]Rebecca S. et al. Accurate detection of MET exon 14 skipping using a liquid biopsy assay in NSCLC patients in the GEOMETRY mono-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB056.
[7]Dziadziuszko R, et al. Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort. J Thorac Oncol. 2021;16(12):2040-2050.
[8]Solange Peters, et al. Efficacy/safety of enrectinib in patients (pts) with ROS1-positive (ROS1+) advanced/metastatic NSCLC from the Blood First Assay Screening Trial (BFAST). 2022 ASCO, LBA9023.
This material is provided by AstraZeneca and is for reference only for medical and health professionals
Approval number: CN-106132 Expiry date: 2023-2-17
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
In oncogene-driven NSCLC, ctDNA is preferred to evaluate the mechanism of resistance (plasma priority) when acquired resistance occurs after treatment with tyrosine kinase inhibitors (TKI); if plasma ctDNA does not provide information, tissue biopsy is repeated. Due to its ease of continuous sampling and high patient acceptance, ctDNA has gradually become the preferred method for real-time monitoring [2]. In addition, the consensus points out that for NSCLC patients carrying oncogenes, liquid biopsy can not only be used as a supplement to tissue analysis, but also as an initial method for evaluating and monitoring the efficacy of targeted therapy in biomarker at diagnosis (plasma priority). Plasma-first approaches are suitable for identifying drug-resistant mechanisms for targeted therapy in a variety of clinical settings [2]. What are the detection of rare NSCLC targets that ctDNA can be used for?
In addition, this year, the European Society of Oncology (ESMO) Precision Medicine Working Group released a report on the application of ctDNA in the clinical practice of tumors, which recommended ctDNA detection in advanced NSCLC [4]. In addition to common EGFR mutations, the expert group also recommends ctDNA for detection of rare NSCLC targets such as ALK fusion, MET14 exon jump mutation, MET amplification, and RET fusion. The specific indications and recommendations are shown in the following table:
Table 1 NSCLC ctDNA detection recommendation
targets different rare target mutations NSCLC. Several studies have confirmed the value of ctDNA liquid biopsy. VISION and GEOMETRY mono-1 studies show that ctDNA can be used to detect exon jump mutations in MET14, but when the test result is negative, tissue sample retest [5,6] should be considered. The BFAST trial is the first clinical study to prospectively identify NSCLC patients with driver gene mutations using plasma-based NGS. Of the 2219 patients who were screened, 98.6% obtained plasma-based NGS results. Among them, 5.4% of the patients tested positive for ALK, which was consistent with the results reported in previous literature; the median follow-up time was 12.6 months, the confirmed objective response rate (ORR) evaluated by the investigator was 87.4%, and the confirmed ORR evaluated by the independent review agency (IRF) was 92.0%, which was close to the results reported by the ALEX study [7]. In addition, the ROS1 cohort results of the BFAST study published at the 2022 American Society of Clinical Oncology (ASCO) also support the use of plasma-based NGS for detection of ROS1 gene fusion status and guide the treatment of [8].
In short, although tissue testing is still the "gold standard" for NSCLC gene detection, the role of liquid biopsy cannot be ignored. Especially when tissue specimens are out of reach or insufficient, liquid biopsy will provide more NSCLC with opportunities for accurate diagnosis, improve the detection rate of rare targets such as ALK, MET, and ROS1, and then guide subsequent precise treatment, so that patients can benefit more. In the future, we hope that with the development of detection technology, liquid biopsy will play a greater value in the entire NSCLC management.
References
[1]Li W, et al. Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring. Mol Cancer. 2022;21(1):25.
[2]Rolfo C, et al. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16(10):1647-1662.
[3]Leighl NB, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res. 2019;25(15):4691-4700.
[4]Pascual J, et al. ESMO recommendations on the use of circulation tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022;33(8):750-768.
[5]Xiuning Le, et al. Liquid biopsy to detect MET exon 14 skipping (METex14) and MET amplification in patients with advanced NSCLC: Biomarker analysis from VISION study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3385.
[6]Rebecca S. et al. Accurate detection of MET exon 14 skipping using a liquid biopsy assay in NSCLC patients in the GEOMETRY mono-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB056.
[7]Dziadziuszko R, et al. Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort. J Thorac Oncol. 2021;16(12):2040-2050.
[8]Solange Peters, et al. Efficacy/safety of enrectinib in patients (pts) with ROS1-positive (ROS1+) advanced/metastatic NSCLC from the Blood First Assay Screening Trial (BFAST). 2022 ASCO, LBA9023.
This material is provided by AstraZeneca and is for reference only for medical and health professionals
Approval number: CN-106132 Expiry date: 2023-2-17
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform
