Lung cancer is one of the malignancies with the highest incidence and mortality rates in the world, and seriously endangers human health [1]. Due to the lack of effective and accurate early diagnosis methods, many patients are diagnosed with advanced lung cancer and miss the optimal time for treatment, resulting in poor prognostic outcomes [2]. Traditional diagnostic methods include endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), magnetic resonance imaging (MRI), low-dose spiral CT (LDCT), and histopathological diagnosis, but these methods have some drawbacks, such as invasiveness and radiation risks [3]. As a result, liquid biopsies are gaining attention due to their non-invasive and continuous sampling capabilities. At present, liquid biopsy biomarkers have achieved many results in the early diagnosis and prognosis assessment of lung cancer. In April 2024, the Journal of Experimental & Clinical Cancer Research published an online review titled "Liquid biopsy techniques and lung cancer: diagnosis, monitoring and evaluation", which aims to provide an overview of the molecular biomarkers and detection methods used in liquid biopsy of lung cancer. and elaborate its practical application [4]. This article focuses on the section "The potential of liquid biopsy in lung cancer" in this review.
Potential for the clinical application of liquid biopsy in lung cancer
In recent years, liquid biopsy has been seamlessly integrated into clinical practice. Identifying multiple tumor biomarkers in body fluids enables liquid biopsy to play a key role in the early screening and diagnosis of lung cancer. At the same time, liquid biopsy is also essential in monitoring response to treatment and assessing the prognosis of tumor recurrence and metastasis.
Diagnosis of lung cancer
Current methods for detecting and diagnosing lung cancer include endoscopic ultrasound-guided fine-needle aspiration biopsy, magnetic resonance imaging and computed tomography, and pathological diagnosis. Although pathological tissue testing is the gold standard, invasive procedures are unavoidable. Given that the time lag between the formation of lung cancer and the onset of symptoms can be years, liquid biopsy has emerged as an important tool for early screening. This provides a valuable opportunity to improve treatment outcomes and survival rates for lung cancer patients.
Circulating tumor cells (CTCs) can be present at all stages of lung cancer progression, but they are more easily detectable in the blood at an advanced stage due to the critical role of CTCs in distant metastasis. In the early stage of cancer, the limited amount of circulating tumor cells in the blood has become a major challenge for the early diagnosis of lung cancer. Fortunately, technological advances have increased the detection rate of CTCs and identified high-frequency mutant genes through next-generation sequencing (NGS) of CTCs, providing hope for early diagnosis. In the future, more technologies may be developed and optimized to further improve the sensitivity of CTC detection.
Circulating tumor DNA (ctDNA), derived from apoptotic or necrotic tumor cells, has shown compelling potential in the diagnosis of early lung cancer. Significantly higher plasma ctDNA levels in lung cancer patients compared to patients with respiratory tract inflammation highlight the diagnostic relevance of ctDNA to lung cancer. At the same time, the methylation status of ctDNA provides hope for early diagnosis of lung cancer. Although further exploratory studies in clinical trials are needed, methylation markers provide a non-invasive ctDNA diagnostic strategy that may be used for early diagnosis of lung cancer in the future.
MicroRNAs (miRNAs) also have potential as biomarkers, but there is still a gap between them and clinical applications. Specific miRNAs are associated with tumor stage and clinical response in NSCLC. Long non-coding RNAs and circular RNAs exhibit different expressions in lung cancer blood and tissues, which may provide insights into the clinical features of lung cancer, but more experimental and clinical studies are needed to confirm and confirm their diagnostic value in lung cancer diagnosis. Exosomes (EVs) carry tumor-related bioinformation and can be used as potential biomarkers for early-stage lung cancer. Among them, standardized EVs isolation and detection technology is essential to promote its full implementation in the early diagnosis of lung cancer, and at the same time, more extensive clinical studies are still needed to verify the diagnostic value of EVs in the future. Tumor metabolites are detected by high-resolution mass spectrometry to analyze metabolite changes in the blood, providing potential markers for early diagnosis. In the early stages of tumorigenesis, both RNA and proteins in tumor-induced platelets (TEPs) are altered, and detection of these molecular information may provide a means for early diagnosis. In addition, the identification of abnormal changes in TAAs in the serum of patients during tumor growth also provides a way for early diagnosis.
Monitor response to treatment
Surgical resection remains the most effective treatment for early-stage lung cancer. However, for patients with advanced lung cancer, chemotherapy becomes a key option for remission of clinical symptoms and prolongation of survival if they are not candidates for surgical resection. Although chemotherapy is effective, chemoresistance poses a significant challenge, prompting the exploration of strategies such as liquid biopsy to assess treatment response and develop a personalized protocol.
At present, a variety of sequencing technologies can characterize the molecular signatures in CTCs and provide a reference for the treatment response of cancer patients. Sequencing technology for CTCs provides a pathway for monitoring chemoresistance by analyzing the genes they carry, including mutations in KRAS, HER2, and TP53. Assessment of programmed death-ligand 1 (PD-L1) status on CTCs allows for an assessment of the effectiveness of immunotherapy in lung cancer patients. The persistence of CTCs during treatment may predict poor prognosis and chemoresistance in patients with advanced NSCLC. Overall, the detection and analysis of CTCs is of great value for assessing and monitoring patient response to treatment and is expected to inform future clinical decision-making.
Comprehensive elucidation of ctDNA can be used as a biomarker to effectively track lung cancer progression by dynamically monitoring disease trajectories, gaining insight into patient response to treatment, and detecting minimal residual disease (MRD). Previous studies have demonstrated the value of ctDNA in monitoring disease progression, particularly in patients treated with tyrosine kinase inhibitors (TKIs). By identifying chemoresistance mechanisms, ctDNA can help adjust clinical treatment strategies.
Treatment resistance is a major challenge for cancer patients receiving conservative treatment, and specific non-coding RNAs (ncRNAs) have been implicated in the development of treatment resistance in lung cancer. The study confirmed that miRNA levels have the potential to be used as an informative indicator of disease progression for dynamic monitoring and evaluation of treatment response in cancer patients. EVs play an important role in acquired drug resistance, and monitoring the formation and release of EVs can help assess response to lung cancer cell therapy. Metabolic reprogramming plays an important role in tumor progression, and detection of metabolites can serve as an option to monitor treatment response. TEPs are not only biomarkers for lung cancer diagnosis, but also monitor the response to cancer treatment. As potential predictors, TAAs can be used to predict the survival prognosis of cancer patients and the effectiveness of immunotherapy, as well as to provide emerging targets for personalized tumor immunotherapy.
Prognostic assessment, recurrence monitoring, and metastasis monitoring
Accurate prognostic assessment is essential to determine appropriate treatment strategies for patients with resectable lung cancer. Ideally, biomarkers for prognostic assessment should have both high sensitivity and specificity, although finding markers that meet both criteria can be challenging. The selection of markers for lung cancer diagnosis and prognostic assessment should strike a balance between high sensitivity and specificity to meet different clinical needs and goals.
CTCs and ctDNA have great potential in the prognostic assessment and metastatic recurrence monitoring of lung cancer patients, and these biomarkers are mainly used to predict the survival prognosis and metastatic recurrence trend of patients, which is helpful for the development of personalized clinical strategies. Previous studies have shown that CTC counts can not only enable early diagnosis of lung cancer, but also that specific CTC subsets can also reflect tumor status, including its metastatic tendency. In addition, CTC testing and plasma metabolite analysis may be helpful in diagnosing early-stage lung cancer and identifying patients at risk of disease recurrence.
Currently, ctDNA studies are focusing on analyzing multiple mutations, including EGFR, ALK, and KRAS, to assess the prognosis and disease recurrence of lung cancer patients. Detection of EGFR mutations in lung cancer using ctDNA can assess a variety of clinical information, such as response to osimertinib therapy, survival time, and risk of distant metastasis of lung cancer. Perioperative ctDNA analysis can detect MRD in resectable NSCLC earlier than traditional radiological imaging, providing a means to monitor tumor recurrence and metastasis. In addition, ctDNA can not only monitor lung cancer recurrence and metastasis, but also provide a new avenue for ctDNA-driven therapeutic research through the development trajectory of lung cancer characterization.
This study confirmed that non-coding RNA has potential clinical applications as liquid biopsy in the prognostic assessment and tumor metastasis monitoring of lung cancer, and it uses a multivariate risk prediction model to evaluate the prognosis and metastatic risk of lung cancer through survival analysis and tumor TMN staging. Proteins carried by EVs, such as WASL, STK10 and WNK1, have potential in the diagnosis and prognosis evaluation of lung cancer. The expression of PD-L1 in EVs is associated with lung cancer cells evading the immune system. Metabolism-related gene expression can facilitate the analysis of prognosis and metastasis of lung cancer. Specific genes such as PSMC6, SMOX, and SMS are independent prognostic factors for lung cancer. TEP RNA, as a form of liquid biopsy, is promising in tumor prognosis, recurrence monitoring, and metastasis assessment. Changes in the expression levels of specific TEP RNAs can be used for the diagnosis and prediction of progression of lung cancer. The expression levels of TAAs can be used to monitor tumor recurrence and metastasis. For example, TAA-L6, PD-L1, and MAGE-B2 are potential biomarkers in liquid biopsies to monitor lung cancer.
Liquid biopsy and immunotherapy for lung cancer
Tumor immunotherapy aims to activate the body's immune response to tumors by enhancing the immunogenicity of tumor cells so that they are more susceptible to destruction by effector cells. In the field of lung cancer immunotherapy, liquid biopsy has become a valuable tool for assessing and monitoring the effects of treatment.
A large body of evidence-based medical data now supports the use of CTCs for the prognosis of lung cancer patients and the evaluation of the effectiveness of immunotherapy. Among them, CTCs in liquid biopsies provide valuable information about PD-L1 expression, and multiple studies have explored the effect of PD-L1-positive CTCs on clinical outcomes in lung cancer patients treated with immune checkpoint inhibitors. Due to the lack of standardized PD-L1 expression measurement procedures, further research is needed in the future to establish a unified method for the detection of CTCs and the analysis of PD-L1 antibodies.
Studies evaluating blood cfDNA levels as predictors of clinical outcomes in patients receiving immunotherapy have found that lower cfDNA levels are associated with improved clinical outcomes with immunotherapy for non-small cell lung cancer (NSCLC). However, due to the variability of cfDNA in different lung cancer subtypes, the application of total cfDNA levels as a biomarker for lung cancer still needs to be verified by further studies in the future. In addition, ctDNA analysis can identify mutations associated with immunotherapy sensitivity, helping to develop personalized treatment strategies.
Changes in PD-L1 mRNA and protein levels in EVs can be used as a method to assess the success of immunotherapy. The genetic content within EVs, including miRNAs, is critical in assessing the success of immunotherapy. The study of plasma metabolites provides a potential target for prognostic assessment and metastatic monitoring in lung cancer patients, although their effectiveness in lung cancer immunotherapy still needs further research. Increased PD-L1 expression in TEP and the immunopeptidome of TAA are associated with immunotherapy response, but the current literature is limited, and more research is needed to validate these potential therapeutic pathways.
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Disclaimer: This article is published with the support of AstraZeneca and is intended for healthcare professionals only
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