Identification of biomarkers for the early detection of non-small cell lung cancer: a systematic review and meta-analysis

Abstract

Lung cancer (LC) causes few symptoms in the earliest stages, leading to one of the highest mortality rates among cancers. Low-dose computerised tomography (LDCT) is used to screen high-risk individuals, reducing the mortality rate by 20%. However, LDCT results in a high number of false positives and is associated with unnecessary follow-up and cost. Biomarkers with high sensitivities and specificities could assist in the early detection of LC, especially in patients with high-risk features. Carcinoembryonic antigen (CEA), cytokeratin 19 fragments, and cancer antigen 125 have been found to be highly expressed during the later stages of LC but have low sensitivity in the earliest stages. We determined the best biomarkers for the early diagnosis of LC, using a systematic review of eight databases. We identified 98 articles that focused on the identification and assessment of diagnostic biomarkers and achieved a pooled area under curve of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. Of the studies, 30 focussed on single/antigen panels, 22 on autoantibodies, 31 on miRNA and RNA panels, and 15 suggested the use of circulating DNA combined with CEA or NSE for early LC detection. Verification of blood biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFR21-1, antiHE4, OPNV), or both (HSP90α, CEA) along with miR-15b and miR-27b/miR-21 from sputum may improve early lung cancer detection. Further assessment is needed using appropriate sample sizes, control groups that include patients with non-malignant conditions, and standardised cut-off levels for each biomarker.

Can Tumour Antigens Provide Diagnostic Biomarkers for Early-Stage Non-small Cell Lung Cancer?

“…Tumour antigens have been investigated as biomarkers for the early diagnosis of LC [100], but most have low sensitivity and specificity, and are more accurate at identifying advanced disease. Further research will need to engage advanced methodologies to identify protein signatures associated with the specific cancer type.…”

“…We recently used the Preferred Reporting Items for Systematic Review (PRISMA) guidelines [98,99] to perform a systematic review of the literature [100] to address the research question -what are the most promising biomarkers for an early diagnosis of LC? The protocol was registered with PROSPERO (CRD42022336488) and we screened seven literature databases (CINAHL, MEDLINE, PubMed, Scopus, Web of Science, Cochrane library and Clinicaltrial.gov) from 1 January 1970 until 21st May 2023 using the following MeSH terms (cancer* or tumor* or tumour* or neoplasm* or carcinoma* or malignancy*) AND (lung* or pulmonary) AND (antigen* OR protein* OR RNA* OR ctDNA* OR miRNA* OR cell surface marker* OR inflammatory cell*) AND (early detection OR early diagnosis OR early biomarker OR early marker).…”

Can Tumour Antigens Act as Biomarkers for the Early Detection of Non-Small Cell Lung Cancer?

“…Biomarkers can be useful tools to evaluate effective treatment, monitor for disease recurrence after therapy, and enable prognostic prediction. miRNAs combined with autoantibodies/TAAs may aid in detecting early NSCLC [17], as the early stages have better survival rates and assist in decreasing the associated costs of the healthcare system.…”

“…We recently used the Preferred Reporting Items for Systematic Review (PRISMA) guidelines [37,38] to perform a systematic review of the literature [17] We identified 98 articles that focused on the identification and assessment of diagnostic biomarkers and achieved a pooled AUC of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. However, the heterogeneity was also considerable (I 2 = 98%, p < 0.00001).…”

Microbes for lung cancer detection: feasibility and limitations

“…Since tumor cells are transformed from normal cells, biomarkers are an objective assessment for the early detection of tumors. Some circulating antigens such as CYFRA21-1, CEA, NSE, and SCC-Ag have been used as markers for the clinical detection of lung cancer ( 7 , 8 ) ( Table 1 ).…”