Biomarkers Suitable for Early Detection of Intrathoracic Cancers in Primary Care: A Systematic Review

Our plain-English summary of Biomarkers Suitable for Early Detection of Intrathoracic Cancers in Primary Care: A Systematic Review, by W. Hamad, B. Grigore, H. Walford, et al (Cancer Epidemiology, Biomarkers & Prevention, 2025).

The study

• Authors: W. Hamad, B. Grigore, H. Walford, J. Peters, P. Alexandris, S. Bonfield, L. Standen, R. Boscott, D. Behiyat, I. Kuhn, R.D. Neal, F.M. Walter, N. Calanzani
• Journal: Cancer Epidemiology, Biomarkers & Prevention
• Published: 2025;34(1):19-34
• Type of article: Systematic review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Intrathoracic cancers, including lung cancer, mesothelioma, and thymoma, present diagnostic challenges in primary care. Biomarkers could resolve some challenges. We synthesized evidence on biomarker performance for intrathoracic cancer detection in low-prevalence settings. A search in Embase and MEDLINE included studies that recruited participants with suspected intrathoracic cancer and reported on at least one diagnostic measure for a validated, noninvasive biomarker. Studies were excluded if participants were recruited based on a preestablished diagnosis. A total of 52 studies were included, reporting on 108 individual biomarkers and panels. Carcinoembryonic antigen, CYFRA 21-1, and VEGF were evaluated for lung cancer and mesothelioma. For lung cancer, carcinoembryonic antigen and CYFRA 21-1 were the most studied, with AUCs of 0.48 to -0.90 and 0.48 to -0.83, respectively. Pro-gastrin-releasing peptide (Pro-GRP) and neuron-specific enolase (NSE) had the highest negative predictive values (NPV) (98.2% and 96.9%, respectively), whereas Early Cancer Detection Test - Lung (Early CDT) and miRNA signature classifier panels showed NPVs of 99.3% and 99.0%, respectively, in smokers. For mesothelioma, fibrillin-3 and mesothelin plus osteopontin had AUCs of 0.93 and 0.91, respectively. Thymoma panels (binding AcHR + StrAb and binding AcHR + modulating AcHR + StrAb) had 100% NPVs in patients with myasthenia gravis. The review highlights the performance of some biomarkers. However, few were evaluated in low-prevalence settings. Further evaluation is necessary before implementing these biomarkers for intrathoracic cancers in primary care.

©2024 The Authors; Published by the American Association for Cancer Research.

In plain English

This article was a systematic review, not a new patient study. The authors searched MEDLINE and Embase (January 1, 2000, to September 19, 2023) for studies of noninvasive tests, mostly blood tests, in people suspected of lung cancer, mesothelioma or thymoma before diagnosis. They included 52 studies with 28,655 participants, 11,566 with an intrathoracic cancer. Of these, 45 studies were on lung cancer, six on mesothelioma (three in people with asbestos exposure) and one on thymoma. Findings were described in words, not pooled statistically. For mesothelioma, one study of patients with pleural effusion reported an AUC (a measure of how well a test separates people with and without cancer; higher is better) of 0.93 for a marker the review calls fibrillin-3. Serum mesothelin combined with plasma osteopontin gave an AUC of 0.912 in symptomatic patients. In the one study of asbestos-exposed participants that reported it, mesothelin had a negative predictive value of 96.9% (95% CI, 92.4%–99.2%). The authors noted that few studies came from low-prevalence settings such as primary care. They concluded that further assessment is required before these biomarkers are used there.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Systematic review of diagnostic accuracy studies with narrative synthesis (no meta-analysis)
• Who was studied: 52 studies (45 on lung cancer, 6 on mesothelioma, 1 on thymoma) found in MEDLINE and Embase, published January 1, 2000, to September 19, 2023. They involved 28,655 adults suspected of intrathoracic cancer: 11,566 diagnosed with cancer and 17,089 without cancer. 46 studies were in hospital settings and 6 in community settings.
• Exposure: Noninvasive biomarkers (mainly blood proteins; also DNA, cells, breath and sputum markers) tested to detect lung cancer, mesothelioma and thymoma. Three of the mesothelioma studies recruited participants with asbestos exposure; no fiber types were reported.
• Main results:
  • Of the 52 included studies, six focused on mesothelioma and one on thymoma.
  • For lung cancer, CEA sensitivity in the 14 studies reporting it ranged from 16.4% to 88.4%.
  • In one lung cancer study of participants with clinical suspicion, NSE had an NPV of 96.9% and an AUC of 0.89, and pro-GRP had an NPV of 98.2% and an AUC of 0.94. In the table, these values are for small cell lung cancer.
  • In higher-risk populations for lung cancer, Early CDT had an NPV of 99.3% (95% CI, 99.1%–99.5%) and the miRNA signature classifier panel had an NPV of 99%. Their reported sensitivities were 32.1% and 87% respectively.
  • For mesothelioma in participants with pleural effusion, CEA had a sensitivity of 3.1% and a specificity of 91%. Fibrillin-3 had an AUC of 0.93 and was reported in the text as having 100% sensitivity and specificity.
  • In symptomatic patients evaluated for mesothelioma, mesothelin had an AUC of 0.8. Serum mesothelin combined with plasma osteopontin had an AUC of 0.912.
  • Among participants with asbestos exposure studied for mesothelioma, HMGB1 had a sensitivity of 100% but an AUC of 0.56 (0.39–0.73). Mesothelin had an NPV of 96.9% (95% CI, 92.4%–99.2%). Table 4 shows this mesothelin result came from a single included study (Smolkova and colleagues).
  • For thymoma, the NPVs of four antibody biomarkers in participants with myasthenia gravis ranged from 99.3% to 100%.
  • The risk of bias assessment found the most high-risk ratings in the index test domain (27 studies). This was mainly due to thresholds that were not prespecified or test interpretation that may not have been independent of the reference standard.
• The authors' conclusion: The authors concluded that few studies were done in low-prevalence settings. They stated that further assessment is required before biomarkers are used to detect intrathoracic cancers in low-prevalence settings such as primary care.
• Limitations the authors state:
  • Heterogeneity, particularly in the populations of the included studies, was the primary limitation and prevented meta-analysis.
  • Most of the evidence came from settings with higher cancer prevalence, which limits applicability to primary care.
  • No minimum sample size was set for mesothelioma and thymoma studies, so studies with lower statistical power may have been included.
  • Some included studies used two-gate designs, and external validation was limited, which decreased the reliability of the findings.
  • Lung nodule studies often did not describe why participants were imaged.
  • Data extraction was done by one reviewer and checked by a second.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Intrathoracic, Systematic Review, Lung Cancer, Mesothelioma, Carcinoembryonic Antigen (CEA), Mesothelin, Osteopontin.

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