G. Taino et al.: Radioprotection 2025, 60( 1), 76 – 83 79
The researchers showed also that 18 % of patients with lung cancer detected through LDCT, 22 % of patients with nonsmall cell lung cancer( non-small cell lung cancer, NSCLC) and up to 78.9 % of patients initially diagnosed with bronchioalveolar carcinoma were overdiagnosed, leading to further examinations with a significant percentage of comorbidities( 1.4 % in the LDCT group and 1.6 % in the chest x-ray group), such as hemothorax, lung collapse, and psychosocial consequences, therefore casting shadows on the cost-effectiveness of LDCT screening( Patz et al., 2014).
5 Biomarkers in the diagnosis of lung cancer
In view of the high sensitivity of LDCT, capable of identifying a non-calcific pulmonary nodule in one out of two tested subjects, the need to identify suspicious nodules more accurately has arisen. Many studies have considered blood biomarkers for early diagnosis: such markers should be able to distinguish aggressive from indolent disease to have a significant impact on mortality and lead to a change in treatments.
Research has focused on organ and tissue specific markers, such as microRNAs( miRNAs). MiRNAs are short sequences of non-coding RNA that regulate gene expression by linking to specific sequences of messenger RNA( mRNA), degrading it and inhibiting its translation. They could be ideal candidates in early-stage cancer screening, because by acting as extracellular messengers of biological signals deriving from the communication between the tumor and its surrounding microenvironment, they allow the identification of early changes relating to the biological reactivity of the host( Uso et al., 2014).
The use of these non-invasive tests, such as those based on miRNA, could help reduce the number of false positives of LDCT. The results of the bioMILD study showed that the combination of miRNA signature classifer( MSC) and LDCT reduced the false positive rate identified by the LDCT from 19.4 % to 3.7 % and that the risk groups identified by the MSC were found to be significantly associated with shorter survival. Furthermore, the MSC showed a high sensitivity( 87 %) and specificity( 81 %) and a negative predictive value of 99 %( Sozzi et al., 2014).
A systematic review was published in 2018 on the studies carried out between 2000 and 2015 about biomarkers in the diagnosis of lung cancer.( Chu et al., 2018):
Out of a total of 99 studies examined, only 3 were included, all phase 3 studies. The other studies did not meet the inclusion criteria.
The first study( Jett et al., 2014) evaluated the use and diagnostic performance of the Early CDT Lung ELISA test in 1613 patients in 48 different states. The positivity of the test included any antigen titration that had a dose response and one or more of these 7 autoantibodies: P53, NY-ESO-1, CAGE, GBU4-5, SOX2, HuD, MAGE A4. The patients were then followed up for a period of 6 months and then the clinician decided whether to make the diagnosis of neoplasm. Limitations of this study include unclear eligibility criteria, unclear diagnosis and cancer staging criteria.
The second study( Sozzi et al., 2014) evaluated the diagnostic performance of the MSC test in 1000 plasma samples from 4099 patients enrolled in the Multicenter Italian Lung Detection( MILD) Trial. These were smokers or former smokers ≥ 50 years of age with no history of cancer. Patients were followed up for 5 years. The limitations of this study are the lack of criteria in determining the size of the sample and the lack of identification of other pathologies and of alternative diagnoses to lung cancer.
The third study( Montani et al., 2015) evaluated the diagnostic relevance of the miR-test in a group of 1008 patients enrolled in the COSMOS study( Continuous Observation of Smoking Subjects) and in patients with diagnostic lung cancer outside the study( subjects > 50 years, smoking history > 20 pack years). The limitations of this study lie in the lack of available clinical information, the lack of sample determination criteria and the lack of other diagnoses of lung diseases.
All three groups of biomarkers studied showed a good diagnostic performance in the early diagnosis of lung cancer. The MSC test( 24 mRNA Classifier) is currently the best tool in terms of specificity, sensitivity and likelihood ratio. Its effectiveness is greater when combined with LDCT.
This leads to the concrete hypothesis that these biomarkers can be used complementarily to imaging in the cancer screening process. The limitations of these methods lie in the lack of data and scientific evidence, which are being sought through prospective phase 4 studies, which are still in progress.
Another review conducted by Gasparri et al.( 2018), looking at articles from 1976 to date regarding biomarkers in the diagnosis of lung cancer, have been examined with the aim of identifying a substance produced specifically by the tumor and easily found in the urine or blood. The following biomakers emerged from the analysis of the review. – miRNA: fluctuations in circulating miRNA levels are associated with various malignant and non-malignant diseases including lung neoplasms. In 2015 Wang et al.( 2015) identified a set of 5 miRNAs associated with the presence of cancer in a cohort of affected patients and healthy controls. Bianchi et al.( 2011) analyzed 174 serum samples from patients in the COSMOS study where they identified 34 miRNAs, then reduced to 13, which can be used in early diagnosis in asymptomatic individuals, with a specificity of 80 %. The advantages of using miRNAs are in the ease of sample collection and in its high stability. It is also possible to classify patients in different histological subtypes and in different disease stages. Studies are currently moving towards the development of a standardization of sample collection, identification and analysis procedures.
– VOLATILE ORGANIC COMPOUND( VOC). They are easily found by analyzing the exhaled air. They can be divided into different classes: saturated( ethane, pentane, aldehydes) and unsaturated( isoprene) hydrocarbons, compounds containing oxygen( acetone), sulfur( ethylmercaptan, dimethyl-sulfur) and nitrogen( dimethylamine, ammonium). The most commonly used are isoprene, acetone, ethanol, methanol and other alcohols and alkanes. These may be related to oxidative stress, the Warng effect