Study Links Baseline Symptoms to Increased Lung Cancer Risk After Screening

Patients undergoing lung cancer screening who have respiratory or red flag symptoms are more likely to be diagnosed with lung cancer within one year, according to results of a study published in Chest. The study, based on data from the prospective observational SUMMIT study (ClinicalTrials.gov Identifier: NCT03934866), assessed the impact of respiratory and red flag symptoms on lung cancer screening outcomes after 1 year.

Eligible patients were aged 55 to 77 years, had a history of at least 30 pack-years of smoking, and were either currently smoking or had quit within the past 15 years. Other inclusion criteria were a 6-year lung cancer risk of at least 1.3% per validated prostate, lung, colorectal and ovarian risk-scoring models. Low-dose computed tomography was used for lung cancer screening. Between April 2019 and May 2021, patients underwent a baseline clinical assessment that evaluated self-reported respiratory history, demographics, and spirometry. They also provided information on common respiratory (cough and dyspnea) and red flag (hemoptysis and weight loss) symptoms.

A total of 13,035 patients (median age, 65 years; 57% men) were eligible for lung cancer screening and included in the final analysis. The majority of patients were symptomatic at baseline, with 759 (6%) reporting red flag symptoms and 9100 (70%) reporting nonspecific symptoms. Compared with the asymptomatic group, patients with red flag or nonspecific symptoms showed significantly greater smoking history and higher rates of airflow obstruction and active smoking (all P <.01). Among the total cohort, 4704 patients reported cough, which had been ongoing for at least 6 months in more than half (53%) the group. The most common prior diagnoses in patients with cough were chronic obstructive pulmonary disease (39%) and asthma (21%). Of patients with red flag symptoms, 475 (3.6%) reported unintentional weight loss, 313 (2.4%) reported hemoptysis, and 29 (4%) had both symptoms.

Overall, 375 (2.88%) patients were diagnosed with lung cancer within 2 years of screening. In the adjusted analysis, the presence of any baseline symptom (adjusted odds ratio [aOR], 1.45; 95% CI, 1.04-2.04; P = .03) and cough (aOR, 1.33; 95% CI, 1.03-1.71; P = .03) were associated with increased risk for lung cancer within the first year after screening. However, the association between baseline symptoms and lung cancer risk was not significant in the second year after screening (aOR, 0.85; 95% CI, 0.55-1.32; P =.47). Study limitations include the use of data from a secondary analysis of a prospective cohort, the small number of patients with red flag symptoms, and insufficient statistical power. “This study supports enrolling individuals in lung cancer screening despite the presence of symptoms, though expedited diagnostic workup of red flag symptoms and consideration of participant treatment tolerance is still recommended,” the researchers concluded.

In a separate study published in Nature, researchers investigated glucocorticoid-related genes (GRGs) and their causal association with non-small cell lung cancer (NSCLC). The study performed Mendelian randomization analysis based on cis-eQTL data from GTEx and eQTLGen databases, combined with SMR and Bayesian colocalization analyses, to identify GRGs with significant causal links to NSCLC. TCGA transcriptomic data verified the differential expression of core GRGs. Single-cell transcriptomic analysis revealed elevated GRGs cellular module scores in M2 macrophages of NSCLC tissues relative to adjacent normal tissues, while the MuSiC algorithm estimated cell-type abundance in bulk transcriptomic datasets.

The researchers integrated three intersecting genes (MRPS7, IQGAP1, EXOC2), M2 macrophage abundance, clinical parameters and radiomics features (extracted via nnU-Net-based segmentation) to construct a multi-omics Cox prognostic risk model. This model achieved an AUC > 0.9 for 1-year survival prediction in the training cohort and maintained robust performance (AUC 0.7–0.9) for 1–5-year survival in the independent test cohort. NSCLC tissue microarrays combined with cellular functional assays confirmed that MRPS7 not only exhibits aberrant overexpression in both NSCLC tissues and cell lines but also reveals a potential role in promoting the progression of NSCLC. The authors stated this is the first study to systematically elucidate the potential causal relationship between GRGs and NSCLC risk, which may be mediated by regulating M2 macrophage function, providing novel biomarkers for precise prognosis prediction and uncovering potential mechanisms underlying NSCLC oncogenesis.