Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers

Our plain-English summary of Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers, by B. Dalal, T. Tada, D.P. Patel, et al (Clinical Cancer Research, 2024).

The study

• Authors: B. Dalal, T. Tada, D.P. Patel, S.R. Pine, M. Khan, T. Oike, Y. Kanke, A.L. Parker, M. Haznadar, L. Toulabi, K.W. Krausz, A.I. Robles, E.D. Bowman, F.J. Gonzalez, C.C. Harris
• Journal: Clinical Cancer Research
• Published: 2024;30(16):3592-3602
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT).

Experimental Design: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening.

Results: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts.

Conclusions: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

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

In plain English

This study measured two substances in urine, creatine riboside (CR) and N-acetylneuraminic acid (NANA), in patients with non-small cell lung cancer and in population controls, comparing people who did not smoke with tobacco smokers. Asbestos appeared only in the background as a known risk factor; this study did not examine asbestos exposure. The authors used an exploratory group of 846 people from the greater Baltimore area (375 patients, 471 controls) and a validation group of 505 people (285 patients, 220 controls). In both groups, median CR and NANA levels were significantly higher in patients, both nonsmokers and smokers, than in controls. For nonsmokers, the two substances combined gave an AUC, a measure of how well a test separates patients from controls, of 0.94 (95% CI 0.91–0.96) in the exploratory group and 0.8 (95% CI 0.74–0.86) in the validation group. Among nonsmoking patients, high levels of both substances were associated with worse survival in both groups after adjustment for other factors. The authors concluded the substances could be potential diagnostic and prognostic markers regardless of smoking. They noted the study was retrospective and that prospective trials are needed.

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: Retrospective case-control comparison of urine biomarkers in lung cancer cases and population controls, with an exploratory cohort and an independent validation cohort
• Who was studied: Exploratory cohort: 375 patients with non-small cell lung cancer (NSCLC) and 471 population controls, made up of 529 smokers and 317 nonsmokers, from the greater Baltimore, MD, area, August 1997 to June 2019. Validation cohort: 285 NSCLC patients and 220 population controls, made up of 315 smokers and 190 nonsmokers.
• Exposure: Smoking status (nonsmokers compared with current and former tobacco smokers) and, in nonsmokers, secondhand smoke exposure. The measured outcomes were urinary CR and NANA levels. Asbestos exposure was not studied.
• Main results:
  • Exploratory cohort: median CR and NANA levels were significantly higher in nonsmoker cases (1.4 and 27.3 μmol/L) than in smoker cases (1.0 and 18.1 μmol/L) and population controls (0.6 and 11.6 μmol/L).
  • Validation cohort: median CR and NANA levels were significantly higher in both nonsmoker cases (1.0 and 17.1 μmol/L) and smoker cases (1.1 and 16.6 μmol/L) than in population controls (0.7 and 13.8 μmol/L).
  • In nonsmokers, CR and NANA combined gave an AUC of 0.94 (95% CI 0.91–0.96) in the exploratory cohort and 0.8 (0.74–0.86) in the validation cohort.
  • In smokers, CR and NANA combined gave an AUC of 0.81 (0.77–0.85) in the exploratory cohort and 0.7 (0.65–0.78) in the validation cohort.
  • Among nonsmoker cases, the high CR + NANA category was an independent predictor of survival in multivariate analysis, with a hazard ratio of 2.74 (95% CI 1.40–5.38) in the exploratory cohort and 2.92 (1.13–7.50) in the validation cohort.
  • Median CR and NANA levels were elevated in nonsmoker cases both with and without secondhand smoke and childhood parental smoking exposure, compared with population controls.
• The authors' conclusion: The authors concluded that high urinary CR and NANA levels could be potential diagnostic and prognostic biomarkers of NSCLC regardless of smoking, and could help define eligibility for low-dose CT screening.
• Limitations the authors state:
  • The study was retrospective, and prospective trials in nonsmokers are needed to determine clinical usefulness.
  • The biomarkers could not be validated in Asian nonsmokers, and it is unknown whether they predict equally well in other racial/ethnic groups.
  • The study did not test which metabolic pathways explain the increase in these substances.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Liquid Biopsy, Biomarker, Lung Cancer, Etiology, Low-Dose CT Screening.

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