Exhaled breath and urinary volatile organic compounds (VOCs) for cancer diagnoses, and microbial-related VOC metabolic pathway analysis: a systematic review and meta-analysis

Abstract

Background: The gradual evolution of the detection and quantification of volatile organic compounds (VOCs) has been instrumental in cancer diagnosis. The primary objective of this study was to assess the diagnostic potential of exhaled breath and urinary VOCs in cancer detection. As VOCs are indicative of tumor and human metabolism, our work also sought to investigate the metabolic pathways linked to the development of cancerous tumors.

Materials and methods: An electronic search was performed in the PubMed database. Original studies on VOCs within exhaled breath and urine for cancer detection with a control group were included. A meta-analysis was conducted using a bivariate model to assess the sensitivity and specificity of the VOCs for cancer detection. Fagan's nomogram was designed to leverage the findings from our diagnostic analysis for the purpose of estimating the likelihood of cancer in patients. Ultimately, MetOrigin was employed to conduct an analysis of the metabolic pathways associated with VOCs in relation to both human and/or microbiota.

Results: The pooled sensitivity, specificity and the area under the curve for cancer screening utilizing exhaled breath and urinary VOCs were determined to be 0.89, 0.88, and 0.95, respectively. A pretest probability of 51% can be considered as the threshold for diagnosing cancers with VOCs. As the estimated pretest probability of cancer exceeds 51%, it becomes more appropriate to emphasize the 'ruling in' approach. Conversely, when the estimated pretest probability of cancer falls below 51%, it is more suitable to emphasize the 'ruling out' approach. A total of 14, 14, 6, and 7 microbiota-related VOCs were identified in relation to lung, colorectal, breast, and liver cancers, respectively. The enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in the aforementioned tumor types.

Conclusions: The analysis of exhaled breath and urinary VOCs showed promise for cancer screening. In addition, the enrichment analysis of volatile metabolites revealed a significant enrichment of butanoate metabolism in four tumor types, namely lung, colorectum, breast and liver. These findings hold significant implications for the prospective clinical application of multiomics correlation in disease management and the exploration of potential therapeutic targets.

Figure 1

Flow diagram showing the study selection process.

Figure 2

Asymmetrical funnel plots indicated no publication bias (bias=0.73, P=0.469).

Figure 3

Pooled sensitivity and specificity analyses of all 90 studies.

Figure 4

Summary receiver operating characteristic curve analysis of all studies, the pooled area under the curve was 0.95 (95% CI: 0.92–0.96).

Figure 5

Fagan nomograms for the elucidation of post-test probabilities with different pretest probabilities. (A) The pretest probability was 0.25, yielding a PPV of 71% and a NPV of 4%. (B) The pretest probability was 0.51, yielding a PPV of 88% and a NPV of 12%. (C) The pretest probability was 0.75, yielding a PPV of 96% and a NPV of 28%.

Figure 6

Univariable meta-regression and subgroup analysis for differentiating cancers.