Abstract
Late diagnosis limits therapeutic options and survival rate of non-small cell lung cancer (NSCLC) patients. Therefore the identification of biomarkers represents an emerging medical need.A highly sensitive and specific test was developed to identify/quantify a novel/selective diagnostic biomarker for NSCLC patients, caspase-4. This test was validated by using i) plasma from 125 NSCLC patients and 79 healthy (non-pathological) subjects, ii) plasma from 139 smokers and iii) from 70 chronic-obstructive pulmonary disease (COPD) patients. Caspase-4 quantification was also assessed in the lung tumor mass of 98 paired NSCLC patients compared to 10 non-tumor lung tissues (i.e. tuberculosis).Circulating caspase-4 was detected in both healthy and NSCLC patients; however at different range values: 2.603–3.372 ng/ml for NSCLC patients (95% CI) compared to 0.3994-0.6219 ng/ml for healthy subjects (95% CI). The sensitivity of the test ranged from 97.07% to 100%; the specificity was 88.1% with a positive predictive value of 92.54%, accuracy of 95.19% and AUC of 0.971. Smokers (95% CI, 0.3947–0.6197 ng/ml) and COPD patients (95% CI, 1.703–2.995 ng/ml) showed intermediate values of circulating caspase-4. Tissue levels of caspase-4 in the tumor mass showed that 72 (72.7%) out of 99 patients were positive. More importantly, higher levels (cut-off value = 0.307 ng/ml) of caspase-4 in the tumor mass were associated to reduced overall survival (median 0.92 years) compared to NSCLC patients with lower levels (median 3.02 years).We report for the first time caspase-4 as a novel diagnostic and prognostic biomarker, opening new therapeutic perspectives for NSCLC patients.
Highlights
Lung cancer is the third common cancer-related disease worldwide; it is the leading cause of cancer-related deaths and it counts more deaths than other solid tumors [1]
The circulating levels of caspase-4 were significantly low (p < 0.0001) in the plasma of patients (n = 10) who were diagnosed of chronic respiratory diseases, pathologies that were not related to COPD and/or lung cancer, compared to non-small cell lung cancer (NSCLC) patients (Figure 1B)
We found that the levels of the circulating caspase-4 in COPD patients was three times higher than healthy subjects (Figure 3C), these levels were still lower than those observed in lung cancer patients (Figure 3C)
Summary
Lung cancer is the third common cancer-related disease worldwide; it is the leading cause of cancer-related deaths and it counts more deaths than other solid tumors [1]. The number of new cases is expected to rise by about 70% over the two decades; but more dramatically, over half of people with lung cancer die within one year from time of diagnosis with a survival rate less than 10% [1]. This dramatic condition is primarily due to the lack of early detection tools and to the recognition of the symptoms at the sole late stages, combined to poor pharmacological efficiency/benefit of the available therapeutic approaches. One of the limitation to early diagnose lung cancer is that its initial development is radiologically occult
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