Diagnostic and prognostic role of plasma levels of two forms of cytokeratin 18 in patients with non-small-cell lung cancer.
OBJECTIVE
Cytokeratin 18 (CK18) can be used as a serum biomarker for carcinoma cell death, whereas caspase-cleaved (ccCK18) fragments reflect tumour apoptosis. We explored the potential diagnostic and prognostic role of circulating CK18 and ccCK18 in patients with non-small-cell lung cancer (NSCLC) in comparison with Cyfra 21.1, a fragment of cytokeratin 19.


METHODS
Subject cohorts consisted of 200 healthy blood donors (HBD), 113 patients with benign lung diseases (BLD) and 179 NSCLC cases. Plasma levels of ccCK18, total CK18 and Cyfra 21.1 were determined with ELISA assays.


RESULTS
Plasma levels of ccCK18 and total CK18 were higher in the NSCLC group compared to the HBD and BLD cohorts (p<0.0001). Using a cut-off of 104 U/L for ccCK18 and 302 U/L for total CK18 (95% specificity in the HBD group) the diagnostic accuracy of both CK18 forms to distinguish between NSCLC and BLD cases was 56%, whereas it was 94% for Cyfra 21.1. Multivariate survival analysis showed that total CK18 was a stronger prognostic factor than both ccCK18 and Cyfra 21.1 (HR 0.64 for low versus high total CK18 levels, 95% confidence interval (CI) 0.50-0.82; p=0.0004) in the entire NSCLC cohort and in 78 patients with locally advanced or metastatic disease treated with chemoradiotherapy or first-line chemotherapy (HR 0.70 95% CI 0.52-0.94; p=0.018).


CONCLUSIONS
Cyfra 21.1 is a useful diagnostic biomarker for NSCLC. Total CK18 shows a promising potential as prognostic marker in NSCLC patients, independently of the therapeutical intervention. In contrast, ccCK18 was not of prognostic value in NSCLC, suggesting that tumour necrosis is of particular importance in this disease.
De Petris
Luigi
L
Clinical Proteomics, Karolinska Biomics Center, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. luigi.depetris@ki.se
Brandén
Eva
E
Herrmann
Richard
R
Sanchez
Betzabe Chavez
BC
Koyi
Hirsh
H
Linderholm
Barbro
B
Lewensohn
Rolf
R
Linder
Stig
S
Lehtiö
Janne
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality; D003937:Diagnosis, Differential; D004797:Enzyme-Linked Immunosorbent Assay / Q000592:standards; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000737:chemistry / Q000378:metabolism*; D053539:Keratin-19 / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011379:Prognosis; D012680:Sensitivity and Specificity
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D053538:Keratin-18; D053539:Keratin-19; D010446:Peptide Fragments; C102012:antigen CYFRA21.1