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DETECTION OF EXTRA-COLONIC CANCERS IN SUBJECTS, WHO HAVE CLEAN LARGE BOWEL AT DIAGNOSTIC COLONOSCOPY: APPLICATION OF ORGAN SPECIFIC PLASMA PROTEIN BIOMARKERS
Michael Wilhelmsen*2, Gerard J. Davis1, Susan H. Gawel1, Xiaoqing Yang1, Annemieke Heijboer3, Frans Martens3, Ib J. Christensen2, Hans J. Nielsen2
1Abbott Laboratories R & D, Abbott Laboatories, Chicago, IL; 2Dept. of surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark; 3Dept. clinical chemistry, VU medical center, Amsterdam, Netherlands
Introduction:
Results indicate that a combination of plasma protein biomarkers may detect bowel neoplasia. However, some subjects with increased biomarker levels may yield clean bowel at colonoscopy. It is important to identify biomarkers that may guide further examination for specific extra-colonic neoplasia. The present study aimed to examine the use of organ associated cancer biomarkers in identifying subjects at risk of having specific extra-colonic cancer.
Material and Methods:
The cohort included 3,732 subjects scheduled for colonoscopy due to symptoms of colorectal cancer(CRC). Blood samples were collected just before the examination; data included findings at the colonoscopy. Some subjects had clean bowel, but had persisting symptoms that prompted subsequent examinations to identify the source of the symptoms. Plasma protein biomarkers (n=18) were measured by the Abbott ARCHITECT® i2000 platform. The biomarkers included Alpha-fetoprotein (AFP), Beta-2-microglobulin (B2M), Cancer Antigen 125(CA125), Cancer Antigen 15-3(CA15-3), Cancer Antigen 19-9(CA19-9), Carcinoembryonic Antigen(CEA), Cytokeratin Fragment 21-1(CyFra21-1), Ferritin, Galectin-3, Human Epididymis protein 4(HE4), high sensitive C-Reactive Protein(hsCRP), Neuron Specific Enolase(NSE), Pepsinogen-1, Pepsinogen-2, Progastrin Releasing Peptide(ProGRP), Total Prostate Specific Antigen(TPSA), Squamous Cell Carcinoma antigen(SCC), and Tissue Inhibitor of Metalloproteinase-1(TIMP-1). The clinical end-points were: 1) CRC, 2) extra-colonic cancers, 3) CRC plus extra-colonic cancers. Extra-colonic cancers with at least 10 cases were included in the statistical analyses. Univariable and multivariable logistic analyses were done on predefined patient/subject groups: CRC, extra-colonic cancers, adenomas, other benign bowel findings, and clean colorectum. In addition, univariable statistics were performed for single specific biomarkers for the various extra-colonic cancers.
Results:
Findings at colonoscopy or subsequent examinations were: 400 patients with CRC, 177 extra-colonic cancers, 502 adenomas, 1,022 other benign bowel findings and 1,632 clean bowels. None of the 18 single biomarkers identified the pre-defined cancer groups. However, combinations of 6 different protein biomarkers plus age and gender were able to identify CRC, extra-colonic cancer or CRC plus extra-colonic cancers with AUCs of 0.82-0.85(Table 1). Univariable analyses of single biomarkers associated with specific cancers showed AUCs of 0.81-0.99(Table 2), which also shows the number of patients in each cancer group of 10-33 patients.
Conclusion:
The present results indicate that organ specific plasma biomarkers may direct examination of subjects, who have persisting symptoms after a diagnosis of clean bowel at colonoscopy. Indeed, the limitations of this small study will direct further evaluation in additional larger studies.
Multivariable analysis of the 6 best biomarkers plus age and gender for various outcomes
| Oucome | Identified Markers | Number of covariates | AUC | | CRC | Age, gender, Pepsinogen-2, HE4, hs-crp, CEA, Ferritin, Cyfra 21-1 | 8 | 0.84 | | Extra-colonic cancer | Age, gender, CA 125, hs-crp, CEA, Galectin 3, CA 19-9, Cyfra 21-1 | 8 | 0.85 | | CRC+ Extra-colonic cancer | Age, gender, HE4, CA 125, hs-crp, CEA, Ferritin, Cyfra 21-1 | 8 | 0.82 |
Univariable analysis of other cancers with more than 10 case | Cancer | Biomarker | Number of cases | AUC | | Lung cancer | Cyfra 21-1 | 33 | 0.87 | | Non-hodgkin lymphoma | B2M | 17 | 0.81 | | Ovary | CA 125 | 16 | 0.95 | | Pancreas | CA 19-9 | 22 | 0.85 | | Prostate | TPSA | 10 | 0.99 |
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