SEROLOGICAL BIOMARKER LEVELS AT DIAGNOSTIC COLONOSCOPY; RISK OF SUBSEQUENT PRIMARY MALIGNANCY
Thomas B. Piper*1, Ib J. Christensen1, Gerard J. Davis2, Hans J. Nielsen1
1Department of Surgical Gastroenterology, Hvidovre Hospital - Copenhagen - Denmark, Hvidovre, Copenhagen, Denmark; 2Abbott Diagnostics Division, Cancer Core R&D, Chicago, IL
Introduction: Previously, it was shown that subjects without findings of malignancy at diagnostic colonoscopy, but with increased levels of plasma proteins CEA, CA19-9 and TIMP-1, have an elevated risk of being diagnosed with subsequent primary malignancy. The present validation study was performed in an independent population. Additional protein combinations were analyzed with the aim of improving the current risk stratification model.
Methods: A total of 4,698 subjects were included in a prospective study from May 1, 2010 to November 30, 2012. Non-malignant findings were identified 4,009 of the subjects, who had blood samples collected before first time ever diagnostic colonoscopy. Plasma analyses of CEA, CA19-9, TIMP-1 and 5 additional protein biomarkers (hs-CRP, Ferritin, AFP, Galectin-3, CyFra21-1) were performed. Biomarkers were scored as elevated when levels were above the 90th percentile adjusted for age and gender versus those below or scored by the log transformed value of the actual concentration. The cumulative incidences and hazard ratios (HR) were calculated. Cox regression analyses were performed on time to cancer and with death as a competing risk.
Results: For each biomarker in the validation set compared to the training set (previous study), the HR comparing elevated to normal levels are shown in Table 1. The cumulative incidences for the 3 biomarkers in the validation set are shown in Figure 1.
The additional biomarkers tested in the validation set showed significant associations for hs-CRP (HR=1.06 (1.00-1.12)), Galectin-3 (HR=1.29 (1.04-1.61)), CyFra21-1 (1.29 (1.17-1.42)). Multivariable analysis demonstrated that CEA, TIMP-1 and CyFra21-1 were statistically significant (p=0.004, 0.007, 0.027 respectively). Multivariable analysis with biomarkers log transformed and including age and gender showed CEA as independently significant (HR=1.58 (1.02-2.44, p=0.04)) for risk of subsequent primary malignancy. In addition, a significant interaction between age and TIMP-1 levels (p=0.001) was shown in the multivariable analysis, thus identifying a risk-stratification model: Subjects 40 years of age with increased TIMP-1 levels were shown to have significantly elevated risk of developing subsequent, primary malignancy: HR=2.60 (1.60-42), while subjects 70 years of age and increased TIMP-1 levels did not have elevated risk of developing subsequent, primary malignancy HR=1.06 (0.79-1.43).
Conclusion: Overall, the present independent results validate the results of the previous study. Multivariable analysis of all biomarkers showed that CEA and TIMP-1 were significant predictors of enhanced risk of subsequent primary malignancy with TIMP-1 dependent on age.
Key words: Malignancy, colorectal cancer, biomarkers, endoscopy, colonoscopy
Table 1: Hazard ratios, comparing elevated to normal biomarker levels
| Biomarker | Validation set: HR (95% CI) | Training set: HR (95% CI) |
| CEA | 1.80 (1.41-2.29) | 1.88 (1.47-2.39) |
| CA19-9 | 0.88 (0.62-1.24) | 1.85 (1.40-2.44) |
| TIMP-1 | 1.44 (1.15-1.80) | 2.00 (1.61-2.49) |
Figure 1: Cumulative incidence of malignancy according to plasma levels of A: CEA, B: CA19-9, C: TIMP-1. The solid blue lines represent normal levels of the cancer-associated biomarkers with 95% CI. The solid red lines represent elevated levels of the cancer-associated biomarkers with 95% CI.
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