SEROLOGICAL CANCER-ASSOCIATED PROTEIN BIOMARKER LEVELS AT NEGATIVE BOWEL ENDOSCOPY; INCREASED RISK OF SUBSEQUENT PRIMARY MALIGNANCY?
Thomas B. Piper*, Ib J. Christensen, Linnea Ferm, Hans J. Nielsen
Department of Surgical Gastroenterology, Hvidovre Hospital - Copenhagen - Denmark, Hvidovre, Copenhagen, Denmark
Background: It was shown previously that subjects without colorectal cancer (CRC) at bowel endoscopy, but with increased serological cancer-associated protein biomarker levels have an increased risk of being diagnosed with subsequent malignant diseases. The aim of the present study was to perform a pooled analysis of the published results updated recently. The statistical analysis of this study denoted the training set includes relevant clinical covariates as well as the biomarkers (N=4,205). The obtained results were then validated in a second study, an independent study of symptomatic subjects referred to colonoscopy (N=4,009).
Methods: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy. Subjects with HNPCC or FAP were excluded. Follow-up of the subjects, who were not diagnosed with CRC at colonoscopy, was ten years and identified subjects diagnosed with primary intra- or extra-colonic malignant diseases. Events registered within 6 months from the initial bowel endoscopy were not included for further analysis (N=127), leaving 4,078 subjects for analysis. The primary analysis was time to a newly diagnosed malignant disease and was analyzed with death as a competing risk. The resulting model was then validated in the second study.
Results: Primary malignancies were identified in 524 (12.8%) of the 4,078 subjects with clean colorectum or diagnosed with a non-malignant disease at the primary bowel endoscopy. In detail, 33 were subsequently diagnosed with CRC and 491 subjects with various extra-colonic cancers. Multivariate analysis demonstrated that CEA (HR=1.58, 95% CI:1.28-1.96, p<0.001) and CA19-9 (HR=1.50, 95% CI:1.17-1.93, p=0.001) were significant predictors of subsequent malignancy. The cumulated incidence at 3 years landmark time was 9.4% for those subjects with elevated CEA and CA19-9 versus 5.0% for those with low levels of both. The overall cumulative incidence at 3 years landmark time was 5.7% for the training set. These results were similar in the validation study which showed a cumulative incidence at 3 years landmark time of 8.7%. for upregulated CEA and CA19-9 and 3.8% where both are downregulated. The overall cumulative incidence of the validation set at the same time point was 4.0%.
Conclusion: Elevated cancer-associated protein biomarker levels in subjects with cancer negative findings at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy. CEA and Ca19-9 were significant predictors of malignant disease in this pooled analysis. The Validation confirmed these results.
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