Serological cancer-associated protein biomarker levels at bowel endoscopy: Increased risk of subsequent primary malignancy
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BACKGROUND: It was previously shown in three subpopulations that subjects not identified with colorectal cancer (CRC) at bowel endoscopy, but with increased serological cancer-associated protein biomarker levels had an increased risk of being diagnosed with subsequent malignant diseases. Objective: The aim of the present study was to perform a pooled analysis of subjects from the three subpopulations and subsequently validate the results in an independent study. The study population denoted the training set includes N = 4,076 subjects with symptoms attributable to CRC and the independent validation set N = 3,774 similar subjects. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy. Follow-up of subjects not diagnosed with CRC at endoscopy, was ten years and identified subjects diagnosed with primary intra- or extra-colonic malignant diseases. The primary analysis was time to a newly diagnosed malignant disease and was analyzed with death as a competing risk in the training set. Subjects with HNPCC or FAP were excluded. The cumulated incidence was estimated for each biomarker and in a multivariate model. The resulting model was then validated on the second study population. RESULTS: In the training set primary malignancies were identified in 515 (12.6%) of the 4,076 subjects, who had a colorectal endoscopy with non-malignant findings. In detail, 33 subjects were subsequently diagnosed with CRC and 482 subjects with various extra-colonic cancers. Multivariate additive analysis of the dichotomized biomarkers demonstrated that CEA (HR = 1.50, 95% CI:1.21-1.86, p < 0.001), CA19-9 (HR = 1.41, 95% CI:1.10-1.81, p = 0.007) and TIMP-1 (HR = 1.25 95% CI: 1.01-1.54, p = 0.041) were significant predictors of subsequent malignancy. The cumulated incidence at 5 years landmark time was 17% for those subjects with elevated CEA, CA19-9 and TIMP-1 versus 6.7% for those with low levels of all. When the model was applied to the validation set the cumulated 5-year incidence was 10.5% for subjects with elevated CEA, CA19-9 and TIMP-1 and 5.6% for subjects with low levels of all biomarkers. Further analysis demonstrated a significant interaction between TIMP-1 and age in the training set. The age dependency of TIMP-1 indicated a greater risk of malignancy in younger subjects if the biomarker was elevated. This observation was validated in the second set. CONCLUSION: Elevated cancer-associated protein biomarker levels in subjects with non-malignant findings at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy. CEA, CA19-9 and TIMP-1 were significant predictors of malignant disease in this analysis. TIMP-1 was found dependent on age. The results were validated in an independent symptomatic population.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Tumor Biology |
| Vol/bind | 44 |
| Udgave nummer | 1 |
| Sider (fra-til) | 1-16 |
| Antal sider | 16 |
| ISSN | 1010-4283 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
The validation study received financial support from The Andersen Isted Fund, The Augustinus Foundation, The Beckett Fund, The Inger Bonnén Fund, The Hans & Nora Buchard Fund, CEO Jens Bærentsen (private donation, The Walter Christensen Family Fund, The P.M. Christiansen Family Fund, The Aase & Ejnar Danielsen Fund, The Erichsen Family Fund, The Knud & Edith Eriksen Fund, The Svend Espersen Fund, The Elna and Jørgen Fagerholt Fund, The Sofus Carl Emil Friis Fund, The Torben & Alice Frimodt Fund, The Eva & Henry Frænkel Fund, The Gangsted Fund, The Thora & Viggo Grove Fund, The H Foundation, The Erna Hamilton Fund, The Sven & Ina Hansen Fund, The Søren & Helene Hempel Fund, The Henrik Henriksen Fund, The Jørgen Holm Family Fund, Foundation Jochum, The KID Fund, The Kornerup Fund, The Linex Fund, The Dagmar Marshall Fund, The ‘Midtjyske Bladfund’, The Axel Muusfeldt Fund, The Børge Nielsen Family Fund, The Michael Hermann Nielsen Fund, The Arvid Nilsson Fund, The Obel Family Fund, The Krista & Viggo Petersen Fund, The Willy & Ingeborg Reinhard Fund, The Kathrine & Vigo Skovgaard Fund, The Toyota Fund, The Vissing Fund, The Wedell-Wedellsborg Fund, Hvidovre University Hospital (The Capital Region of Denmark).
Funding Information:
The training study received financial support from The Danish Cancer Society, The Kornerup Fund, The Aage and Johanne Louis-Hansen Fund, The Aase and Ejnar Danielsen Fund, The Walter and O. Kristiane Christensen Fund, The Kathrine and Vigo Skovgaard Fund, The ‘Midtjyske Bladfund’, The Agnes and Poul Friis Fund, The Glunz and Jensen Fund, The Sophus and Astrid Jacobsen Fund, The Arvid Nilsson Fund, The Danish Bank Fund, The Johannes Fog Fund, The Eva and Henry Fraenkel Fund, The Hartmann Bros. Fund, The KID Fund, The Henrik Henriksen Fund, The King Christian X’s Fund, The Oda and Hans Svenningsen Fund, The Else and Mogens Wedell-Wedellsborg Fund, The Einar Willumsen Fund, The Willy and Ingeborg Reinhard Fund, The Friedrich and Else Boehm Fund, The Toyota Fund, The IMK Fund, The Danish Medical Research Fund, The Beckett Fund and Hvidovre University Hospital.
Funding Information:
The validation study received financial support from The Andersen Isted Fund, The Augustinus Foundation, The Beckett Fund, The Inger Bonn?n Fund, The Hans & Nora Buchard Fund, CEO Jens B?rentsen (private donation, The Walter Christensen Family Fund, The P.M. Christiansen Family Fund, The Aase & Ejnar Danielsen Fund, The Erichsen Family Fund, The Knud & Edith Eriksen Fund, The Svend Espersen Fund, The Elna and J?rgen Fagerholt Fund, The Sofus Carl Emil Friis Fund, The Torben & Alice Frimodt Fund, The Eva & Henry Fr?nkel Fund, The Gangsted Fund, The Thora & Viggo Grove Fund, The H Foundation, The Erna Hamilton Fund, The Sven & Ina Hansen Fund, The S?ren & Helene Hempel Fund, The Henrik Henriksen Fund, The J?rgen Holm Family Fund, Foundation Jochum, The KID Fund, The Kornerup Fund, The Linex Fund, The Dagmar Marshall Fund, The 'Midtjyske Bladfund', The Axel Muusfeldt Fund, The B?rge Nielsen Family Fund, The Michael Hermann Nielsen Fund, The Arvid Nilsson Fund, The Obel Family Fund, The Krista & Viggo Petersen Fund, The Willy & Ingeborg Reinhard Fund, The Kathrine & Vigo Skovgaard Fund, The Toyota Fund, The Vissing Fund, The Wedell-Wedellsborg Fund, Hvidovre University Hospital (The Capital Region of Denmark).
Publisher Copyright:
© 2022 - The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).
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