Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?

BACKGROUND: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated. RESULTS: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: ≥2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009). CONCLUSION: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy.

Clean Colorectum at Diagnostic Colonoscopy: Subsequent Detection of Extracolonic Malignancies by Plasma Protein Biomarkers?

INTRODUCTION: Most of the subjects undergoing diagnostic colonoscopy do not have neoplastic bowel lesions. Potentially, some of the symptoms may therefore be caused by extracolonic malignancy, and subjects with persisting symptoms may need subsequent examinations. Blood-based, cancer-associated biomarkers may aid in directing the examinations for other specific malignant diseases. METHODS: EDTA plasma samples available from a previous prospective study of subjects undergoing diagnostic colonoscopy were used for analysis of 18 protein biomarkers. The study population of 3732 subjects included 400 patients with colorectal cancer (CRC) and 177 patients with extracolonic malignancies. Univariable analysis of the association of specific biomarkers and extracolonic cancers included those with 10 or more cases. Subsequently, reduced models of 4 or 6 biomarkers, respectively, were established by choosing those with the highest likelihood; age and sex were included as well. RESULTS: Univariable analyses showed that CyFra21-1 had an area under curve (AUC) of 0.87 for lung cancers (n = 33), CA19-9 had an AUC of 0.85 for pancreatic cancer (n = 22), CA125 had an AUC of 0.95 for ovary cancer (n = 16), B2M had an AUC of 0.81 for non-Hodgkin lymphoma (n = 12), and total prostate-specific antigen had an AUC of 0.99 for prostate cancer (n = 10). The multivariable analysis of 4 or 6 biomarkers plus age and sex as explanatory variables showed AUCs of 0.82 to 0.85 both for extracolonic cancers and CRC. The 4 biomarkers included in the model for detection of extracolonic cancers were CA125, hsCRP, CA19-9, and CyFra21-1; the 2 additional for the 6 biomarkers model were CEA and Galectin-3. Similarly, the 4 biomarkers included in the model for detection of CRC were CEA, CyFra21-1, Ferritin, and HE4; the two additional for the 6 biomarkers model were hsCRP and Pepsinogen 2. CONCLUSIONS: Results of this study indicate that it may be possible to detect subjects that have an increased risk of extracolonic cancer following a colonoscopy without findings of neoplastic lesions. Combinations of various protein biomarkers may direct subsequent examination after colonoscopy with clean colorectum. The results, although preliminary, may form the basis for additional research directed both for primary examinations of subjects with symptoms of malignancy and subsequent examinations after colonoscopy.

Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high-risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had 'clean' colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC.

Increased serological cancer-associated biomarker levels at large bowel endoscopy and risk of subsequent primary cancer (†).

BACKGROUND: Frequently, subjects offered colonoscopy due to symptoms of colorectal neoplasia are diagnosed with diverticula. The symptoms may, however, also be related to extra-colonic neoplasia. The present retrospective study evaluated a possible association between increased levels of predefined biomarkers in subjects diagnosed with diverticula and risk of developing a primary malignant disease. METHODS: During 2004/2005, about 4509 subjects were included in a multicenter study with collection of blood samples before bowel endoscopy. The aim was to evaluate a relation between the protein biomarkers CEA, TIMP-1, CA19-9 and YKL-40 and findings at endoscopy. Diverticula were diagnosed in 1021 subjects. By 31 December 2012, subjects who had developed primary malignancy were identified retrospectively and relation between biomarker levels at endoscopy and risk of developing primary malignancy was calculated. The relation with the four biomarkers was divided into three groups: 0 = none increased; 1 = one increased and 2 = two or more increased. RESULTS: In the observation period, 148 subjects developed a primary malignant disease. Univariable analyzes of the biomarker levels showed that CEA, TIMP-1 and CA19-9 were significantly associated with development of primary malignancy. A multivariable analysis showed that increased levels were associated with development of malignancy (p < 0.0001). The 1- and 5-year cumulative risks of being diagnosed with a primary malignancy were: group 0: 1.1%/5.5%; group 1: 4.2%/10.1% and group 2: 11.4%/18.8%, respectively. CONCLUSION: Increased levels of CEA, TIMP-1 and CA19-9 at endoscopy with findings of diverticula were associated with a significantly increased risk of being diagnosed with a subsequent primary malignant disease.

Discovery and Validation of Plasma-Protein Biomarker Panels for the Detection of Colorectal Cancer and Advanced Adenoma in a Danish Collection of Samples from Patients Referred for Diagnostic Colonoscopy.

BACKGROUND: Well-collected and well-documented sample repositories are necessary for disease biomarker development. The availability of significant numbers of samples with the associated patient information enables biomarker validation to proceed with maximum efficacy and minimum bias. The creation and utilization of such a resource is an important step in the development of blood-based biomarker tests for colorectal cancer. METHODS: We have created a subject data and biological sample resource, Endoscopy II, which is based on 4698 individuals referred for diagnostic colonoscopy in Denmark between May 2010 and November 2012. Of the patients referred based on 1 or more clinical symptoms of colorectal neoplasia, 512 were confirmed by pathology to have colorectal cancer and 399 were confirmed to have advanced adenoma. Using subsets of these sample groups in case-control study designs (300 patients for colorectal cancer, 302 patients for advanced adenoma), 2 panels of plasma-based proteins for colorectal cancer and 1 panel for advanced adenoma were identified and validated based on ELISA data obtained for 28 proteins from the samples. RESULTS: One of the validated colorectal cancer panels was comprised of 8 proteins (CATD, CEA, CO3, CO9, SEPR, AACT, MIF, and PSGL) and had a validation ROC curve area under the curve (AUC) of 0.82 (CI 0.75-0.88). There was no significant difference in the performance between early- and late-stage cancer. The advanced adenoma panel was comprised of 4 proteins (CATD, CLUS, GDF15, SAA1) and had a validation ROC curve AUC of 0.65 (CI 0.56-0.74). CONCLUSIONS: These results suggest that the development of blood-based aids to colorectal cancer detection and diagnosis is feasible.

Blood-based Biomarkers at Large Bowel Endoscopy and Prediction of Future Malignancies.

Soluble cancer-related protein biomarker levels may be increased in subjects without findings at large bowel endoscopy performed due to symptoms associated with colorectal cancer. The present study focused on a possible association between increased biomarker levels in such subjects and subsequent development of malignant diseases. In a major study of 4,990 subjects undergoing large bowel endoscopy, 691 were without pathology and comorbidity. Plasma levels of TIMP-1, CEA, CA19-9, and YKL-40 were determined in samples collected just before endoscopy and compared with subsequent development of a malignant disease within a period of 7-8 years. The upper 90% limits of the reference levels of every single protein were used to differentiate between normal and increased levels. The levels were separated into three groups: 0, none of the biomarkers increased; 1, one biomarker increased; 2, two or more biomarkers increased. A total of 43 subjects developed a primary malignant disease in the observation period. Univariatly, increase of all four biomarkers was significantly associated with subsequent development of a malignant disease. A multivariate analysis showed that increased biomarker levels were associated with subsequent development of a malignant disease (P = 0.002). The cumulative risk of developing malignant disease within the first 5 years after endoscopy was group 0, 3.3%; group 1, 5.8%; group 2, 7.8%. It is concluded that increased levels of plasma TIMP-1, CEA, CA19-9, and serum YKL-40 at large bowel endoscopy without findings may be associated with an increased risk of developing a subsequent malignant disease.

Serum YKL-40 in risk assessment for colorectal cancer: a prospective study of 4,496 subjects at risk of colorectal cancer.

The aim of the present study was to test the hypothesis that high serum YKL-40 associates with colorectal cancer in subjects at risk of colorectal cancer. We measured serum YKL-40 in a prospective study of 4,496 Danish subjects [2,064 men, 2,432 women, median age 61 years (range, 18-97)] referred to endoscopy due to symptoms or other risk factors for colorectal cancer. Blood samples were collected just before large bowel endoscopy. Serum YKL-40 was determined by ELISA. Serum YKL-40 was higher (P < 0.0001, unadjusted for confounding covariates) in subjects diagnosed with colon cancer (median 126 µg/L, 25%-75%: 80-206 µg/L) and rectal cancer (104, 72-204 µg/L) compared with subjects with adenoma (84, 53-154 µg/L), other nonmalignant findings (79, 49-138 µg/L), and no findings (62, 41-109 µg/L). Serum YKL-40 independently predicted colorectal cancer [OR, 1.53; 95% confidence interval (CI), 1.40-1.67; AUC = 0.68, P < 0.0001]. Restricting the analysis to subjects with no comorbidity increased the OR for serum YKL-40 to predict colorectal cancer (OR, 1.82; 1.58-2.08; AUC = 0.73, P < 0.0001). Combining serum YKL-40 and CEA demonstrated that both were significant [(YKL-40, OR, 1.27; 95% CI, 1.16-1.40); (CEA, OR, 1.92; 1.75-2.10; AUC = 0.75, P < 0.0001; OR for a 2-fold difference in marker level)]. Multivariable analysis (YKL-40, CEA, age, gender, body mass index, and center) showed that serum YKL-40 was a predictor for colorectal cancer in individuals without comorbidity (OR, 1.25; 95% CI, 1.05-1.40; P = 0.012), whereas this was not the case for those with comorbidity (OR, 0.98; 95% CI, 0.84-1.14; P = 0.80). In conclusion, high serum YKL-40 in subjects suspected of colorectal cancer and without comorbidity associates with colorectal cancer. Determination of serum YKL-40 may be useful in combination with other biomarkers in risk assessment for colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 621-6. ©2015 AACR.

[Screening methods for colorectal cancer can be improved].

Screening programmes for colorectal cancer (CRC) are being implemented in various countries worldwide including Denmark. The majority of programmes rely on faecal occult blood testing with subsequent colonoscopy. This approach is challenged by limited compliance, which reduces the efficiency of the screening programme. Current research into improve-ments of screening of CRC includes biological markers identified in blood. Combining blood-based biological markers with clinical and demographical parameters have shown promising results, which may improve the present approach to screening.