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

Abstract

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.

Discovery and validation of a colorectal cancer classifier in a new blood test with improved performance for high-risk subjects

“…By focusing on CRC risk stratification within symptomatic patients, the expectation is that the colonoscopy compliance of patients with the apparent highest need can be increased. Other groups [11, 13] have also approached the development of tests for symptomatic patients, though none have yet validated their tests and the tests’ proposed uses have varied. Our view is that CRC tests for symptomatic patients are most helpful when directed to patients who resist colonoscopies despite the presence of symptoms.…”

“…Given the attractiveness of a low-burden CRC test for symptomatic patients, several groups have focused efforts here [10, 11, 13, 14]. The highest performing test, and the only validated test to date, was a blood-based test developed earlier in our laboratory [10, 14] using a sample set mirroring the composition of the intent-to-test (ITT) symptomatic population [14].…”

Cancer-Type OATP1B3 mRNA in Extracellular Vesicles as a Promising Candidate for a Serum-Based Colorectal Cancer Biomarker

“…It will also be important to seek its combination partners because it has become evident that the usage of multiple biomarkers show preferable results when used in CRC diagnosis. 16,17) Furthermore, considering that only a small portion of human serum is currently available for routine CRC screening, improvement of Ct-OATP1B3 mRNA detection method is necessary. For example, development of a pre-amplification of EV mRNA or a more sensitive quantification method.…”

Serum CNPY2 isoform 2 represents a novel biomarker for early detection of colorectal cancer

“…They found that the AUC of the combination of these markers was greater than that of each tumor marker detected individually for both GC and CRC, which suggested that the combined detection of these four tumor markers may prove to be useful for the diagnosis of GC and CRC [ 20 ]. Wilhelmsen M et al found that a combination of all 8 serological protein biomarkers, including alpha fetoprotein (AFP), CA19-9, CEA, high-sensitivity C-reaction protein (hs-CRP), CyFra21-1, ferritin, galectin-3 and tissue inhibitor of metalloproteinases-1 (TIMP-1), provided a significant improvement for the identification of subjects with a high risk of CRC [ 21 ]. Werner S et al tested serum samples from 1660 blood samples from participants in a colonoscopy screening with a 5-marker blood test (CEA, anti-p53, osteopontin, seprase and ferritin) and found that the diagnostic performance for CRC of the 5-marker test was comparable with that of the guaiac-based fecal occult blood test (gFOBT), as they both identify 39% of all CRC cases at the specificity of 96% [ 22 ].…”