Abstract
Blood‐based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two‐stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age‐ and gender‐matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early‐ or late‐stage CRC was derived by least absolute shrinkage and selection operator regression with .632+ bootstrap method, and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n = 56 and 102, respectively). Three different signatures for all‐, early‐, and late‐stage CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.92, 0.91, and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 [95% confidence interval (95% CI), 0.67–0.84], 0.75 (95% CI, 0.62–0.87), and 0.80 (95% CI, 0.68–0.89) for all‐, early‐, and late‐stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood‐based tests for CRC early detection in the future.
Highlights
With 1.85 million incident cases and ~ 880 000 deaths per year, colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer mortality globally (Bray et al, 2018)
The majority of studies were conducted in clinical settings and lacked proper validation in true screening settings, which may have resulted in highly overoptimistic results of diagnostic performance
The study was performed in a two-stage design, and the independent external validation was performed on 56 CRC and 102 controls recruited among 9245 participants of a true screening study
Summary
With 1.85 million incident cases and ~ 880 000 deaths per year, colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer mortality globally (Bray et al, 2018). The participation rates in screening programs are often low because of limitations such as invasiveness, costs and resources, inconvenience, and adherence (Bretthauer et al, 2016; Klabunde et al, 2015; Navarro et al, 2017; Pox et al, 2012; Schreuders et al, 2015; Segnan et al, 2007). Invasive blood-based tests might improve the participation rates in population-based screening programs, given their straightforward applicability in routine medical assessments. Extensive research has been conducted to identify blood-based biomarkers for early detection of CRC. Numerous studies searched for blood-based protein biomarkers or biomarker signatures, and some of them reported seemingly good diagnostic performance (Bhardwaj et al, 2017a; Bhardwaj et al, 2017b).
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