Detector-C 2.0: A highly accurate blood-based IVD test for early detection of colorectal cancer with sensitivity and specificity over 90%.

Abstract

393 Background: We previously reported on the discovery and prospective validation of a blood based test (Detector C) for early detection of colorectal cancer (CRC). Detector C measures 202 RNA markers in white blood cells as a response of the host to tumor formation and growth. Detector C was validated using a prospective, multicenter case-control study with 343 patients (pts), 210 cases with confirmed CRC and 133 controls undergoing a complete screening colonoscopy. Detector C has a validated sensitivity (S+) of 90% (95% CI 0.851-0.937) and specificity (S-) of 88% (95% CI 0.812-0.930) (Rosental A. et al, J Clin Oncol 28:7s, 2010 (suppl; abstr 3580)). We now present the discovery of Detector C 2.0 based on 445 samples representing most of the pts previously used in the discovery and validation sets of Detector C. Methods: We used Affymetrix U133 plus 2.0 expression data of 291 CRC cases and 154 controls for discovery of Detector C 2.0. Random forest was used for feature (gene) selection and the support vector machine algorithm was employed as classifier in 600 repetitions of double-nested bootstraps to discriminate between cases and controls. Within each repetition, randomly chosen 23 controls and 160 CRC cases served as prospective validation set. The most frequent chosen genes for discrimination between cases and controls formed the consensus signature, namely Detector C 2.0. Results: Choosing a signature length of 1000 genes resulted in the following second order unbiased prospective performance estimates: S+=0.916 (95% CI 0.863-0.954) and S-= 0.948 (95% CI 0.773-0.994). S+ for UICC stage I and stage II cases were 0.93 and 0.94. S+ for high-grade intraepithelial neoplasia was ∼ 0.67 and S+ for adenoma ≥ 10 mm was ∼ 0.45. Conclusions: Using a three times larger discovery set for Detector C 2.0 than for Detector C we improved S+ (cancer detection rate) by 1.6% to 91.6%. The most important enhancement is the high S- of 94.8% of Detector C 2.0 which is six percent higher than the S- of Detector C. Detector C 2.0 is based on a much larger pts set and should be even more robust than Detector C. We will prospectively validate this test in the largest case-control study ever performed in early detection of CRC.

Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer

“…Marshall and colleagues recently published a 7-gene signature with a sensitivity of 72% and a specificity of 70% (8). Rosenthal and colleagues also reported a panel of 202 genes with 90% sensitivity and 88% specificity (9).…”