Abstract
Abstract
Background: Multi-biomarker blood tests have the potential to detect a broad range of cancer types and stages. Herein, we assessed the performance of a methylation and protein (MP) classifier using samples from a large, multi-center, prospectively collected case-control study. As part of the assay development process, we performed an exploratory analysis investigating the addition of a somatic mutation reflex approach (MP-reflex) on samples with scores below the threshold for a positive MP call but above a clear negative MP call. Methods: This study included 6,352 samples (1,438 cancer; 4,914 non-cancer) representing all stages among 21 tumor organ types divided approximately equally between a training and a test set. The sensitivity of the MP classifier was determined at a high specificity. The MP-reflex approach was investigated on MP samples at the same specificity threshold and detectable MP signals above pre-specified lower thresholds. Results: Overall sensitivity for MP biomarkers was 50.9% (98.5% specificity), with sensitivities of 15.4%, 26.1%, 38.0%, 67.8%, 85.5%, and 37.5% for stages I, I and II combined, II, III, IV, and unknown, respectively. With breast and prostate cancers excluded, overall test sensitivity was 56.8%, with sensitivities of 17.2%, 30.7%, 48.6%, 73.5%, 86.5%, and 40.0% for stages I, I and II combined, II, III, IV, and unknown, respectively. Conclusions: MP biomarkers detected all solid cancers analyzed, including those without recommended screening and aggressive cancers with poor 5-year survival. Impact: These results demonstrate the potential clinical validity of multi-biomarker testing for the detection of several cancer types.