Analytical validation of the PROphet test for treatment decision-making guidance in metastatic non-small cell lung cancer

Abstract

The PROphet test provides a decision-making tool for first-line treatment of non-small cell lung cancer (NSCLC) patients without driver mutations. The test is based on plasma proteomics profiling using the SomaScan platform, followed by a machine learning-based analysis. During the PROphet predictor development, a set of predictive proteins was identified, termed resistance-associated proteins (RAPs). Here we set to examine the analytical validity of the SomaScan assay as the biomarker measurement method in the PROphet test, focusing either on all proteins measured using this platform, or specifically on the RAPs. Experimental precision analysis displayed a median coefficient of variation (CV) of 3.9% and 4.7% for intra-plate and inter-plate examination, respectively, when studying all proteins, with no difference between technicians. Notably, the RAPs displayed lower median CV values and lower CV range. The median accuracy rate of measurements obtained in sites was 88% and 94% for all proteins and for the RAPs, respectively, with no significant difference between technicians. Computational precision examination displayed high precision for 13 out of 14 examined samples, with median standard error of 0.1689. Cross-platform comparison between SomaScan platform and other proteomics platforms, including immunoassays, proximity extension assay (PEA) and mass spectrometry, displayed a median Spearman coefficient of 0.51 and 0.53 for all examined proteins and RAPs, with no significant difference between the two protein sets. Last, the effect of the cross-platform correlations on the prediction capabilities was examined, displaying only a minor effect of the correlation on the prediction capabilities of the PROphet predictor, with a median of 80% agreement between predictions obtained between the two examined proteomic platforms. Taken together, these results demonstrate strong analytical performance for the SomaScan technology, while the RAPs displayed improved capabilities in most of the analytical performance analyses.