David C Christiani

Lung cancer risk assessment by prediction model: a global perspective

Background Numerous lung cancer risk prediction models have been developed and validated worldwide. It is imperative to offer a comprehensive overview and comparative analysis of their performances. Methods We conducted an extensive literature search to identify studies developing and/or validating lung cancer risk prediction models. Then we summarised and compared the external performance of these models, focusing on discriminative accuracy (C-index) and calibration performance (E:O ratio). Results After an initial screening of 10 210 articles, 35 studies on 21 distinct prediction models were identified, which used 42 different types of predictors spanning seven categories. Notable performance variations were observed in external validations. In North American cohorts, the C-index ranged from 0.60 to 0.87, with E:O ratios from 0.62 to 3.70. Among the European cohorts, the Trøndelag health study HUNT and CanPredict exhibited C-indices surpassing 0.870. Conversely, the Bach, lung cancer risk assessment tool (LCRAT), prostate, lung, colorectal and ovarian cancer screening (PLCO) m2012 and PLCO all2014 performed poorly in electronic health records of the Qresearch database subgroup, with C-indices falling below 0.60. PLCO m2012 reached the best E:O ratio of 1.00 (95% CI: 0.93 to 1.08) in the UK Biobank subgroup. In Asian cohorts, the C-index ranged from 0.54 to 0.87. Only three models, Korean Men, LCRAT and Liverpool lung project incidence risk model (LLPi), achieved a C-index exceeding 0.80. LCRAT demonstrated the best calibration, while Hoggart performed the worst. Conclusions Performance of lung cancer risk prediction models, despite being well developed and validated, varies in diverse populations. Significant regional imbalance persists in the development of these models. Rigorous external validation or recalibration study in the target population is crucial in accordance with the guidance prior to model implementation. PROSPERO registration number CRD42022324602.

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Abstract Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. Significance: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489