Circulating Proteome for Pulmonary Nodule Malignancy
Elham Khodayari Moez 1 , Matthew T Warkentin 1 2 , Yonathan Brhane 1 , Stephen Lam 3 , John K Field 4 , Geoffrey Liu 5 , Javier J Zulueta 6 , Karmele Valencia 7 , Miguel Mesa-Guzman 8 , Andrea Pasquier Nialet 7 , Sukhinder Atkar-Khattra 3 , Michael P A Davies 4 , Benjamin Grant 5 , Kiera Murison 1 , Luis M Montuenga 7 , Christopher I Amos 9 , Hilary A Robbins 10 , Mattias Johansson 10 , Rayjean J Hung 1 2
Background: While lung cancer screening with low-dose computed tomography (LDCT) is rolling out in many areas of the world, differentiating indeterminate pulmonary nodules remains a major challenge. We conducted one of the first systematic investigations of circulating protein markers to differentiate malignant versus benign screen-detected pulmonary nodules.
Methods: Based on four international LDCT screening studies, we assayed 1078 protein markers using pre-diagnostic blood samples from 1253 participants based on a nested case-control design. Protein markers were measured using proximity extension assays and data were analyzed using multivariable logistic regression, random forest, and penalized regressions. Protein burden scores for overall nodule malignancy (PBS-overall) and imminent tumors (PBS-imminent) were estimated.
Results: We identified 36 potentially informative circulating protein markers differentiating malignant from benign nodules, representing a tightly connected biological network. Ten markers were found to be particularly relevant for imminent lung cancer diagnoses within one year. Increases in PBS-overall and PBS-imminent by 1 standard deviation were associated with odds ratios of 2.29(95%CI = 1.95-2.72), and 2.81(95%CI = 2.27-3.54) for nodule malignancy overall, and within 1 year of diagnosis, respectively. Both PBS-overall and PBS-imminent were substantially higher for those with malignant nodules compared to those with benign nodules even when limited to LungRADS category 4 (p < 0.001).
Conclusions: Circulating protein markers can help to differentiate malignant from benign pulmonary nodules. Validation with an independent CT-screening study will be required prior to clinical implementation.
CITA DEL ARTÍCULO J Natl Cancer Inst. 2023 Jun 27;djad122. doi: 10.1093/jnci/djad122