• Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.
• Biostatistics Program, Fred Hutchinson Cancer Research Center, Seattle, WA.
• Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
• Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
• Department of Medicine, Baylor College of Medicine, Houston, TX.
• Department of Integrative Oncology, British Columbia Cancer Research Institute, Vancouver, British Columbia, Canada.
• Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
• Department of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, MI.
• Prevention and Cancer Control, Ontario Health (Cancer Care Ontario), Toronto, Ontario, Canada.

PURPOSE: To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.

METHODS: A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCO_m2012) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera.

RESULTS: The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCO_m2012 model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCO_m2012 model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCO_m2012 model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.

CONCLUSION: A blood-based biomarker panel in combination with PLCO_m2012 significantly improves lung cancer risk assessment for lung cancer screening.