Blood proteins may flag lung cancer risk in never-smokers

Clinical takeaway: Do not use these biomarkers clinically yet, but watch this space as blood-based risk assessment tools for never-smokers evolve. If validated in larger studies, CEACAM5 and CEACAM6 could help identify never-smokers who may benefit from lung cancer screening despite lacking traditional smoking-related risk factors.

About 20% to 25% of lung cancers occur in people who never smoked, yet current screening programs are largely built around smoking exposure. Because most never-smokers have a low absolute risk of lung cancer, broad screening may lead to overdiagnosis and unnecessary procedures, highlighting the need for more precise risk-stratification tools.

Researchers analyzed 2,821 circulating proteins in blood samples collected up to 5 years before diagnosis from 180 never-smokers who later developed lung cancer and 180 matched controls. Of all proteins evaluated, only two, CEACAM5 and CEACAM6, remained significantly associated with future lung cancer risk after correction for multiple comparisons.

The findings held up in a replication analysis involving more than 49,000 UK Biobank participants. The two proteins were only weakly correlated with one another, suggesting they provide complementary risk information. Notably, most protein biomarkers previously linked to smoking-related lung cancer showed little or no association in never-smokers, reinforcing the idea that lung cancer in never-smokers may have a distinct biology.

Researchers conducted a nested case-control study across four prospective cohorts in the US and China, using blood samples obtained before cancer diagnosis. Candidate biomarkers identified in the discovery phase were then evaluated in the UK Biobank replication cohort.

Future work will focus on validating these findings in larger cohorts of never-smokers and determining how the biomarkers can be integrated with factors such as family history, occupational exposures, air pollution, radon exposure, and secondhand smoke to estimate individual risk.

An accompanying editorial notes that risk-based screening remains essential for never-smokers and argues that biological markers such as CEACAM5 and CEACAM6 may eventually help identify the subset whose lung cancer risk approaches that of currently screen-eligible smokers.

“Screening could then be directed at a defined subgroup of this population rather than withheld from all of it,” wrote editorialists Antonio Vitale, MD, and Emilio Bria, MD.

Source: Zahed H, et al. (2026 Nov 2) JAMA Network Open. Protein Biomarkers of Lung Cancer Risk Among Individuals Who Never Smoked