Integrating Biomarkers into Lung Cancer Risk Profiling

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Project 2: Integrating Biomarkers into Lung Cancer Risk Profiling Summary Screening by low-dose computed tomography (LDCT) has revolutionized early detection of lung cancer, the leading cause of cancer death. However, current eligibility criteria require participants to have a history of heavy smoking exposure. People with many years of cessation are excluded, as are those who never smoked. Currently, 30-50% of lung cancers occur in individuals who are not eligible for screening, and with decreasing smoking rates, these numbers will increase. The overarching aim of Project 2 is to address this challenge by leveraging complementary information from blood-based biomarkers to identify individuals who have high lung cancer risk despite not meeting screening eligibility criteria. Our project is a natural extension of the initial INTEGRAL program where we developed the novel INTEGRAL protein biomarker panel which measures absolute concentrations of key risk biomarkers. In INTEGRAL-AT Project 2, we aim to move the INTEGRAL panel towards clinical implementation, and also update the panel with risk markers of lung cancer in never smokers. We will first establish a biomarker- informed risk prediction model for smoking-related lung cancer. This will involve using the INTEGRAL panel protein measurements on 1,700 lung cancer cases and 2,900 cohort representatives from the Lung Cancer Cohort Consortium (LC3) to develop and independently validate a model that estimates the 3-year absolute risk of lung cancer. Second, we will evaluate the acceptability of applying such a biomarker-based eligibility criterion to screening participants. This will involve recruiting 1,000 individuals who are ‘nearly eligible’ by US Preventive Services Task Force criteria within the St Elizabeth community based LDCT screening program. Finally, we will carry out a de-novo proteomics discovery analysis on 616 never-smoking cases and 616 matched controls from LC3 to identify novel protein markers for lung cancer in never smokers and update the INTEGRAL panel to include these markers. Our long-term vision is that by using personalized information from a risk-informative and readily implementable multiplex protein-panel, lung cancer screening can be more precisely targeted to people at high risk of lung cancer. This would allow a higher fraction of lung cancer cases to be detected early without subjecting more individuals to LDCT screening, thus optimizing the benefit-to-harm ratio. We also envisage that this panel will be highly useful outside the screening context to work up never-smoking patients with a family history of lung cancer, with occupational exposures, or who present with symptoms.