A Prospective Study of Inflammation-Based Markers for Lung Cancer Risk and Survival in African Americans
Lung cancer has the second highest cancer incidence in the United States and is the leading cause of cancer-related mortality. AA have the highest lung cancer incidence and mortality rates when compared with other racial/ethnic group in the U.S.
Lung cancer screening is an effective strategy for early detection, but current eligibility criteria under-represent AA in the at-risk population. The combined use of screening and biomarkers for risk prediction can improve clinical outcomes. Our lab has demonstrated differences in lung tumor biology between AA and European Americans (EA). Further, our recent data (submitted) show that racial differences in cancer inflammation and tumor immunobiology exist. We analyzed 30 circulating inflammation proteins in AA NSCLC patients and population controls to investigate the relationship between circulating inflammation proteins and lung cancer in AA. We validated evidence of diagnostic markers of lung cancer for AA using two independent case-control datasets of self-reported AA (715 cases and 909 controls) for testing and validation (CRP, IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-15, IP-10, MIP-1α, MCP-4 and TNF-β).
Our case-control results highlight a distinct inflammatory profile associated with lung cancer diagnosis in AA compared with EA, which may provide insight into the etiology of lung cancer in AA and, as many markers were macrophage-associated, immunotherapy response. Moreover, if these inflammation proteins are also associated with lung cancer risk, they could be further explored as a companion tool for LDCT screening and the triage of high-risk patients. As such, our initial studies need to be tested within prospective cohorts. We are aware that there are now 117 AA lung cases with available serum making this an ideal opportunity to investigate lung cancer risk markers in this underserved, disproportionately risk-burdened, population. Access to these samples would enable us to look not just at diagnostic attributes, but also whether these proteins are associated with risk and survival. Based on first-round review feedback we have strengthened our study design by expanding our research team and including a pooled analysis of prospective samples including AA serum samples from the Southern Community Cohort Study (SCCS) and DECAMP to increase power, especially for samples taken before diagnosis.
Our aim is to define clinically relevant circulating inflammation signatures in AA lung cancer patients that can be incorporated into early-detection models and identify prognostic markers than may help guide the treatment regimen for AA.
We hypothesize that measurement of circulating inflammation proteins in PLCO will validate the distinct inflammation profile we previously discovered associated with lung cancer diagnosis in African Americans (AA). Further, we seek to ask whether these proteins are also associated with lung cancer risk in a pooled prospective study, including PLCO, SCCS and DECMAP. The specific aims designed to test these hypotheses are:
SA1: To measure a panel of 10 key inflammatory proteins in pre-diagnostic case and control serum samples from African Americans and test the relationship between these proteins with lung cancer risk and diagnosis.
We recently validated an association between elevated CRP, IFN-γ, IL-6, IL-8, IL-10, IL-15, IP-10, and MIP-1α and reduced levels of MCP-4 and TNF-β and lung cancer diagnosis in AA in both a serum-based test dataset (National Cancer Institute-Maryland case-control study) and a plasma-based validation dataset (Wayne State University case-control study) (manuscript under review). Although there was some commonality in the inflammation-related profile of lung cancer in AA and European Americans (EA) (based on results from an NLST study conducted in our group—manuscript under review—and other studies in PLCO by us and DCEG investigators(1, 2)), our results from these case-control studies highlight a distinct inflammation profile associated with lung cancer in AA compared with EA. These results were obtained using the Mesoscale Discovery (MSD) V-PLEX Human Cytokine 30-Plex Kit to measure protein levels within the biospecimens. Using data obtained from this proposed prospective study together with data from available AA samples from SCCS and DECAMP, we will test the relationship between these 10 proteins with lung cancer risk and diagnosis in African Americans. We propose using the same MSD platform to measure the protein levels of the 10 inflammation markers of interest, this pooled analysis approach will increase the statistical power of the study.
SA2: To examine the relationship between circulating inflammation protein levels and prognosis in African American PLCO lung cancer serum samples
We recently demonstrated that high levels of both IL-6 and CRP were associated with poor prognosis, as compared with low levels of both proteins. This observation was initially observed using data from the NCI-MD study and subsequently validated in the Wayne State University case control study. Therefore, we propose to leverage the data generated from this study and to validate the relationship between IL-6 and CRP with patient survival. This analysis will involve samples taken at the time of diagnosis and we will pool data from the three prospective studies.
We have strengthened our study design, based on feedback from the PLCO review panel, by expanding our research team and including a pooled analysis of prospective samples including AA serum samples from the Southern Community Cohort Study (SCCS) and DECAMP to increase power, especially for samples taken before diagnosis.
Brid Ryan (National Cancer Institute)
Claire Meaney (National Cancer Institute)
Bin Zhu (National Cancer Institute)