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Detecting Lung Cancer by Screening Serology
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Among three distinct cohorts of lung cancer patients and matched controls (without tumor), the authors present data on the capacity for an assay that detects antibody to tumor-associated antigens to discriminate those with lung cancer and those without. Using a panel of six antigens, they found their assay to have sensitivity/specificity of approximately 40%/90%. If confirmed in an independent prospective study, such screening may be a very effective adjunct to imaging studies in the early recognition of lung cancer.
Source: Boyle P, et al. Clinical validation of an autoantibody test for lung cancer. Ann Oncol 2011;22:383-389.
The early detection of lung cancer remains the greatest chance for cure, but effective screening programs have yet to be developed, even for those at high risk such as cigarette smokers. Previous work has indicated that autoantibodies to certain tumor-associated antigens develop in some patients with non-small cell and small cell lung cancer.1-6 Boyle and colleagues propose that detection of such antibodies may be an early clue to the presence of tumor and therefore may become a useful screening technique. These investigators now report the clinical validation of an autoantibody panel in newly diagnosed patients with lung cancer.
For this work, they developed an ELISA technique7 for measuring antibody to six distinct antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1, and SOX2), all of which had been shown to stimulate antibody production in patients with lung cancer. In three distinct cohorts of newly diagnosed lung cancer patients, patient serum was examined after diagnosis was confirmed, but before therapy. In total, there were 655 patients, and for each, a control was sampled. Controls were matched for age, sex, and smoking history.
The autoantibody panel demonstrated a sensitivity/specificity of 36%/91%, 39%/89%, and 37%/90% in cohorts 1, 2, and 3, respectively, with good reproducibility. There was no significant difference between different stages of disease.
This paper describes the methodological details of what the authors intend to ultimately promote as a screening tool to detect early lung cancer. Some of the methodology changed from cohort 1 to 2 to 3, including the criteria for determining positive and negative results. Nonetheless, it is apparent that those with lung cancer had a greater chance of having positive results (sensitivity nearly 40%) and if the results were positive, the chance of having lung cancer was high (specificity 90%). Thus, screening for antibody using this panel may become a useful tool, particularly for those at high risk. Additional work is required to refine and standardize the methodology and the work will need to be confirmed by other groups. One also has the sense that other antigens also may be added to the panel, thereby improving sensitivity to an even greater extent.
Furthermore, it is not clear from the current work that detection of such antibody will lead to early diagnosis, as the study was conducted in patients with already clinically apparent disease. It will take a prospective large-scale trial conducted in either the general population, or more likely, in those at high risk (e.g., active smokers) to determine if early detection of lung cancer by the appearance of autoantibody to one or more of these tumor-associated antigens will result in a greater cure rate.
It should be noted that lung cancer screening by spiral CT scanning is currently under active investigation.8-10
Of course, the practicality of such an approach is somewhat limited by expense, radiation dose, and a fairly significant false positive rate. Perhaps a screening program that includes serologic assessment for autoantibody may be utilized on a broader scale with reflex CT imaging for those with positive results.
1. Brichory FM, et al. An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc Natl Acad Sci U S A 2001;98:9824-9829.
2. Chapman CJ, et al. Autoantibodies in lung cancer: Possibilities for early detection and subsequent cure. Thorax 2008;63:228-233.
3. Tan EM. Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis. J Clin Invest 2001;108:1411-1415.
4. Yang D, et al. Specific potentiation of endothelium-dependent contractions in SHR by tetrahydrobiopterin. Hypertension 2003;41:136-142.
5. Zhang JY, et al. Enhancement of antibody detection in cancer using panel of recombinant tumor-associated antigens. Cancer Epidemiol Biomarkers Prev 2003;12:136-143.
6. Zhong L, et al. Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thorac Oncol 2006;1:513-519.
7. Murray A, et al. Technical validation of an autoantibody test for lung cancer. Ann Oncol 2010;21:1687-1693.
8. Berrington de Gonzalez A, et al. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med 2009;169:2071-2077.
9. Sone S, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84:25-32.
10. Swensen SJ, et al. CT screening for lung cancer: Five-year prospective experience. Radiology 2005;235:259-265.