he clinical value of immunologic-based testing has a long, clinically significant history, and has served diagnostic medicine for decades. The basic scientific construct of “Antigen + Antibody = Complex” allows immunologic-based test systems to tag and identify these complexes on large automated platforms that perform immunoassays. What began as clinical utility in the field of transfusion medicine, and more recently in clinical chemistry, has now found a role in the early detection of solid tumor cancers through newly identified “immuno-biomarkers.”
A significant body of literature reports the presence of autoantibodies against cancer antigens in the peripheral circulation of cancer patients — shown to be true in lung, breast, cervical, and colorectal cancers, among others. These autoantibodies can be detected up to five years before the tumors are detectable using diagnostic-imaging procedures such as computed tomography (CT),1 suggesting that these immuno-biomarkers occur in the early stages of disease.
The importance of these observations has led to the development of a simple blood-based test that detects immuno-biomarkers to provide risk assessment and aid in the detection of lung cancer, even in stage I and stage II.
A significant clinical need exists for such a diagnostic test to detect lung cancer early. Fully 85% of lung-cancer patients remain undiagnosed until late-stage symptomatic disease, and 90% of those diagnosed die of the disease within five years of diagnosis.2 Screening CT studies have shown that patients with lung cancer identified at stage I or II have greatly increased survival times.
Data from the National Cancer Institute SEER Review (1973-2006) shows lung-cancer patients treated while tumors were still localized in the lung had a five-year survival rate of 53% compared to the overall lung-cancer rate of 16%, a threefold increase. This test detects cancer developing very early and should lead to more cancers being identified at earlier stages with subsequent improved prognosis for patients.3
Until now, diagnostic testing has not taken advantage of the ability to detect these immuno-biomarkers. At a recent American Society of Clinical Oncology (ASCO) meeting, additional evidence was presented showing that the new test system using a panel of six cancer antigens (p53, NY-ESO-1, CAGE, GBU4-5, Annexin 1, and SOX2), when run on an ELISA platform, was able to detect autoantibodies, or “immuno-biomarkers,” to lung cancer.4 The rationale for the selection of these six tumor antigens has recently been published.3
Clinical validation studies show a highly reproducible assay system,5 and a successful scale-up of the assay platform and associated reagents have allowed the test to be used on large numbers of patients in clinical studies. Over 80,000 assays (cancers versus normals) have been run over more than five years to validate the immuno-biomarker platform and to specifically validate the performance of the lung-cancer test.
Final validation utilized three different sample sets, one of which contained only early-stage cancers (stages I and II), another which was a combination of early and later-stage cancers, and a third set that focused mainly on later-stage lung cancers. In all three data sets, the lung-cancer patients’ samples were compared versus age, sex, and smoking history with matched normals. In total, more than 1,000 samples were tested in the final validation studies representing ~500 high-risk normals and ~500 known lung cancers, all stages and all types. With an integrated control and calibration system,5 this is the first reproducible assay panel shown to have the potential to detect early-stage lung cancers in conjunction with imaging techniques such as CT.
These results confirmed that the test has 40% sensitivity and 90% specificity.4 This means that the test detects 40% of lung cancers, including early-stage disease (stages I and II), and the overall accuracy of the test is greater than 88%. This performance compares favorably with other well-known tests such as mammography in younger women. Studies also confirm that the test, in the case of lung cancer, is at least twice as good as CT’s performance. For example, if one looks at the absolute number of cancers, this new autoantibody panel of immuno-biomarkers should detect more lung cancers for every 1,000 high-risk patients than would mammography, even if mammography is 100% sensitive versus its current 40% sensitivity.6 These robust studies demonstrate the technical performance of the test system itself5 while newly published data demonstrate clinical utility.3 Results require no interpretation — they are either negative or positive if any one of the six immuno-biomarkers exceeds a pre-determined cutoff point. The test is now available commercially.
A hypothetical model of 100,000 high-risk, screening-na”ive patients who were at high risk for lung cancer were followed using both the immuno-biomarker panel and CT. Sensitivity and specificity for the blood test were assumed to be 40% and 90%, respectively. Based on this model, screening high-risk patients with the blood test in conjunction with CT would likely be cost effective compared to screening with CT alone or no screening whatsoever.7
The science of immunology continues to serve scientists and patients alike — from the visible identification of red-cell agglutination in blood-banking tubes to the detection of immuno-biomarkers in cancer. This elegant science may one day be capable of monitoring immuno-biomarker levels over time with the potential for personalized therapeutic intervention based on these markers.
Laura J. Peek, PhD, is principal scientist and QA manager at Oncimmune USA LLC, headquartered in De Soto, KS.
- Zhong L, Coe SP, and Stromberg AJ, et al.: Profiling tumor-associated antibodies for early detection of non-small cell lung cancer. J Thor Oncol. 2006;1:513-519. suggesting that autoantibodies to a carcinogenic process occur quite early in the disease.
- Horner MJ, Ries LAG, Krapcho M et al. (Eds). SEER Cancer Statistics Review, 1975-2006. Bethesda, MD: National Cancer Institute 2009.
- Boyle P, Chapman CJ, Holdenrieder S, et al. Clinical validation of an autoantibody test for lung cancer. Annals of Oncology. Epub July 2010.
- Peek LJ, Lam S, Healey GF, et al. Use of serum autoantibodies to identify early-stage lung cancer: A significant step forward in early detection. J Clin Oncology. 2010;28:15s (suppl; abstr 7032).
- Murray A, Chapman CJ, Healey G, et al Technical validation of an autoantibody test for lung cancer. Annals of Oncology. 2010;21:1687-1693.
- Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of digital versus film mammography for breast cancer screening. NEJM. 2005;353:1773-1783.
- Weycker D, Jett JR, Detterbeck FC, et al. Cost-effectiveness of an autoantibody test as an aid to diagnosis of lung cancer. J Clin Oncology. 2010; 28:15s (suppl; abstr 7030).