This report confirms a validated assay for the detection of autoantibodies to selected cancer-associated antigens in the peripheral blood. The value of a test for early cancer detection is usually defined via a number of related parameters, including sensitivity, specificity, PPV and NPV. A percentage of smokers/ex-smokers are ‘harbouring’ an asymptomatic LC at any one time. Even with the most conservative estimation of occult LCs, the panel of autoantibodies can identify 40% of primary LCs, including early stage of disease, with a specificity of 90% against age-matched, gender-matched and smoking history-matched controls. The specificity was similar (at least 89%) for patients with benign disease.
Autoantibodies to p53 [26
], NY-ESO-1 [30
], CAGE [29
], GBU4-5 [31
], Annexin 1 [16
] and SOX2 [44
] have all been shown to be capable of inducing autoantibodies in patients with LC. The data in this manuscript further confirm the value of a panel of autoantibodies over a single autoantibody assay [19
]. Recent publications have reported autoantibodies to a natural form of Annexin 1 [43
] and other antigens (e.g. 14-3-3 theta [43
] and LAMR1 [43
]), which are elevated in LC and up to 1 year before clinical diagnosis. The combination of 14-3-3 theta, Annexin 1 and LAMR1 gave an AUC on a combined ROC curve of 0.73. While these results were based on a research assay, it is possible that adding 14-3-3 theta and/or LAMR1 to the current panel might increase the sensitivity.
Group 3 data confirm that there was no significant difference between different stages of LC, although due to sample size the confidence intervals were sometimes wide. Further evaluation of the data was, therefore, carried out by comparing early-stage (stage I/II NSCLC plus limited SCLC) with late-stage (stage III/IV NSCLC plus extensive SCLC) disease, which again showed no difference. The presence of such a signal in early-stage disease is precisely what would be expected of an in vivo
amplification signal such as the humoural immune response. This is in contrast to cancer-associated antigens, which are markers of tumour burden and not useful for the early detection or screening of breast [46
] or colorectal cancer [48
Previous publications [16
] have highlighted the potential value of a panel of autoantibodies for the early detection of cancer. Using a panel of antigens, autoantibodies have been reported up to 5 years before screening CT scans [22
] in LC and up to 4 years before screening mammography in young women at increased risk [21
]. Other authors have highlighted individual autoantibodies such as p53 autoantibodies detected before diagnosis of cancer in smokers with chronic obstructive pulmonary disease [27
] or in patients with asbestosis [41
]. In the latter publication, the average lead time (time from first positive sample to diagnosis) was 3.5 years (range 1–12 years). There are similar publications on other single autoantibodies [45
]. These findings all indicate the induction of autoantibodies happening relatively early in the process of carcinogenesis.
This panel assay is the first to show reproducible results with a calibration and control system and offers a potential system for monitoring a population at high risk of LC, either alone or in conjunction with imaging modalities (e.g. CT). The similar sensitivities and specificities measured for these three datasets and with different batches of proteins utilised emphasise the robustness of these autoantibody assays and also confirm the value of a panel of autoantibodies over a single autoantibody assay.
At a fixed 90% specificity, the sensitivity of 40% is a conservative estimate of the performance of the assay both in terms of estimating the level of clinically occult LCs (supplemental Table S2, available at Annals of Oncology online) and also the sensitivity reported for SCLC (n = 73) in group 3. The latter is lower than the 55% sensitivity and 90% specificity, which the authors will report in a larger consecutive series (n = 242) from a single centre (C. J. Chapman, A. J. Thorpe, A. Murray et al., unpublished data).
The sensitivity of 40% with a specificity of 90% are similar to mammography in high-risk young women [53
], while the incidence of LCs in heavy smokers is at least three times the incidence of breast cancer in a typical cohort of high-risk young women [5
]. Therefore, in terms of absolute number of cancers, this test should detect more LCs for every 1000 high-risk persons tested than screening mammography would detect breast cancers in a high-risk group of young women, even if mammography were 100% sensitive rather than its current 40% [53
]. This has to be seen in the context of a disease (i.e. LC), which has a mortality rate between 85% and 95%. By way of contrast, annual CT in the Mayo CT screening trial had a specificity of 49% (with a sensitivity of 67%) in the prevalence round. In an at-risk group of 20 of the 1000, CT gave a PPV of 2.5% (i.e. 1:40) and an NPV of 98.7%. The autoantibody test with a sensitivity of 40% and a specificity of 90% would have a PPV of 7.5% (i.e. 1 in 13.3) and an NPV of 98.7% in a similar-risk group.
While such comparisons serve to highlight the potential value of an autoantibody test for LC that has a specificity of 90%, the authors envisage the autoantibody technology and imaging as being complementary.