Improved blood tests for cancer screening: general or specific?
© Cree; licensee BioMed Central Ltd. 2011
Received: 28 April 2011
Accepted: 30 November 2011
Published: 30 November 2011
Diagnosis of cancer at an early stage leads to improved survival. However, most current blood tests detect single biomarkers that are of limited suitability for screening, and existing screening programmes look only for cancers of one particular type. A new approach is needed. Recent developments suggest the possibility of blood-based screening for multiple tumour types. It may be feasible to develop a high-sensitivity general screen for cancer using multiple proteins and nucleic acids present in the blood of cancer patients, based on the biological characteristics of cancer. Positive samples in the general screen would be submitted automatically for secondary screening using tests to help define the likelihood of cancer and provide some indication of its type. Only those at high risk would be referred for further clinical assessment to permit early treatment and mitigate potential overdiagnosis. While the assays required for each step exist, they have not been used in this way. Recent experience of screening for breast, cervical and ovarian cancers suggest that there is likely to be widespread acceptance of such a strategy.
Several successful screening programmes are already well established, but these are currently applicable only to common cancers such as the faecal occult blood test  for colorectal cancer, mammography for breast cancer  and, of course, cervical cytology for cervical cancer and dysplasia, which is becoming ever more sophisticated [3, 4]. Despite many attempts, blood tests have a less distinguished record. For instance, prostate-specific antigen screening is widely used despite its well-publicised problems . It remains controversial and generates large numbers of papers every year (2, 032 were indexed in PubMed through 2010 using the search terms 'screening', 'prostate specific antigen' and 'cancer'). Many other tumour markers have been described, usually in relatively small studies, and few make it through to clinical use. Cancer antigen 125 (CA 125) was first described as a marker of ovarian cancer in 1981  and is still being evaluated as a potential screening test [7, 8].
The question, therefore, is, Is it possible to use a general screen that might select a set of individuals from the general population who could then be screened further, initially by using the same blood sample, to confirm whether they have cancer and give some guidance as to type? While the objective of general population screening is to identify individuals with a high risk of cancer, the aims of secondary and finally diagnostic screening would be, respectively, to (1) confirm positivity and (2) determine the type of cancer to assist in the choice of further investigations to perform in a selected at-risk group. The advantage of the two-stage method proposed is that those tests showing greatest specificity often have limited sensitivity. Circulating free DNA is a good example of a test with considerable sensitivity [32, 33], but measurement of this alone in patients with inflammatory or other conditions could lead to an unacceptably high false-positive rate and might give little indication of the site of the tumour [34, 35]. Equally true is that studies of gene mutations or autoantibodies may have greater specificity but lower sensitivity [21, 30].
Preventive maintenance is routine for any complex mechanical device and is increasingly acceptable to healthy people. In most European countries, general medical checkups are encouraged to ensure blood pressure control, and blood tests are used to guide the use of lipid-lowering drugs . Highly successful screening methods are used for specific cancers, as discussed above. However, other common cancers for which no effective screening methods exist include cancers of the lung, stomach, oesophagus, pancreas, liver, head and neck, and kidney. Further, about 25% of cancer deaths occur as a result of cancers outside the 'top 10' common cancer types (Cancer Research UK: Cancer Mortality: UK Statistics. Available at http://info.cancerresearchuk.org/cancerstats/mortality/). Although the economic implications require careful study, it is possible that such screening tests could be cost-neutral to health care providers, since it is likely to be very much more expensive to treat a small number of patients for advanced cancer than to screen and treat a larger number of individuals with early cancer or precancerous conditions. The benefit to patients would be that a frequent, simple, low-risk and relatively painless investigation could prevent serious or life-threatening disease.
If the development of this strategy is successful, we will see a general change from self-referral for cancer symptoms, when treatment is often difficult, costly and unsuccessful, to regular screening using a simple blood test, permitting the treatment of small, localised tumours. New, less invasive radiological and treatment strategies are required, but these are already being introduced, such as laparoscopic surgery for colorectal carcinoma  and endomucosal resection of oesophageal cancers . Some of the patients undergoing screening are likely to have anxieties related to the outcomes of their yearly tests, but these are arguably balanced by the knowledge that many cancers caught early are in most cases unlikely to be fatal. The excellent take-up of existing screening procedures (some quite unpleasant for patients) suggests that this is not a major issue, though it is certainly a research need and the introduction of screening procedures requires careful evaluation .
The major risk to patients is overdiagnosis, which has been highlighted by other screening programmes . For quantitative blood tests, mitigation of this risk may be feasible by setting test thresholds appropriately so that only those at high risk are referred for further investigation, but this does require careful monitoring and quality assurance is essential.
Stages of translation from diagnostic to clinic for diagnostic devicesa
Development of test using clinical samples
Early clinical testing of efficacy (sensitivity, specificity, NPV, PPV, AUROC)
Validation (larger numbers, defined by confidence intervals on AUROC)
Implementation and impact (trials or modelling to answer effectiveness questions)
Last, at each stage, the dissemination of results is essential. A quick search of PubMed using the terms 'early', 'detection', 'cancer' and 'validation' produced 481 articles, 100 of which were classified as reviews and only 178 of which were available as free full-text articles. BMC Cancer is, of course, a free full-text journal, and our experience is that publication in this format aids in the dissemination of results beyond the well-funded libraries at major universities and hospitals.
General screens for cancer may be feasible but are unlikely to grow out of existing specialist screening programmes, which concentrate on particular cancer types. Multiplex approaches are likely to be most effective and, with appropriate translational support, could be practicable. There are a number of risks, mainly of overdiagnosis, which need careful management. Implementation depends on dissemination of research, and open access journals have their role to play if this is to be become a reality.
- CA 125:
cancer antigen 125
enzyme-linked immunosorbent assay
I am grateful to many colleagues for discussion of this subject, particularly Dr Pradeep Bhandari and Prof Doug Altman.
- Ahlquist DA, Sargent DJ, Loprinzi CL, Levin TR, Rex DK, Ahnen DJ, Knigge K, Lance MP, Burgart LJ, Hamilton SR, Allison JE, Lawson MJ, Devens ME, Harrington JJ, Hillman SL: Stool DNA and occult blood testing for screen detection of colorectal neoplasia. Ann Intern Med. 2008, 149: 441-450. W81View ArticlePubMedPubMed CentralGoogle Scholar
- Vinnicombe S, Pinto Pereira SM, McCormack VA, Shiel S, Perry N, Dos Santos Silva IM: Full-field digital versus screen-film mammography: comparison within the UK breast screening program and systematic review of published data. Radiology. 2009, 251: 347-358. 10.1148/radiol.2512081235.View ArticlePubMedGoogle Scholar
- Kitchener HC, Blanks R, Cubie H, Desai M, Dunn G, Legood R, Gray A, Sadique Z, Moss S, MAVARIC Trial Study Group: MAVARIC: a comparison of automation-assisted and manual cervical screening: a randomised controlled trial. Health Technol Assess. 2011, 15: iii-iv. ix-xi, 1-170View ArticlePubMedGoogle Scholar
- Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, de Sanjose S, Naucler P, Lloveras B, Kjaer S, Cuzick J, van Ballegooijen M, Clavel C, Iftner T, Joint European Cohort Study: Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008, 337: a1754-10.1136/bmj.a1754.View ArticlePubMedPubMed CentralGoogle Scholar
- Zeliadt SB, Hoffman RM, Etzioni R, Gore JL, Kessler LG, Lin DW: Influence of publication of US and European prostate cancer screening trials on PSA testing practices. J Natl Cancer Inst. 103: 520-523.
- Bast RC, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC: Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest. 1981, 68: 1331-1337. 10.1172/JCI110380.View ArticlePubMedPubMed CentralGoogle Scholar
- Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, Lewis S, Davies S, Philpott S, Lopes A, Godfrey K, Oram D, Herod J, Williamson K, Seif MW, Scott I, Mould T, Woolas R, Murdoch J, Dobbs S, Amso NN, Leeson S, Cruickshank D, McGuire A, Campbell S, Fallowfield L, Singh N, Dawnay A, Skates SJ, Parmar M, Jacobs I: Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009, 10: 327-340. 10.1016/S1470-2045(09)70026-9.View ArticlePubMedGoogle Scholar
- Tiss A, Timms JF, Smith C, Devetyarov D, Gentry-Maharaj A, Camuzeaux S, Burford B, Nouretdinov I, Ford J, Luo Z, Jacobs I, Menon U, Gammerman A, Cramer R: Highly accurate detection of ovarian cancer using CA125 but limited improvement with serum matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiling. Int J Gynecol Cancer. 2011, 20: 1518-1524.Google Scholar
- Hanash SM, Baik CS, Kallioniemi O: Emerging molecular biomarkers: blood-based strategies to detect and monitor cancer. Nat Rev Clin Oncol. 2011, 8: 142-150. 10.1038/nrclinonc.2010.220.View ArticlePubMedGoogle Scholar
- Hanahan D, Weinberg RA: The Hallmarks of Cancer. Cell. 2000, 100: 57-70. 10.1016/S0092-8674(00)81683-9.View ArticlePubMedGoogle Scholar
- Bast RC, Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, Baggerly KA, Atkinson EN, Skates S, Zhang Z, Lokshin A, Menon U, Jacobs I, Lu K: New tumor markers: CA125 and beyond. Int J Gynecol Cancer. 2005, 15 (Suppl 3): 274-281.View ArticlePubMedGoogle Scholar
- Asiago VM, Alvarado LZ, Shanaiah N, Gowda GA, Owusu-Sarfo K, Ballas RA, Raftery D: Early detection of recurrent breast cancer using metabolite profiling. Cancer Res. 2010, 70: 8309-8318. 10.1158/0008-5472.CAN-10-1319.View ArticlePubMedPubMed CentralGoogle Scholar
- Tiziani S, Lopes V, Günther UL: Early stage diagnosis of oral cancer using 1H NMR-based metabolomics. Neoplasia. 2009, 11: 269-276.View ArticlePubMedPubMed CentralGoogle Scholar
- Nordström A, Lewensohn R: Metabolomics: moving to the clinic. J Neuroimmune Pharmacol. 2010, 5: 4-17. 10.1007/s11481-009-9156-4.View ArticlePubMedGoogle Scholar
- Johansson M, McKay JD, Rinaldi S, Wiklund F, Adami HO, Grönberg H, Kaaks R, Stattin P: Genetic and plasma variation of insulin-like growth factor binding proteins in relation to prostate cancer incidence and survival. Prostate. 2009, 69: 1281-1291. 10.1002/pros.20972.View ArticlePubMedGoogle Scholar
- Carbone A, Rodeck U, Mauri FA, Sozzi M, Gaspari F, Smirne C, Prati A, Addeo A, Novarino A, Robecchi A, Bertetto O, Emanuelli G, Bellone G: Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: implications for anti-tumor immune response. Cancer Biol Ther. 2005, 4: 231-241. 10.4161/cbt.4.2.1476.View ArticlePubMedGoogle Scholar
- Ueno T, Toi M, Linder S: Detection of epithelial cell death in the body by cytokeratin 18 measurement. Biomed Pharmacother. 2005, 59 (Suppl 2): S359-S362.View ArticlePubMedGoogle Scholar
- Inaba N, Negishi Y, Fukasawa I, Okajima Y, Ota Y, Tanaka K, Matsui H, Iwasaki H, Sudo H, Tanaka N, Pakk C, Suzuki N, Sekiya S: Cytokeratin fragment 21-1 in gynecologic malignancy: comparison with cancer antigen 125 and squamous cell carcinoma-related antigen. Tumor Biol. 1995, 16: 345-352. 10.1159/000217951.View ArticleGoogle Scholar
- Wang J, Yi Y, Li B, Wang Z, Sun H, Zhang P, Huang W: CYFRA21-1 can predict the sensitivity to chemoradiotherapy of non-small-cell lung carcinoma. Biomarkers. 2010, 15: 594-601. 10.3109/1354750X.2010.504308.View ArticlePubMedGoogle Scholar
- Chen Z, Feng J, Buzin CH, Liu Q, Weiss L, Kernstine K, Somlo G, Sommer SS: Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. PLoS One. 2009, 4: e7220-10.1371/journal.pone.0007220.View ArticlePubMedPubMed CentralGoogle Scholar
- Board RE, Wardley AM, Dixon JM, Armstrong AC, Howell S, Renshaw L, Donald E, Greystoke A, Ranson M, Hughes A, Dive C: Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2011, 120: 461-467.View ArticleGoogle Scholar
- Dobrzycka B, Terlikowski SJ, Mazurek A, Kowalczuk O, Niklinska W, Chyczewski L, Kulikowski M: Circulating free DNA, p53 antibody and mutations of KRAS gene in endometrial cancer. Int J Cancer. 2010, 127: 612-621. 10.1002/ijc.25077.View ArticlePubMedGoogle Scholar
- Liggett T, Melnikov A, Yi QL, Replogle C, Brand R, Kaul K, Talamonti M, Abrams RA, Levenson V: Differential methylation of cell-free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis. Cancer. 2010, 116: 1674-1680. 10.1002/cncr.24893.View ArticlePubMedGoogle Scholar
- Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le QT, Koong AC: Circulating miR-210 as a novel hypoxia marker in pancreatic cancer. Transl Oncol. 2003, 3: 109-113.View ArticleGoogle Scholar
- Iguchi H, Kosaka N, Ochiya T: Secretory microRNAs as a versatile communication tool. Commun Integr Biol. 2010, 3: 478-481. 10.4161/cib.3.5.12693.View ArticlePubMedPubMed CentralGoogle Scholar
- Zomer A, Vendrig T, Hopmans ES, van Eijndhoven M, Middeldorp JM, Pegtel DM: Exosomes: fit to deliver small RNA. Commun Integr Biol. 2010, 3: 447-450. 10.4161/cib.3.5.12339.View ArticlePubMedPubMed CentralGoogle Scholar
- Orozco AF, Lewis DE: Flow cytometric analysis of circulating microparticles in plasma. Cytometry A. 2010, 77: 502-514.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu FTH, Stefanini MO, Mac Gabhann F, Kontos CD, Annex BH, Popel AS: A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med. 2010, 14: 528-552.PubMedGoogle Scholar
- Chouaib S, Kieda C, Benlalam H, Noman MZ, Mami-Chouaib F, Rüegg C: Endothelial cells as key determinants of the tumor microenvironment: interaction with tumor cells, extracellular matrix and immune killer cells. Crit Rev Immunol. 2010, 30: 529-545.View ArticlePubMedGoogle Scholar
- Taylor DD, Gercel-Taylor C, Parker LP: Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer. Gynecol Oncol. 2009, 115: 112-120. 10.1016/j.ygyno.2009.06.031.View ArticlePubMedPubMed CentralGoogle Scholar
- Nakagawa T, Martinez SR, Goto Y, Koyanagi K, Kitago M, Shingai T, Elashoff DA, Ye X, Singer FR, Giuliano AE, Hoon DSB: Detection of circulating tumor cells in early-stage breast cancer metastasis to axillary lymph nodes. Clin Cancer Res. 2007, 13: 4105-4110. 10.1158/1078-0432.CCR-07-0419.View ArticlePubMedGoogle Scholar
- Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA: Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008, 14: 985-990. 10.1038/nm.1789.View ArticlePubMedGoogle Scholar
- Sunami E, Vu AT, Nguyen SL, Giuliano AE, Hoon DSB: Quantification of LINE1 in circulating DNA as a molecular biomarker of breast cancer. Ann N Y Acad Sci. 2008, 1137: 171-174. 10.1196/annals.1448.011.View ArticlePubMedGoogle Scholar
- Moreira VG, Prieto B, Rodríguez JS, Alvarez FV: Usefulness of cell-free plasma DNA, procalcitonin and C-reactive protein as markers of infection in febrile patients. Ann Clin Biochem. 2010, 47: 253-258. 10.1258/acb.2010.009173.View ArticlePubMedGoogle Scholar
- Zhong XY, von Mühlenen I, Li Y, Kang A, Gupta AK, Tyndall A, Holzgreve W, Hahn S, Hasler P: Increased concentrations of antibody-bound circulatory cell-free DNA in rheumatoid arthritis. Clin Chem. 2007, 53: 1609-1614. 10.1373/clinchem.2006.084509.View ArticlePubMedGoogle Scholar
- Glasziou PP, Irwig L, Heritier S, Simes RJ, Tonkin A, LIPID Study Investigators: Monitoring cholesterol levels: measurement error or true change?. Ann Intern Med. 2008, 148: 656-661.View ArticlePubMedGoogle Scholar
- Künzli BM, Friess H, Shrikhande SV: Is laparoscopic colorectal cancer surgery equal to open surgery? An evidence based perspective. World J Gastrointest Surg. 2010, 2: 101-108. 10.4240/wjgs.v2.i4.101.View ArticlePubMedPubMed CentralGoogle Scholar
- Green S, Tawil A, Barr H, Bennett C, Bhandari P, Decaestecker J, Ragunath K, Singh R, Jankowski J: Surgery versus radical endotherapies for early cancer and high grade dysplasia in Barrett's oesophagus. Cochrane Database Syst Rev. 2009, 2: CD007334-PubMedGoogle Scholar
- Hoff G, Dominitz JA: Contrasting US and European approaches to colorectal cancer screening: which is best?. Gut. 2010, 59: 407-414. 10.1136/gut.2009.192948.View ArticlePubMedGoogle Scholar
- Gøtzsche PC, Nielsen M: Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2011, 1: CD001877-PubMedGoogle Scholar
- Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, Gajewski W, Kurman R, Bast RC, Skates SJ: A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009, 112: 40-46. 10.1016/j.ygyno.2008.08.031.View ArticlePubMedGoogle Scholar
- Pirmohamed M: Acceptance of biomarker-based tests for application in clinical practice: criteria and obstacles. Clin Pharmacol Ther. 2010, 88: 862-866. 10.1038/clpt.2010.245.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/499/prepub
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