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  • br Methods br Discussion We systematically searched the

    2018-10-23


    Methods
    Discussion We systematically searched the literature from the last five years to identify potential blood biomarkers for cancer (Hanahan & Weinberg, 2011; Cree, 2011). The data mining process retrieved 3990 citations from the initial 19, 724 records, screening the abstracts of these citations identified 814 biomarkers that may be relevant. After data-cleaning, 788 biomarkers were fitted into 13 categories as described above as having potential for use as early cancer detection biomarkers present within blood samples. Biomarkers were grouped by molecular function. Further analysis such as grouping by cancer type may be possible only once the utility of each biomarker has been reviewed independently. As this is a mapping review, it JSH-23 cost is not possible to speculate the definitive clinical utility for each biomarker. Most studies reviewed tended to concentrate on single common cancers, and few papers show evidence of a systematic approach to biomarker discovery but were limited by the clinical samples and techniques of their laboratories. Our intention is to use the list of biomarkers identified by this review to generate a set of biomarkers that can be subjected to analytical validation within pathology blood science laboratories, then clinically validated within a large, prospective, multicentre clinical study to develop a generic cancer testing strategy for subsequent clinical trial. The primary aim is to produce a screening test strategy for cancer that does more good than harm at reasonable cost. Good includes decreased morbidity and mortality from early detection, diagnosis and treatment of cancers, while harm is usually regarded as significant risk of overdiagnosis, and consequent overtreatment. The entire strategy needs to be cost effective to achieve eventual approval from the UK National Screening Committee (NSC), which defines 22 criteria according to the condition, the test, the treatment and the screening programme (http://www.screening.nhs.uk/criteria) based on those developed by Wilson & Jungner (1968). Within the list, there are some interesting results. Firstly, it is clear that current tumour markers, which considered in isolation, few would regard as sensible diagnostic tests in patients with a possible diagnosis of cancer, are collectively quite good at detection if used concurrently. The bulk of the work on this comes from one group in Barcelona (Molina et al., 2012), with other important contributions from others (Barak et al., 2010). The validation of biomarkers needs a point of reference, for direct comparison and it is clear that tumour marker lists used by Molina et al. (2012) represent such a standard. We would encourage those active in the field to use this list as their comparator for future work to allow comparison between studies. The biomarkers can be grouped by the technology used for their detection. Taken to its logical conclusion, this results in a reduction of the thirteen groups above to seven groups as outlined in Box 3. The concept of combining high sensitivity/low specificity tests with reflex low sensitivity/high specificity tests to detect cancers early (Cree, 2011), seems feasible from the results we have obtained. We need to combine biomarkers with high sensitivity for screening the general population with biomarkers of high specificity to determine the relevance of the screening results. The next task is clearly to try this in practice to determine its real potential for early cancer detection, and to determine the best analytical methods to process the data for individual patients. Our preferred strategy is to examine the biomarkers in each category in greater detail, and undertake direct comparison of these biomarkers in a large cohort of samples following independent analytical validation. In our view, the same caveats around retrospective studies apply to biomarker validation as they do to drug trials: the potential for bias from sample collections is high and large prospective studies are necessary. This review is therefore the first step in an ambitious programme of work which will inevitably require careful evaluation of clinical, cost and ethical implications at each stage. However, there is no doubt that if such an approach to early cancer detection proved successful, it could be invaluable.