Over the last few years, biomarker science has been advancing rapidly; there does not seem to be any pharmaceutical or diagnostics company that does not include a biomarker strategy in its development concept. Biomarkers have even been identified in the fields of nuclear medicine and psychiatry as important diagnostic tools. This dossier will mainly focus on single molecular and cell-based parameters and multi-marker panels that can be used for the diagnosis and prediction of diseases, the prognosis of disease progression, assessing the effect of drugs in patients and helping doctors make diagnosis decisions and select a course of treatment.

The search for and development of new biomarkers is driven by the need for specific and reliable criteria for assessing pathological situations and the effectiveness of therapeutic interventions. Most currently used molecular biomarkers, set to remain an integral part of medical practice also in the future, are relatively unspecific and ambiguous. Examples include biomarkers used for assessing blood glucose level, cholesterol and blood fat values as well as "cancer markers" such as CEA and PSA.

In the meantime, a growing number of novel biomarkers with a much higher specificity and informative value are being identified using genomics, proteomics and metabolomics approaches. Gene variants, long DNA sequences, microRNAs, protein modifications as well as low molecular substances such as peptides and certain hormones have thus been identified as biomarkers for a broad range of diseases. In addition, cancer research requires biomarkers to identify genetic modifications in tumours that will enable conclusive disease classification and make effective therapeutic decisions possible. The International Cancer Genome Consortium is aiming to develop a comprehensive description of genomic, transgenomic and epigenomic changes in different tumour types and subtypes. The present dossier will not deal with the individual genetic differences and population variants as these have already been covered elsewhere, in the dossier entitled "Personalised Medicine", amongst others.

Over the last few years, molecular biomarker research has shifted its priorities from proteins to nucleic acids. This is mainly due to the rapid speed of innovation in the field of nucleic acid analysis, including the development of microarrays and next-generation sequencing, which are quick, simple and cost-efficient DNA analysis tools. The present hot topic is the use of microRNA profiles as biomarkers for the identification of complex diseases. However, proteins in their role as the classic molecular biomarkers for biological processes and states, have not suddenly gone out of fashion. New technologies like mass spectrometry, immunological methods or high-throughput assays are also setting new standards for the analysis of proteomes. Intensive research focuses especially on elucidating the potential of using protein classes such as kinases, phosphatases and proteases that are involved in regulatory mechanisms and signalling chains as disease biomarkers.

Disease-related and drug-related biomarkers 

The differentiation that is generally made between disease-related and drug-related biomarkers, as is seen, for example on Wikipedia, does not always appear to be particularly useful because it does not take into account the many overlaps. Instead, we would like to propose grouping biomarkers as follows:

• Diagnostic biomarkers: parameters used as indicators for the presence of disease in an individua
• Prognostic biomarkers: parameters that allow the diagnosis of the risk and likely development of diseases
• Drug-related biomarkers: parameters that provide information about a patient’s response to therapy

For all biomarkers routinely used in clinical application the following applies:

1. In order for a biomarker to be used for diagnostics, it must be relatively easy to obtain the sample material, using methods such as the non-invasive taking of blood, urine or saliva samples.
   
2. The time it takes to obtain results from the biomarker test is highly critical. The optimal scenario is a rapid test that can be carried out by a doctor and delivers a result within a few minutes. The doctor is then able to immediately discuss the procedure and possible treatment with the patient.
   
3. Any biomarkers that are used must have been thoroughly evaluated, which means that they must deliver reproducible results that can be used for the identification of well-defined diseases or biological processes.

It is fairly unlikely that any prognostic or diagnostic biomarkers will allow absolutely unambiguous conclusions to be drawn. It will always be necessary to include additional parameters in diagnostic decisions as well as taking into account the patient’s overall state of health. The PSA test, for example, which is used to determine prostate-specific antigen in the blood of men, permits the early identification of prostate cancer (editor's note: PSA is present in small quantities in healthy men, but the levels are often elevated in the presence of prostate cancer.) Nevertheless, prostate cancer screening is highly controversial: a long-term European study found that out of 10,000 men screened, seven fatal outcomes from prostate cancer were avoided. However, the study also found hundreds of cases in which false-positive test results required the men to undergo biopsies and surgery that was associated with massive side effects in some patients. That said, it is difficult for urologists to avoid using the PSA test, as alterations in the serum PSA level during the course of treatment provide them with information about treatment outcome. As a drug-related biomarker, the PSA test is currently the best indicator for the assessment of treatment outcome in patients suffering from prostate diseases. However, there is huge demand for newer and more accurate biomarkers.

EJ, BioRegion Rhein-Neckar-Dreieck (8th Dec. 2011)
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