Chapter 1
Biomarkers - Past and Future

Siegfried Neumann

1.1 Introduction

Biomarker is a term used for a characteristic property that can be precisely measured and objectively validated. Biomarkers serve as indicators of biological processes in health, disease or disease stages, or in the body's response to a therapeutic intervention. "Biomarker" is relatively new as a buzz word as it was recently coined in conjunction with the advent of molecular analysis in research programs and in exploratory medical diagnosis. However, quantitative data on the characteristics of physiological reactions in relation to functional changes and on molecular analytes in blood, serum, or other body fluids have been used in research and laboratory medicine for long, for example, some since the beginning of the preceding century.

Key advances in analytical instrumentation and its development for analytical precision and sensitivity revolutionized our knowledge of molecular and cellular biology of body functions. On the other hand, discoveries in basic biology science continuously pushed the demands on increasing the resolution power of technologies. This is true for science and technology in the high-speed sequencing of whole genomes and their transcription profiles, for the differentiation of protein patterns in a biological sample toward unprecedented borders of resolution, and for high-resolution submicroscopic cellular imaging. The convergence of many disruptive developments in instrument-based analytical precision with scientific discoveries in the molecular universe of genomic DNA, various types of RNA molecules as their transcripts, and proteins as the translation products led to the elucidation of crucial molecular interactions and allowed modeling of regulatory networks. In the field of malignant diseases, new paradigms for the molecular biology of pathogenetic processes lead to a deeper understanding of pathophysiological mechanisms working in the onset and spread of cancer.

As a consequence, one can expect that in medical practice the classification of diseases and the rules and decisions on their treatment will see dramatic changes in the near future. In a variety of diseases, the canonical definitions based on clinical symptoms, for example, a descriptional classification, and treatment based on an afflicted organ will both change toward molecular diagnosis, altered molecular markers, and a targeted intervention directed toward causative mechanisms that drive a pathological process. In the best case, identification of those molecular drivers can lead to early intervention and also provide options for prophylaxis.

In biomedicine, there are an ever-increasing number of new molecular markers for metabolic disorders, cardiovascular diseases, neurological disorders, chronic inflammatory diseases, and cancer. Accumulating data from molecular diagnostics offer physicians various complex marker panels to stratify patients for subtypes of a disease, evaluate the disease stage, and adjust their therapy regimen accordingly. This direction is now overarchingly termed as "precision medicine." Such a research-driven direction in medicine is nourished by activities in laboratory medicine, in vivo diagnostics for body/tissue imaging and cytology, and histology research by pathologists. This short overview illuminates the technologic status of biomarkers through selected examples, for example, with a main focus on oncology, and tries to anticipate where the developments on biomarkers might go in the coming years.

1.2 Definitions of Biomarkers

In 2001 the Biomarkers Definitions Working group termed "biomarker" as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention [1].

In a similar understanding the term "cancer biomarker" was described as a "biomarker that is present in tumor tissue or serum and includes many different molecules, such as DNA, mRNA, or proteins: Tumor biomarkers are measured in tumor tissue and, tumor DNA biomarkers are measured from tumor tissue" [2]. In addition, there is now evidence that a tumor biomarker may also become delineated from the titer and genotype of circulating tumor cells [3] and from the circulating tumor cell DNA.

Biomarkers signal differences in biological states. The many potential applications of using biomarkers also include detection of pharmacologic profiles in a given group of probands, for instance, for detecting kidney toxicity after drug exposure in clinical trials with novel drugs or after the approval of drugs [4]. The term biomarker is not restricted by how the marker is measured. Thus, a valuable quantitative data profile may be obtained by means of a physical, optical, or enzyme assay, immunochemistry, mass spectrometry, cytological and histochemical analyses or by in vivo imaging techniques such as magnetic resonance tomography or positron emission tomography. In addition, a combination of data from various analytical levels is frequently in use.

In preclinical drug research and development biomarkers can address different key questions. They can contribute selectively to either one of the following research aims:

• Pharmacodynamic biomarkers: are related to the mechanisms of the action of a drug and give answers on whether the drug reaches and interacts with its target and whether this creates downstream effects.
• Disease biomarkers: are related to a disease type or subtype and answer questions such as whether the drug affects a disease-relevant or a disease-relevant intermittent phenotype, which can be measured with a biomarker or biomarker panel.
• Predictive biomarkers: are associated with the response or lack of response to a particular therapy.
• Surrogate biomarkers: substitute a clinical endpoint. They are expected to predict a clinical benefit or harm or - on the contrary - a lack of benefit or harm. They inform on whether the treatment can reduce the disease burden as measured by clinical endpoints.

For the use of biomarkers in clinical practice a solid understanding and knowledge of their role in molecular and cellular biology of disease processes is a prerequisite in order to demonstrate a benefit in reduction of disease burden. Response monitoring by using imaging biomarkers in clinical trials will support identification of effective versus ineffective drugs and dose finding, and might correlate with the overall clinical efficacy. In conclusion, biomarkers can serve for a variety of crucial medical objectives, both in preclinical research and clinical development of drugs as well as in diagnosis, treatment decisions, and prognosis in clinical practice [5].

1.3 Biomarkers in the Past

Biomarkers of various molecular classes have been in medical use since the beginning of the twentieth century, for instance, since the impact of inborn errors of metabolism on neurological development was recognized by Garrod (1908) [6]. In the middle of the twentieth century the development accelerated when filter-based and spectral photometers became available to the laboratories and when the analytical portfolio for enzyme assays was continuously expanding. This step allowed measuring the presence and levels of many enzymes in samples from healthy and diseased individuals by clinical chemistry. The introduction of protein separation by electrophoresis and the quantitation of proteins and peptide hormones by radioimmunoassays and later by enzyme-linked immunoassays helped discover the presence of various tissue-derived oligo- and polypeptides as well as glycoproteins as disease markers in circulating blood, cerebrospinal fluid, and other body fluids as well as in tissue extracts. This then lead to the introduction of many enzymes, proteins, peptide markers, steroids, and metabolite-like lipids and cholesterol as measurable entities in panels of diagnostic parameters.

Table 1.1 as a selected listing makes a case on how the detection of tissue-derived markers, in the form of enzyme activities, protein concentrations, and metabolite levels, helped in the detection and staging of organ damage in a variety of classes of human disease.

Table 1.1 Established diagnostic measurements by clinical chemistry on serum, selected by organ, or systemic disease