Abstract
Over the last 2 decades the significance and the role of biomarkers in oncology have changed in several aspects. First, the concept of biomarker has been broadly extended. In fact, the potential clinical utility of biomarkers, which was initially restricted to cancer monitoring and, in a few instances, cancer diagnosis, has been reconsidered in many other possible applications. In 2010, the AACR-FDA-NCI Cancer Biomarkers Collaborative published a consensus report in which cancer biomarkers were defined as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” (1). This novel definition focuses on the need to consider biomarkers also as tools for therapeutic decisions, and formally extends the field of biomarkers outside the area of only biochemical or molecular markers; indeed, “a characteristic” may be a sign obtained from imaging techniques, as well as a clinical indication. For example, in patients with advanced NSCLC, first-cycle acne-like rash has been reported to be a clinical marker to identify patients that have a higher likelihood to gain significant benefit from cetuximab (2). Likewise, hypertension has been shown to be a predictive clinical marker for treatment efficacy in patients with metastatic colorectal cancer receiving first-line bevacizumab (3) and patients with metastatic renal cell carcinoma treated with sunitinib (4).
The AACR-FDA-NCI Cancer Biomarkers Collaborative also revised the classification of biomarkers with the goal of driving the discovery of novel biomarkers and their implementation into the pipeline of cancer drug development. Thus biomarkers have been operationally grouped into diverse families, including diagnostic biomarkers, predictive biomarkers, metabolism biomarkers and outcome biomarkers (1). Unsurprisingly, these “families” cannot be embodied by the tiny number of circulating biomarkers used in clinical practice today, consisting mostly of tumor-associated antigens, which are related to tumor bulk and are therefore not expected to provide information on the tumor cell machinery nor on the signals involved in the host microenvironment. Consequently, the new classification requires new biomarkers capable of providing information different from the actual amount of tumor tissue.
Hence, a second challenge in the arena of cancer biomarkers concerns the discovery of a continuously increasing number of diverse types of markers. This increasing pace of biomarker identification is due to 3 major factors interacting with each other: the availability of more and more sophisticated laboratory techniques and methods; the development of bioinformatics; and the astounding increase in the knowledge of mechanisms that regulate carcinogenesis and tumor progression.
One of the most relevant knowledge advancements in oncology is the comprehension of the relationships between chronic inflammation and malignancies (5), an understanding that has opened new perspectives in the prevention, diagnosis and treatment of cancer. As a result, many molecules related to cell regulation are being considered as putative biomarkers, potentially capable of providing mechanism-related information. Emblematic examples are the molecules related to inflammation and angiogenesis (6, 7).
Scientists operating in the field of cancer biomarkers have to deal with the challenge of managing an increasing number of new markers in order to verify their reliability and effectiveness prior to translating them into clinical practice. This enterprise is appearing more complex than expected. The issues with the mechanism-related biomarkers concern the concept of specificity. As is well known, the classical tumor associated-antigens are not cancer specific; increased circulating levels found in healthy subjects and patients with benign diseases are considered “noise” and classified as false positive results. The case of mechanism-related markers is totally different. In fact, they may be produced and released by both the tumor and the host microenvironment. The point is that the markers released by the microenvironment cannot be classified as “noise” nor their increased circulating levels categorized as false positive, since they may elicit several effects on cancer development and progression. In addition, the same molecule may be released at the same time by either the tumor, or the microenvironment, or both. From a biochemical point of view, it seems tricky to discriminate the origin of a given marker circulating in the bloodstream. This pitfall impairs a direct approach to the study of the role of inflammation markers – and angiogenesis markers as well – in cancer development and progression. Alternatively, the issue may be faced through an indirect approach. In fact, inflammation-related markers can be studied in diseases other than cancer, with the goal of exploring and eventually defining their general behavior in benign inflammatory conditions. In order to use soluble inflammatory markers in cancer management, it would ideally be necessary to define their background behavior in the presence of inflammation independently of the presence of cancer; an example would be any pattern of cytokine expression possibly specific of a given inflammatory disease. Needless to say, this task is complicated by many factors: (i) the number of potentially involved molecules; (ii) the extreme interindividual variability of both inflammatory diseases and the degree of inflammation; (iii) the complexity and the individuality of the relationship between inflammation and cancer; (iv) the interference with marker production and release by antiinflammatory agents frequently administered in chronic inflammatory statuses.
In the present issue, IJBM's editorial board has decided to accept for publication manuscripts concerning circulating biomarkers measurable in periodontitis (8-10), one of the most prevalent human inflammatory diseases, also considered a precancerous lesion for head and neck squamous cell carcinoma (11). This editorial decision is based on the necessity to shed light on the importance of studying inflammation-related biomarkers in several benign diseases to improve knowledge translation in the cancer biomarker field.