Biomarkers in Oncology: An Evolving Concept
المؤلف:
Marcello Ciaccio
المصدر:
Clinical and Laboratory Medicine Textbook 2021
الجزء والصفحة:
p455-456
2025-12-02
8
The concept of a biomarker as a biochemical signal associated with the presence of a malignancy dates back to 1845, when Henry Bence-Jones published the article “On a new substance occurring in the urine of a patient with mollities ossium.” He accurately described the identification process of the “substance,” but, more importantly, he hypothesized the role of the “new substance” as a disease biomarker, suggesting its clinical application and indicating its importance for understanding the pathophysiology of the associated disease.
However, the clinical importance of biomarkers in oncology emerged only in the early 1960s of the last century, thanks to two breakthroughs: the uncovering of immunoassays by Rosalyn S. Yalow and Solomon Berson, which led to the development of easy-to-use immunometric assays to analyze a large number of samples simultaneously and in a reasonably short working time, and the measurement of estrogen receptors by Elwood V. Jensen through the development of radioligand binding assay methods. The determination of estrogen receptors in the breast cancer tissue was first used by clinicians to predict the response to ablative hormonal therapies, such as ovariectomy, and then to additive therapies (progestins, antiestrogens, aromatase inhibitors, etc.) in women with breast cancer. Immunoassays were widely used to measure circulating levels of an increasing number of bio markers, such as α-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), and many others progressively identified, initially classified as tumor-associated antigens and conventionally known as “tumor markers.” The discovery of hybridoma technology by Georges Köhler and César Milstein, and the resulting avail ability of monoclonal antibodies in the 1980s, fueled the discovery of new biomarkers, the development of more sensitive and specific immunoassays, and the optimization of assay techniques. This was followed by a phase of great interest and enthusiasm, in which it was widely believed that the early diagnosis of several malignancies could be ultimately feasible through the determination of “tumor markers.” The clinical role of tumor markers was progressively scaled down thereafter as their limitations began to be highlighted. The first one is the fact that tumor markers are not specific to cancer and can be elevated in many non-oncological conditions; the second one is related to the direct relationship between circulating levels of the marker and the extent of tumor tissue; therefore, it is unlikely that an early – and thus a small – malignancy can produce and release significant amounts of the marker. The awareness of these limitations has considerably constrained the potential role of circulating “tumor markers” for the early diagnosis of cancer. On the other hand, as concerns predictive biomarkers, the last two decades have witnessed extraordinary progress in the knowl edge of the molecular mechanisms controlling cell growth, which has led to the development of many new anticancer drugs directed against specific molecular targets. The approach to the treatment of malignancies has therefore progressively changed with the introduction of an increasing number of molecular, targeted anticancer agents. This has led to an in-depth investigation of the association between the drugs and their biological targets, finally developing the concept of a mandatory drug–biomarker association, thus coining the term “companion diagnostics,” to the extent that today several molecular targeted anticancer agents can be prescribed only if the specific target has been determined.
Thus, the concept of a biomarker has undergone a pro found change over time, which has extended its biological meaning and broadened its areas of clinical application. The American Association for Cancer Research in partnership with the Food and Drug Administration and the National Cancer Institute (AACR-FDA-NCI) Cancer Biomarkers Collaborative consensus report has operationally defined a biomarker as “an objectively measurable characteristic and evaluated as an indicator of a normal biological process, of a pathological process, or the pharmacological response to a therapeutic intervention.” From this definition, it follows that the term “biomarker” also includes, together with molecular indicators, clinical signs or metabolic information derived from imaging techniques. This more inclusive definition is intended to support the development and application of those new anticancer drugs directed at known biological mechanisms but still lacking a precise molecular target, as in the case of tumor neoangiogenesis. Thus, hypertension associated with bevacizumab administration has been considered a predictor of response in patients receiving this drug as the first-line therapy for metastatic colorectal cancer. Similarly, acneiform rash occurring at the first cycle of cetuximab therapy in patients with non-small cell lung cancer was found to be a clinical biomarker of response to the drug. Concerning imaging, changes of tumor metabolic activity evidenced by positron emission tomography–computed tomography (PET–CT) seems to be an early predictor of response to treatment. Humbert et al. reported that a maximum standardized uptake value (SUV) ≤2.0 after the first cycle of therapy is the most effective predictor of response to trastuzumab- containing regimen in women with breast cancer positive for human epidermal growth factor receptor 2 (HER2).
These biomarkers represent a pragmatic approach to clinical application, but they are only the epiphenomenon of a complex biological cascade. The need for their use testifies that more specific molecular biomarkers associated with the different steps of the signaling mechanism of interest suit able for clinical use have not yet been identified.
الاكثر قراءة في الاورام
اخر الاخبار
اخبار العتبة العباسية المقدسة
