Screening endpoints. ? Assays for biomarkers are

Screening for premalignant lesions or early invasive disease has the potential to reduce mortality from cancer. Potential screening tests for malignancy include measurement of biomarkers. Currently, only a small number of screening tests have been shown to reduce mortality from cancer. These include mammography in screening for breast cancer (especially in women >50 years of age), the Papanicalaou (PAP) test in screening for cervical cancer and fecal occult blood testing (FOBT) in screening for colorectal cancer (CRC) (Brawley and Kramer 2005, Smith, Cokkinides et al. 2007). Compared to procedures such as radiology, cytology and endoscopy, the use of biomarkers as cancer screening tests have several advantages (Duffy 2001). These advantages include:
? Biomarkers can be measured in biological fluids such as blood and urine that can be obtained with minimal inconvenience to subjects undergoing screening. This in turn should lead to high compliance rates.
? For many biomarkers, automated assays are available, thus allowing the processing of large numbers of samples in a relatively short period of time.
? Tests for biomarkers provide quantitative results with objective endpoints.
? Assays for biomarkers are relatively cheap.
A biomarker is defined as a quantifiable characteristic that is objectively measured and evaluated as an indicator of a normal biologic process, a pathogenic process, or a pharmacologic response to a therapeutic intervention. Typically, they are endogenous molecules that can be measured in bodily fluids or tissues with the ability to distinguish between disease and normal states.
Cancer biomarkers may appear in different types and forms, including DNA, mRNA, proteins, metabolites, or processes such as apoptosis, angiogenesis or proliferation (Hayes, Bast et al. 1996). Additionally, different functional subgroups of proteins, such as enzymes, glycoproteins, oncofetal antigens and receptors, may serve as useful biomarkers. Furthermore, tumor changes such as genetic mutations, amplifications, translocations and changes in microarray profiles (signatures) may also be utilized as tumor markers. Tumor markers may be detected in a variety of fluids, tissues and cell lines as they are often produced by the tumor itself or by other tissues in response to the presence of cancer or other associated conditions, such as inflammation. By measuring the levels of such markers through a simple test, tumor markers can be used for population screening, differential diagnosis in symptomatic patients, and for clinical staging of cancer. Cancer cells provide the biomarker material that can lead to their own detection, which then provides the opportunity for their non-invasive detection in body fluids and tissues so as to reveal the presence of tumors or the level of tumor burden (Isonishi 2004).
In practice however, lack of sensitivity for early invasive disease or premalignant lesions and lack of specificity for malignancy limit the use of existing biomarkers in screening asymptomatic subjects for early malignancy (Roulston 1990, Duffy 2001). Despite of the limitations, a number of biomarkers have either undergone or are currently undergoing evaluation as potential cancer screening tests.
The World Health Organization (WHO) lists specific criteria that a biomarker must satisfy. According to WHO, a good screening test must meet the following criteria (Chu and Rubin 2006):
? There are significant mortality statistics for the target disease and occurrence in the population
? Disease progression should be well characterized
? Early stage treatment of the disease should offer improved outcome
? Public acceptance of the screening test
? Availability of effective treatment options for individuals with advanced disease
? Suitable treatment and diagnostic facilities
? Policy outlining who can be subjected to treatment
? Cost-effective screening
? High positive predictive value, negative predictive value, sensitivity and specificity
The ideal marker should be produced by the tumor cells and enter the circulation in order for it to be detected by a non-invasive serological test. The marker should be present at low levels in serum of healthy or benign disease patients and increase significantly in cancer (preferably in one cancer type). Optimally, an ideal marker is present in detectable (or higher than normal) quantities at early or preclinical stages and the quantitative levels of the tumor marker should reflect the tumor burden. The assay for this marker should demonstrate high diagnostic sensitivity (low false negatives) and high specificity (low false positives) (Duffy 2001).


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