Use of Biomarkers in Screening for Cancer

BACKGROUND: Screening for premalignant lesions or early invasive disease has the potential to reduce mortality from cancer. Potential screening tests for malignancy include measurement of (bio)markers. CONTENT: The literature relevant to the use of biomarkers as screening tests for cancer was reviewed with particular attention given to systematic reviews, prospective randomised trials and guidelines published by Expert Panels. Because of their ease of measurement, several biomarkers have been evaluated or are currently undergoing evaluation as screening tests for early malignancy. These include the use of vanillymandelic acid and homovanillic acid in screening for neuroblastoma in newborn infants, AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for ovarian cancer, PSA in screening for prostate cancer and fecal occult blood testing (FOBT) in screening for CRC. Of these markers, only the use of FOBT in screening for CRC has been shown to reduce mortality from cancer. Large randomized prospective trials are currently in progress aimed at evaluating the potential value of PSA screening in reducing mortality from prostate cancer and CA 125 in combination with TVU in reducing mortality form ovarian cancer. CONCLUSION: Although biomarkers have many attractions as screening tests, inadequate sensitivity and specificity, when combined with the low prevalence of cancer in asymptomatic subjects, limit their value for the early detection of malignancy. Screening has been defined as the systematic application of a test to identify subjects at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, among persons who have not sought medical attention on account of symptoms of that disorder (1). To be of value, screening must detect disease earlier and result in an efficacious treatment and the earlier use of efficacious treatment must lead to better outcome compared to treatment available at the onset of symptoms (2). Screening differs from diagnosis in that the aim is to detect disease or a predisease state when subjects are asymptomatic. 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) (for review, see refs. 2,3). Compared to procedures such as radiology, cytology and endoscopy, the use of biomarkers as cancer screening tests have several advantages (4). 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. 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 (4,5). This lack of sensitivity and specificity when combined with the low prevalence of cancers in the general population means that most biomarkers, if used alone, have a low positive predictive value in screening asymptomatic populations. Indeed, it is the low prevalence of cancer in the general population that prohibits most biomarkers from being used alone, in screening for cancer (4,5). Despite these limitations, a number of biomarkers have either undergone or are currently undergoing evaluation as potential cancer screening tests. These markers include the use of vanillymandelic acid (VMA) and homovanillic acid (HVA) in screening for neuroblastoma in newborns, AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for ovarian cancer, PSA in screening for prostate cancer and fecal occult blood testing (FOBT) in screening for CRC. The aim of this article is to critically review the role of these biomarkers in screening normal-risk asymptomatic subjects for early cancer. Screening subjects with a genetic predisposition to cancer will not be discussed.