The Search for Cancer Diagnostic Markers: A Race Against Time - The knowledge that early detection and treatment offers the best outcome for the patient has long driven the search for effective diagno

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The Search for Cancer Diagnostic Markers: A Race Against Time
The knowledge that early detection and treatment offers the best outcome for the patient has long driven the search for effective diagnostics.


BioPharm International


The second approach has evolved with sophisticated instrumentation for multiplexing and has become more widely available. In this permutation, a number of markers are monitored simultaneously with the expectation that the combined statistical power of numerous markers will yield an assay with a much higher specificity than any one marker counted singularly. In most cases the identity of the markers is not known, but an empirical profile of the particular cancer is developed. This approach has been described by Espina et al.2 who argue that each patient's cancer has a unique profile of genetic alterations. They have used genomic and proteomic tools to categorize the molecular derangements of individual tumors. The concept that measuring multiple analytes will yield superior diagnostic results is an appealing one. Carpelan-Holmstrom et al.3 employed a logistic regression algorithm combining the serum markers CEA, CA72-4, and CA 19-9 to improve diagnostic performance for gastrointestinal malignancy. A comparable study by Louhimo et al.4 investigated the combined performance of HGCß, CEA, CA 242, CA 72-4, and CA19-9, also with improved accuracy. While these results are encouraging, they have not yet resulted in a practical clinical assay.

A number of investigators are pursuing a search for cancer markers by screening the serum proteome using SELDI-TOF, 2-D gel analysis, and other approaches.5,6 However, this is an extremely challenging area, as there are many difficult problems to be resolved. Some of these technologies allow for multiplexed measurement of specific proteins in a rapid, low-cost format, which generates a tremendous amount of data from a single experiment. At this time protein microarray applications have been largely confined to basic research problems and such screening has not yet generated useful cancer markers.1

Yet a third approach is a more indirect way of identifying tumor-specific antibodies in the serum of affected individuals. In many cases when the antigens were identified, they have been found not to be tumor-specific.

CANCER MARKERS CURRENTLY IN USE

Kits for the detection of disease states through antibody interactions have been widely used for many years. Not only the PSA-based kits, but also CEA, AFP, and many other markers have been employed in both diagnostic and therapeutic products.

While one of the most widely used markers for cancer screening is the prostate specific antigen (PSA) test, its reliability has been widely questioned.7 There are many kits available (such as the Biosafe PSA test) but despite years of screening and intensive investigation, Vicini et al. assert "the overall benefit of monitoring serum PSA after treatment for prostate cancer remains controversial."8 These researchers point out that the negative consequences of incorrect diagnosis in terms of cost, patient risk, and psychological anxiety are so substantial that much more investigation is warranted to define an appropriate application of therapy. Debate concerning the sensitivity, specificity, and positive predictive value for clinical response is widespread, and no pattern of PSA kinetics after treatment has conclusively been associated with a specific outcome. Indeed, the authors assert that 5 to 25 percent of patients ultimately experience failure and disease recurrence (beyond five years) even among those whose PSA levels predict the most optimal consequence.

Recently "PSA velocity," the rate of increased PSA levels over time, has been evaluated as a marker of malignancy risk.9 These authors determined that individuals with a velocity significantly greater than 2 ng/year had an increased risk of death from prostate cancer, despite radical prostatectomy. However, the size of the group examined was small, and additional studies will be required to establish the utility of this diagnostic approach. These questions regarding the PSA test illustrate the urgent need for new markers of malignancy.

Ekström et al.10 have explored an interesting means of protein discovery. They have developed a microplatform for analyzing samples of seminal plasma in a search for new protein markers of prostatic disease. They characterized proteins coisolated in affinity chromatography runs (using anti-PSA monoclonals) of prostate-specific antigen, and identified a protein known as prolactin-inducible protein, which may play a role in both tumor progression and fertilization. Proteins that copurify with PSA might serve as defining markers of degree or type of malignancy.


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