test for HER2, you can have antibodies that might be associated perhaps with different epitopes of the antigen that might convey with that somewhat different performance characteristics associated with the test,” he said. “You can find, for example, that the very same analyte … might show up in a different clinical context” (for example, two different tumor types that vary in their expression of the analyte).

Using HER2 as an example, Dr. Becker offered further explanation of considerations regarding “follow-on” tests based on biomarkers. HER2 is expressed at a variety of levels that can be assessed from the perspective of either biochemistry or cellular physiology, with one method measuring the HER2 protein itself while the other method relies on reverse-transcriptase polymerase chain reaction (RT-PCR) to monitor expression of the HER2 gene. “These different approaches to measuring the biomarker bring with them different aspects of analytical performance,” he said, to the extent that “you wonder at what point they actually diverge in terms of the[ir] biological implications.” In addition, two tests might measure the same biomarker in different matrices (for example, within a tumor versus serum levels).

The science associated with biomarkers and their applications is iterative and continually evolving, and it is important to recognize that scientific understanding of a biomarker can be “outrun by technical progress,” said Dr. Becker. For example, gene signatures represent a descriptive or empirical compilation of biomarkers that might be shown to correlate with clinical outcomes or features, but for which the underlying biological significance is unknown. He noted that an ongoing, resource-intensive process of biomarker qualification and utilization, as recommended by the committee, could lead to increased understanding of the biological role of each biomarker and the expansion and refinement of its uses.



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