NCI’s New BRCA1 Test: Broader Utility and Another Challenge to Traditional Genetic Tests

switchContributed by Allison Williams Dobson of the Center for Genomics and Society at the University of North Carolina at Chapel Hill.

As reported last week by GenomeWeb, on September 21, 2009, a team led by Shyam Sharan from the National Cancer Institute (NCI) published the development of a new BRCA1 test based on mouse embryonic stem cells. Potentially, the test could prove useful for a much broader range of patients than the controversial Myriad Genetics BRCA1 tests.

The NCI approach focuses more on protein production than DNA analysis. The BRCA1 gene serves as the blueprint for an important tumor suppressor protein. If BRCA1 protein is not produced in sufficient quality and/or quantity, a propensity to develop cancer in the breast tissue often results. The traditional genetic testing approach asks whether a subject carries any of the BRCA1 gene variants that have been associated with increased risk for breast cancer in studies of afflicted families. NCI’s approach asks a significantly different question—rather than focusing on an identified set of “bad” gene variants, NCI asks whether a subject carries BRCA1 variants that serve as adequate blueprints for a functional protein, whether those variants have been previously identified or not. It does this by testing the protein product of the gene.

Until now, women with a family history of breast cancer have been most likely to seek a BRCA genetic test and represent the principal source of BRCA genetic data. Thus Myriad’s patented tests are based on a set of culprit BRCA gene variants found by studying primarily families with a strong propensity toward breast cancer, despite the fact that only 5-7 % of breast cancers are familial. As a result, the Myriad tests only offer useful information about a subset of BRCA1 variants. But many people (both with and without family history) carry other BRCA1 variants of unknown significance (VUS). There just are not enough empirical data yet to support conclusions about the risk associated with VUS.

The new NCI test can theoretically detect any bad BRCA1 variant, regardless of whether it is manifest in family history data. As the title of one commentary notes, the test works by “separat[ing] the harmful from the harmless,” rather than just identifying gene variants known to run in families with high rates of breast cancer. Consequently, the NCI test should be reliable as a tool for estimating breast cancer risk for any patient, regardless of family history or ancestry. What’s more, the data previously available for familial variants serve as an accuracy check to prove that the NCI test works.

For non-biologists who want to better understand the new test, consider the following: The NCI team created a little blueprint reader that was installed in the nucleus of the mouse embryonic stem (ES) cells. This reader is designed to read the instructions contained in a BRCA1 gene. The scientist can insert the sequence of either one of your two BRCA1 genes into this reader, and the ES cell’s natural machinery then uses those instructions to build the protein.

At the same time as the test BRCA1 gene is examined by the reader, another “switch” is thrown, and the ES cell inside which all of this is going on suddenly has to have BRCA1 protein coming from the test BRCA1 gene blueprint in order to survive. If the BRCA1 protein is sufficiently functional, the ES cell survives. If the protein is defective or lacking, the cell dies. In reality the test is much more complicated (as well as time- and labor-intensive), but the basic idea is an elegant one.

What does this new NCI test mean for Myriad, its BRCA1 and BRCA2 patents and patients interested in determining their risk of breast cancer? It is possible that aspects of the new test might infringe some of Myriad’s broadest patent claims to “isolated DNA” with specific BRCA1 sequences, because testing a subject using the NCI method seems to require “isolation” of BRCA1 sequences at some point. However, the sequences used do not necessarily have to be the exact sequences claimed by Myriad.

Moreover, depending on assignments, licenses, or cooperative agreements that may exist between federal health agencies, Utah and Myriad, a government lab such as NCI may have the right to use or even license the technology. And NCI senior author Shyam Sharan has indicated that, while clinical testing is still needed, NCI ultimately wants to license the test. However, at the moment it is unclear whether such licensing (e.g., to Medicare, Medicaid or to private diagnostic providers) will go unchallenged. As Robert Cook-Deegan, of the Duke University Center for Genome Ethics, Law & Policy and Institute for Genome Sciences & Policy, notes: “This makes the point that just knowing patents and claims, which are public, does not give you the info you need to know about freedom to operate. Lack of transparency is a really important source of uncertainty and high transaction costs in this system.”

Ultimately, the infringement issue, at least with respect to NCI’s BRCA1 test, is unlikely to be tested in the immediate future. Although, technically speaking, even the development of such a test might infringe Myriad’s patents, it is extremely doubtful, for pragmatic reasons, that Myriad would bring an infringement claim against a government laboratory engaged in the development of a novel and potentially valuable test that is neither commercialized nor widely available at this time. Although NCI has indicated its intent to out-license its test, further development and testing is needed before the test will be available for clinical diagnostic purposes and, depending on how long that process takes, Myriad’s original BRCA1 patents (derived from a 1994 application) could be in their final years before the new test gets to market.

Stepping back to look at the bigger picture, however, shows Myriad and other gene patent holders facing a host of challenges to their patents that are arriving with accelerating speed and from all directions. From constitutional challenges brought by the ACLU to potential patent policy reforms (pdf), and from the widespread availability of whole-genome sequencing to novel forms of genetic testing, which suggest the possibility that science may be able to invent around existing gene patents, gene patent holders interested in preserving the status quo must be increasingly prepared to respond to litigation, policy reform attempts, and scientific advances all designed to bring genetic information into the hands of patients and consumers more quickly and at a lower cost.

Allison Williams Dobson

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