The Amsterdam signature is not the only gene panel that has been developed to predict breast cancer recurrence. Jan G. M. Klijn, M.D., Ph.D., and colleagues at Erasmus Medical Center in Rotterdam, the Netherlands, have identified a 76-gene signature that also identifies women at high and low risk of disease recurrence. Like the Amsterdam group, the Rotterdam group focused on women with node-negative disease, using microarrays to examine samples from 286 patients treated prior to 1996 who did not receive adjuvant chemotherapy.
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The Amsterdam and Rotterdam signatures share only three genes. Laura J. Van't Veer, Ph.D., of the Netherlands Cancer Institute and co-developer of the Amsterdam signature, and Klijn agree that the lack of overlap is not about biology or samples but rather the result of using different array platforms during the development of the two signatures. Van't Veer's group used Agilent chips, whereas Klijn's group used Affymetrix chips. "Roughly 25 genes included in our profile are not present on their chip, and, on their side, 20 genes in their profile are not on our chip," said Klijn.
When Klijn's team compared the signatures at the level of pathway activity instead of looking at single genes, they found that 21 pathways are shared between the two signatures, suggesting that the signatures are getting at the same underlying biology.
Fatima Cardoso, M.D., scientific director of the translational research network that is coordinating MINDACT, the trial of the Amsterdam signature (see related story, p. 331), said that "it would be of extreme scientific value to validate the Rotterdam signature on the MINDACT samplesthat would strengthen the value of microarray data. It would say that it doesn't matter what platform you use; you get the same outcome if you look at the same population."
Although both prognostic signatures might safely reduce the proportion of women with node-negative breast cancer who are treated with adjuvant chemotherapy by about 30%, few of the women in the poor-prognosis category will actually develop metastatic disease. (Both signatures were developed with the aim of achieving very high specificity for the low-risk group, even at the risk of lowered sensitivity, because the scientists did not want to put women at risk of recurrence.) Therefore, the team has room to refine the high-risk category. With this aim, Van't Veer's team has recently collaborated with the research group of Patrick Brown, Ph.D., at Stanford University to use two prognostic signatures in tandem.
Scientists noted previously that cancer and wounds share various processes, including angiogenesis, matrix remodeling, and proliferation. Brown's laboratory found that fibroblasts exposed to serum, a situation that only occurs in vivo when tissue is damaged, activate a large number of genes compared with untreated cells. They identified a 512-gene signature that consistently distinguishes these serum-exposed activated fibroblasts from quiescent ones.
Testing that 512-gene wound signature on the original 295 breast cancer samples used to develop the Amsterdam signature, Brown and colleagues found that 126 samples had the activated profile and 189 showed the quiescent pattern. The activated pattern correlated with metastasis and overall survival.
In the end, Brown and colleagues concluded in the publication of this study in the Proceedings of the National Academy of Sciences in early February, "the wound-response signature improves risk stratification independently of known clinico-pathologic risk factors and previously established prognostic signatures based on unsupervised hierarchical clustering or [the Amsterdam signature]."
Combining such methods in a clinical setting is not likely at this point, however, said Van't Veer. "Currently, such tests can only really be used at specialized centers. We need black box [microarray] tests, which are in development, to allow community hospitals to do such testing."
Related News Article in JNCI
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