Molecular Medicine News Analyses

In the scientific literature:

Multiple Signatures of Breast Cancer

The power of current microarray technology to find genetic “signatures” of any given disease has resulted in a flurry of published results. These papers are undoubtedly just the tip of the iceberg. But what does it mean when very different genetic signatures are associated with one particular disease?

Perhaps nowhere is this variation more problematic than in cancer. A recent paper in the January 18, 2007 issue of the New England Journal of Medicine (1) underlines this problem. In this paper, the authors describe a 186-gene “invasiveness” signature associated with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer. Yet this signature, as interesting as it is, does not overlap significantly with several other signatures for breast cancer previously described in the literature.

This apparent contradiction is undoubtedly explained by the incredible biological complexity of breast cancers, and each of these signatures may simply be a different way of “seeing” the same elephant. If this theory is true, then there are several immediate implications.

1. Clinical trials must be performed.

Understanding which signatures or combination of signatures are truly prognostic will require sufficiently-powered clinical trials, across multiple sites, with multiple expertises. In addition, these trials will need to be tied to a range of specific therapies in ways that do not mask the genetic contributions, but still determine the best therapeutic regimen/genetic signature combination. In addition, this work will also require enormous resources.

2. Breast cancer treatment will be increasingly personalized.

The growing number of apparently valid genomic signatures supports a more sophisticated understanding of “breast cancer” (or any complex disease) as actually several different diseases, each with particular prognoses and, thus, unique therapeutic requirements. However, this hypothesis needs to be born out by actual evidence.

3. Communications are the key to progress.

It is critical that the complexities of the science – and the resulting areas of uncertainty – are clearly and honestly translated for patients (particularly those accrued to the trials), health care providers, and even the general public. Such communications to multiple audiences may be as complex as the biology itself, but they are absolutely required to procure the public support and understanding needed if discoveries are to be translated into regular clinical practice.

(1) Liu et al. (2007).The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356:217-226