Gene Signature Linked to Outcome in Breast Cancer

ANN ARBOR, Mich., Jan. 18 -- The clinical outcome of breast cancer and three other tumor types can be deduced by a "genetic signature" made up of 186 genes, according to researchers here.

The invasiveness gene signature is highly associated with overall and metastasis-free survival in breast cancer, reported Michael Clarke, M.D., of the University of Michigan, and colleagues, in the Jan. 18 issue of the New England Journal of Medicine.

The invasiveness gene signature was also associated with prognoses in medulloblastoma, lung cancer, and prostate cancer, said Dr. Clarke and colleagues.

The findings hint that "the invasiveness gene signature represents general biologic features shared by several different types of tumors," the researchers said.

The invasiveness gene signature arises from the finding by Dr. Clarke and colleagues that only a minority of cells in a breast tumor are capable of generating new tumors if transferred into experimental animals.

These "tumorigenic" cells are characterized by the expression of the surface molecule CD44, but low or undetectable levels of CD24, the researchers said.

Comparison of the genes expressed in the tumorigenic cells with normal breast epithelium showed that 186 genes -- of various types -- were more highly expressed in the tumor-causing cells.

When the researchers looked at archived tissue samples from breast cancer patients, they found that those whose tissues were more closely correlated with the invasiveness gene signature were more likely to have gone on to have metastatic disease or to die of breast cancer.

Specifically, they found that each increase of 0.1 in the Pearson correlation coefficient between an individual patient's genes and the invasiveness gene signature resulted in a 40% increase in the risk of death and a 30% increase in the risk of metastatic disease. Both increases were statistically significant at P<0.001.

Combined with the National Institutes of Health prognostic criteria, the invasiveness gene signature was used to stratify patients with high-risk early breast cancer into good or poor prognostic categories, Dr. Clarke and colleagues wrote. Among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%. Among those with a poor prognosis, it was 57%.

Using other tissue samples, the researchers found the invasiveness gene signature was significantly associated with outcomes in medulloblastoma, lung cancer, and prostate cancer, at P=0.004, P=0.03, and P=0.01, respectively.

The new genetic signature is the latest attempt to characterize aggressive tumors by the genes that are turned on in their cells. But four earlier genetic profiles "show considerable overlap" in predicting clinical outcomes, commented Joan Massagu, Ph.D., of the Memorial Sloan-Kettering Cancer Center in New York.

Writing in an accompanying editorial, Dr. Massagu said the four genetic profiles "may be regarded as different pictures of the same beast" in terms of their predictive power, even though they share few of the same genes.

How the invasiveness gene signature fits into the picture is still not clear, she said. Interestingly, the prognostic power of the invasiveness gene signature was increased when it was combined with one of the earlier signatures, the "wound-response signature."

The researchers were supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation, the Morton Foundation, the Virginia and D.K. Ludwig Foundation, the Fondazione Italiana per la Ricerca sul Cancro, and the California Institute for Regenerative Medicine. Four of the authors are employees of Oncomed Pharmaceuticals and Dr. Clarke is a paid member of the advisory board of Oncomed Pharmaceuticals and owns stock in the company. The remaining authors did not report any relevant conflicts.

Dr. Massagu reported receiving consulting fees from Acceleron Pharma.