Scientists at the University of North Carolina at Chapel Hill say they have helped develop a new genomic test that can help clinicians predict which breast cancer patients are most likely to survive the disease and which treatments may be most effective in increasing those chances of survival.

By specifically measuring the activity level of a small subset of the 20,000 plus genes that may be “turned on” or “turned off” within each tumor, this genomic test can give patients a more accurate picture of how their disease might progress.

The relatively simple test can be performed in many hospital pathology laboratories, an advantage over other recently developed genomic tests that require more sophisticated technology and expertise. That is because the researchers specifically designed this test to analyze cancer tissues using equipment currently present in many hospitals.

“Here we have developed a method which can be used in the everyday clinic and has the potential to benefit all breast cancer patients,” said Charles Perou, Ph.D., associate professor of genetics and pathology at UNC School of Medicine;. “Based on the genomics of a tumor we can make good predictions about how a patient might do, but we can also define predictive markers which tell us which drugs to give patients.”

One in eight women in the United States will receive a diagnosis of breast cancer in their lifetime. The disease occurs when mutations accumulate in critical genes — such as those that control cell growth and division or the repair of damaged DNA — allowing cells to grow and divide uncontrollably to form a tumor. The specific genetic changes that are acquired in these tumor cells determine in large part how aggressively the cancer will behave.

In the last five years, clinicians have begun using this genomic information to better inform the prognosis of their patients and to assist in making decisions regarding their treatment. Two genomic tests that are making their way into common clinical practice are MammaPrint -- which predicts whether existing cancer will spread to other parts of the body or metastasize -- and OncotypeDx – which assesses the likely benefit from certain types of chemotherapy as well as the likelihood of disease recurrence.

“These genomic tests have provided us with clinical information that none of the previous factors used in breast cancer care provide, and these new tests are complementary with the existing tests and the combination of the two is best” Perou said.

A major focus of Perou’s research is to provide more biological information that can be mobilized in the fight against breast cancer. He and his colleagues used DNA microarrays or “gene chips” to scan the thousands of genes within tumor samples from breast cancer patients whose disease outcomes were known. They found the samples that defined five biologic groups – called as Luminal A, Luminal B, HER2-enriched, Basal-like and Normal-like -- that demonstrated a specific genomic signature corresponding to distinct disease outcomes. The researchers then used statistics to hone in on a small subset of 50 genes that can still identify these biologic groups as robustly as the original list of thousands of genes.

In this study, Perou and his colleagues modified their approach to measure the activity levels of those 50 genes using a technology – called RT-PCR -- that is both available in the pathology clinic and that is compatible with the paraffin-embedded tissues that are routinely collected during cancer diagnosis. The multi-institutional team of scientists then validated the ability of their genomic test to predict the actual outcomes in a separate set of 761 patients. They also showed that the test was able to predict response to a common chemotherapy regimen, namely one that contains a taxane and an anthracycline, in another set of 133 patients. Clinical trials are ongoing to confirm these results in even larger numbers of patients.

“Here we’ve demonstrated that this assay can predict a patient’s probability of relapse and can define a patient’s biologic subtype, which are pieces of information that together could be used to make treatment decisions,” Perou said. “We also found that patients in just two groups actually benefited from the chemotherapy we studied, whereas the patients in the other three groups showed a much lower response rate. The idea is for clinicians to use this knowledge to help determine what drugs a patient should get and should not get.”

Perou is now looking at the responses of these subtypes to other chemotherapeutic and biologically based drugs. He thinks that over time associations will emerge that clearly define which patient will respond to which type of therapy. For example, he has already found that Luminal A patients have the worst response rate to chemotherapeutics but the best response to hormone therapy, suggesting that it may be best for these patients to forgo chemotherapy and its detrimental side effects and rely solely on therapies that target the hormonal responsiveness of these tumors.

The multi-center study was led by researchers at the UNC Lineberger Comprehensive Cancer Center, the University of Utah Huntsman Cancer Institute, Salt Lake City; and Washington University Siteman Cancer Center, St. Louis, Missouri. Other senior authors were Matthew Ellis, M.D., associate professor of medicine, Washington University School of Medicine; and Philip S. Bernard, M.D., assistant professor of pathology and medical director of Huntsman’s molecular pathology laboratory.

A report of the study appears in the February 9 issue of the Journal of Clinical Oncology.

The research was supported by the National Institutes of Health. Study co-authors from Perou’s laboratory at UNC include Joel S. Parker, the lead author and graduate student; Xiaping He, research associate; and Zhiyuan Hu, former postdoctoral fellow and current director of UNC pathology-genomics laboratory. J.S. Marron and Andrew B. Nobel, both professors of statistics at UNC, also contributed to the study. Laboratories at the University of Utah, the University of British Columbia and Washington University contributed to the study as well.