Genetic Origins of Cancers to Help in Targeting the Disease with Specific Drugs

The researchers at the Medical Oncology at Washington University reveal that the deadly subtypes of breast cancer are genetically more similar to ovarian tumors.

"Most basal-like breast tumors and ovarian tumors have similar genetic origins and potentially could be treated with the same drugs," says the study's co-leader Matthew J. Ellis, MD, PhD, the Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine in St. Louis

Charles M. Perou, PhD, at the University of North Carolina was the co leader of the study that was published in the Sept 2 Nature and is a part of  The Cancer Genome Atlas project, which brings together leading genetic sequencing centers, including The Genome Institute at Washington University, to identify and catalog mutations involved in many common cancers.

Basal-like tumors account for about 10 percent of all breast cancers and disproportionately affect younger women and African-American.

"With this study, we're one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer," says Ellis, who treats breast cancer patients at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "Now, we can investigate which drugs work best for patients based on the genetic profiles of their tumors. For basal-like breast tumors, it's clear they are genetically more similar to ovarian tumors than to other breast cancers. Whether they can be treated the same way is an intriguing possibility that needs to be explored."

"Currently, for example, basal-like breast tumors often are treated like many other breast cancers, using anthracycline-based chemotherapy. But another of Ellis's studies recently showed that women with basal-like tumors don't benefit from these drugs, which also have severe side effects. At the very least the new data indicates that clinical trials should be designed to avoid the use of these drugs in basal-like tumors," he says.

For the study the researchers analyzed tumors from 825 women with breast cancer. They used six different technologies to examine subsets of the tumors for defects in DNA, RNA (a close chemical cousin of DNA) and proteins. Nearly 350 tumors were analyzed using all six technologies.

"By tying together those different data sets, we can build a story around the biology of each breast cancer subtype that is dictated by the genome, interpreted by the RNA and played out by the proteins at work inside each tumor," says co-author Elaine Mardis, PhD, co-director of The Genome Institute. "These data can serve as a backdrop for other questions about how particular mutations affect survival or response to certain drugs."

The researchers confirmed the presence of four main subtypes of breast cancer: Luminal A, luminal B, HER2 and basal-like.

The latter includes most triple-negative breast tumors, so-named because they lack receptors for the hormones estrogen, progesterone or human epidermal growth factor 2 (HER2). These tumors often are aggressive and do not respond to therapies that target hormone receptors or to standard chemotherapies.

They noticed mutations occur in only three genes in more than 10 percent of patients' tumors. But, the scientists found unique genetic and molecular signatures within each of the subtypes. The study shows that tumors should be cataloged and treated based on the genes that are disrupted rather than the location in the body.

"Now, we're much closer to understanding the true origins of the different types of breast cancer," Ellis says. "With this information, physicians and scientists can look at their own samples to correlate patients' tumor profiles with treatment response and overall outcomes. That's the challenge for the future -- translating a patient's genetic profile into new treatment strategies."