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Genes reveal four breast cancer subtypes

WASHINGTON U. – ST. LOUIS / UNC-CHAPEL HILL (US) — One of the most deadly subtypes of breast cancer is genetically more similar to ovarian tumors than to other breast cancers, report researchers.

The most comprehensive analysis yet of breast cancer, published online September 23 in Nature, suggests that 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, chair in medical oncology at Washington University School of Medicine in St. Louis.

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

The new research is 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. The effort is funded by the National Institutes of Health (NIH).

“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.”

New framework

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, he says, the new data indicates that clinical trials should be designed to avoid the use of these drugs in basal-like tumors.

“This study has now provided a near complete framework for the genetic causes of breast cancer, which will significantly impact clinical medicine in the coming years as these genetic markers are evaluated as possible markers of therapeutic responsiveness,” says study co-leader Charles M. Perou, professor of molecular oncology of the University of North Carolina School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center.

As part of the new research, a nationwide consortium of researchers analyzed tumors from 825 women with breast cancer. The scientists 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.”

Four subtypes

The study confirmed the existence 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.

Across the four subtypes, mutations in only three genes—TP53, PIK3CA, and GATA3—occurred in more than 10 percent of patients’ tumors. But, the scientists found unique genetic and molecular signatures within each of the subtypes. Their findings add to the growing body of evidence suggesting that tumors should be cataloged and treated based on the genes that are disrupted rather than the location in the body.

In general, compared to the other subtypes, basal-like and HER2 tumors had the highest mutation rates but the shortest list of significantly mutated genes. These genes are thought to be major drivers of cancer progression.

For example, 80 percent of basal-like tumors had mutations in the TP53 gene, which have been linked to poor outcomes. About 20 percent of the tumors also had inherited mutations in BRCA1 or BRCA2 genes, which are known to increase the risk of breast and ovarian cancer.

“This suggests that it only takes a few hits to key genes that drive cancer growth,” Mardis explains.

New targets for treatment

A high frequency of TP53 mutations also occurs in ovarian cancer, the researchers note. Overall, the genetic profiles of basal-like and ovarian tumors were strikingly similar, with widespread genomic instability and mutations occurring at similar frequencies and in similar genes.

Finding new drug targets for basal-like breast tumors is critical, and the research suggests that patients with mutations in the BRCA genes may benefit from PARP inhibitors or platinum-based chemotherapy, which are already used to treat ovarian cancer.

By comparison, luminal cancers (which include estrogen receptor-positive and progesterone-receptor positive tumors) had the lowest mutation frequencies and longer lists of significantly mutated genes. This suggests defects in multiple genetic pathways can lead to the development of luminal breast cancers.

Most patients with luminal A cancer have good outcomes, and the most common mutation in that subtype occurred in PIK3CA, which was present in 45 percent of tumors. TP53 mutations only occurred in 12 percent.

Some patients with luminal B tumors do well but many experience recurrence years after treatment. Interestingly, the most common mutations in these tumors occurred in TP53 (linked to poor outcomes) and PIK3CA (linked to good outcomes), which may explain the disparate results seen in patients with this subtype.

“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.”

Additional investigators contributed to the findings from UNC Chapel Hill, Washington University in St. Louis, University of Texas, Indiana University, Duke University, Stanford University, University of Pittsburgh, and University of Chicago, among other institutions.

The work was supported by the National Institutes of Health as well as the Susan G. Komen for the Cure, the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the Breast Cancer Research Foundation.

Sources: Washington University in St. Louis & UNC-Chapel Hill

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