A striking revelation in the most comprehensive analysis of breast cancer to date finds that one of the most deadly forms – the triple negative – which disproportionately affects African American and younger women – is genetically more similar to ovarian cancer tumors than breast cancers.
The study was co-led in St. Louis by Matthew J. Ellis, M.D., Ph.D., the Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine and Charles M. Perou, Ph.D. at the University of North Carolina.
“With this study, we’re one giant step closer to understanding the genetic origins of the four major subtypes of breast cancer,” Ellis said.
The research is part of The Cancer Genome Atlas project, which includes The Genome Institute at Washington University and other leading genetic sequencing centers that identify and catalog mutations involved in many common cancers. The effort is funded by the National Institutes of Health (NIH).
Study findings published online Sept. 23 in the journal Nature, suggest that because most basal-like breast tumors and ovarian tumors have similar genetic origins, they can potentially be treated with the same drugs.
“Now, we can investigate which drugs work best for patients based on the genetic profiles of their tumors,” Ellis said. “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.”
Ellis said how close we are to seeing new treatments for breast cancer based on this research depends on the hypothesis.
“For fine tuning the standard chemotherapy approach by subtype, this research can start immediately because we are focused on generic drugs,” Ellis said. “For repurposing drugs approved for other cancers that require collaboration with Pharma – logistically more complex, studies [are] likely to be activated in one year or so.”
For drugs not yet approved for any type of cancer, Ellis said it will take even longer.
“However, we have a clearer road map that should help select patients for investigational drug studies more effectively which should lead to faster approvals,” he said.
Basal-like tumors account for about 10 percent of all breast cancers and current anthracycline-based chemotherapy drug regimens are less successful against this type of cancer. Ellis said the new data indicates that clinical trials should be designed to avoid the use of these drugs in basal-like tumors.
Ellis does anticipate human clinical trials on women with basal-like breast cancer being treated with ovarian cancer drugs.
“Some doctors will want further randomized studies to get definitive data to establish a new standard of care for basal-like breast cancer,” Ellis said.
For this research, a nationwide consortium of researchers analyzed tumors from 825 women with breast cancer. 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.
“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,” said 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 study also confirmed the existence of four main subtypes of breast cancer: Luminal A, luminal B, HER2 and basal-like - which includes most triple-negative breast tumors, so-named because they lack receptors (to receive signals that could promote their growth) 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.
Mutations in only three genes – TP53, PIK3CA and GATA3 – occurred in more than 10 percent of patients’ tumors across the four subtypes. However, 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.
“Now, we’re much closer to understanding the true origins of the different types of breast cancer,” Ellis added. “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.”
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