Michelle Burns had three things working against her in getting a more aggressive breast cancer. She was relatively young, just 40 years old. Her mother had gotten breast cancer.
“And then I’m an African American female,” Burns said. She was diagnosed with what is often called triple-negative breast cancer, where her breast cancer lacks receptors for estrogen, progesterone and human epidermal growth factor receptor 2 or HER2, which are targets for the more specific breast cancer treatments. It disproportionately strikes young black women and because of the lack of targeted therapies has a poorer prognosis.
Burns is relying on her faith in God to sustain her but she knows the odds are higher for her that it will come back.
“It makes you feel like you need to live each day as if it is your last because you never just know what tomorrow will bring,” she said.
It is precisely these kinds of difficult breast cancers that some researchers at Georgia Regents University Cancer Center are zeroing in on because of the lack of good therapies and the higher prevalence in the area.
In some ways that makes the GRU Cancer Center better positioned to study it than others. For instance, when GRU researchers downloaded the triple negative tumor gene sequences from The Cancer Genome Atlas, it contained many samples from whites but only 12 from blacks, while GRU has already sequenced tumors from 19 black patients, said Dr. Lesleyann Hawthorn, an associate professor of pathology. The center also has just started a collaboration to get triple negative tumor samples from hospitals in Albany and Savannah, she said.
“In the African American population, it occurs at a younger age and it is much more aggressive so we are thinking it must be a different kind of tumor,” Hawthorn said.
HER LAB SEQUENCES the tumor sample and compares it to the sequence from the patient’s blood that would contain the normal genetic makeup and then looks at the differences. From about 20,000 single genetic variations, they were able to narrow it down to 300 that were tumor-specific and have since been able to narrow that to 45 candidates that could point the way toward a genetic target for drug therapy, Hawthorn said. The problem is choosing the right ones to focus on, she said.
“The sequencing part is really easy but the other part of it, the analysis, is very hard,” Hawthorn said. “We’re trying to use as many different approaches as we can to see if we can just pinpoint something that is showing up across samples in different analysis methods.”
While triple negative is well-known, another highly aggressive breast cancer has only recently been characterized. Called molecular apocrine breast cancer, it is unusual in that it doesn’t respond to estrogen but it does to the male hormone androgen, which seems to drive the same genes that estrogen does in estrogen-sensitive breast cancers, said Dr. Ahmed Chadli, an assistant professor of medicine and a researcher at the cancer center. Androgen is already a well-known driver of prostate cancer, he said.
“This has been really very puzzling and very exciting,” Chadli said. “It is also an opportunity because we have drugs used in prostate cancer that can be used in breast cancer in women. That’s opened a very nice door and there are some clinical trials that are ongoing.”
GRU’s research is focusing in on a molecular chaperone, a protein that alters other proteins to help them function. In the case of the receptor needed for androgen to interact with the breast cancer cell, it must be folded by a protein called UNC45A, Chadli said. By finding a way to block UNC45, “we will actually destabilize the androgen receptor and consequently we will kill the cancer cells that are dependent on it,” Chadli said. The next step would be to run it against a library of 80,000 compounds to see if any of them are a candidate to block that target protein, he said.
“It is always important to find the next generation of therapeutics that will help the patients because we know from previous experience the cancer cells always find their way around the chemotherapy,” he said.
Part of how tumors do that might be through a molecule first identified in the ’90s but now studied worldwide that might be helping it evade the host immune system. It is known that the molecule indoleamine 2,3 dioxygenase or IDO helps create localized tolerance for the fetus to help protect it from the mother’s immune system but how it might also be playing a role in breast cancer is unclear, said Dr. Ravindra Kohle, an assistant professor of pathology who has molecular and breast pathology practice at the cancer center.
“We don’t know the status of the immune system in the breast,” he said. “That’s the fundamental goal of this project is to get a picture of what IDO does at what stage and what population.”
THE PLAN WOULD be to add IDO to the panel of markers they are already looking at in breast biopsies, along with another marker for programmed death 1 or PD1, to see where they are showing up, he said. There are already IDO inhibitors in clinical trials against cancer, usually involving other chemotherapies, and the plan would be to start a clinical trial in breast cancer if warranted, Kohle said. As a pathologist who sees 10-15 breast biopsies a day, he can give them important information such as HER2 status. But Kohle said he would like to be able to do more.
“We want to expand the panel to include immune markers to predict whether this particular disease has metastatic potential (to spread)” and if it is going to be more aggressive, he said.
And that is why GRU is going after these breast cancers because they are aggressive and the outcomes are not good, Hawthorn said. The five-year survival rate for triple negative breast cancer is 14 percent compared to 98 percent for early stage estrogen-receptor positive breast cancer, she said.
“That’s really bad because especially the women who are African-American are getting it in their 30s and 40s when they’ve got young kids,” Hawthorn said. “It’s a pretty nasty disease.”
Burns knows the numbers but chooses not to dwell on them.
“Because of my faith in God, I feel like there’s a lot of hope,” she said. “And I have to give all of the credit to God. Because when I focus on the statistics, when I focus on the facts and the medical information that is out there, I could easily see myself worrying a lot.”
But she does not ignore medical science – she has been to two national conventions already seeking answers.
“I trust God but I want to know what’s the latest research,” Burns said.