How does cancer spread, and what can we do to stop it? In this Q&A, clinical researcher and breast oncologist Linda T. Vahdat, MD, MBA, explains how cancer cells are master manipulators in the body and a promising way to stop them that she is studying in a new clinical trial for triple-negative breast cancer.
Q: How do cancer tumors spread?
Vahdat: When breast cancer cells want to spread, they hijack cells from your bone marrow to leave a popcorn trail to follow to a different site in the body. Once there, the cancer cells create a landing pad and protective collagen "moat." Then, the tumors again hijack other cells to bring in blood vessels to feed the tumor and create an ideal environment to grow. This is essentially metastasis or the spread of cancer.
Detailed scientific investigation has taught us that metals are essential for all these processes. Especially copper. We have found, both in the lab and in our patients who are at high risk of their cancer coming back, that if we're able to deplete copper to a level where normal cell function can still take place, immunotherapy works better, and tumor metastasis likely does not occur. These findings are the foundation of our newly opened clinical trial studying copper depletion in patients with triple-negative breast cancer.
Q: What is triple-negative breast cancer?
Vahdat: Not all breast cancer is created equal. There are subtypes of breast cancer, which basically tell us how the breast cancer grows and, therefore, give us some indication about how best to treat it.
Triple-negative breast cancer means that the estrogen and progesterone receptors, which are hormone receptors in the tumor, are negative. Another receptor, the HER2/Neu receptor, which is a growth accelerator, is also negative. When we put these three things together, they're all negative, so we call that triple-negative breast cancer.
Triple-negative represents about 17 to 20 percent of all breast cancers. It tends to be more aggressive than non-triple-negative breast cancers, and we tend to see more of this subtype in African Americans and in women who carry a mutation in their BRCA1 gene. It's important to really understand triple-negative breast cancer because it grows differently and, therefore, needs to be treated differently to improve outcomes.
Q: What gave you the idea for a copper depletion clinical trial for breast cancer?
Vahdat: Previous work was done at the University of Michigan to see if copper depletion could shrink tumors. The study found that while the tumors didn’t shrink, copper depletion did keep them from spreading. My team has been building on that concept. In 2007, we designed a clinical trial and enrolled 75 breast cancer patients who had completed standard treatment but were at very high risk of their tumor coming back. We gave them an oral copper depletion compound and then tested their blood to see if factors that we know promote metastasis were decreased.
We found that the drug compound was safe and well-tolerated, with less than 3% complications or side effects. We also had many fewer tumor recurrences than expected. For example, in our patients who had stage IV, no evidence of disease after standard treatment, the cancer did not come back in almost 60% of these patients at a median follow-up of 10 years. That's super unusual because, at the time, the average lifespan was 11 months. That made us take notice that there's something special about copper and tumor metastasis in triple-negative.
We have since figured out that not only are there certain techniques that triple-negative breast cancer uses to overcome standard treatment, but copper depletion cuts short those techniques. These important early findings led us to design our new trial, which we have just opened to enrollment at Dartmouth Cancer Center, with several other wonderful participating cancer centers.
This is a clinical trial that will let us know, pretty much once and for all, whether influencing the tumor microenvironment with a copper depletion approach prevents breast cancer metastasis.
Q: How does copper depletion work?
Vahdat: When we deplete copper, we get rid of the enzyme responsible for making that tumor-protective collagen moat I talked about earlier. Without the moat, immune cells can get in and kill the cancer.
There may be other applications for copper depletion as well. For example, copper depletion decreases B6 levels. We know that leukemia cells are addicted to B6. Copper depletion may benefit patients who have undergone induction therapy to get rid of their leukemia but are at high risk of their tumor coming back. Maybe there's a role for this non-toxic, well-tolerated, cheap pill to keep them in remission.
We have a critical mass of scientists working to understand all the places where we could potentially insert this method. We also have the infrastructure to support the clinical research.
Q: Who is eligible for the breast cancer copper trial?
Vahdat: Eligible patients who may choose to participate are those who have received standard-of-care treatment for triple-negative breast cancer, which is chemotherapy and immunotherapy before surgery, but still have residual disease after treatment. We're going to help them by seeing if adding an oral copper depletion pill to change what we call the “tumor microenvironment” can prevent their disease from spreading, prevent recurrence, and ultimately improve their outcome.
This is a multi-center study, with seven other cancer centers participating. With more grant money, we hope to expand it to more sites. We want to thank all of our partners who have helped move this forward, specifically the Breast Cancer Research Foundation, Gateway Foundation, the Margaret Claire Pisani Fund, and the NCI Next program, as well as other philanthropic donors.
We really feel we're poised to make a difference and we can't wait.
Have you been treated for triple-negative breast cancer? To find out if you are eligible for the copper trial, contact CopperStudyTNBC@hitchcock.org.