Marina Sharifi, MD, PhD, a breast cancer medical oncologist and assistant professor in the Department of Medicine, is developing a blood test that can better match the best cancer treatment to an individual patient.
As a physician scientist in the UW Carbone Cancer Center, Sharifi treats patients with breast cancer. She sees the need for a better way to determine which patients will likely do well with the standard of care for estrogen-driven breast cancer, and which ones need a different treatment plan.
Her WPP New Investigator Program grant involves examining blood samples from estrogen-positive breast cancer patients to find cancer DNA fragments shed by the tumors. Sharifi will use artificial intelligence to predict whether the cancer is more likely to respond to standard treatment or more likely to be resistant.
“In the last 20 years we’ve developed so many new treatments that we can use for our patients, but our ability to select the right treatment for a specific patient has lagged behind,’’ Dr. Sharifi said. “In the clinic, I may be sitting with a patient and saying, ‘I have three different treatment options that we could move forward with. I actually don’t know for sure which one is right for your specific cancer. I can tell you that if we look at a group of patients, this one is 50 percent effective, and this one is 40 percent effective. But I can’t tell you if it is going to work for your cancer.’”
“That’s the thing that I find so hard and frustrating, and that’s what my research is really trying to address: Can I learn something about this patient that will tell me that this treatment is going to have a 90 percent chance of working for their cancer?”
What health challenge is your research attempting to solve?
The most common type of metastatic breast cancer is estrogen-driven breast cancer. It’s the most common kind of breast cancer in the United States, and usually it has the best outcomes. We have a number of different estrogen-blocking treatments that we can use to control it, often for many years. Those will be effective for many patients, but not for all. We also know that for any woman who’s living with a metastatic estrogen-driven breast cancer, at some point on her cancer journey, her cancer is going to figure out how to not be dependent on estrogen anymore. Once the cancer figures that out, it becomes what we call estrogen refractory or estrogen resistant, and then we can’t keep using these estrogen-blocking approaches, because the cancer doesn’t care.
We know that there are some different ways that estrogen-positive, metastatic breast cancers can become estrogen-resistant. Right now, we don’t have a great way to know if a cancer is still estrogen-sensitive, or if it’s become estrogen-resistant, meaning we don’t know if we should keep doing different types of estrogen blockers, or if we should switch to a different type of treatment approach. We do have other ways to treat this cancer, but they have more side effects, so we wouldn’t want to switch unless we needed to, but we also don’t want to give a woman an estrogen blocker that is not going to work.
What methods are currently used to determine how a cancer may be changing?
Right now, one of the ways we can find out whether cancers are changing is to take a needle biopsy; we remove cancer cells to see if the estrogen receptor is still there and whether there is a mutation in the gene. But a tissue biopsy doesn’t give us any information about all those other things that can cause cancer to become estrogen-resistant.
It also involves sticking a needle into a breast mass, or a spot of cancer in the liver or something like that. It can be painful, it carries some risk and it isn’t something that is easy for patients to do multiple times, so we really try to limit that as much as possible. But for a long time, that was our only way to get a sample of a patient’s cancer to understand the DNA changes and changes to how the cancer cells behave.
Liquid biopsies try to do the same thing from a regular blood draw. A liquid biopsy is a fancy term for taking a regular blood sample from a patient and then doing some special things to it to be able to extract any cancer cells or cancer DNA fragments that are in that sample.
I have a lot of patients who live far from the nearest hospital, but all you need is a lab that can do a blood draw and send the blood sample to a central processing site like the University of Wisconsin. I think that’s one of the strengths of this type of approach. It’s less invasive for patients, and it’s also much more accessible.
How do you plan to do your study and what are your goals?
We have developed a circulating tumor DNA platform, to find DNA fragments that allow us to predict the behavior of the cancer cells. A small pilot study showed it can tell us which genes were turned on and which genes were turned off in the cancer cells. The WPP project is helping us expand the study to a larger group of patients.
We plan to take regular blood draws from 50 patients who are starting their first estrogen-blocking medication for estrogen-positive breast cancer, and from another 50 patients who are starting their second or third estrogen-blocking medication. For each group, we’re going to look at circulating tumor DNA, and see if we can predict which patients are going to have a good benefit from their estrogen-blocking drug, and which patients are estrogen-resistant in both groups. Most patients starting their first treatment are going to have a good response, but there’s still about 20 to 30 percent of patients who don’t. We’re hoping to be able to pick those patients out so that we can give them a different treatment that’s going to be more effective right from the start.
How does the WPP New Investigator Grant help advance your research?
It was exciting when (in the pilot study) we were able to predict some of this estrogen signaling from the DNA, because I knew that it was going to be much more scalable. But I didn’t have previous funding in this area, so I wanted to get enough data that I could then go and propose a big clinical trial. The WPP grant is supporting moving my research in the slightly new direction of focusing on the circulating DNA, as opposed to the tumor cells, and supporting me to test the method on samples from 100 patients. If this study goes well, and we show we can predict that the estrogen blocker is going to work or not, it will help us apply for a larger clinical trial where we could enroll patients across Wisconsin with the Wisconsin Oncology Network or even expand it across the country.
Photo by Clint Thayer, UW Department of Medicine
