When most of us think of breast cancer, we envision a malignant lump. It might be large. It might be small. But it’s all the same. It’s cancer.
The reality is a lot more complicated.
“We know now that no two cancers are alike,” says Dr. Adrian Lee, Professor of Pharmacology, Chemical Biology and Human Genetics at the University of Pittsburgh, Director for the Women’s Cancer Research Center at Magee-Womens Research Institute, Director of the Institute for Precision Medicine, and member of UPMC Hillman Cancer Center. “Unfortunately, it’s like your fingerprint. In breast cancer, we’ve been good at finding groups of tumors that share the same properties. But when we look deeper within those groups, there are many different subtypes that show different responses to hormone therapy. The goal is to make the treatment and risk stratification personalized yet practical.” There are three main groups of breast cancer: Estrogen Receptor Positive (ERP), HER2 Positive, and Triple Negative. Researchers at Magee-Womens Research Institute are studying the DNA and RNA of these cancers to learn their different characteristics, create tests that can determine a prognosis, and develop novel therapies that are more targeted and less toxic.
“The concept is, with our ability to more comprehensively understand the genetic basis of the disease, we can more precisely understand the disease, and then treat the disease and/or predict risk,” says Dr. Lee, whose research focuses exclusively on women who have advanced, metastatic breast cancer. “That’s ultimately the disease that women with breast cancer are going to die of, and we know very little about it. Most research is focused on early detection and prevention, yet the problem of mortality is with the advanced cancer.”
Dr. Lee and other researchers at Magee are trying to find predictors as to why some cancers metastasize and others do not. They are also studying why some metastasize to a specific organ. The good news is they are making major headway.
“By sequencing the DNA and the RNA in metastatic tissues from patients who’ve suffered a relapse in the bone, brain, ovary or gastrointestinal (GI) tract, we are finding the unique features that determine why the breast cancer went to those specific sites. If we can understand why it goes to a certain organ, we can hopefully prevent it from going there in the first place,” states Lee.
“The concept is, with our ability to more comprehensively understand the genetic basis of the disease, we can more precisely understand the disease, and then treat the disease and or predict risk.” Adrian Lee, PhD
Looking for answers in genes
Researchers at Magee-Womens Research Institute are making progress in unraveling the molecular mysteries of metastatic breast cancer. Dr. Lee and his team are working to understand how we can improve therapies through blocking pathways that are critical for a tumor to grow. Their second major research area is sequencing breast cancers to try to understand the genetics of breast cancer and breast cancer progression. “We did something pretty unique,” Dr. Lee says. “Few groups in the country could do this. We took a series of patients with primary breast cancer that had relapsed to the brain. Both breast cancers were surgically removed, so we had these paired patient match samples where we could look at what’s different in the brain metastasis than in the primary breast cancer. We found that in about 20% of those cases, the cancers had gained the HER2 oncogene. HER2 is one of the main therapeutic targets in breast cancer, so this is very exciting. It would suggest that in those cases, we could give them anti-HER2 therapy.” Lee explains that anti-HER2 therapy is one of the oldest therapies in breast cancer. While it’s been approved for twenty years, its use in the last few years has changed dramatically. “Now many groups similar to ours have shown that these therapeutic targets occur only in the metastasis. That’s now changing the paradigm.”His ultimate goal? “We’re trying to find features in the primary breast cancer that say these will likely be metastatic, so we can give more therapy,” Lee said.
Another investigation at Magee is studying the differences between Invasive Ductal Breast Cancer (IDC) and Invasive Lobular Breast Cancer (ILC). The less common ILC makes up 10-15% of all breast cancers. Although it’s molecularly different, right now the treatment for the two kinds of cancer is the same. “We want to be more precise,” states Dr. Steffi Oesterreich, Professor and Vice Chair in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh, Director of Education in the Women’s Cancer Research Center at Magee-Womens Research Institute, and member of UPMC Hillman Cancer Center. “We want to understand how this tumor is not the same as IDC, and personalize treatment.” One of the biggest challenges with ILC tumors is that they grow in single lines in the breast, not forming a lump like IDC tumors. “They’re much harder to see by mammography,” says Oesterreich.
“They’re picked up later, because there’s not a lump of dense tissue. It’s more like a spider web.” The way they behave is tricky, too. When pathologists study ILC tumors, they look more “friendly.” They present favorable prognostic markers like high levels of estrogen receptors, which can be targeted by hormonal therapy. They also grow slowly, and that can be misleading. “In the first few years, we have very few recurrences,” Oesterreich says. “But after five to six years, unfortunately a substantial amount of patients suffer from recurrence. The cancer cells seem to hang out somewhere in the body in dormancy. They hide and years later start growing. Suddenly you have metastasis. The sites of metastasis are also different. The IDCs often go to the lung, liver, brain, or bone. But with ILCs, we also see unusual sites like the ovaries and the GI tract, in addition to bone, and other sites.”
“There are mutations in the estrogen receptors in approximately 30% of patients with hormone receptor positive metastatic disease. Basically the tumors become resistant to antiestrogen therapy because the estrogen receptors change. Suddenly the drugs become much less effective.” Dr. Steffi Oesterreich
Oesterreich and her lab have published pre-clinical research data suggesting that ILC tumors might respond differently to different endocrine therapies. They are now working with clinicians at Magee, including Dr. Rachel Jankowitz, in a trial studying clinical specimens of patients with ILC. Before surgery, they take a biopsy and then treat the patient with one of three different endocrine therapies. After surgery, they take another biopsy to compare which of the three therapies changes biomarkers in the ILC tissue. “We have a piece of tissue before and after three different endocrine therapies, then we use gene sequencing to see which affected growth of the tissue the most,” says Oesterreich. “We are the main site for this trial, but it’s also open to other institutions like the University of Alabama, University of North Carolina, Mayo Clinic and others. We are the lead center. It’s a three to four year trial, and the goal is to look at 150 women.”
Meanwhile, to increase awareness and education about ILC, Oesterreich and colleages organized the first ILC Symposium, held here in Pittsburgh in September 2016. Leaders, researchers, and patients attended the meeting on lobular tumors and, as a result, patients formed a national advocacy group called the Lobular Breast Cancer Alliance. The group’s goal is to educate other patients, researchers, and physicians about the need to better understand ILC as a unique breast cancer disease with unique features.
Oesterreich is working on another project to understand endocrine-resistant metastasis—tumors that stop responding to therapies which target the estrogen receptor. “Estrogen receptors are the target of endocrine therapy,” she explains. “There are mutations in the estrogen receptors in approximately 30% of patients with hormone receptor positive metastatic disease. Basically the tumors become resistant to anti-estrogen therapy because the estrogen receptors change. Suddenly the drugs become much less effective.” Oesterreich and her team perform modeling in the lab to try to understand why these mutations cause resistance and how they behave. “Do they grow faster or move faster? We work very closely with clinicians at Magee to obtain clinical specimens from patients with metastasis, then we look for estrogen receptor mutations.”
One of the recent innovations is that they can use liquid biopsies. “We can look at blood from patients without a biopsy of the metastatic site. We can identify these estrogen receptor mutations in the blood. We think we can see it before the metastasis is actually visible by other means such as imaging. It’s very sensitive technology,” she adds. “We can look for these mutations in the DNA, determine if they’ve developed resistance, and say there’s a need for change in therapy.” Oesterreich hopes one day to have a blood test that can find the mutation and predict metastasis. “Once we detect resistant tumors, we can say the therapy doesn’t work any longer. Then the question becomes what do we switch to? What is the better therapy? This is leading the way to personalized, precision medicine.”
Magee’s unique bio-bank moves the needle
For the last three to four years, the big movement in breast cancer research has been matching DNA with therapies. Now that DNA sequencing is faster and more available, research has really taken off. And Magee-Womens Research Institute is at the forefront.
One reason for that is Magee’s large tissue bank.
“Our research is dependent on human tissue,” says Dr. Lee. “The majority of advances we’ve made in the treatment of breast cancer have come from basic research that’s been done on tissues and cell lines. Getting that tissue is key to making significant findings. One of the reasons I came here was this large clinical program and their ability to bank clinical tissue. Our bio-banking program has national accreditation. It’s state-of-the-art.”
“We’re involved in a National Cancer Institute match trial looking at DNA sequencing and various therapies, and we are number four in the country in recruitment for that study.” Adam Brufsky, MD
Dr. Oesterreich adds, “Magee has a great reputation for treating breast cancer patients. There are 1,300 new patients with breast cancer seen every year. That large volume gives us a large base for tumor collection and clinical trials. Plus many people in Pittsburgh don’t move away, because it’s so beautiful here. So if the tumor recurs, we have access to the primary and metastatic tissue. That’s highly valuable tumor material because we can compare what’s different, what has changed.”
The tissue bank has allowed Magee to participate in a number of important efforts around the world. “We’re involved in a National Cancer Institute match trial looking at DNA sequencing and various therapies, and we are number four in the country in recruitment for that study,” says Dr. Adam Brufsky, Professor of Medicine, medical oncologist at Magee-Womens Hospital of UPMC Womens Cancer Center, and Associate Director for Clinical Investigations, UPMC Hillman Cancer Center. He also points out that Magee took part in The Cancer Genome Atlas Project, an international effort by the National Institutes of Health to perform DNA sequencing on more than 1,000 breast tumors. “Of those cancers, 144 came from Magee because our pathology and tissue bank was so good. We are extremely grateful to our patients for donating their tissue.” In fact, Magee was the number one contributor to the study.
Magee’s collaborative approach is another feature that puts it at the forefront of breast cancer research. “What we do here is very trans-disciplinary,” says Oesterreich. “We work with medical oncologists. We interact with people who are experts in biostatistics and bio informatics. We’ve started to work with immunologists because there’s a hope that a subset of breast cancer patients will respond to immunotherapy, and we work with surgeons to get access to fresh tissue. We also interact critically with pathologists. These are our most critical partners.”
And they’re all right across the street from each other.
Dr. Brufsky points out that collaboration is better when everyone and everything is only a few floors apart. “Magee is one of the top ten breast cancer programs in the country, and it’s all in one place. That allows us to communicate effectively and closely. This makes Magee stand apart. It allows things to be done more quickly and in a more patient-centered way. It’s easier for women who are participating, as well as for the physicians and scientists.”
Magee’s patient population also offers exceptional data for understanding specific patterns of patients and tumors and associating them with outcomes. “The disease in advanced breast cancer is different than in primary,” states Dr. Lee. “Its features change. Having longitudinal data is key, and what we have here is very unique when you look at other programs. People who come to Magee are people from the surrounding region. Most of the large competitive cancer centers are mainly referral sites, so they don’t have the longitudinal data.”
Because Magee is first and foremost a women’s hospital, women deliver their babies here and remember Magee when it comes time to do their breast cancer screening. “We do about 150,000-200,000 mammograms per year,” Brufsky states. “We then filter those patients to surgeons who are dedicated breast surgeons, who refer to dedicated breast medical oncologists and dedicated breast pathologists and dedicated breast radiation therapists. Most of the therapies for breast cancer that we’ve developed in some way, shape or form, started at the University of Pittsburgh with Dr. Bernie Fisher. He was the founder of the breast cancer program at Magee in the late 50’s. He pioneered the use of lumpectomies at a time when debilitating mastectomies were the treatment standard. We have that important historical perspective.”
Keeping up the good work
When it comes to finding cures for cancer, there is no shortage of passion in the researchers and clinicians at Magee. But maintaining the momentum does take funding.
“To do good clinical research that’s safe, with all the paperwork filled out properly, you need a lot of people. It’s very labor intensive,” according to Dr. Brufsky. “The cures will never happen unless you fund the administrative work, as well. We’re doing better and better at breast cancer. Now women live an average of five years or more with metastatic breast cancer. Ten to fifteen years ago, it was maybe half that. We’re learning more about the disease, and we’re coming up with better therapies. But to do that, we need to be able to support all those research nurses, data managers, and regulatory specialists. Funding the human element of research is always going to be the limiting factor. We all have great ideas and want to try new things, but my role is to get those new and innovative things out of animal models and to the bedside helping people. For that, we need to fund the infrastructure.”
More argument for funding comes from the fact that breast cancer is, as Dr. Lee puts it, “the poster child for precision medicine.” It was the first disease to establish biomarkers and have targeted therapy with tamoxifen. “Breast cancer has shown the personalization of surgery, the personalization of radiotherapy, the personalization of chemotherapy and targeted therapy,” says Lee. “That has resulted in incredible improvements in outcomes. But still too many women die of breast cancer. We have over 200,000 new cases a year and 40,000 deaths. We should be able to improve that. It’s donor money that funds things like the tissue bank. Philanthropy has become a key component for those types of operations, stimulating new science, doing high risk, high reward work.”
The end game
“Breast cancer isn’t suddenly going to be cured,” says Brufsky. “What happens is that women start living longer. Today, 80-90% of the people who walk in the door with early stage breast cancer are cured. If women develop a relapse of breast cancer elsewhere in the body, they’re generally going to live at least 4-5 years, if not longer, for the most common forms. That’s how the cure for breast cancer happens. We fi nd that people who would have died in a year or two are coming back to our clinic 3-5 years later. Through a group effort, people are living longer. That’s what the cure for cancer looks like. That’s happening now. It’s a cool time to be involved.”
A Special Thank-You from the Researchers
Drs. Brufsky, Lee and Oesterreich would like to recognize the support their programs have received from generous individuals, as well as foundations such as the following:
- Breast Cancer Research Foundation
- Fashion Footwear of New York
- Glimmer of Hope
- Magee-Womens Foundation
- Mario Lemieux Foundation
- Metastatic Breast Cancer Network
- Nicole Meloche Funds
- Penguins Alumni Foundation
- Penguins Foundation
- Shear Family Foundation
- Susan G. Komen