BCRF grantees Drs. James Hicks and Peter Kuhn answer questions about their cutting-edge research in personalized medicine.
What is personalized medicine as it relates to breast cancer treatment?
KUHN: The practice of medicine has always been personalized through the patient–physician interaction, but the technologies have not been able to provide truly biologically informed, complete knowledge of the disease at every point in time of its progression. It is the latter that we need to bring to breast-cancer care.
HICKS: In every clinical trial there are patients who respond well and those who do not. Personalized treatment results when you know ahead of time which patients will respond best to a particular treatment. The goal is to find characteristics that mark certain cases as potential responders to specific treatments. Breast cancer currently has two strong drivers: expression of the estrogen receptor in about 50 percent of cases, leading to treatments focused on that hormone, and overexpression of the HER2/neu protein in another 25 percent, which indicates treatment with drugs, such as Herceptin, that block that growth pathway. But neither treatment is 100 percent successful, and 25 percent of patients have “triple negative” disease, meaning they lack both biomarkers, so more work needs to be done.
We also know that cancers can change as they progress, so decisions made by testing a single surgical sample at the beginning of treatment may not be relevant a few months or years later. The breakthrough potential of the fluid biopsy is that through repeated tests, using a simple blood draw, we can follow the changes in a cancer in real time and adjust treatments to target the altered cells.
What are circulating tumor cells (CTCs), and what do they mean in terms of prognosis?
KUHN: The cell is the biological unit of disease. From that, it just becomes a question of, How many cells do I need to study to understand the patient’s disease, and where do I get these cells from?
Back in 1868 it was first discovered that cells similar to those of the primary tumor exist in the blood. It is the transition of localized tumor to distant metastasis via the spread through the blood that results in the fatal form of the disease. A cancer patient who succumbs to the disease typically dies from the last metastasis and rarely from the initial cancer. That metastasis is initiated through cells traveling through the body. While the traveling cells are most likely to stick again when they come by their “home,” i.e., the primary tumor, they do eventually gain the ability to settle elsewhere. Given that this is a very fundamental process that we believe initiates the ultimately lethal form of the disease, it is obvious that we really need to understand it.
Given that it happens in the blood and blood travels at an RPM of about 1 complete cycle per 45 seconds, the process of cells migrating through the blood and exploring the rest of the body is a fascinating process, which, once understood, should provide us with a direct access to understanding of the current state of the disease as well as dynamic changes due to natural evolution or therapeutic intervention. Given that it is the blood, we can access it routinely. Given that we can do this with every patient, we can truly personalize cancer research.
Does everyone have CTCs?
KUHN: We don’t. And we don't know if every cancer patient has CTCs. But just like there are many forms of tumors, some benign and some malignant, we should expect to have different types of these traveling cells in the blood of patients who have certain conditions. Scientifically, we want to understand which ones are bad and which ones are not so bad, appreciating that we barely know what “bad” means.
Clinically, we want to know what CTCs mean from a diagnostic, predictive, and prognostic perspective. We have shown that we can indeed use them to diagnose lung cancer. Can we use them to understand which breast cancer has the potential of lethal consequences? (We have not shown that, yet.) Once I know which breast cancer has lethal potential, can I use these cells to manipulate the disease in such a way that the patient maintains a high quality of life with long-term survival?
If we find cells in the blood, we know that the disease has access to the blood. It does not yet mean that the disease has spread to another organ. We start the scientific process at clinical inflection points, i.e., time points that have emerged, often historically as specific office visits, where the oncologist recognizes that the disease has changed. We use those time points to understand the clinical observations and then extend them by obtaining biological insights at those time points. That cycle should get us to a biologically informed and clinically actionable framework that will ultimately inform the clinical decisions made by oncologists.
How did your career paths lead you to breast cancer research?
HICKS: I’m a molecular geneticist, a DNA guy. Back in 2004 at Cold Spring Harbor Laboratory (CSHL), I started applying then-novel genomic techniques to breast-cancer samples with the goal of finding new markers for personalized treatment. Another BCRF investigator—Michael Wigler, PhD—and I worked together and discovered that a single surgical specimen was often made up of many distinct genetic lineages. We realized we had to look more deeply if we were to understand the biology. This so-called cancer heterogeneity—or variety of cancer lineages—eventually led to honing our genomic analysis down to the level of single cancer cells, profiling one cell at a time. Once we nailed the method, it seemed ideal to apply it to characterizing rare cancer cells, the type that can be found in the blood of cancer patients, so I started talking to the folks who had ways of isolating them.
KUHN: I am a physicist; I enjoy providing high-impact solutions by solving hard problems. My mom is a long-term breast cancer survivor because of her participation in a clinical trial in 1985. Research can impact individual outcomes and improve the human condition. Working together we can achieve important progress if all stakeholders work together. We must take responsibility for our work by not stopping until our research outcomes have real impact in daily care for individual patients.
How did you come to work together as a team?
HICKS: We met at a workshop in the Netherlands. I was looking at all the different methods to catch CTCs, but Peter knew all about what we were doing with single cells, and when Peter described his method for analyzing biomarkers, we decided we had to combine the technologies. For two years we worked long distance, traveling back and forth and sending test cells across the country to CSHL for genomics and the genomic data back to Scripps to be combined with cellular data. The success of these early prototype experiments, supported by the BCRF and the National Cancer Institute, motivated us to collocate our efforts.
KUHN: Jim is the best-in-class single-cell genomics guy, and I knew that I needed help in that arena. We complemented each other scientifically and technically and shared the same vision for the future of improving outcomes for individual patients. Jim is now an integral part of the overall team, from mathematics to molecular to cellular to human-scale research, that we are formulating in our new effort of convergent science at the University of Southern California, where we will all be located by the end of 2014.
What is a fluid or liquid biopsy, and can it replace a mammogram?
KUHN: The liquid biopsy is a sampling of the blood to find tumor cells. We knew we needed to have an approach that identifies relevant populations of cells in the blood and provides them to us in a framework useful for biological investigation. The disease is complicated, and we really knew very little about its behavior in the blood. This motivated us to develop a liquid biopsy, i.e., an approach that identifies candidate cells. This is different from setting out to find a specific subclass of well-understood cancer cells and is more similar to a solid-tissue biopsy, where doctors try to extract relevant cells from the total mass.
The liquid biopsy that we developed in my laboratory is a direct-analysis imaging approach that uses many parameters to computationally eliminate normal cells and to highlight candidate cells that might be useful for diagnostic, predictive, and prognostic purposes.
In its fullest form, the liquid biopsy is a complement to imaging and other diagnostic tools. It provides us with insights into what is happening on the highways of the body as a critical addition to the mammogram and other imaging approaches that provide more of an insight to what happens in the house. Houses plus highways equals total system.
If we know that metastasis is the primary cause of breast cancer deaths, why can’t we prevent it from happening?
HICKS: It is clear that after surgery, even in breast cancers that have been diagnosed at an early stage, cancer cells may have escaped the tumor and taken up residence elsewhere in the body, where they can remain dormant for months or years before becoming activated to return to circulation and find places where they can once again begin growing and become metastatic sites.
These pre-metastatic cells are extremely rare; however, Peter’s work with our colleague Paul Newton at the University of Southern California and with Larry Norton, MD, at Memorial Sloan Kettering Cancer Center has shown that there are patterns to this spread in the body, with certain tissues being “sponges” that accumulate cells and “spreaders” that tend to release cells back into the circulation. This behavior provides a blueprint of where to look for such cells, even before they become activated, and further provides evidence that there are likely to be unique characteristics, in either phenotype or genotype, that can make these cells detectable in the body and eventually treatable. That would be a fabulous outcome for our research.
Where do you hope to go with your research?
HICKS: Our work has three major targets: first, to provide the means to monitor breast cancer in real time. Second, to identify predictive biomarkers on CTCs and other rare cells that can direct and redirect treatment to the most effective targeted treatments. Third, to use these ultrasensitive methods to identify potentially metastatic cells before they manifest as metastasis. In short, we want to make a difference in actual breast-cancer care as soon as possible.
KUHN: Now that we have a means to physically isolate CTCs according to their cellular characteristics (phenotypes) and combine that with their genetic makeup (genotypes), we can begin to explore the varieties of cells in blood and identify their roles in disease progression, especially metastasis. We are now participating in a very large clinical trial where we will use our high-resolution single-cell assay to examine CTCs from 800 patients undergoing treatment for metastatic, estrogen-receptor-positive breast cancer with a combination of three different drugs. The goal of our part of the study is to identify the characteristics (which may be predictive biomarkers) in the CTCs that are associated with positive response to each treatment. These characteristics will be potential predictive biomarkers for directing the best therapies for certain subgroups of patients, the goal of personalized or precision medicine.
HICKS: Further extending our studies, support from BCRF is facilitating another level of investigation into the fluid biopsy, comparing the genetic information that can be obtained from DNA found freely floating in the blood of most metastatic patients (and perhaps earlier-stage patients as well) to the total information that can be obtained from CTCs for the same patient. Through this work, we’ll determine how best to coordinate the two types of assays to optimize the fluid-biopsy concept.
This story was originally published on The Robb Report.
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