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Ductal carcinoma in situ (DCIS) is the most commonly diagnosed, noninvasive type of breast cancer in women. In this interview, Dr. Lance Liotta, codirector of the Center for Applied Proteomics and Molecular Medicine at George Mason University, and Professor Virginia Espina, the proteomics clinical laboratory director at George Mason University, discuss novel ways to stop breast cancer before it becomes invasive and malignant.
Dr. Liotta is a pioneer of the study of molecular mechanisms of tumor invasion and metastasis. Professor Espina's research focuses on the mechanisms of how breast cancer neoplasms become invasive; her laboratory has been one the first to successfully culture living DCIS cells.
DCIS has a favorable prognosis because it is confined to the mammary duct. It is generally characterized as the precursor to most and maybe all invasive breast cancers. However, it is currently not clear to what extent DCIS already has precursor carcinoma cells that have a malignant phenotype and when exactly this invasive cancer phenotype arises.
CancerNetwork: Dr. Liotta, what do we currently know about DCIS in terms of its potential to become an invasive cancer?
Dr. Liotta: Breast ductal carcinoma in situ is recognized, as you said, as a precursor lesion from which invasive breast cancer is spawned. Neoplastic cells grow and accumulate inside the duct but have not yet invaded the blood vessels, lymphatics, and stroma that are outside of the duct. It is estimated that one in five DCIS lesions, if left untreated, will escape from the confines of the duct as an invasive breast cancer. We and many other scientists have been trying to understand which DCIS lesions will go on to become invasive and which will remain dormant. We have found that genetic changes thought to be drivers of invasive breast cancer are already present within preinvasive lesions such as DCIS. We have also found that genetically abnormal cells can be grown out of patients’ DCIS lesions, and that these cells have the ability to invade and form tumors when transplanted in animals. Thus, the invasive capacity may already be present within these cells, but these cells are held in check or not yet activated in many DCIS lesions.
CancerNetwork: Do we know some of the pathways or genes that are activated specifically in cells that are more likely to become invasive? Another way to ask this is, can we predict if a certain patient with DCIS may have more cells that are more likely to become invasive?
Dr. Liotta: This is a subject of intense study by teams of scientists around the world. We would all like to know the answer to this question. Many scientists propose candidate genes or proteins that are involved in the process of invasion, such as degradative enzymes that break down the extracellular matrix and open up a passageway for the invading cells, or other factors that regulate cell migration and draw the cells out of the DCIS lesion into the surrounding stroma. Other scientists are studying candidate protein and gene markers, in the DCIS cells themselves or in the surrounding stroma, that appear to correlate with a higher risk of recurrence 5 or 10 years later. But none of these markers have yet been validated in prospective clinical studies so this is all work in progress.
CancerNetwork: So it seems the microenvironment is probably a major factor in influencing the capacity of these cells to become invasive?
Dr. Liotta: Yes, I think that is a very good and very important point. The microenvironment may be holding in check the cells that we have already demonstrated have the invasive capacity but are just waiting in the duct to realize that capacity. Now we recognize that the breast microenvironment is a major determinant of how and when these DCIS cells become invasive and we believe that cells or soluble factors in the microenvironment can promote or suppress invasion. These include suppressor factors such as those derived from myoepithelial cells inside the duct or invasion-regulating factors produced by immune cells, fat cells, endothelial cells, and even stromal cells outside the duct.
CancerNetwork: Professor Espina, your laboratory has shown that autophagy is used by DCIS cells to survive in stressful, often nutrient-depleted environments, and that suppression of autophagy can kill DCIS cells. Can you describe this research further and the potential for it as a neoadjuvant therapy?
Dr. Espina: Oh, absolutely. So as you said, we found that autophagy allows the DCIS cells to survive and even thrive within the crowded, hypoxic, and nutrient-deprived breast duct. Autophagy is simply a normal cell process in which the cell digests some of its protein and cytoplasmic contents in order to create energy. During autophagy, the cell forms a vesicle in which it engulfs and transports proteins to a special organelle called a lysosome. The lysosome is like a stomach that contains enzymes to digest the proteins and release energy.
We and others have shown that chloroquine(Drug information on chloroquine), which is an oral drug used to treat malaria infections, inhibits autophagy by disrupting the digestion of the proteins in the lysosome. It works kind of like taking an antacid. It disrupts the pH of the lysosome, and the cell is not able to make energy. The potential for neoadjuvant therapy is the use of chloroquine which can reduce the number of DCIS cells that are proliferating within the duct and possibly reduce the overall size of the breast DCIS lesion in the patient. Reducing the size of the lesion prior to the current standard of care, surgical therapy, may provide a breast-sparing surgical option for the woman. And we can imagine that shrinking the DCIS lesion with chloroquine may allow the surgeon to perform a lumpectomy rather than a mastectomy. So, based on autophagy inhibition and the potential to reduce the DCIS lesion size, we’ve opened a clinical trial in northern Virginia under the leadership of Dr. Kirsten Edmiston. We call it the PINC trial, an acronym for Preventing Invasive Neoplasia with Chloroquine. We are currently enrolling patients with all stages or grades of DCIS. The patient receives oral chloroquine therapy for 30 days between the time of diagnosis and surgery. If our PINC trial is successful it could lead to new neoadjuvant strategies for preventing DCIS before it becomes invasive.
CancerNetwork: So it sounds like this approach could work for any subtype of breast cancer?
Dr. Espina: Yes. Treating patients with oral autophagy inhibitors such as chloroquine will work for any subtype of breast cancer because autophagy is independent of subtype. For example, women whose breast cancer is estrogen receptor (ER) negative are currently not candidates for estrogen-inhibitor therapy. Similarly, women who are HER2 negative are not candidates for anti-HER2 therapy. However, chloroquine functions to inhibit autophagy by disrupting the pH of the lysosome, and this process is completely independent of the hormone receptor status.
CancerNetwork: I see. When can we expect any data readout from this trial?
Dr. Espina: The trial is funded through 2014, and as I said, we are accruing patients now. We have already published the preliminary studies. So in 1 to 2 years we will have a readout.
CancerNetwork: Are there other unique approaches such as this one that are looking at neoadjuvant treatment for all subtypes of breast cancer?
Dr. Liotta: There are investigators who are exploring anti-estrogen or anti-HER2 treatments prior to surgical therapy for subsets of patients that are ER positive or HER2 positive, respectively. So this is a very exciting field for future clinical research. We look forward to the next couple years in which some of these other trials will probably be yielding their results.
CancerNetwork: Thank you so much for joining us today.
Dr. Liotta: Thank you.
Dr. Espina: Thank you.