Prognostic Indicators in DCIS

David Euhus, MD

Ahead of the annual San Antonio Breast Cancer Symposium held December 8 to 12 in San Antonio, Texas, we are speaking with David Euhus, MD, director of breast surgery at the Johns Hopkins Hospital in Baltimore, Maryland, about ductal carcinoma in situ, or DCIS. Dr. Euhus will be discussing prognostic indicators in the treatment of DCIS at the conference on Tuesday, December 8.

- Interviewed by Anna Azvolinsky 

Cancer Network:Can you first talk about the biology of DCIS? What do we know about its ability to turn into invasive disease?

Dr. Euhus: Biologically, DCIS is an abnormal proliferation of the luminal cells that line the milk ducts. These cells have acquired nearly all of the genetic and genomic changes that we normally associate with invasive cancer, but they can’t always penetrate out through the basal layer of the milk duct or the myoepithelial cell layer. We are just learning about the biology of how we progress from DCIS to invasive cancer and there are a couple of models, ways of thinking about it.

Generally, the milk duct system is generated from pluripotent stem cells that then divide and differentiate into bipotent progenitor cells that have the ability to become luminal cells or basal cells. From there they can divide and differentiate further to become luminal progenitor cells and those are cells that are committed to being luminal rather than myoepithelial cells, and that is the cell that we believe is the origin of most breast cancers and possibly also DCIS. Biologically, you have to imagine that these luminal progenitor cells would become damaged and begin dividing in an uncontrolled way, filling up the milk duct, not posing a threat yet, until a second event occurs that leads to damage to myoepithelial cells and then cooperation with invasion.

That is one theory of DCIS. If that is the correct theory or the dominant way that DCIS becomes invasive cancer, then I suppose that looking for markers in the DCIS cells themselves may be able to tell us which ones are at higher risk for invasion in the future. The other model, though, is that it is not the luminal cells but the cell before that, the bipotent progenitor cell, that becomes damaged and you end up with a tiny focal area of abnormal myoepithelial cells and a larger area of luminal cells that are proliferating and looking like cancer cells. And if that is the case then it is going to be the events occurring in those myoepithelial cells that will truly predict the risk of invasion. Those will be hard to find because that will be a focal thing. As people have looked for markers of invasive risk, they either focus on the luminal cells or these myoepithelial cells.

Cancer Network:Just briefly, how is DCIS generally treated?

Dr. Euhus: DCIS is generally treated like invasive breast cancer. If the size of the DCIS is favorable compared to the size of the breast, then the usual recommendation is a wide excision or lumpectomy followed by radiation therapy, and if it is estrogen receptor–positive, followed by tamoxifen. If the size is too large compared to the size of the breast, then the recommendation is mastectomy.

There has been a lot of controversy recently about the value of treating DCIS at all. We have this recent paper from SEER data that told us that our treatments didn’t seem to affect mortality. And that is probably true to a point. But the reason we treat DCIS at all is to avoid invasive breast cancer in the future. So you can ask, what is the natural history of untreated DCIS? There are just a few small observational studies of women that have had core needle biopsy that showed a low-grade DCIS that somehow got overlooked and they never got treated and some of these women were followed for up to 30 years.

Even with these good prognoses, low-grade DCIS, there is at least a 40% risk of progression to invasive cancer if you just wait long enough. But at the same time, maybe half of these women never would have progressed to invasive cancer and would not have needed any treatment at all. That is what the discussion is currently about. Can we identify people whose risk of progression to invasive cancer is so low that they don’t need treatment or they need minimal treatment?

Cancer Network:On that note, are there any known markers that may be associated with a higher risk of DCIS turning into invasive cancer or, conversely, lower risk?

Dr. Euhus: Clinical, pathological studies have pointed to age less than 45 and especially less than 40 as something that is associated with a significantly increased risk of invasive cancer. Another marker is if the DCIS presents as a palpable mass, rather than as a microcalcification on a mammogram. That makes sense biologically because if you are making a palpable mass, it means that your stromal cells are already cooperating with these abnormal luminal breast epithelial cells and you are developing a desmoplastic reaction, and you can understand how that could be associated with a higher risk of invasion. Another marker is if you have positive margins on excision. Those are the main clinical factors associated with increased risk of invasive cancer. Size may be a risk factor but it is really hard to measure DCIS. Grade is pretty inconsistent. Some studies suggest it is a risk factor and others suggest that it is not.

Mel Silverstein has put four of these clinical factors together-size, margin status after excision, grade and presence of necrosis, and age-and came up with what we call the Van Nuys Prognostic Index. This does stratify patients to some extent but it doesn’t really identify an ultra low-risk group that may not need treatment at all. One thing that is interesting from his data is that margins are important with DCIS, so excision with clear margins is one of the most important things for avoiding invasive breast cancer

As for biological markers, there is the 21-Gene Recurrence Score for estrogen receptor–positive invasive breast cancer that tells us the risk of recurrence if we do tamoxifen only without chemo, and this score has been adapted pretty widely for risk-stratifying estrogen receptor–positive invasive cancer. Some work has been done on those 21 genes in DCIS. Twelve of them have been adapted to a DCIS score and, interestingly, most of those are markers of proliferation. They correlate with cell division more than anything else. The DCIS score that was adapted from that 21-gene score was validated in a large Eastern Cooperative Oncology Group (ECOG) cohort and it did pretty well, separating out low-, intermediate-, and high-risk women who would have low recurrence risk if they were treated with excision but not radiation. They compared the score with the Van Nuys Prognostic Index and it did better than that, it did some risk stratification, actually, within the Van Nuys groups, and the Van Nuys score did not perform particularly well in that cohort.

Other people have done some studies looking at estrogen receptor, a proliferation marker known as Ki-67, p53, HER2, and COX-2, and they did achieve some risk stratification when they looked at over 1,000 DCIS patients, but they didn’t identify an ultra low-risk group that might be able to avoid treatment or radiation. Other groups, in Toronto specifically, found that the combination of HER2/neu and the proliferation marker Ki-67 did pretty well at risk stratifying, but the low-risk group, the group that was HER2-negative and had low Ki-67, still had a recurrence risk of 1% per year, which to me is not an ultra low-risk group.

With a focus on myoepithelial markers, a group looked at CD10, which is a protein expressed on the cell membranes of benign cell tissue, and they found that DCIS was very heterogeneous. Some expressed CD10 at the same level as benign tissue and some barely expressed it at all or not at all. What they found is that if you had high CD10 expression in your myoepithelial cells, the cells that are embracing or containing DCIS, it was a marker of very healthy myoepithelial cells and recurrence rates were essentially zero. If you had low CD10, you would get recurrence risk that could be as high as 4% per year. To me, that was very interesting, focusing on the myoepithelial cells and gauging the health of the myoepithelial cells, which could identify an ultra low-risk group.

Cancer Network:Thank you so much for joining us today, Dr. Euhus.

Dr. Euhus: Thank you very much.