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Breast density stirs debate over screening standards

From the September ACP Observer, copyright 2007 by the American College of Physicians.

By Jessica Berthold

Breast cancer screening has been on the minds of doctors and laypeople alike in the past few months, with recent research calling standard practices into question. An April study cast doubt upon the accuracy of computer-aided detection for mammograms, while top medical groups such as ACP and the American Cancer Society have issued differing guidelines on when women should start getting mammograms.

Norman F. Boyd, ACP Member


Norman F. Boyd, ACP Member



Currently, the American Cancer Society recommends that most women start annual screenings at age 40, while those at high risk should get mammograms and MRIs starting at age 30. ACP, on the other hand, recently issued guidelines recommending that women age 40-49 have an individualized risk assessment before making a screening decision.

Several studies have suggested women with dense breasts are more sensitive to mammography screening, according to the background literature review for ACP’s mammography guidelines, which were published in the April 3 Annals of Internal Medicine. One analysis of about 330,000 women, published Feb. 4, 2003 in Annals, found sensitivity was 62.2% in women with extremely dense breasts compared with 88.2% in women whose breasts were almost entirely fat. Another, published in the Sept. 18, 2002 Journal of the National Cancer Institute, found that among women age 40 to 44 years, 9.7% with extremely dense breasts had a false-positive mammogram compared with 4.2% of women with breasts that were almost entirely fat.

Adding to the conversation, and potentially changing guidelines down the road, is a study published in the Jan. 18, 2007 New England Journal of Medicine that found women with dense breasts are more likely to develop breast cancer. Not only did researchers confirm previous studies that dense breasts make tumors more difficult to spot on X-rays, the study also suggested that, detection aside, cancer risk increases significantly with breast density.

Lead study author Norman F. Boyd, ACP Member, Senior Scientist at the Campbell Family Institute for Breast Cancer Research at the Ontario Cancer Institute in Toronto spoke with ACP Observer about the practical ramifications of these findings, and about the kind of research that should come next.

Q: What is your opinion of the ACP’s recommendation to screen women from age 40-49 on the basis of individual risk?

A: In doing it on the basis of risk, women with family histories, or who are mutation carriers, are being sent for screening before the age of 50. If one were to [screen] on the basis of family history, then it would be logical to also do it on the basis of density. There is a kind of catch-22 here because you don’t know if someone has density until you do a mammogram. If someone, for whatever reason, is known to have density, it is as rational to send them for mammography before age 50 as it is for someone with a family history.

Q: Do you think guidelines will eventually change to account for increased risk among women with dense breasts?

A: I think they have to. It’s not only a matter of risk, it is a matter of risk and detection. People at high risk are the ones in whom you are most likely to have the most difficulty finding the cancers. Having a one-size-fits-all, “We’ll see everybody every two years regardless of what the breast tissue is like” policy doesn’t make any sense at all. It has to be tailored to the individual. But exactly how to tailor it is research that needs to be done.

Q: Should there be a preliminary screening simply to see if a woman has dense breasts?

A: Ultimately there does need to be. But we don’t know enough yet to say when that should occur. At the moment we are doing a research project in which we are characterizing the breast tissue of really young women, age 15 and up, using MRI, which of course doesn’t expose them to X-rays in any way. We hope to learn something about the factors that are associated with the formation of density, because we don’t really know when it starts. All the data published has been on women age 40 and up. It could easily be that when the breast develops, it either develops with a lot of density, or not, and women just sort of track that way for the rest of their lives.

Q: If a woman were found to have dense breasts in a preliminary screening, how should she be treated?

A: Ultimately, when we understand the time course of density over a lifespan, and the factors that affect it, we will then be interested in intervening. A teenager who is found to have a lot of density, for example, might be someone in whom one wishes to intervene with some safe agent that will affect the biological processes in the breast that will reduce their risk. I don’t expect to see that in my lifetime, though.

Q: What should a physician do if s/he has a patient who screens as having dense breasts but a negative mammogram?

A: We don’t know at present. The options are to do another mammogram before the regularly scheduled one, or to do another form of examination. The alternatives would seem to be digital mammography, which has shown to be slightly more effective in detecting cancer in people with dense breasts than regular film mammography, or ultrasound or MRI. There is obviously a great deal of variation in the availability of those things.

Not everyone has access to breast MRI, and how effective any of them would be is really unknown at the moment. I think the strategy for managing people at screening with extensive density has to be the subject of future research. Our data suggests a year return, for example, with someone with extensive density is unlikely to achieve very much because most of the cancers occurring after a negative mammogram occur within the year, rather than after it.

Q: Is there a certain percentage of density that should be a threshold for concern?

A: There is no evidence that a cutoff is actually useful. If you look at our data, there is a continuous increase in risk across all categories, so even the category of 10%-25% density is at higher risk than the category of less than 10%. Our previous estimates are that there is roughly a 2% increase in the relative risk for breast cancer for every 1% increase in density. So the decision as to which group of people you choose to either reexamine earlier or examine with different methods is really one based on economics.

Q: Why is breast density more common in young people?

A: We think the key thing is cumulative exposure. We think density starts off at a high level when the breast forms and then declines as women get older, and that its decline is accelerated by events like pregnancies and menopause.

Q: Do you have any theories as to why women with dense breasts are more at risk of cancer, apart from the lack of detection?

A: Histologically, people with a lot of density have more cells in the breast, both epithelial cells in lobules and stromal cells between lobules, and they have more collagen, so we think the greater number of cells associated with density almost certainly means that the cells are proliferating more, and they are under various stimuli to proliferate.

Researchers have now found insulin-like growth factor levels in the blood, which we know causes breast cells to divide and are associated with an increased risk of cancer. Insulin-like growth factor levels are higher in people with a lot of density, so it looks as though these, and probably other hormones that we haven’t found yet, are acting on the breast, causing cells to divide, and causing the stromal fibroblasts to lay down collagen. So there is a larger target of cells for mutagens that are made in the body to act on.

Q: Your article talks about other methods of screening which may reduce the “masking” effect. Should these be done in combination with regular mammograms?

A: We really don’t have much data. The kinds of concerns that are raised are that if ultrasound is done, it may indeed find some cancers that are missed by mammography, but it may throw up a whole lot of other false positive findings that weren’t seen on mammography either. My colleagues tell me MRI probably isn’t affected by density at all, and it may be the best way of finding cancer in people with dense breasts, but it is also a very limited and expensive resource that isn’t available everywhere.

Q: Given the evidence that breast density runs in families, should women with a family history of breast density get a mammogram done earlier?

A: I think that is stretching it a little bit. If somebody had density and breast cancer, it is a clear reason for at least finding out what this other first-degree relative has. But it’s true that density is heritable to a remarkable degree. Somewhere between 60%-70% of the variance in density is explained by inheritance, after taking into account all the other things that affect it.

Q: The editorial accompanying your study says that practitioners routinely get measures of density with mammography reports but that interpretation is subjective. Does this hinder the identification of women with breast density?

A: I don’t think the subjective nature of radiologist reporting is likely to be a limiting factor. In our paper, we have one set of data that comes from radiologists and the other comes from measuring density, and they give us very similar answers. There are some advantages to doing measurements, but they don’t really change very much the risk protections that one can get from a radiologist classification of density.

Q: The article mentions that automated measures of density are being developed. Is this something that could affect clinical practice anytime soon?

A: My colleague Martin J. Yaffe, PhD, and I are trying to develop volumetric approaches. The methods that are in our paper, of course, are all based on areas, on two-dimensional film. Because the breast has three dimensions, we may well be underestimating the risk associated with density because we are only taking into account two of them. It would seem technically feasible for mammography equipment to be set up in a way to automatically measure density and give that as part of the readout from the examination. I’m not sure what the manufacturers are up to, but I would think it likely that they are at least thinking of this.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.

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