Mammographic Density Tied to Higher Risk of Cancer and Poorer Detection

TORONTO, Jan. 17 -- Extensive density revealed by a mammogram sharply increases the likelihood of a lurking breast cancer but, at the same time, makes the lesion significantly harder to find on the film.

Mammographic density in 75% or more of the breast was linked to an almost fivefold increased risk of breast cancer, and the risk persisted for an extended period of time, according to a report in the Jan. 18 issue of the New England Journal of Medicine.

In addition, for women with extensively dense breasts, the masking effect of dense epithelial and connective tissue in the breast increased the odds more than 17 times of a cancer being missed and then detected by non-screening methods, said Norman Boyd, M.D., D.Sc., of the Ontario Cancer Institute here, and colleagues.

Since 1976, it has been known that women with dense breast tissue in 75% or more of the breast have a risk of breast cancer four to six times as great as that for women with little or no dense tissue, Dr. Boyd wrote.

However, the risk may be underestimated if based solely on cancers found at screening because cancers masked by density may be omitted. On the other hand, the risk may be overestimated if it is based only on cancer found by means other than screening, because cancers not detected by screening will be over-represented.

These results further suggest that annual screening examinations in women with extensive mammographic density are not likely to increase the cancer detection rate.

Therefore, they said, attention should be directed to the development and evaluation of alternative imaging techniques for such women.

Digital mammography, ultrasonography, and magnetic resonance imaging may increase the detection of cancer in women who have extensive mammographic density and in whom the risk of breast cancer, detected at screening and between screening examinations, is greatest, Dr. Boyd and his colleagues concluded.

There are few data, the researchers noted, that examine the extent to which mammographic density, assessed quantitatively and using modern mammography, influences the breast cancer risk at screening, between screening, or over time.

In an analysis of three Canadian nested-case-control studies providing 1,112 matched pairs, the researchers examined the association of the measured percentage of density in the baseline mammogram with the risk of breast cancer, according to the method of cancer detection, the time since the start of screening, and age.

The mammography studies came from the National Breast Screening Study (ages 40 to 59), the Screening Mammography Program of British Columbia (ages 4o to 70), and the Ontario Breast Screening Program (ages 50 to 69).

The findings were:

• Compared with women with density in less than 10% of the mammogram, women with a mammographic density of 75% or more had a 4.7 times greater risk of breast cancer (95% confidence interval [CI], 3.0 to 7.4).
• In the 717 cases of breast cancer detected by screening, the risk was 3.5 greater (95% CI, 2.0 to 6.2).
• In the 124 cases detected less than 12 months after the last negative screening, the risk of breast cancer in the high-density women was 17.8 times greater (CI, 4.8 to 65.9).
• For cancers detected 12 months or more after the last screening, the odds ratio for the high-density women was 5.7 (CI, 2.1 to 15.5).
• An increased risk of breast cancer, whether detected by screening or other means, persisted for at least eight years after study entry and was greater in younger than in older women.
• For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram.

These results show that after adjustment for other risk factors, extensive mammographic density was strongly and reproducibly associated with an increased risk of breast cancer, regardless of whether the cancer was detected by screening or by other means, the researchers said.

The increased risk also persisted for an extended period of time. Calculations of attributable risk showed that mammographic

density accounted for a substantial proportion of cases of breast cancer, particularly in younger women.

The marked increase in the risk of breast cancer associated with extensive mammographic density up to 12 months after screening was probably due to cancers that were present at screening but were not detected because of masking by dense breast tissue, the researchers said.

Because the increase, by a factor greater than 17, in the risk of breast cancer associated with extensive mammographic density is apparently limited to the 12 months after a screening examination, masking - rather than rapid growth - seems likely to be the principal mechanism at work.

In a review of study limitations, the investigators said that it was unlikely that bias, confounding, or chance could explain these results. Measurement of mammographic density was made by two independent methods, and findings were sufficiently similar in the populations of the three studies used. Also, recall bias in the three studies was unlikely.

In an editorial, Karla Kerlikowske, M.D., of the University of California San Francisco, wrote that only two other factors increase the risk of breast cancer more than mammographic density, and they are age and mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2.

The eight years during which density was observed even before a diagnosis of breast cancer suggests that the link between extensive mammographic density and breast cancer is due not only to a masking effect but to a biologic connection between breast density and breast cancer.

More research is needed to learn how this occurs, Dr. Kerlikowske said. "Mammogaphic density is known to be influenced by genetic factors that may increase susceptibility more in young women than in older women."

Should women with increased mammographic density be screened more often or with a different screening method? Digital mammography might detect more tumors in these women, but there is no evidence that deaths from breast cancers are reduced among women given digital screening. Nevertheless, she added, early detection could provide benefits.

As noted by Dr. Boyd and colleagues, increasing the frequency of screening is not likely to be helpful because the tumors are not visible, and because the tumors may grow quickly between examinations, or both.

In summary, Dr. Kerlikowske said that measures of breast density can be used in combination with other risk factors to determine a woman's risk of breast cancer. Routine screening mammography could include an assessment of risk factors and a measurement of breast density, which together would give a woman and her physician an estimate of her risk of breast cancer.

Including risk assessment at the time of screening mammography could substantially increase the identification of high-risk women and provide an opportunity to consider pharmacologic and nonpharmacologic means to reduce their risk.

"The time has come," she said, "to acknowledge breast density as a major risk factor for breast cancer and to determine, develop, and test the best ways to measure breast density in clinical practice and use this measurement to maximize primary and secondary prevention of breast cancer."