The Meaning of Mammographic Breast Density
August 1, 2001 7 minutes read
Special Feature
The Meaning of Mammographic Breast Density
By Leon Speroff, MD
High breast density on mammography is associated with a 4 to 6-fold increased risk of breast cancer.1,2 A review of 8 cohort studies concluded that women with the highest breast density compared with the lowest density have a relative risk of 5.2 (CI = 3.6-7.5) for breast cancer.3 Increased density is also a problem because it impairs the detection of breast masses (microcalcifications are less obscured by surrounding dense tissue than masses). A failure to detect masses because of high density would cause an increase in interval cancers (cancers that present between mammographic screenings). Difficulties in reading high-density mammograms also produce false-positive recalls (patients who are recalled for assessment and found not to have cancer). Being recalled for reassessment after an initial mammogram is a cause of significant psychological stress.4 In addition, at least 25% of the overall cost of mammographic screening in 1 US program was attributed to investigations of false-positive readings.5
These 2 problems, an increase in interval cancers (a decrease in mammographic sensitivity) and an increase in false-positive recalls (a decrease in mammographic specificity), are consistent with a decrease in the detection of cancer. Thus, the concern with dense breasts in postmenopausal women is a reduced quality of mammograms with a decrease in the ability to detect early breast cancers. Factors that are associated with greater breast density are nulliparity, older age at first birth, and current use of hormone therapy.6 Mammographically dense breasts reflect a high proportion of stromal, ductal, and glandular tissue. The likelihood of dense breasts decreases with advancing age and increasing body weight as glandular tissue is replaced by fat. The link with nulliparity supports the contention that a full-term pregnancy early in life produces a change in structure in the breast that persists throughout life and is associated with resistance to proliferation.
Summary
1. High density on mammography is associated with an increased risk of breast cancer.
2. High breast density can reduce mammographic sensitivity and specificity.
There is no doubt that postmenopausal hormone therapy can affect breast density, but because hormone use has reached a relatively high prevalence only in recent years, studies are just now documenting the effect on mammographic screening. More current users of hormone therapy have dense breasts than nonusers.7-10 In the Seattle area, 49% of current users had dense breasts compared with 33% of nonusers, and the effect was greater with increasing age.6 Indeed, in women younger than age 55, it is difficult to find any differences between hormone users and nonusers.11 But how large is the effect on older than age 55? In one study, breast density increased in only 8% of hormone users older than age 55 (two-thirds of the patients used estrogen alone, one-third used estrogen and progestin); in the large majority of the patients, the breasts remained the same.11
The effect of hormone therapy occurs rapidly; thus, duration of use has no effect.11 In the PEPI 3-year randomized trial, almost all increases occurred within the first year, with an increase in breast density observed in 8% of estrogen users and 19-24% of estrogen-progestin users, and only 2% in the placebo group.12 The users of estrogen and progestin-combined regimens had a greater risk of developing denser breasts compared with estrogen alone treatment (7-13-fold greater in the PEPI trial with no differences observed comparing medroxyprogesterone acetate to micronized progesterone).12 In careful studies, the daily, continuous combined estrogen-progestin regimens have been reported to have a greater effect than sequential regimens, with an increase in density occurring within the first months of treatment and then maintained with no change.13,14 Therefore, hormone therapy increases breast density mainly in older postmenopausal women, more women respond to combined estrogen-progestin regimens (especially the daily, continuous programs), and the effect occurs within the first months of use and remains stable with no changes with increasing duration of use. But this effect is only seen in about 20% more users compared to nonusers; indeed, not all women respond in this fashion (in fact, most do not). And most importantly, in those women who respond with an increase in breast density, discontinuation of treatment is followed by a decrease in density.10,15,16
Summary
1. Postmenopausal hormone therapy increases breast density in about 10% of estrogen users and about 20% of estrogen-progestin users, an effect that occurs within the first months of treatment.
2. An increase in breast density is observed most often in women receiving a daily, continuous combination of estrogen-progestin.
3. In those women who have an increase in breast density with hormone therapy, cessation of treatment is followed by a decrease in density.
Does this hormonal effect on breast density impair mammographic screening? In other words, is there an increase in interval cancers and false-positive recalls in postmenopausal hormone users? In a review of 7 studies, there were relatively few interval cancers in the user groups (from 1 to 46), nevertheless, 6 of the 7 studies reported decreased mammographic sensitivity in hormone users with increases in interval cancers in users compared with nonusers.17 Excluding women younger than age 50, the relative risk for an interval cancer was summarized as 1.7 (1.2-2.4). The risk of false-positive recall (mammographic specificity) was investigated in 5 studies. The rate of false-positive recall in nonusers ranges from 2.1% in the United Kingdom to as high as 14.7% in an American program; 3 of the 5 studies found a slight increase in the risk of false-positive recalls. In a French study, mammographic sensitivity was reduced from 92% to 71% in users because of an incidence of interval cancers that was 3.5 times that of nonusers within the first year of the initial exam, and 1.7 times greater during the following 2 years.18 Most of the hormone users were on combined estrogen-progestin regimens. The false-positive recall rate was only slightly higher, 3.3% in users and 2.8% in nonusers. A Finnish study concluded that women with the most dense breasts and using hormones had the highest relative risk of breast cancer, but this conclusion was based on only 4 cases of cancer in women with dense breasts.19 American, Scottish, and Australian studies have indicated a 15-20% decrease in mammographic sensitivity in hormone users who have dense breasts.20-23 Recent retrospective and prospective studies from Massachusetts General Hospital concluded that recall rates were essentially the same comparing hormone users and nonusers.24
Summary
1. The sensitivity of mammography is slightly decreased in women who develop high breast density on hormone therapy; the magnitude and consequences are still uncertain.
2. Postmenopausal hormone therapy does not have a major effect on mammographic specificity.
It seems to me that there are several reasons to suspect that the increase in breast density reported with postmenopausal hormone therapy may not be identical to the high breast density associated with an increased risk of breast cancer.
Overall, studies have suggested a decrease in mammographic sensitivity with little effect on specificity (false recall rates). The studies are based on small numbers of interval cancers, and it is uncertain how real or how large this effect is because of the difficulty in controlling for confounding factors (eg, age, age of menopause, and time since menopause). If the effectiveness of breast cancer screening is reduced by postmenopausal hormone therapy, one would expect an adverse impact on breast cancer mortality. Instead, a study that indicated a reduction in mammographic sensitivity also reported smaller, more differentiated (Grade I) tumors among the users compared with the nonusers,18 and most of the studies that have examined the breast cancer mortality rates of women who had used postmenopausal hormone therapy have documented improved survival rates.25-34 Evidence indicates that estrogen users develop smaller, better-differentiated (lower grade) tumors, and that surveillance/detection bias is not the only explanation for better survival.35-40 Lower grade tumors are present even when there is no difference in the prevalence of mammography comparing hormone users and nonusers, or when the data are adjusted for the method of detection.32,34,40
The mammographic pattern of breast density and the risk of breast cancer do not always go together. For example, women with increasing body weight have a decreasing prevalence of high-risk patterns, yet overweight postmenopausal women have an increased risk of breast cancer.
Another reason to believe that the increase in breast density associated with postmenopausal hormone therapy is different than that associated with an increased risk of breast cancer is that it is a transient, reversible change. After discontinuing hormone therapy, breast density rapidly decreases.10,15,16 Rather than epithelial proliferation, this change in response to hormone therapy could be a combination of edema and vasodilatation. In a retrospective analysis, regression of hormone-induced abnormalities was found to occur within 2 weeks of cessation of treatment.16 In the 12 patients who exhibited no change after discontinuing therapy, 8 were biopsied after ultrasonography, revealing one cancer and one case of atypical hyperplasia. Bigger and better studies of this approach are needed, but it suggests a clinical recommendation.
Clinical Summary
The older a patient is, the greater the risk of developing an increase in breast density with hormone therapy. Therefore, there is a good reason to recommend the discontinuation of hormone therapy for 2 weeks prior to mammography in women older than age 65 who have dense breasts. In younger women who are recalled for a suspicious or difficult-to-read mammogram, it would be worthwhile to discontinue hormone treatment for 2 weeks prior to the repeat evaluation.
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