Breast cancer is the most common malignancy in women in numerous industrialized countries, and its incidence is increasing in many countries around the world. Breast cancer is more common in elderly women with incidence increasing after the age of 40 years and especially after the menopause, but breast cancer sometimes develops in very young women, even, albeit rarely, before the age of 20. A woman’s menstrual and reproductive history may have a substantial impact on her risk of developing breast cancer. Early age at menopause, also due to oophorectomy, has been reported to be a protective factor in breast cancer. Parity, age at first childbirth, length of menstrual cycle and regularity, late menopause, breast-feeding, etc. also seem to be related to breast cancer incidence, but no factors have yet been found that can be used to prevent breast cancer or reduce breast cancer incidence. During the past decade, interest in hereditary reasons for breast cancer development has increased, especially since women with the BRCA1 and/or BRCA2 gene have been shown to have a high risk of developing breast cancer during their lifetime, especially at an early age.

Breast Cancer Prognosis And Early Detection

Since there is no way as yet to prevent women from developing breast cancer, most interest has stemmed from reducing the effects of breast cancer, which, especially in young women, is an important cause of death. Numerous studies have shown the prognosis of breast cancer to vary according to the size of the tumor and the presence or absence of metastases to axillary lymph nodes at the time of diagnosis. In many patients who die from breast cancer, distal metastases are already present at the time of diagnosis. The best way to reduce mortality from breast cancer is to detect and treat tumors at an early stage before any metastases have occurred. Self-breast examination is important, but it is very difficult for a woman to find a tumor that is less than 1 cm in size. Such a small tumor can only be detected if it is superficially sited close to the skin, or in a small breast which is soft and easy to examine. Even clinical examination performed by experienced physicians rarely detects cancers less than 1 cm in diameter. In large breasts and in breasts with only little fatty tissue and rich in glandular tissue, even tumors with a diameter exceeding 2 cm are readily concealed by surrounding tissue.

Mammography has been used for almost 40 years to diagnose breast cancer in patients with various breast-related symptoms. This method has proved to be excellent for detecting breast tumors less than 1 cm in size, and many tumors, especially in fatty breasts, of less than 5 mm size have been detected. During the past three decades, mammography has been the method of choice to detect breast cancer at a nonpalpable stage. Screening programs have shown that mammography is an excellent tool for early detection of breast cancer as well as a mass survey examination method. A 20-40% reduced breast cancer mortality rate has been noted in randomized screening programs when the study group has been compared with a control group. In the above randomized screening studies, comparison of mortality was made between women who received an invitation to undergo mammography examination, the study group, and those who were not invited, the control group. Comparison was not performed between those who accepted the invitation and underwent a mammography examination and those who were not examined. Other studies have compared mortality rates for women who accepted the invitation and actually underwent a mammography examination and for those who did not. These studies have found the reduction in breast cancer mortality to be over 40%. In another study, Tabar and colleagues compared breast cancer-specific mortality for three different time periods in women 20-69 years old. The first period was when no mammography screening was taking place, the second when a randomized screening trial in women 40-74 years was ongoing and the last period when service screening had started for women aged 40-69 years of age. The invitation to mammography screening seemed to have reduced mortality from breast cancer by 50%. However, breast cancer mortality decreased by 63% among women who were actually screened. Mammography is now widely used as a population-based screening tool in many countries to detect breast cancer at an early stage, before any clinical symptoms have occurred. However, the age group invited to or included in the screening program differs not only between countries but also sometimes within the same country. Nevertheless, women older than 50 years of age are invited to participate in most screening programs.

Mammographic Breast Density

Most breasts have both radiologically translucent and dense areas. The dense parts consist of fibrous connective tissue and glandular tissue, while the translucent parts consist of mainly fat. In general, the proportion of dense tissue will decrease with age owing to fatty involution of the breast. In a study from Finland, Salminen and co-workers found the incidence of fatty breasts to be two times higher among women aged 45 or more, compared with women under 45 years.

Mammography screening programs today mostly include the whole female population within a specific age group. Most of these women will never develop breast cancer, and it would be more efficient, if possible, to invite just a high-risk group of women to mammography examination instead of inviting everyone as in current screening programs. Just who is at high risk, and whether the mammographic appearance of the breast parenchyma can be used to predict the risk of developing breast cancer in the future are questions that have been asked many times. In the 1970s, Wolfe suggested the answer to the latter question to be yes. He classified the breast parenchymal pattern into four categories depending upon the proportions of fat tissue and fibroglandular tissue, and also the pattern of the fibroglandular tissue. The four classes were: N1, the breast is composed of primarily fat; PI, ducts and glandular tissue occupy up to 25% of the breast volume; P2, ducts and glandular tissue occupy more than 25% of the breast volume; and DY, extremely dense breast with hyperplasia or dysplasia. Breast density can also be classified in percentages, usually in steps of 20%. Wolfe suggested that the radiologic appearance of the breast parenchyma could be useful in the appraisal of a predisposition to cancer of the breast. He reported a 30-fold increase in breast cancer incidence for patients with the DY pattern, compared with patients with the N1 pattern, over a 3-year period. The PI and P2 patterns were associated with an intermediate risk. Other studies have also found an increased risk for women with the P2/DY pattern. Salminen and colleagues reported the age-adjusted relative risk of breast cancer to be 2.5 among women with the P2/DY pattern, compared with women with N1 and PI patterns. Salminen’s group also found that the odds ratio of the P2/DYpattern for women with body mass index (BMI) 25 kg/m or more was 0.2 (95% confidence interval (CI) 0.1-0.6), compared with women with BMI less than 20. In a randomized mammography screening study from Malmo, women between 45 and 69 years of age were invited to screening. Andersson reported the overall attendance rate in this study to be 74%. He classified mammograms as N1 in 11%, PI in 38%, P2 in 16.2% and DY in 34.8%. P2 and DY patterns were found to correlate with an increased risk for cancer. The percentage of women with P2 and DY patterns decreased with advancing age, and also correlated with the age of the woman’s first childbirth.

Evaluation Of Breast Density

The density of the parenchyma can be evaluated visually using more or less subjective methods.

The most frequent method of evaluating density is visually, by the naked eye, from the mammograms. The proportions of dense and fatty parts are evaluated from one or two views. Today there are also computerized methods, which might turn out to be more precise and more reproducible. A quantitative assessment of mammographic density can be carried out using digitized mammograms. However, there are difficulties with all methods, and the precision of the evaluation might be influenced by choice of mammographic view, craniocaudal or mediolateral oblique or both. High variation between individual women, concerning not only the amount of dense tissue but also the distribution, makes assessment even more difficult. The dense tissue might be situated in all quadrants of the breast, only centrally or in the upper-outer quadrant, or be more irregularly spread in the breast and split by small or large fatty lobules. In some women the mammograhic pattern appears very irregular, and in such cases breast density is more difficult to evaluate both with the naked eye and using a computerized system. However, the difference in assessment of density when two experienced radiologists visually evaluate the mammograms has been shown to be minor. In a prospective, randomized, double-blind placebo-controlled study of 166 patients, one-third were given tibolone 2.5 mg, one-third estradiol 2 mg plus norethisterone acetate 1 mg and one-third placebo. Patients were examined by mammography before inclusion in the study and 6 months later. All mammograms were evaluated visually using both a percentage scale and Wolfe’s system. Only five mammography examinations were evaluated differently by the two radiologists. The difference occurred when a percentage scale in five steps was used, and not when Wolfe’s classification was used. Nevertheless, the differences were minor, for example one radiologist suggested slightly less than 20% and PI and the other suggested also PI but slightly over20%

Influence Of Endogenous And Exogenous Hormones On Breast Density

It is well established that breast density decreases with age, but individual variations are enormous. Endogenous and exogenous hormones may influence mammographic density. Riza and co-workers studied urinary estrogen metabolites and mammographic patterns in postmenopausal women participating in a population-based breast screening program in Northern Greece. Seventy women with a P2/DY pattern were individually matched with 70 women with an N1 pattern. Urinary levels of 2-hydroxyestrone (2-OHE1) and 16α-hydroxy- estrone (16α-OHE1) were measured. These authors found that women with a P2/DYpattern had 58% higher levels of 2-OHEj and 15% higher levels of 16α-OHE1 than women with an N1 pattern. They suggested that a high ratio of 2-OHE1/16α-OHE1 might be associated with an increase in breast cancer risk in postmenopausal women, since this ratio was 35% higher in the studied women with P2/DY patterns. Women in the highest one-third of this ratio were six times more likely to have P2/DY patterns than those in the lowest one-third. The odds ratio was 6.2. In another study, Boyd and colleagues examined the association of circulating levels of hormones and growth factors with mammographic density. Mammograms were digitized, and the density was measured by a computer-assisted method. These authors found that in postmenopausal women, serum levels of prolactin and in premenopausal women, serum insulin-like growth factor-I levels were significantly and positively associated with percentage density. In postmenopausal women, sex hormone-binding globulin was positively and free estradiol was negatively associated with percentage density. These results suggest a biologic basis for mammographic density which is associated with increased risk of breast cancer. In another study, Boyd and associates studied 353 pairs of monozygotic and 246 pairs of zygotic twins from the Australian Twin Registry, and 218 pairs of monozygotic twins and 134 pairs of dizygotic twins in Canada and the USA. The mammograms were digitized. They were then randomly ordered and read by a blinded investigator. The authors found the correlation coefficient for percentage of dense tissue to be 0.67 for monozygotic pairs in North America and 0.61 for monozygotic pairs in Australia, and 0.27 for dizygotic pairs in North America and 0.25 for dizygotic pairs in Australia, after adjustment for age and measured covariates. They suggested that the percentage of dense tissue on mammograms at a given age has high heritability, and that ‘finding the genes responsible for this phenotype could be important for understanding the causes of the disease.

Saftlas and Szklo reported an increased proportion of N1 and PI, the low-risk patterns, in women who ever used contraceptive pills. However, in another study, Gram and colleagues found that ever-users of contraceptive pills were 20% more likely to have high-risk mammographic patterns compared with those who had never used contraceptive pills. They did not find any dose-response differences. Nulliparous women who had used contraceptive pills had a four times increased risk of having high-risk patterns. De Stavola and associates also found an association between mammographic breast density and the use of contraceptive pills. However, they reported different effects for premenopausal and postmenopausal women.

Hormone replacement therapy may increase mammographic density. It may also increase the size and the number of cysts and fibroadenomas. hormone replacement therapy might inhibit involutional processes within the breast, and therefore women with ongoing hormone replacement therapy have higher-risk mammographic patterns compared with women without hormone replacement therapy and, hence, a higher risk of developing breast cancer. Some authors have suggested that mammographically dense breasts may be a contraindication to hormone replacement therapy. However, the risk of an increase in mammographic density differs between different hormonal therapies and also between individuals. The highest risk of increased density seems to be associated with estrogen in continous combination with progesterone, where up to 50% of postmenopausal women showed increased density. The mammographic pattern can change from N1 to P2 in some women. Women receiving estrogen in cyclic combination with progesterone and those receiving estrogen-only treatment showed a less frequent increase in breast density of around 6-20%. Only very few (2%) women using transdermal treatment showed an increase in density. Some studies found an increased risk of breast cancer after many years of hormone replacement therapy. Persson and colleagues carried out multivariate analyses which showed an increased risk among users of hormone replacement therapy of any type for more than 10 years. The odds ratio was 2.1. The risk was higher for women using estradiol-progestin combined treatment, compared with women using estradiol or conjugated estrogens alone. The odds ratio was 2.4 and 1.3, respectively. In a population-based case-control study of women aged 50-74 years of age, Magnusson and coworkers found breast cancer risk to increase with duration of hormone replacement therapy use. The odds ratio for women treated for at least 10 years with estrogen with and without progestins was 2.23, compared with women who had never used hormone replacement therapy. An excess risk was shown for both women who were current users and those who had used hormone replacement therapy in the past. The increase was less pronounced with cyclic compared with continuous combinations. The use of oral estriol and topical treatment was not associated with increased breast cancer risk.

In a study from Florence, Ciatto and associates showed that both radiologic density and exposure to hormone replacement therapy were found to correlate with age, radiologic density decreasing with increasing age. They also found the duration of hormone replacement therapy to be associated with radiologic density, a higher density occurring in women using hormone replacement therapy for many years. Boyd and co-workers suggested that mammographic density may be a short-term marker of the effect on the breast of potential preventive interventions for breast cancer, and that a variety of interventions such as tamoxifen, gonadotropin-releasing hormone inhibitor, stopping hormone replacement therapy and adopting a low-fat, high-carbohydrate diet might influence and reduce the density of the breast.

Mammographic Sensitivity And Specificity

Salminen and co-workers found the sensitivity of mammography to increase statistically significantly with increasing age of the woman. An increase in sensitivity of mammography was also found to occur with a decrease in density of the breast. However, the effect of age was larger than the effect of density on sensitivity when considered simultaneously. It is well known that it is easier to read mammograms when the breast is mostly composed of fatty tissue than when the breast is very dense with much glandular and fibrous tissue. Technical progress in recent decades has resulted in improved image quality, and dense breasts can be examined more efficiently today than 20 years ago. However, dense breasts are in general still more difficult to examine than fatty breasts, and the examination might be slightly painful. It is sometimes more difficult to position and compress the breast properly in the case of a dense breast and more views are sometimes needed. The standard views usually used are the mediolateral oblique, the lateromedial and the craniocaudal views. Special views such as coned-down views, rolled views or magnification views can sometimes allow correct prediction of palpable masses not seen on standard views. The experience of the radiologist reading the mammograms is more important in dense breasts, compared with fatty breasts. Some types of cancer, such as lobular cancer, can be more difficult to detect in a dense breast compared with a more fatty breast. However, ductal cancer in situ, which mostly presents as microcalcifications only, and invasive cancers with microcalcifications in combination with distortion or increased density, can be found quite easily even in a dense breast. In an overview study, Banks found an increased risk of interval cancer and also false positive recall for more mammographic views and further investigations in current users of hormone replacement therapy, compared with women without hormone replacement therapy. In a study from Uppsala, Thurfjell and colleagues estimated differences in sensitivity and specificity of screening in women who had previously used and in women who had never used hormone replacement therapy. They found a marginal decrease in specificity varying with the hormone replacement therapy regimen and duration of treatment, but there was no decrease in sensitivity of screening in women using hormone replacement therapy. However, the sensitivity of mammography might be different for women with the BRCA1/2 gene. These carriers develop breast cancer before age 50 years in up to 50% of cases. In a study from Rotterdam, Tilanus-Linthorst and co-workers compared 34 sporadic cases of breast cancer in patients matched for age and year of diagnosis with 34 cases of breast cancer in patients with BRCA1/2. Mammography resulted in more false negatives in carriers than in controls, despite comparable mammographic density, but false-negative mammography correlated with high density. These authors also found that breast cancer in women with BRCA1/2 showed more prominent pushing margins of the tumor than in tumors of non-carriers. This mammographic appearance caused the tumor to resemble a benign lesion rather than cancer.

Future Research

There is a reported association between P2 and DY mammographic density patterns and an increased risk of developing cancer in the future. The risk of breast cancer in general increases with age, while a fatty involution of the breast takes place after the menopause and the percentage of P2 and DY patterns decreases with advancing age. hormone replacement therapy increases breast density in some women. However, there seems to be no increased breast cancer risk for women who have used hormone replacement therapy in the short term but a moderately increased risk after long-term use. Whether this increased risk is associated only with women in whom an increase in breast density has occurred is still not known. Salminen and colleagues found that women taking hormone replacement therapy and with DY pattern s h a d a rela risk of 11.6 (95% CI 2.5-53.6) of developing breast cancer, compared with women not using hormone replacement therapy and with an N1 pattern. Some studies have reported that an increase in density, especially at older ages, due to hormone replacement therapy will further increase the breast cancer incidence. Further studies are needed to evaluate this. Nevertheless, an increase in breast density seems to be an unwanted side effect of hormone replacement therapy. There is a need to clarify the significance of a change in mammographic density and its relation to breast cancer risk, and to improve knowledge about the effects of both endogenous and exogenous hormones on breast density, breast parenchymal pattern and breast cancer risk.

Selections from the book: The management of the menopause (2003)

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