Update on Breast Cancer Risk Reduction Therapy

In women at increased risk of breast cancer age ≥35 years, the selective estrogen receptor modulator (SERM) tamoxifen should be discussed as an option to reduce the risk of estrogen receptor (ER)-positive breast cancer. In postmenopausal women, raloxifene, anastrozole, and exemestane should also be discussed as options for breast cancer risk reduction. Risk reduction with SERMs continues for at least 10 years in both premenopausal and postmenopausal women. Tamoxifen is not recommended for women with a history of deep vein thrombosis, pulmonary embolus, stroke, transient ischemic attack, or during prolonged immobilization. Chemoprevention with a SERM may be particularly beneficial to women with atypical hyperplasia, a 5-year risk of more than 5 %, in women with increased mammographic density, or in women with lobular carcinoma in situ. Aromatase inhibitor therapy is of value in high-risk postmenopausal women. Toxicity with tamoxifen is minimal in premenopausal women and is less with either raloxifene or an aromatase inhibitor in postmenopausal women.     

戈舍瑞林联合三苯氧胺治疗绝经前ER~＋PR~＋及ER~＋PR~-复发转移性乳腺癌疗效观察

目的：探讨戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前雌激素（ER）、孕激素（PR）双阳性及ER＋/PR-两种复发转移乳腺癌的临床疗效,对比两种乳腺癌的治疗效果。方法：将104例绝经前、原癌基因（c-erbB-2）均为（＋）、淋巴结1-3个阳性的复发转移乳腺癌患者分成两组,52例ER＋/PR＋,52例为ER＋/PR-。两组患者均为手术后和辅助化疗后发现复发转移的乳腺癌接受戈舍瑞林3.6mg皮下注射,每28天1次,连续6个月以上;联合三苯氧胺口服,10mg/次,每日2次,连用6个月以上。结果：104例患者完全缓解（CR）3例,部分缓解（PR）31例,稳定（SD）31例,进展（PD）39例,总有效率（OR=CR＋PR）为32.7%,临床获益率（CBR=CR＋PR＋SD≥6个月）62.5%;其中ER＋、PR-组,CR 2例,PR 21例,SD 16例,PD 13例,OR为44.1%,CBR 74.9%;ER＋、PR-组CR 1例,PR 10例,SD 15例,PD 26例,OR 21.1%,CBR 49.9%。结论：戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前ER阳性、淋巴结1-3阳性、复发转移性的乳腺癌患者临床疗效显著,而ER＋/PR＋组患者效果明显优于ER＋、PR-组患者,临床治疗效果更佳。对于在辅助内分泌治疗期间发生PD,应立即中止辅助内分泌治疗,进行手术、解救化疗、放疗或分子靶向等治疗后再序贯内分泌治疗。     

High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients.

PURPOSE: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. EXPERIMENTAL DESIGN: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. RESULTS: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival. CONCLUSIONS: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.     

An overview of mammographic density and its association with breast cancer

In 2017, breast cancer became the most commonly diagnosed cancer among women in the US. After lung cancer, breast cancer is the leading cause of cancer-related mortality in women. The breast consists of several components, including milk storage glands, milk ducts made of epithelial cells, adipose tissue, and stromal tissue. Mammographic density (MD) is based on the proportion of stromal, epithelial, and adipose tissue. Women with high MD have more stromal and epithelial cells and less fatty adipose tissue, and are more likely to develop breast cancer in their lifetime compared to women with low MD. Because of this correlation, high MD is an independent risk factor for breast cancer. Further, mammographic screening is less effective in detecting suspicious lesions in dense breast tissue, which can lead to late-stage diagnosis. Molecular differences between dense and non-dense breast tissues explain the underlying biological reasons for why women with dense breasts are at a higher risk for developing breast cancer. The goal of this review is to highlight the current molecular understanding of MD, its association with breast cancer risk, the demographics pertaining to MD, and the environmental factors that modulate MD. Finally, we will review the current legislation regarding the disclosure of MD on a traditional screening mammogram and the supplemental screening options available to women with dense breast tissue.     

戈舍瑞林联合三苯氧胺治疗绝经前ER+PR+及ER+PR-复发转移性乳腺癌疗效观察

目的:探讨戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前雌激素(ER)、孕激素(PR)双阳性及ER+/PR-两种复发转移乳腺癌的临床疗效,对比两种乳腺癌的治疗效果.方法:将104例绝经前、原癌基因(c-erbB-2)均为(+)、淋巴结1-3个阳性的复发转移乳腺癌患者分成两组,52例ER+/PR+,52例为ER+/PR-.两组患者均为手术后和辅助化疗后发现复发转移的乳腺癌接受戈舍瑞林3.6mg皮下注射,每28天1次,连续6个月以上;联合三苯氧胺口服,10mg/次,每日2次,连用6个月以上.结果:104例患者完全缓解(CR)3例,部分缓解(PR)31例,稳定(SD)31例,进展(PD)39例,总有效率(OR=CR+PR)为32.7%,临床获益率(CBR=CR+PR+SD≥6个月)62.5%;其中ER+、PR-组,CR 2例,PR 21例,SD 16例,PD 13例,OR为44.1%,CBR 74.9%;ER+、PR-组CR 1例,PR 10例,SD 15例,PD 26例,OR 21.1%,CBR 49.9%.结论:戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前ER阳性、淋巴结1-3阳性、复发转移性的乳腺癌患者临床疗效显著,而ER+/PR+组患者效果明显优于ER+、PR-组患者,临床治疗效果更佳.对于在辅助内分泌治疗期间发生PD,应立即中止辅助内分泌治疗,进行手术、解救化疗、放疗或分子靶向等治疗后再序贯内分泌治疗.     

Evaluation of estrogen and progesterone receptors in non-neoplastic breast tissue of women of reproductive age exposed to tamoxifen and raloxifene: a randomized, double-blind study

The objective of the present study was to compare the effects of tamoxifen and raloxifene in non-neoplastic breast epithelium. A randomized, double-blind study was carried out in 57 ovulatory, premenopausal women of 18–40 years of age, who had been diagnosed with fibroadenoma of the breast. The patients were divided into three groups: Group A: placebo, n = 20; Group B: tamoxifen 20 mg/day, n = 21; and Group C: raloxifene 60 mg/day, n = 16. The study medication was given for 22 days starting on the first day of the menstrual cycle. On the 23rd day, the fibroadenoma was removed and a sample of non-neoplastic breast tissue was collected for immunohistochemical evaluation of estrogen and progesterone receptors. Comparison between the mean percentages of stained nuclei in the three groups was performed by analysis of variance and multiple comparisons, using Tukey’s method to compare pairwise means, with significance established at P < 0.05. Exposition to tamoxifen or raloxifene resulted in a significant and similar reduction in the mean percentage of stained nuclei for estrogen and progesterone receptors (P < 0.0001). Tamoxifen and raloxifene reduce progesterone and estrogen receptor alpha expression significantly and to a similar extent in the non-neoplastic breast tissue of women of reproductive age.     

Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial

BackgroundAdjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial.Patients and methodsPremenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years.ResultsIn the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients <40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40–49 years of age or ?50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time.ConclusionIn this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women <40 years of age. The effect of tamoxifen was not significantly dependent on time.     

Association of reproductive history with breast tissue characteristics and receptor status in the normal breast

Introduction

Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma).

Materials and methods

Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI.

Results

Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial–stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial–stromal ratio amongst all participants and among pre- and postmenopausal women separately.

Conclusion

Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer.

     

Growth-inhibitory effect of adiponectin via adiponectin receptor 1 on human breast cancer cells through inhibition of S-phase entry without inducing apoptosis

Background The mammographic features of triple receptor-negative [TRN] breast cancers, a distinct cancer subtype with a poor prognosis have not been reported to our knowledge. The aim of this study was to compare the mammographic breast density, visibility, and tumor features of different breast cancer immunophenotypes. Patients and methods We identified all premenopausal women aged 45 years or less who had been diagnosed with primary breast cancer between January 1999 and November 2005 at a single institution and who had undergone mammography at initial diagnosis. Patient characteristics including clinical, histologic, and mammographic features of breast cancers were tabulated by immunophenotype and compared with the chi-square test or the Kruskal–Wallis test. The P values less than 0.05 were considered statistically significant. Results We identified 198 premenopausal women who had been diagnosed with breast cancer. Thirty-eight (19%) women had TRN cancer, 67 (34%) had HER2+ cancer, and 93 (47%) had ER+ cancer. Mammographic density and cancer visibility were similar between all immunophenotypes of cancers. TRN cancers were more frequently associated with a mass (33/33 [100%]) than were HER2+ (35/64 [55%]) and ER+ cancers (42/87 [48%]) (P < 0.0001), and were less frequently associated with calcifications (5/33 [15%]) than were HER2+ (43/64 [67%]) and ER+ (53/87 [61%]) cancers (P < 0.0001). Associated ductal carcinoma in situ was reported in 18% (7/38), 57% (38/67), and 48% (52/93) of TRN, HER2+, and ER+ patients, respectively (P = 0.0003). Conclusion The mammographic features of TRN breast cancer suggest more rapid carcinogenesis leading directly to invasive cancer, that may require adjunct imaging tools for early diagnosis.     

Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention

Differences in the parenchymal pattern of the breast on mammography reflect differences in the amounts of stromal, epithelial, and fat tissue present in the breast. Stroma and epithelium are radiologically dense, whereas fat is lucent. Extensive areas of mammographically dense breast tissue are strongly associated with an increased risk of breast cancer. A variety of interventions, including gonadotropin-releasing hormone inhibitor, tamoxifen, stopping hormone replacement therapy (HRT), and adopting a low-fat, high-carbohydrate diet, all influence the tissue composition of the breast and reduce mammographic densities. Of the interventions examined to date, only tamoxifen has been shown to reduce the incidence of breast cancer, at least in the short term. Conversely, HRT, which increases density, also increases risk of breast cancer. These results suggest that mammographic density may be a short-term marker of the effect on the breast of potential preventive interventions for breast cancer.     

Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up

Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n=276) or no treatment (n=288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48-0.89, P=0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.     

Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women

Tamoxifen improves outcome in women with breast cancer and reduces the incidence of estrogen receptor-positive (ER+) breast tumors in prevention trials. Tamoxifen use is associated with an increased risk of potentially serious adverse events, principally endometrial cancer and venous thromboembolic events and, therefore, detailed knowledge of the effects of tamoxifen is important. With more cases of breast cancer being found as the follow-up time increases, it is now possible to perform more detailed analysis of the Italian Randomized Trial of Tamoxifen. Women with hysterectomy (N = 5408) were randomly assigned to receive 20 mg tamoxifen per day (N = 2700) or placebo (N = 2708). After a median of 81.2 months of follow-up, 79 case subjects (34 in the tamoxifen arm and 45 in the placebo arm) were diagnosed with breast cancer. We were able to identify a group of women at increased risk of ER+ breast cancers (high-risk group) on the basis of baseline as well as reproductive and hormonal characteristics (height, age at menarche, parity, age at first birth, and oophorectomy). Tamoxifen administered to women in the high-risk group showed statistically significantly reduced incidence of breast cancer (tamoxifen, 3 and placebo, 15; P =.003), but no such effect was seen in the low-risk group (tamoxifen, 31 and placebo, 30; P =.89). The positive effect of tamoxifen on breast cancer among high-risk women is most marked for ER+ tumors (tamoxifen, 1 and placebo, 11; P =.002). Chemoprevention of breast cancer with tamoxifen appears to be effective in women at high risk of ER+ tumors but not among women at low risk, who may well be protected naturally by late age at menarche or early first pregnancy, or artificially by removal of the ovaries. Tamoxifen could be offered as a preventive agent to women identified at high-risk of breast cancer because of hormone-related risk factors. Such a strategy would greatly reduce the numbers of women who would need to take tamoxifen to obtain the same absolute reduction in breast cancer. These findings are exploratory and need to be confirmed in other randomized trials.     

Variation of estrogen and progesterone receptor status in breast cancer after tamoxifen therapy

In the present paper we have studied the quantitative variations in estrogen (ER) and progesterone receptor (PR) content of breast cancer induced by tamoxifen. In addition to receptors, hormonal levels of estradiol, progesterone, prolactin, FSH, LH and testosterone were also measured. The cases included in our study were consecutively selected among those breast cancers in which an aliquot of the tissue sample sent for analysis of the steroid receptors was positive for cancer and also found to have at least one of the steroid receptors positive, not only in the biopsy but also in the surgical specimen. Following this criterion, we finally collected 14 cases of breast cancer treated daily with 30 mg of tamoxifen during an interval of 3 weeks from the initial biopsy to the final surgery. From our results we can conclude that tamoxifen reduced significantly the ER concentration while no changes were observed in PR values. Concerning hormones, while in premenopausal patients tamoxifen induced a rise in plasma estradiol, in postmenopausal women the only modification observed was a decrease in plasma FSH. The variation in steroid receptor content under tamoxifen therapy may also contribute to the evaluation of the hormone dependency of gynecologic malignancies.     

A cross-sectional investigation of breast density and insulin-like growth factor I

Our study investigated the association of breast cancer risk as assessed by mammographic density with insulin-like growth factor I (IGF-I) and one of its binding proteins (IGFBP-3) in healthy premenopausal women with different ethnic backgrounds. In a cross-sectional design, we analyzed the baseline mammograms and fasting serum samples (collected 5 days after ovulation) of premenopausal women entering a nutritional intervention. Serum concentrations of IGF-I and IGFBP-3 were measured by double-antibody ELISA. Mammographic densities were assessed using a computer-assisted method. We calculated Spearman correlation coefficients between mammographic characteristics and analytes and estimated means of mammographic characteristics by quartiles of IGF-I and IGFBP-3 while adjusting for age, body mass index (BMI) and reproductive factors. In this group of 240 women, IGF-I, IGFBP-3 and percent densities did not differ significantly by ethnicity. Whereas mammographic densities were not associated with IGF-I, we found an inverse relation with IGFBP-3 (r(s) = -0.15, p = 0.02) and a positive association with the IGF-I/IGFBP-3 ratio (r(s) = 0.13, p = 0.04). The size of the dense areas was not associated with the analytes, but the size of the nondense areas was correlated directly with IGFBP-3 (r(s) = 0.20, p = 0.002) and inversely with the molar ratio (r(s) = -0.19, p = 0.004). These associations were limited to women with a BMI of less than 25 kg/m(2). These results suggest that the balance of circulating IGF-I and IGFBP-3 levels may influence the growth of the fatty part of the breast more than the epithelial and stromal breast tissue, but the exact mechanism of action needs to be explored in more detail.     

Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques

The purpose of this work was to examine the mammary glands of adult, ovariectomized female cynomolgus macaques (Macaca fascicularis) in a long-term study of the effects of hormone treatments on chronic disease. Treatments included conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE+MPA, and tamoxifen. Doses were scaled from those given women. Treatments were given in the diet for three years, followed by necropsy and tissue collection. Endpoints evaluated included glandular histology, histomorphometry, and immunohistochemical detection of the proliferation marker Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in mammary epithelial cells. Major findings were as follows: CEE induced PR expression and focal to diffuse lobuloalveolar proliferation. Proliferation was increased by the addition of MPA, but was not induced by MPA alone. Tamoxifen induced ER and PR but not Ki-67 expression or glandular hyperplasia. Neoplasms were not seen. These findings indicate that progestogens may exacerbate, not antagonize mammary gland proliferation induced by estrogen replacement therapy, and that tamoxifen has both estrogen agonist and antagonist effects on sex steroid receptor expression in the normal primate breast.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

The Stockholm trial on adjuvant tamoxifen in early breast cancer

Summary The paper presents interim results of an on-going randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no endocrine adjuvant therapy in postmenopausal women with early breast cancer. A total of 1407 patients were included in the study between November 1976 through June 1984. Estrogen receptor (ER) data were available on 1184 patients (84%). The median follow-up was 53 months. Adjuvant tamoxifen increased the recurrence-free interval (P<0.01) but had no significant effect on overall survival. Treatment failures were reduced by 25% (P<0.01) and deaths by 7% (P>0.05). Tamoxifen mainly decreased the frequency of loco-regional recurrence whereas distant metastases were less affected. The treatment effect was independent of tumor stage but was significantly related to the estrogen receptor (ER) content of the primary tumor. Tamoxifen appeared ineffective among ER negative patients, and the greatest effect was seen among those with high levels of ER. The results indicate that the main mechanism of action of adjuvant tamoxifen is similar to that suggested in advanced disease, i.e. an interaction with the estrogen receptor.     

Targeting cholesterol-rich microdomains to circumvent tamoxifen-resistant breast cancer

Introduction  

Adjuvant treatment with tamoxifen substantially improves survival of women with estrogen-receptor positive (ER+) tumors. Tamoxifen resistance (TAMR) limits clinical benefit. RRR-α-tocopherol ether-linked acetic acid analogue (α-TEA) is a small bioactive lipid with potent anticancer activity. We evaluated the ability of α-TEA in the presence of tamoxifen to circumvent TAMR in human breast cancer cell lines.     

Mammographic density is related to stroma and stromal proteoglycan expression

Background

Mammographic density and certain histological changes in breast tissues are both risk factors for breast cancer. However, the relationship between these factors remains uncertain. Previous studies have focused on the histology of the epithelial changes, even though breast stroma is the major tissue compartment by volume. We have previously identified lumican and decorin as abundant small leucine-rich proteoglycans in breast stroma that show altered expression after breast tumorigenesis. In this study we have examined breast biopsies for a relationship between mammographic density and stromal alterations.

Methods

We reviewed mammograms from women aged 50–69 years who had enrolled in a provincial mammography screening program and had undergone an excision biopsy for an abnormality that was subsequently diagnosed as benign or pre-invasive breast disease. The overall mammographic density was classified into density categories. All biopsy tissue sections were reviewed and tissue blocks from excision margins distant from the diagnostic lesion were selected. Histological composition was assessed in sections stained with haematoxylin and eosin, and the expression of lumican and decorin was assessed by immunohistochemistry; both were quantified by semi-quantitative scoring.

Results

Tissue sections corresponding to regions of high in comparison with low mammographic density showed no significant difference in the density of ductal and lobular units but showed significantly higher collagen density and extent of fibrosis. Similarly, the expression of lumican and decorin was significantly increased.

Conclusion

Alteration in stromal composition is correlated with increased mammographic density. Although epithelial changes define the eventual pathway for breast cancer development, mammographic density might correspond more directly to alterations in stromal composition.     

Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women

Background Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density. Methods Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5′ and 3′ ends of IGF1 and one in intron 2. Results The number of 19 alleles at the 5′ polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3′ polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3′ on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models. Conclusions Our results suggest an association between the number of 185 alleles at 3′ with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3′ IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3′ genotype with percentage density. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.