Breast cancer risk associated with changes in mammographic density.

PhD ThesisBreast cancer is the most common cancer in the UK, and mammographic density (‘density’) is one of its strongest known risk factors. At present, most research focuses on static measures of density to determine population effects. The central hypothesis of this thesis is that repeated measures of density are more valuable for personalised breast cancer prevention. This hypothesis was tested through the following research. Study-I investigated within-women associations between body mass index (BMI) and density, to assess whether density (visual/Cumulus/volumetric ‘Stepwedge’) acts as a mediator for breast cancer risk reduction during a premenopausal weight-loss intervention (n=65). Study-II evaluated the benefit of using a woman’s longitudinal history of (BI-RADS) density to improve breast cancer risk estimation (n=132,439). Study-III was a Cochrane systematic review investigating the association between endocrine therapy-induced density reduction and breast cancer risk and mortality. Studies-IV and V (n=575) evaluated visually-assessed density reduction with prophylactic anastrozole during the International Breast Cancer Intervention Study-II, and its use as a biomarker for concurrent breast cancer risk reduction, respectively. In Study-I, change in BMI was associated with change in breast fat but not dense tissue, negating density reduction as a biomarker for risk reduction with weight-loss. In Study-II, longitudinal density provided approximately a quarter more statistical information than most recent density and improved discriminatory accuracy. Study-III found evidence that density reduction may be a biomarker for reduction in risk and mortality with tamoxifen, but the level of evidence was limited by some study quality issues. Study-IV indicated that preventive anastrozole might marginally reduce density, but statistical significance was not obtained. In Study-V, sample size was too small to draw definitive conclusions. Overall, changes in density were useful for the study of breast cancer risk and should be considered for personalised breast cancer prevention strategies

Mammography

In this volume, the topics are constructed from a variety of contents: the bases of mammography systems, optimization of screening mammography with reference to evidence-based research, new technologies of image acquisition and its surrounding systems, and case reports with reference to up-to-date multimodality images of breast cancer. Mammography has been lagged in the transition to digital imaging systems because of the necessity of high resolution for diagnosis. However, in the past ten years, technical improvement has resolved the difficulties and boosted new diagnostic systems. We hope that the reader will learn the essentials of mammography and will be forward-looking for the new technologies. We want to express our sincere gratitude and appreciation?to all the co-authors who have contributed their work to this volume

The Role Of Tissue Sound Speed As A Surrogate Marker Of Breast Density

Breast density is one of the strongest predictors of breast cancer risk as women with the densest breasts have a three- to five-fold increase in risk compared to women with the least dense breasts. Breast density is currently measured by using mammography, the current gold standard for breast imaging. There are many shortcomings to using mammography to measure breast density, including the use of ionizing radiation. Ultrasound tomography (UST) does not use ionizing radiation and can create tomographic breast sound speed images. These sound speed images are useful because breast density is proportional to sound speed. The purpose of this work was to assess the ability of UST to measure breast density and its ability to measure changes in breast density over short periods of time. A cohort of 251 patients was examined using both UST and mammography. Many different associations were found between the UST density measurement, the volume averaged sound speed, and the mammographic percent density. Additional associations were found between many other UST and mammographic imaging characteristics. UST density was found to correlate with various patient characteristics in a similar manner to mammographic density. Additionally, UST was used to examine the effects of tamoxifen on breast density. Tamoxifen has been shown to reduce mammographic density and breast cancer risk for some women. Preliminary data for 52 patients has shown promising results so far. UST density has decreased for approximately a similar percentage of patients as has been measured for mammographic density. These changes have been measured over short time frames that could not be achieved using mammography. These results show that UST\u27s ability to measure breast density is consistent with mammography, the current standard of care. UST has the potential to become a safe and effective device that can be used to reliably assess breast density and serial changes in breast density

A causal investigation of soy isoflavone intake for primary prevention of post-menopausal breast cancer among Asian women

The incidence of breast cancer is increasing at an alarming rate across Asia, by up to 6% annually, compared to near stable incidence rates in many Western countries. While selective oestrogen receptor modulators and aromatase inhibitors are actively being studied as chemoprevention among high-risk Caucasian women, the risks may outweigh the benefits among Asian women with lower population risk of breast cancer. Modifiable lifestyle targets for primary prevention have long been identified, such as post-menopausal obesity, alcohol intake, and hormone replacement therapy use, but these risk factors are less prevalent among women in Asian countries. There remains an urgent need to find primary prevention strategies that are low risk, acceptable, and effective for Asian women. Epidemiological evidence in Asian women suggests that high soy intake is associated with lower risk of breast cancer, but these findings were not observed in epidemiological studies of Caucasian women nor in clinical trials of soy isoflavone supplements. To date, there are no clinical trials that examine the effect of soy isoflavone intake from diet nor supplement on breast cancer risk among Asian women. In this thesis, I present the research studies undertaken to investigate if soy isoflavone intake is causally and inversely associated with post-menopausal breast cancer risk among Asian women. The objective of the first research study was to identify mammographic density measures that are suitable biomarkers of breast cancer risk in the target population (Chapter 3). In this study, volume-based mammographic density measures and breast cancer risk factors were compared between 1,501 Malaysian women and 4,501 age- and BMI-matched Swedish women with no personal history of cancer. The analysis demonstrated that absolute dense volume, rather than percent density, may be a better biomarker of breast cancer risk among post-menopausal Asian women. Based on the above findings, the second research study sought to determine if mammographic density mediates the association between soy intake and breast cancer risk in the target population (Chapter 4). A cross-sectional analysis of 3,277 healthy Malaysian women showed that mammographic density was lower among women with frequent soy intake compared to non-consumers, by up to 2.5cm3 dense volume or 2.0cm2 dense area, but this was not statistically significant. Intriguingly, regular soy intake was associated with lower mammographic density among overweight or obese women, but for leaner women, regular soy intake was associated with higher mammographic density. This interaction was statistically significant among pre-menopausal women (pinteraction = 0.029). Prior to designing a robust clinical trial to test the causal association between soy intake and mammographic density as a biomarker of breast cancer risk, the feasibility of a dietary soy intervention was assessed in a small sample of the target population (n=10, Chapter 5). Overall, women in the study were able to maintain a diet of 70-90mg/day of soy isoflavones for 2 months, but the target of 100mg/day was not feasible and may have led to some adverse events. Thematic analysis of semi-structured interviews revealed that women participated in the study for altruistic reasons and due to emotional attachments to the cause, and that adherence was largely influenced by the practicability of the new diet or routine. Building from the results of the previous three chapters, the primary objective of the last research study was to test the effect of daily soy isoflavone intake for 1 year on breast cancer risk among Asian women, using mammographic density as a biomarker of risk (Chapter 6). In this clinical trial, 57 healthy post-menopausal Malaysian women were randomized into the Supplement arm (100mg/day isoflavones, with >90% daidzein), the Dietary Soy arm (50mg/day isoflavones), or the Control arm. After 1 year of intervention, women in the Supplement arm experienced 4.1cm2 lower dense area and 2.4% lower area-based percent density compared to women in the Control arm, but these associations were not statistically significant. The associations were weaker for women in the Dietary Soy arm and for volume-based mammographic density measures. Interestingly, stronger associations were observed when the analysis was limited to women with high BMI or low dietary fat intake, but the sample size was too small for robust analyses. In conclusion, the data presented in this thesis suggest a causal association between soy isoflavone intake and lower post-menopausal breast cancer risk among Asian women. However, due to the small sample size, the analysis was underpowered to show statistically significant effects and will require confirmation in a larger trial. Nonetheless, the research undertaken here adds to existing evidence that the soy isoflavone daidzein may be responsible for the protective effect of soy. Furthermore, it proposes new hypotheses in understanding the association between soy intake and breast cancer risk across populations, including possible effect modification by BMI or dietary fat intake

A causal investigation of soy isoflavone intake for primary prevention of post-menopausal breast cancer among Asian women

The incidence of breast cancer is increasing at an alarming rate across Asia, by up to 6% annually, compared to near stable incidence rates in many Western countries. While selective oestrogen receptor modulators and aromatase inhibitors are actively being studied as chemoprevention among high-risk Caucasian women, the risks may outweigh the benefits among Asian women with lower population risk of breast cancer. Modifiable lifestyle targets for primary prevention have long been identified, such as post-menopausal obesity, alcohol intake, and hormone replacement therapy use, but these risk factors are less prevalent among women in Asian countries. There remains an urgent need to find primary prevention strategies that are low risk, acceptable, and effective for Asian women. Epidemiological evidence in Asian women suggests that high soy intake is associated with lower risk of breast cancer, but these findings were not observed in epidemiological studies of Caucasian women nor in clinical trials of soy isoflavone supplements. To date, there are no clinical trials that examine the effect of soy isoflavone intake from diet nor supplement on breast cancer risk among Asian women. In this thesis, I present the research studies undertaken to investigate if soy isoflavone intake is causally and inversely associated with post-menopausal breast cancer risk among Asian women. The objective of the first research study was to identify mammographic density measures that are suitable biomarkers of breast cancer risk in the target population (Chapter 3). In this study, volume-based mammographic density measures and breast cancer risk factors were compared between 1,501 Malaysian women and 4,501 age- and BMI-matched Swedish women with no personal history of cancer. The analysis demonstrated that absolute dense volume, rather than percent density, may be a better biomarker of breast cancer risk among post-menopausal Asian women. Based on the above findings, the second research study sought to determine if mammographic density mediates the association between soy intake and breast cancer risk in the target population (Chapter 4). A cross-sectional analysis of 3,277 healthy Malaysian women showed that mammographic density was lower among women with frequent soy intake compared to non-consumers, by up to 2.5cm3 dense volume or 2.0cm2 dense area, but this was not statistically significant. Intriguingly, regular soy intake was associated with lower mammographic density among overweight or obese women, but for leaner women, regular soy intake was associated with higher mammographic density. This interaction was statistically significant among pre-menopausal women (pinteraction = 0.029). Prior to designing a robust clinical trial to test the causal association between soy intake and mammographic density as a biomarker of breast cancer risk, the feasibility of a dietary soy intervention was assessed in a small sample of the target population (n=10, Chapter 5). Overall, women in the study were able to maintain a diet of 70-90mg/day of soy isoflavones for 2 months, but the target of 100mg/day was not feasible and may have led to some adverse events. Thematic analysis of semi-structured interviews revealed that women participated in the study for altruistic reasons and due to emotional attachments to the cause, and that adherence was largely influenced by the practicability of the new diet or routine. Building from the results of the previous three chapters, the primary objective of the last research study was to test the effect of daily soy isoflavone intake for 1 year on breast cancer risk among Asian women, using mammographic density as a biomarker of risk (Chapter 6). In this clinical trial, 57 healthy post-menopausal Malaysian women were randomized into the Supplement arm (100mg/day isoflavones, with >90% daidzein), the Dietary Soy arm (50mg/day isoflavones), or the Control arm. After 1 year of intervention, women in the Supplement arm experienced 4.1cm2 lower dense area and 2.4% lower area-based percent density compared to women in the Control arm, but these associations were not statistically significant. The associations were weaker for women in the Dietary Soy arm and for volume-based mammographic density measures. Interestingly, stronger associations were observed when the analysis was limited to women with high BMI or low dietary fat intake, but the sample size was too small for robust analyses. In conclusion, the data presented in this thesis suggest a causal association between soy isoflavone intake and lower post-menopausal breast cancer risk among Asian women. However, due to the small sample size, the analysis was underpowered to show statistically significant effects and will require confirmation in a larger trial. Nonetheless, the research undertaken here adds to existing evidence that the soy isoflavone daidzein may be responsible for the protective effect of soy. Furthermore, it proposes new hypotheses in understanding the association between soy intake and breast cancer risk across populations, including possible effect modification by BMI or dietary fat intake

Determinants and influence of mammographic features on breast cancer risk

Mammographic density and mammographic microcalcifications are the key imaging features in mammography examination. Mammographic density is known as a strong risk factor for breast cancer and is the radiographic appearance of epithelial and fibrous tissue which appears white on a mammogram. While, the dark part of a mammogram represents the fatty tissue. Mammographic microcalcifications appear as small deposits of calcium and they are one of the earliest sign of breast cancer. Malignant microcalcifications are seen in both in situ and invasive lesions. In this thesis we used the data from the prospective KARMA cohort to study the association between established breast cancer risk factors with mammographic density change over time (Study I), to examine the association between annual mammographic density change and risk of breast cancer (Study II), to investigate the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry (Study III), and finally to elucidate the association between microcalcification clusters, their asymmetry, and risk of overall and subtype specific breast cancer (Study IV). The lifestyle and reproductive factors were assessed using web-based questionnaires. Average mammographic density and total microcalcification clusters were measured using a Computer Aided Detection system (CAD) and the STRATUS method, respectively. In Study I, the average yearly dense area change was -1.0 cm . Body mass index (BMI) and physical activity were statistically associated with density change. Beside age, lean and physically active women had the largest decrease in mammographic density per year. In Study II, overall, 563 women were diagnosed with breast cancer and annual mammographic density change did not seem to influence the risk of breast cancer. Furthermore, density change does not seem to modify the association between baseline density and risk of breast cancer. In Study III, age, mammographic density, genetic factors related to breast cancer, having more children, longer duration of breast-feeding were significantly associated with increased risk of presence of microcalcification clusters. In Study IV, 676 women were diagnosed with breast cancer. Further, women with 33 microcalcification clusters had 2 times higher risk of breast cancer compared to women with no clusters. Microcalcification clusters were associated with both in situ and invasive breast cancer. Finally, during postmenopausal period, microcalcification clusters influence risk of breast cancer to the similar extend as baseline mammographic density. In conclusion, we have identified novel determinants of mammographic density changes and potential predictors of suspicious mammographic microcalcification clusters. Further, our results suggested that annual mammographic density change does not influence breast cancer risk, while presence of suspicious microcalcification clusters was strongly associated with breast cancer risk

Mammographic density and ageing:A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction