High risk mammographic parenchymal patterns and diet: a case–control study

Mammographic parenchymal patterns are related to breast cancer risk and are also thought to be affected by diet. We designed a case–control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of food and nutrient intake on mammographic patterns. Mammograms were evaluated according to the Wolfe classification system. Dietary data were obtained from 7-day food diaries. Mean daily intake of nutrients was computed from standard UK food tables. The adjusted odds ratio (OR) of having a high-risk pattern in women in the highest tertile of total protein and carbohydrate intake was twice that of women in the lowest tertile (OR = 2.00; 95% confidence interval (CI) 1.06–3.77;P = 0.04 and OR = 1.93; 95% CI 1.03–3.59;P = 0.04 respectively). There was no excess risk for fat intake. In addition, there was no association between intake of vitamins and mammographic parenchymal patterns. Total meat intake was strongly and positively associated with high-risk patterns among post-menopausal women (OR = 2.50, 95% CI 1.09–5.69, P = 0.03). Our study suggests that certain macronutrients and foods such as protein, carbohydrate and meat intake influence the risk of breast cancer through their effects on breast tissue morphology, whereas fat and vitamins do not affect mammographic density. It seems that parenchymal pattern acts as an informative biomarker of the effect of some macronutrient and foodstuffs intake on breast cancer risk. © 2000 Cancer Research Campaig

Estrogen Metabolism, Breast Density, and Breast Cancer

BACKGROUND: Estrogen metabolites, sex-steroid hormones, and breast density are associated with breast carcinogenesis. OBJECTIVE: Complete a systematic study of the contribution of two biological measures (breast density and hormone metabolism) to an endocrine-based model of breast cancer risk.METHODS: The study groups included breast cancer-free participants (N=282) in the Study of Osteoporotic Fractures (SOF), and participants in the Mammogram and Masses Study (MAMS), inclusive of 176 cases (55 pre-menopausal, 121 post-menopausal) and 380 controls (124 pre-menopausal, 256 postmenopausal). Sex-steroid hormones, percent breast density, serum concentrations of 2-hydroxyestrone (2-OH) and 16 alpha-hydroxyestrone (16alfa-OH), and breast cancer risk factors were evaluated to determine associations.RESULTS: In SOF,16alfa-OH was positively associated with body mass index (BMI) (r=0.162); however, this association was not significant in multivariate analyses that controlled for the serum sex-steroid hormone concentrations (total estradiol, total testosterone, SHBG). Women who reported a surgical menopause were significantly more likely to have higher levels of 16alfa-OH (OR=(tertile 3 vs tertile 1) 7.37, 95% Confidence Interval (CI) 2.20-24.70), but there was no type of menopause difference with respect to 2-OH tertile. In all MAMS control subjects (N=380), breast density correlated weakly with log-transformed serum concentrations of 16alfa-OH (Pearson correlation coefficient = 0.10, p-value < 0.1). Stratification according to menopausal status substantially reduced or eliminated associations between breast density and the estrogen metabolite concentrations. Logistic regression analyses showed a 3-4 fold increased risk of breast cancer among pre-menopausal women in the highest tertile of breast density compared with those in the lowest tertile of density, even with adjustment for the estrogen metabolites. A statistically non-significant 1.5-fold increased risk of breast cancer in high vs. low tertile of density was observed among post-menopausal women taking hormone therapy (HT) after adjusting for estrogen metabolites, BMI, and age. Breast density did not appear to substantially increase breast cancer risk among post-menopausal women not taking HT. CONCLUSION: In SOF, results did not show consistent associations between risk factors and estrogen metabolites except for a positive association between BMI and 16alfa-OH and surgical menopause and 16alfa-OH. With respect to MAMS, menopausal status may influence substrate estrogen hormone levels primarily, and, estrogen hormone levels may influence breast density secondarily, through pathways not involving the estrogen metabolites. The breast density-breast cancer association remains significant even with adjustment for the estrogen metabolites, at least in pre-menopausal women, suggesting that breast density may relate to breast cancer risk through pathways not involving estrogen metabolism.PUBLIC HEALTH SIGNIFICANCE: Understanding factors that affect breast density and their underlying mechanism is an important public health issue. Such an understanding will help us improve breast cancer screening and may help us identify women who are at an increased risk of breast cancer and for whom prevention strategies may be useful

The association of histological and radiological indicators of breast cancer risk.

Previous work has shown that extensive mammographic dysplasia in women aged less than 50 was strongly associated with breast cancer but that the radiological appearance of ductal prominence was not associated with risk. In the present paper we examine the association between these mammographic signs in the breast and histological patterns in the terminal ductal lobular unit (TDLU), the region of the breast where breast cancer is believed to originate. Surgical biopsies from a consecutive series of women aged less than 50 were reviewed and classified according to the histopathology of the epithelium in the TDLU. Mammograms from the same subjects were independently classified according to the extent of the radiological signs of dysplasia and ductal prominence. Degree of histopathology and the extent of mammographic dysplasia were associated and atypia of the ductal type was found more frequently in patients with extensive dysplasia. However, the strength and statistical significance of the association varied according to the radiologist who classified the mammograms. No association was found between degree of histopathology and ductal prominence. These results add to the evidence that extensive mammographic dysplasia in women aged less than 50 is a risk factor for breast cancer. They do not indicate that the radiological signs of dysplasia are caused by histological changes in the TDLU

Mammographic Findings after Intraoperative Radiotherapy of the Breast

Intraoperative Radiotherapy (IORT) is a form of accelerated partial breast radiation that has been shown to be equivalent to conventional whole breast external beam radiotherapy (EBRT) in terms of local cancer control. However, questions have been raised about the potential of f IORT to produce breast parenchymal changes that could interfere with mammographic surveillance of cancer recurrence. The purpose of this study was to identify, quantify, and compare the mammographic findings of patients who received IORT and EBRT in a prospective, randomized controlled clinical trial of women with early stage invasive breast cancer undergoing breast conserving therapy between July 2005 and December 2009. Treatment groups were compared with regard to the 1, 2 and 4-year incidence of 6 post-operative mammographic findings: architectural distortion, skin thickening, skin retraction, calcifications, fat necrosis, and mass density. Blinded review of 90 sets of mammograms of 15 IORT and 16 EBRT patients demonstrated a higher incidence of fat necrosis among IORT recipients at years 1, 2, and 4. However, none of the subjects were judged to have suspicious mammogram findings and fat necrosis did not interfere with mammographic interpretation

The Effects of Anthropometry and Angiogenesis on Breast Cancer Etiology

Factors such as mammographic breast density and angiogenesis may be related to breast cancer development, though numerous questions about the etiologic mechanisms remain. Percent density is positively associated with breast cancer risk, yet is negatively associated with another breast cancer risk factor, body mass index (BMI). Vascular endothelial growth factor (VEGF) is a primary regulator of angiogenesis, yet its relationship to breast cancer risk is unclear. We evaluated the longitudinal association between BMI and breast density in the Study of Women's Health Across the Nation (SWAN) Mammographic Density Substudy (N=834). Using adjusted random intercept models, changes in BMI were not associated with changes in dense breast area (Beta=-0.0105, p=0.34), but were strongly negatively associated with changes in percent density (Beta=-1.18, p<0.001). Thus, effects of changes in anthropometry on percent breast density may reflect effects on non-dense tissue, rather than on the dense tissue where cancers arise. Breast density was measured from routine screening mammograms which were not timed with SWAN visits. We developed a method to align the off-schedule mammogram data to the study visit times using linear interpolation with multiple imputation. Our method was shown to be valid, with an average bias for dense breast area of 0.11 cm2. In the random intercept models, use of a simple matching algorithm to estimate breast density produced different (Beta=-0.0155, p=0.04), and likely incorrect, results. Our linear interpolation with multiple imputations method may be applicable to other longitudinal datasets with important data collected off-schedule. In a separate case-control study, the Mammograms and Masses Study (MAMS), we evaluated the association between serum VEGF levels and breast cancer (N=407). Geometric mean VEGF levels were higher among cases (331.4 pg/mL) than controls (291.4 pg/mL; p=0.21). In a multivariable logistic regression model, VEGF greater than or equal to 314.2 pg/mL was positively associated with breast cancer (odds ratio 1.37, 95% confidence interval 0.88-2.12), albeit non-significantly. Higher levels of VEGF may increase breast cancer risk. We have identified roles for anthropometry and angiogenesis in breast carcinogenesis. Enhancing knowledge of breast cancer etiology is a significant contribution to public health and may lead to improved opportunities for prevention or early detection

Clinical and epidemiological issues and applications of mammographic density

The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the authorMammographic density, the amount of radiodense tissue on a mammogram, is a strong risk factor for breast cancer, with properties that could be an asset in screening and prevention programmes. Its use in risk prediction contexts is currently limited, however, mainly due to di culties in measuring and interpreting density. This research investigates rstly, the properties of density as an independent marker of breast cancer risk and secondly, how density should be measured. The rst question was addressed by analysing data from a chemoprevention trial, a trial of hormonal treatment, and a cohort study of women with a family history of breast cancer . Tamoxifen-induced density reduction was observed to be a good predictor of breast cancer risk reduction in high-risk una ected subjects. Density and its changes did not predict risk or treatment outcome in subjects with a primary invasive breast tumour. Finally absolute density predicted risk better than percent density and showed a potential to improve existing risk-prediction models, even in a population at enhanced familial risk of breast cancer. The second part of thesis focuses on density measurement and in particular evaluates two fully-automated volumetric methods, Quantra and Volpara. These two methods are highly correlated and in both cases absolute density (cm3) discriminated cases from controls better than percent density. Finally, we evaluated and compared di erent measurement methods. Our ndings suggested good reliability of the Cumulus and visual assessments. Quantra volumetric estimates appeared negligibly a ected by measurement error, but were less variable than visual bi-dimensional ones, a ecting their ability to discriminate cases from controls. Overall, visual assessments showed the strongest association with breast cancer risk in comparison to computerised methods. Our research supports the hypothesis that density should have a role in personalising screening programs and risk management. Volumetric density measuring methods, though promising, could be improved.Cancer Research U

Inflammation and Breast Cancer Risk

Mammographic density is one of the strongest risk factors for breast cancer. Exactly how breast density increases breast cancer risk is unknown, although it is believed that dense breast areas may reflect exposure to estrogen. Breast cancer incidence is highest in postmenopause, when most estrogens are produced in non-ovarian tissues. Cyclooxygenase (COX)-2 and the cytokine tumor necrosis factor (TNF)-alpha may play a role in regulating estrogen synthesis in postmenopausal women. The aim of the present study was to explore the association between inflammation and breast cancer risk in two populations of postmenopausal women. Different exposures associated with inflammation (non-steroidal anti-inflammatory drug (NSAID) use, circulating receptors for TNF-alpha, and a polymorphism in the TNF receptor-II gene) were measured and tested for their association with incident breast cancer or mammographic density. In the first study, the Study of Osteoporotic Fractures (SOF), complete NSAID medication and breast cancer risk factor information was available for 6695 women, mean (SD) age 73 (5) years. During a mean (SD) of 13.2 (3.8) years of follow-up, 372 women were diagnosed with primary breast cancer. There were no differences in incident breast cancer by NSAID use, either before or after adjusting for covariates. In the second study, Mammograms and Masses (MAMS), mean mammographic density was lower among women in the highest quartiles of circulating soluble TNF receptor levels. After adjustment for body mass index, the inverse association disappeared. In evaluating the TNFR2 -196 M/R polymorphism (T>G), the unadjusted mean (SD) mammographic density was higher in women with the TT genotype (32.3% (21.0)) as compared to women with the TG/GG genotypes (26.6% (17.2)), p=0.003. The association remained statistically significant after adjustment for age and BMI (p=0.03); however, inclusion of additional covariates reduced the level of statistical significance (p=0.08). There was no observable difference in circulating sTNFR2 levels between the TNFR2 genotypes. An increased understanding of factors that affect mammographic density and their underlying mechanisms is needed, and inflammation may be involved. An association between breast cancer risk and inflammation would have important pubic health implications for screening and primary prevention of breast cancer

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

INTRODUCTION: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. METHODS: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. RESULTS: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). CONCLUSION: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone

Breast asymmetry and predisposition to breast cancer.

INTRODUCTION: It has been shown in our previous work that breast asymmetry is related to several of the known risk factors for breast cancer, and that patients with diagnosed breast cancer have more breast volume asymmetry, as measured from mammograms, than age-matched healthy women. METHODS: In the present study, we compared the breast asymmetry of women who were free of breast disease at time of mammography, but who had subsequently developed breast cancer, with that of age-matched healthy controls who had remained disease-free to time of the present study. The study group consisted of 252 asymptomatic women who had normal mammography, but went on to develop breast cancer. The control group were 252 age-matched healthy controls whose mammograms were also normal and who remained free of cancer during the study period. Breast volume was calculated from the cranio-caudal mammograms for each group, and the relationships between asymmetry, established risk factors and the presence or absence of breast cancer were explored. RESULTS: The group who went on to develop breast cancer had higher breast asymmetry than controls (absolute asymmetry odds ratio 1.50 per 100 ml, confidence interval (CI) 1.10, 2.04; relative asymmetry 1.09, CI 1.01, 1.18), increased incidence of family history of breast cancer, lower age at menarche, later menopause, later first pregnancies and a higher frequency of high risk breast parenchyma types. Conditional logistic regression analysis showed that breast asymmetry, height, family history of breast cancer, age at menarche, parenchyma type and menopausal status were significant independent predictors of breast cancer. When age at menopause was included in the model for the subgroup of post-menopausal women, absolute breast fluctuating asymmetry (FA) and relative breast FA remained significant effects. CONCLUSION: Breast asymmetry was greater in healthy women who later developed breast cancer than in women who did not

Beyond mammography : an evaluation of complementary modalities in breast imaging

Breast cancer is the main cause of cancer death among women worldwide and the goal of mammography screening is to reduce breast cancer-specific mortality. The reduction of the sensitivity of mammography for detecting cancer among women with dense breasts requires the use of complementary methods for this subset of women. Three of the projects in this thesis examine the performance of such complementary methods and a fourth study investigates the association between the biomarker BPE (background parenchymal enhancement) and risk factors for breast cancer. In study 1, we prospectively compared the sensitivity and specificity of Automated Breast Volume Scanner (ABVS) with handheld ultrasound for detection of breast cancer among women with a suspicious mammographic finding who were recalled after attending the population-based mammography screening program. We performed both methods on 113 women and found 26 malignant lesions. Analysis was performed in two categories: breasts with a suspicious screening mammography and breasts with a negative screening mammography. In the first category (n=118) the sensitivity of both methods was 88% (p=1.0), the specificity of handheld ultrasound was 93.5 % and ABVS was 89.2%. The difference in specificity was not statistically significant (p=0.29). For breasts without a suspicious mammographic finding, the sensitivity of handheld ultrasound and ABVS was 100% (p=1.0), the specificity was 100% and 94.1% respectively. The difference in specificity was statistically significant (p=0.03). In summary, ABVS has similar sensitivity to handheld ultrasound, but lower specificity in breasts with a negative mammogram. In study 2, we explored the incremental cancer detection rate when adding a threedimensional infrared imaging (3DIRI) score to screening mammography among women with dense breasts (Volpara volumetric density >6 % on the previous mammography examination) who attended the population-based mammography screening program. Women with a negative mammogram and positive 3DIRI score were triaged for a DCEMRI examination to verify the presence of cancer. Of 1727 participants, 7 women had a mammography-detected breast cancer. Among women with a negative mammogram and a positive infrared imaging (n=219), an additional 6 cancers in 5 women were detected on MRI resulting in an incremental cancer detection rate of 22.5 per 1000. Among women with a negative mammography and infrared examination, one woman was diagnosed with breast cancer during the two-year follow-up. The study does not provide information on the proportion of cancers that might have been detected had MRI been performed among women with a negative mammogram and 3DIRI score. Consequently, this study does not shed light on the diagnostic accuracy of infrared imaging or whether using an infrared risk score is the optimal method for identifying women who would benefit from additional imaging modalities. In study 3, we used MRI examinations of study 2 among women without breast cancer (n=214) to explore the association between BPE at DCE-MRI and a large array of risk factors for breast cancer. Thanks to the Karma database, we had unique access to data from self-reporting questionnaires on risk factors. BPE and mammographic density were assessed visually by three radiologists and BPE was further dichotomized into low and high. We created categorical variables for other risk factors. We calculated the univariable associations between BPE and each risk factor and fitted an adjusted logistic regression model. In the adjusted model, we found a negative association with age (p=0.002), and a positive association with BMI (p=0.03). There was a statistically significant association with systemic progesterone (p=0.03) but since only five participants used progesterone preparations, the result is uncertain. Although the likelihood for high BPE increased with increase in mammographic density, the association was not statistically significant (p=0.23). We were able to confirm earlier findings that BPE is associated with age, BMI and progesterone, but we could not find an association with other risk factors for breast cancer. In study 4, we compared the diagnostic accuracy, reading-time, and inter-rater agreement of an abbreviated protocol (aMRI) to the routine full protocol (fMRI) of contrast-enhanced breast MRI. The MRI examinations were performed before biopsy and among women who were not part of a surveillance program due to an increased familial risk of breast cancer. Analysis was performed on a per breast basis. Aggregated across three readers, the sensitivity and specificity were 93.0% and 91.7% for aMRI, and 92.0% and 94.3% for the fMRI. Using a generalized estimating equations approach to compare the two protocols, the difference in sensitivity was not statistically significant (p=0.840), and the difference in specificity was significant (p=0.003). There was a statistically significant difference in average reading time of 67 seconds for aMRI and 126 seconds for the fMRI (p= 0.000). The inter-rater agreement was 0.79 for aMRI and 0.83 for fMRI. We were able to demonstrate that the abbreviated protocol has similar sensitivity to the full protocol even if MRI is performed before biopsy and the images lack telltale signs of malignancy. In conclusion, this thesis provides new knowledge about the biomarker BPE, broadens our knowledge on the diagnostic accuracy of two different imaging modalities and highlights the importance of good study design for diagnostic accuracy studies