Martin J. Yaffe

Adiposity changes after a 1-year aerobic exercise intervention among postmenopausal women: a randomized controlled trial

Objective:We examined the effects of an aerobic exercise intervention on adiposity outcomes that may be involved in the association between physical activity and breast cancer risk.Design:This study was a two-centre, two-armed, randomized controlled trial. The 1-year-long exercise intervention included 45u2009min of moderate-to-vigorous aerobic exercise five times per week, with at least three of the sessions being facility based. The control group was asked not to change their activity and both groups were asked not to change their diet.Subjects:A total of 320 postmenopausal, sedentary, normal weight-to-obese women aged 50–74 years who were cancer-free, nondiabetic and nonhormone replacement therapy users were included in this study.Measurements:Anthropometric measurements of height, weight and waist and hip circumferences; dual energy X-ray absorptiometry measurements of total body fat; and computerized tomography measurements of abdominal adiposity were carried out.Results:Women in the exercise group exercised a mean of 3.6 days (s.d.=1.3) per week and 178.5u2009min (s.d.=76.1) per week. Changes in all measures of adiposity favored exercisers relative to controls (P<0.001). The mean difference between groups was: −1.8u2009kg for body weight; −2.0u2009kg for total body fat; −14.9u2009cm2 for intra-abdominal fat area; and −24.1u2009cm2 for subcutaneous abdominal fat area. A linear trend of greater body fat loss with increasing volume of exercise was also observed.Conclusion:A 1-year aerobic exercise program consistent with current public health guidelines resulted in reduced adiposity levels in previously sedentary postmenopausal women at higher risk of breast cancer.

Mammographic Density Change with 1 Year of Aerobic Exercise among Postmenopausal Women: A Randomized Controlled Trial

Background: The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial examined the influence of aerobic exercise on biological factors that are associated with breast cancer risk. Mammographic density, a secondary outcome, is reported here. Methods: The ALPHA Trial was a parallel group randomized controlled trial conducted between May 2003 and July 2007. Postmenopausal, sedentary women ages 50 to 74 years (n = 320) were evenly randomized to aerobic exercise (45 minutes, 5 days per week) or control (usual life-style) for 1 year. Dense fibroglandular tissue and nondense fatty tissue were measured from mammograms at baseline and 1 year using computer-assisted thresholding software for area measurements and a new technique that relies on the calibration of mammography units with a tissue-equivalent phantom for volumetric measurements. Results: Nondense volume decreased in the exercise group relative to the control group (difference between groups = −38.5 cm3; 95% confidence interval, −61.6 to 15.4; P = 0.001). Changes in total body fat accounted for this decrease. Changes in dense area and dense volume, measures that have previously been associated with breast cancer risk, were not significantly different between the groups (P ≥ 0.26). Conclusions: Achieving changes in mammographic measures may require more exercise or a study population with higher baseline levels of sex hormones or a wider range of mammographic density. The data from this study, however, suggest that the protective effect of exercise on breast cancer risk may operate through a mechanism other than mammographic density. Cancer Epidemiol Biomarkers Prev; 19(4); 1112–21. ©2010 AACR.

Volumetric breast density characteristics as determined from digital mammograms.

In this paper we present the results of an automated and entirely reproducible algorithm that estimates the breast volume, dense tissue volume and the volumetric breast density from digital mammograms. The algorithm was applied to 55, 087 digital images (CC view only) from 15u2009351 individual women, acquired between 2008 and 2011 at the Sunnybrook Health Sciences Centre in Toronto, Canada. The algorithm is based on a prior calibration of the digital image signal versus tissue thickness and composition, and the thickness of the compressed breast is estimated using an empirical model that corrects the thickness readout of the mammography system as a function of compression force. The mean volumetric density and breast volumes for our study group were 30% and 687 cm(3), respectively. The left and right volumetric density and breast volume were strongly correlated, with a Pearson correlation of 0.92 and 0.91, respectively. The volumetric density decreased from 45% to 25% as age increased from 35 to 75 years, with an increase to 30% at 80 years. For a given woman, the volumetric density decreased at an average rate of -2 density percentage points per year while the breast volume increased by 2% per year.

Mammographic density, parity and age at first birth, and risk of breast cancer: An analysis of four case-control studies

Mammographic density is strongly and consistently associated with breast cancer risk. To determine if this association was modified by reproductive factors (parity and age at first birth), data were combined from four case–control studies conducted in the United States and Japan. To overcome the issue of variation in mammographic density assessment among the studies, a single observer re-read all the mammograms using one type of interactive thresholding software. Logistic regression was used to estimate odds ratios (OR) while adjusting for other known breast cancer risk factors. Included were 1,699 breast cancer cases and 2,422 controls, 74% of whom were postmenopausal. A positive association between mammographic density and breast cancer risk was evident in every group defined by parity and age at first birth (OR per doubling of percent mammographic density ranged between 1.20 and 1.39). Nonetheless, the association appeared to be stronger among nulliparous than parous women (OR per doubling of percent mammographic densityxa0=xa01.39 vs. 1.24; P interactionxa0=xa00.054). However, when examined by study location, the effect modification by parity was apparent only in women from Hawaii and when examined by menopausal status, it was apparent in postmenopausal, but not premenopausal, women. Effect modification by parity was not significant in subgroups defined by body mass index or ethnicity. Adjusting for mammographic density did not attenuate the OR for the association between parity and breast cancer risk by more than 16.4%, suggesting that mammographic density explains only a small proportion of the reduction in breast cancer risk associated with parity. In conclusion, this study did not support the hypothesis that parity modifies the breast cancer risk attributed to mammographic density. Even though an effect modification was found in Hawaiian women, no such thing was found in women from the other three locations.

Comparative performance of modern digital mammography systems in a large breast screening program.

PURPOSEnTo compare physical measures pertaining to image quality among digital mammography systems utilized in a large breast screening program. To examine qualitatively differences in these measures and differences in clinical cancer detection rates between CR and DR among sites within that program.nnnMETHODSnAs part of the routine quality assurance program for screening, field measurements are made of several variables considered to correlate with the diagnostic quality of medical images including: modulation transfer function, noise equivalent quanta, d (an index of lesion detectability) and air kerma to allow estimation of mean glandular dose. In addition, images of the mammography accreditation phantom are evaluated.nnnRESULTSnIt was found that overall there were marked differences between the performance measures of DR and CR mammography systems. In particular, the modulation transfer functions obtained with the DR systems were found to be higher, even for larger detector element sizes. Similarly, the noise equivalent quanta, d, and the phantom scores were higher, while the failure rates associated with low signal-to-noise ratio and high dose were lower with DR. These results were consistent with previous findings in the authors program that the breast cancer detection rates at sites employing CR technology were, on average, 30.6% lower than those that used DR mammography.nnnCONCLUSIONSnWhile the clinical study was not large enough to allow a statistically powered system-by-system assessment of cancer detection accuracy, the physical measures expressing spatial resolution, and signal-to-noise ratio are consistent with the published finding that sites employing CR systems had lower cancer detection rates than those using DR systems for screening mammography.

Effects of partner proteins on BCA2 RING ligase activity

BackgroundBCA2 is an E3 ligase linked with hormone responsive breast cancers. We have demonstrated previously that the RING E3 ligase BCA2 has autoubiquitination activity and is a very unstable protein. Previously, only Rab7, tetherin, ubiquitin and UBC9 were known to directly interact with BCA2.MethodsHere, additional BCA2 binding proteins were found using yeast two-hybrid and bacterial-II-hybrid screening techniques with Human breast and HeLa cDNA libraries. Co-expression of these proteins was analyzed through IHC of TMAs. Investigation of the molecular interactions and effects were examined through a series of in vivo and in vitro assays.ResultsTen unique BCA2 interacting proteins were identified, two of which were hHR23a and 14-3-3sigma. Both hHR23a and 14-3-3sigma are co-expressed with BCA2 in breast cancer cell lines and patient breast tumors (n = 105). hHR23a and BCA2 expression was significantly correlated (P = < 0.0001 and P = 0.0113) in both nucleus and cytoplasm. BCA2 expression showed a statistically significant correlation with tumor grade. High cytoplasmic hHR23a trended towards negative nodal status. Binding to BCA2 by hHR23a and 14-3-3sigma was confirmed in vitro using tagged partner proteins and BCA2. hHR23a and 14-3-3sigma effect the autoubiquitination and auto-degradation activity of BCA2. Ubiquitination of hHR23a-bound BCA2 was found to be dramatically lower than that of free BCA2, suggesting that hHR23a promotes the stabilization of BCA2 by inactivating its autoubiquitination activity, without degradation of hHR23a. On the other hand, phosphorylated BCA2 protein is stabilized by interaction with 14-3-3sigma both with and without proteasome inhibitor MG-132 suggesting that BCA2 is regulated by multiple degradation pathways.ConclusionsThe interaction between BCA2 and hHR23a in breast cancer cells stabilizes BCA2. High expression of BCA2 is correlated with grade in breast cancer, suggesting regulation of this E3 ligase is important to cancer progression.

Associations between mammographic density and serum and dietary cholesterol

Although high mammographic density is a risk factor for postmenopausal breast cancer, its etiology remains unclear. We examined whether serum and dietary cholesterol, which increase breast cancer risk and are involved in endogenous estrogen formation, were associated with increased mammographic density. We conducted a cross-sectional analysis of 302 healthy, sedentary postmenopausal women, aged 50–74xa0years, enrolled in the Alberta Physical Activity and Breast Cancer Prevention Trial between 2003 and 2006. In multiple linear regression models, no significant associations were observed between serum lipids and percent density or dense tissue area (Percent density: b (change in square root percent density per unit change in cholesterol level)xa0=xa0−0.06 (95%CIxa0=xa0−0.26 to 0.13); bxa0=xa00.06 (95%CIxa0=xa0−0.48 to 0.61); and bxa0=xa0−0.11 (95%CIxa0=xa0−0.33 to 0.10) for total cholesterol, high-, and low-density lipoprotein, respectively; similar results found for dense area). Alcohol consumption modified the association between triglycerides and percent density (>1 drink/day: bxa0=xa0−0.94 (95%CIxa0=xa0−1.79 to −0.10); ≤1 drink/day: bxa0=xa00.19 (95%CIxa0=xa0−0.12 to 0.50); and no alcohol consumption: bxa0=xa00.15 (95%CIxa0=xa0−0.44 to 0.73). We found no evidence indicating any association between dietary and serum cholesterol levels and mammographic density.

Associations of overall and abdominal adiposity with area and volumetric mammographic measures among postmenopausal women

Whereas mammographic density and adiposity are positively associated with postmenopausal breast cancer risk, they are inversely associated with one another. To examine the association between these two risk factors, a secondary analysis of data from a randomized controlled trial of a year‐long aerobic exercise intervention was done. Participants were 302 postmenopausal women aged 50–74 years. Dense fibroglandular and nondense fatty tissue were measured from mammograms using computer‐assisted thresholding software for area measurements and a technique relying on the calibration of mammography machines with a tissue‐equivalent phantom for volumetric measurements. Adiposity was measured by anthropometry (body mass index, waist circumference), whole‐body dual x‐ray absorptiometry scans (body fat) and computed tomography scans (abdominal adiposity). Correlations were estimated between and within women, the latter representing the association between the 1‐year change in adiposity and mammographic measures. Adiposity was correlated with nondense area and volume (0.50 ≤ r ≤ 0.66 between women; 0.18 ≤ r ≤ 0.46 within women). Between women, adiposity was correlated with dense area and volume (−0.12 ≤ r ≤ −0.30) and with percent dense area and volume (−0.28 ≤ r ≤ −0.48). Because measurements made with scans explained at most only 3% more of the variation in absolute or percent density beyond that explained by anthropometric measurements, anthropometric measurements are likely sufficient for adjustment of the association between mammographic density and breast cancer risk. Adiposity is associated with breast fatty tissue and possibly weakly inversely associated with fibroglandular tissue.

Anatomical noise in contrast‐enhanced digital mammography. Part I. Single‐energy imaging

PURPOSEnThe use of an intravenously injected iodinated contrast agent could help increase the sensitivity of digital mammography by adding information on tumor angiogenesis. Two approaches have been made for clinical implementation of contrast-enhanced digital mammography (CEDM), namely, single-energy (SE) and dual-energy (DE) imaging. In each technique, pairs of mammograms are acquired, which are then subtracted with the intent to cancel the appearance of healthy breast tissue to permit sensitive detection and specific characterization of lesions. Patterns of contrast agent uptake in the healthy parenchyma, and uncanceled signal from background tissue create a clutter that can mask or mimic an enhancing lesion. This type of anatomical noise is often the limiting factor in lesion detection tasks, and thus, noise quantification may be useful for cascaded systems analysis of CEDM and for phantom development. In this work, the authors characterize the anatomical noise in CEDM clinical images and the authors evaluate the influence of the x-ray energy used for acquisition, the presence of iodine in the breast, and the timing of imaging postcontrast administration on anatomical noise. The results are presented in a two-part report, with SE CEDM described here, and DE CEDM in Part II.nnnMETHODSnA power law is used to model anatomical noise in CEDM images. The exponent, β, which describes the anatomical structure, and the constant α, which represents the magnitude of the noise, are determined from Wiener spectra (WS) measurements on images. A total of 42 SE CEDM cases from two previous clinical pilot studies are assessed. The parameters α and β are measured both from unprocessed images and from subtracted images.nnnRESULTSnConsistent results were found between the two SE CEDM pilot studies, where a significant decrease in β from a value of approximately 3.1 in the unprocessed images to between about 1.1 and 1.8 in the subtracted images was observed. Increasing the x-ray energy from that used in conventional DM to those of typical SE CEDM spectra with mean energies above 33 keV significantly decreased α by about a factor of 19, in agreement with theory. Compared to precontrast images, in the unprocessed postcontrast images at 30 s postinjection, α was larger by about 7.4 × 10(-7) mm(2) and β was decreased by 0.2. While α did not vary significantly with the time after contrast administration, β from the unprocessed image WS increased linearly, and β from subtracted image WS increased with an initial quadratic relationship that plateaued by about 5 min postinjection.nnnCONCLUSIONSnThe presence of an iodinated contrast agent in the breast produced small, but significant changes in the power law parameters of unprocessed CEDM images compared to the precontrast images. Image subtraction in SE CEDM significantly reduced anatomical noise compared to conventional DM, with a reduction in both α and β by about a factor of 2. The data presented here, and in Part II of this work, will be useful for modeling of CEDM backgrounds, for systems characterization and for lesion detectability experiments using models that account for anatomical noise.

Association between sex hormones, glucose homeostasis, adipokines, and inflammatory markers and mammographic density among postmenopausal women

The biological mechanisms underlying the relationship between mammographic density and breast cancer risk are unknown. Our objective was to examine the association between mammographic density and circulating factors that are putative breast cancer intermediate endpoints. Biologic data from a year-long aerobic exercise intervention trial conducted in 302 postmenopausal women aged 50–74xa0years were analyzed. Sex hormones, markers of glucose homeostasis, inflammatory markers, and adipokines were assayed in fasting blood drawn at baseline and after 1xa0year. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Multiple linear regression was used to examine the association between the circulating factors and mammographic measures and partial correlations were estimated. Mammographic nondense volume was positively correlated with concentrations of estradiol (rxa0=xa00.28), estrone (rxa0=xa00.13), insulin (rxa0=xa00.41), glucose (rxa0=xa00.15), leptin (rxa0=xa00.49), and C-reactive protein (rxa0=xa00.22), and negatively correlated with sex hormone binding globulin (rxa0=xa0−0.30) and adiponectin (rxa0=xa0−0.12) but correlations became null after adjustment for overall body adiposity as represented by body mass index and waist circumference. With adjustment for overall adiposity, mammographic dense volume, a measure that represents fibroglandular tissue, was negatively correlated with leptin (rxa0=xa0−0.19) and C-reactive protein (rxa0=xa0−0.19). As expected, circulating factors originating from or correlated with adipose tissue were also correlated with mammographic measures of breast adipose tissue, but not after adjustment for overall body adiposity. Interpreting correlations between adiposity-derived factors and mammographic measures whose validity may be affected by adiposity is problematic. To rectify this problem, future studies with very good measures of the volume of fibroglandular tissue in the breast will be necessary.