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A letter to the editor is presented in response to an article about mammographic density and the risk of breast cancer, by Colin and Schott.

Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Photoacoustic tomography (PAT) is a non-invasive, high-resolution imaging modality, capable of providing functional and molecular information of various pathologies, such as cancer. One limitation of PAT is the depth and wavelength dependent optical fluence, which results in reduced PA signal amplitude from deeper tissue regions. These factors can therefore introduce errors into quantitative measurements such as oxygen saturation (sO 2 ) or the localization and concentration of various chromophores. The variation in the speed-of-sound between different tissues can also lead to distortions in object location and shape. Compensating for these effects allows PAT to be used more quantitatively. We have developed a proof-of-concept algorithm capable of compensating for the heterogeneity in speed-of-sound and depth dependent optical fluence. Speed-of-sound correction was done by using a straight ray-based algorithm for calculating the family of iso-time-of-flight contours between the transducers and every pixel in the imaging grid, while fluence compensation was done by utilizing the graphics processing unit (GPU) accelerated software MCXCL for Monte Carlo modeling of optical fluence variation. This algorithm was tested on a polyvinyl chloride plastisol (PVCP) phantom, which contained cyst mimics and blood inclusions to test the algorithm under relatively heterogeneous conditions. Our results indicate that our PAT algorithm can compensate for the speed-of-sound variation and depth dependent fluence effects within a heterogeneous phantom. The results of this study will pave the way for further development and evaluation of the proposed method in more complex in-vitro and ex-vivo phantoms, as well as compensating for the wavelength-dependent optical fluence in spectroscopic PAT., Competing Interests: The authors declare that there are no conflicts of interest., (© 2021 Published by Elsevier GmbH.)

Objective: To evaluate the combination of tumor volume and sound speed as a potential imaging marker for assessing neoadjuvant chemotherapy (NAC) response., Methods: This study was carried out under an IRB-approved protocol (written consent required). Fourteen patients undergoing NAC for invasive breast cancer were examined with ultrasound tomography (UST) throughout their treatment. The volume (V) and the volume-averaged sound speed (VASS) of the tumors and their changes were measured for each patient. Time-dependent response curves of V and VASS were constructed individually for each patient and then as averages for the complete versus partial response groups in order to characterize differences between the two groups. Differences in group means were assessed for statistical significance using t -tests. Differences in shapes of group curves were evaluated with Kolmogorov-Smirnoff tests., Results: On average, tumor volume and sound speed in the partial response group showed a gradual decline in the first 60 days of treatment, while the complete response group showed a much steeper decline ( P < 0.05). The shapes of the response curves of the two groups, corresponding to the entire treatment period, were also found to be significantly different ( P < 0.05). Furthermore, large simultaneous drops in volume and sound speed in the first 3 weeks of treatment were characteristic only of the complete responders ( P < 0.05)., Conclusion: This study demonstrates the feasibility of using UST to monitor NAC response, warranting future studies to better define the potential of UST for noninvasive, rapid identification of partial versus complete responders in women undergoing NAC., (© Society of Breast Imaging 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess the feasibility of using tissue sound speed as a quantitative marker of breast density., Methods: This study was carried out under an Institutional Review Board-approved protocol (written consent required). Imaging data were selected retrospectively based on the availability of US tomography (UST) exams, screening mammograms with volumetric breast density data, patient age of 18 to 80 years, and weight less than 300 lbs. Sound speed images from the UST exams were used to measure the volume of dense tissue, the volume averaged sound speed (VASS), and the percent of high sound speed tissue (PHSST). The mammographic breast density and volume of dense tissue were estimated with three-dimensional (3D) software. Differences in volumes were assessed with paired t-tests. Spearman correlation coefficients were calculated to determine the strength of the correlations between the mammographic and UST assessments of breast density., Results: A total of 100 UST and 3D mammographic data sets met the selection criteria. The resulting measurements showed that UST measured a more than 2-fold larger volume of dense tissue compared to mammography. The differences were statistically significant ( P < 0.001). A strong correlation of r S = 0.85 (95% CI: 0.79-0.90) between 3D mammographic breast density (BD) and the VASS was noted. This correlation is significantly stronger than those reported in previous two-dimensional studies (r S = 0.85 vs r S = 0.71). A similar correlation was found for PHSST and mammographic BD with r S = 0.86 (95% CI: 0.80-0.90)., Conclusion: The strong correlations between UST parameters and 3D mammographic BD suggest that breast sound speed should be further studied as a potential new marker for inclusion in clinical risk models., (© Society of Breast Imaging 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mammographic percent density (MPD) is an independent risk factor for developing breast cancer, but its inclusion in clinical risk models provides only modest improvements in individualized risk prediction, and MPD is not typically assessed in younger women because of ionizing radiation concerns. Previous studies have shown that tissue sound speed, derived from whole breast ultrasound tomography (UST), a non-ionizing modality, is a potential surrogate marker of breast density, but prior to this study, sound speed has not been directly linked to breast cancer risk. To that end, we explored the relation of sound speed and MPD with breast cancer risk in a case-control study, including 61 cases with recent breast cancer diagnoses and a comparison group of 165 women, frequency matched to cases on age, race, and menopausal status, and with a recent negative mammogram and no personal history of breast cancer. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the relation of quartiles of MPD and sound speed with breast cancer risk adjusted for matching factors. Elevated MPD was associated with increased breast cancer risk, although the trend did not reach statistical significance (OR per quartile = 1.27, 95% CI: 0.95, 1.70; p trend = 0.10). In contrast, elevated sound speed was significantly associated with breast cancer risk in a dose-response fashion (OR per quartile = 1.83, 95% CI: 1.32, 2.54; p trend = 0.0003). The OR trend for sound speed was statistically significantly different from that observed for MPD ( p = 0.005). These findings suggest that whole breast sound speed may be more strongly associated with breast cancer risk than MPD and offer future opportunities for refining the magnitude and precision of risk associations in larger, population-based studies, including women younger than usual screening ages., Competing Interests: Neb Duric and Peter Littrup have financial interests in Delphinus Medical Technologies, whose ultrasound tomography scanner was used in this study.

Objectives: Ultrasound tomography (UST) is an emerging whole-breast 3-dimensional imaging technique that obtains quantitative tomograms of speed of sound of the entire breast. The imaged parameter is the speed of sound which is used as a surrogate measure of density at each voxel and holds promise as a method to evaluate breast density without ionizing radiation. This study evaluated the technique of UST and compared whole-breast volume averaged speed of sound (VASS) with MR percent water content from noncontrast magnetic resonance imaging (MRI)., Materials and Methods: Forty-three healthy female volunteers (median age, 40 years; range, 29-59 years) underwent bilateral breast UST and MRI using a 2-point Dixon technique. Reproducibility of VASS was evaluated using Bland-Altman analysis. Volume averaged speed of sound and MR percent water were evaluated and compared using Pearson correlation coefficient., Results: The mean ± standard deviation VASS measurement was 1463 ± 29 m s (range, 1434-1542 m s). There was high similarity between right (1464 ± 30 m s) and left (1462 ± 28 m s) breasts (P = 0.113) (intraclass correlation coefficient, 0.98). Mean MR percent water content was 35.7% ± 14.7% (range, 13.2%-75.3%), with small but significant differences between right and left breasts (36.3% ± 14.9% and 35.1% ± 14.7%, respectively; P = 0.004). There was a very strong correlation between VASS and MR percent water density (r = 0.96, P < 0.0001)., Conclusions: Ultrasound tomography holds promise as a reliable and reproducible 3-dimensional technique to provide a surrogate measure of breast density and correlates strongly with MR percent water content.

Ultrasound tomography (UST) is an emerging modality that can offer quantitative measurements of breast density. Recent breakthroughs in UST image reconstruction involve the use of a waveform reconstruction as opposed to a ray-based reconstruction. The sound speed (SS) images that are created using the waveform reconstruction have a much higher image quality. These waveform images offer improved resolution and contrasts between regions of dense and fatty tissues. As part of a study that was designed to assess breast density changes using UST sound speed imaging among women undergoing tamoxifen therapy, UST waveform sound speed images were then reconstructed for a subset of participants. These initial results show that changes to the parenchymal tissue can more clearly be visualized when using the waveform sound speed images. Additional quantitative testing of the waveform images was also started to test the hypothesis that waveform sound speed images are a more robust measure of breast density than ray-based reconstructions. Further analysis is still needed to better understand how tamoxifen affects breast tissue.

A population of 165 women with negative mammographic screens also received an ultrasound tomography (UST) examination at the Karmanos Cancer Institute in Detroit, MI. Standard statistical techniques were employed to measure the associations between the various mammographic- and UST-related density measures and various participant characteristics such as age, weight and height. The mammographic percent density (MPD) was found to have similar strength associations with UST mean sound speed (Spearman coefficient, r s  = 0.722, p < 0.001) and UST median sound speed (r s  = 0.737, p < 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (r s  = 0.568, p < 0.001) or a threshold (r s  = 0.715, p < 0.001) measure. Segmentation of the UST sound speed images into dense and non-dense volumes showed weak to moderate associations with the mammographically equivalent measures. Relationships were found to be inversely and weakly associated between age and the UST mean sound speed (r s  = -0.239, p = 0.002), UST median sound speed (r s  = -0.226, p = 0.004) and MPD (r s  = -0.204, p = 0.008). Relationships were found to be inversely and moderately associated between body mass index (BMI) and the UST mean sound speed (r s  = -0.429, p < 0.001), UST median sound speed (r s  = -0.447, p < 0.001) and MPD (r s  = -0.489, p < 0.001). The results confirm and strengthen findings presented in previous work indicating that UST sound speed imaging yields viable markers of breast density in a manner consistent with mammography, the current clinical standard. These results lay the groundwork for further studies to assess the role of sound speed imaging in risk prediction., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. All rights reserved.)

Women with high breast density are at increased risk of developing breast cancer. Breast density has usually been defined using mammography as the ratio of fibroglandular tissue to total breast area. Ultrasound tomography (UST) is an emerging modality that can also be used to measure breast density. UST creates tomographic sound speed images of the patient's breast which is useful as sound speed is directly proportional to tissue density. Furthermore, the volumetric and quantitative information contained in the sound speed images can be used to describe the distribution of breast density. The work presented here measures the UST sound speed density distributions of 165 women with negative screening mammography. Frequency distributions of the sound speed voxel information were examined for each patient. In a preliminary analysis, the UST sound speed distributions were averaged across patients and grouped by various patient and density-related factors (e.g., age, body mass index, menopausal status, average mammographic breast density). It was found that differences in the distribution of density could be easily visualized for different patient groupings. Furthermore, findings suggest that the shape of the distributions may be used to identify participants with varying amounts of dense and non-dense tissue.

Breast density is one of the strongest predictors of breast cancer risk. Women with the densest breasts are 4 to 6 times more likely to develop cancer compared with those with the lowest densities. Breast density is generally assessed using mammographic imaging; however, this approach has limitations. Magnetic resonance imaging and ultrasound tomography are some alternative imaging modalities that can aid mammography in patient screening and the measurement of breast density. As breast density becomes more commonly discussed, knowledge of the advantages and limitations of breast density as a marker of risk will become more critical. This review article discusses the relationship between breast density and breast cancer risk, lists the benefits and drawbacks of using multiple different imaging modalities to measure density and briefly discusses how breast density will be applied to aid in breast cancer prevention and treatment.

Ultrasound tomography (UST) employs sound waves to produce three-dimensional images of breast tissue and precisely measures the sound speed of breast tissue composition. High breast density is a strong breast cancer risk factor and sound speed is directly proportional to breast density. UST provides a quantitative measure of breast density based on three-dimensional imaging without compression, thereby overcoming the shortcomings of many other imaging modalities. The quantitative nature of the UST breast density measures are tied to an external standard, so sound speed measurement in breast tissue should be independent of specific hardware. The work presented here compares breast sound speed measurement obtained with two different UST devices. The Computerized Ultrasound Risk Evaluation (CURE) system located at the Karmanos Cancer Institute in Detroit, Michigan was recently replaced with the SoftVue ultrasound tomographic device. Ongoing clinical trials have used images generated from both sets of hardware, so maintaining consistency in sound speed measurements is important. During an overlap period when both systems were in the same exam room, a total of 12 patients had one or both of their breasts imaged on both systems on the same day. There were 22 sound speed scans analyzed from each system and the average breast sound speeds were compared. Images were either reconstructed using saved raw data (for both CURE and SoftVue) or were created during the image acquisition (saved in DICOM format for SoftVue scans only). The sound speed measurements from each system were strongly and positively correlated with each other. The average difference in sound speed between the two sets of data was on the order of 1-2 m/s and this result was not statistically significant. The only sets of images that showed a statistical difference were the DICOM images created during the SoftVue scan compared to the SoftVue images reconstructed from the raw data. However, the discrepancy between the sound speed values could be easily handled by uniformly increasing the DICOM sound speed by approximately 0.5 m/s. These results suggest that there is no fundamental difference in sound speed measurement for the two systems and support combining data generated with these instruments in future studies.

Little is known about women's knowledge of breast density or between-race differences in this knowledge. In the current study, we examined knowledge of breast density and awareness of its role as a breast cancer risk factor among women who had previously taken part in a breast imaging study. Seventy-seven women (54.5 % Black) returned a survey assessing perceptions and accuracy of breast density knowledge, knowledge of one's own breast density, and breast cancer risk awareness. White women had greater perceived knowledge of breast density compared to Black women; however, differences in the accuracy of definitions of breast density were due to education. Black women were less likely to know how dense their own breasts were. Black and White women both lacked awareness that having dense breast increased breast cancer risk. The results highlight the need to disseminate information regarding breast density to women, while ensuring that the information is equally accessible to both Black and White women.

Women with high breast density have an increased risk of developing breast cancer. Women treated with the selective estrogen receptor modulator tamoxifen for estrogen receptor positive breast cancer experience a 50% reduction in risk of contralateral breast cancer and overall reduction of similar magnitude has been identified among high-risk women receiving the drug for prevention. Tamoxifen has been shown to reduce mammographic density, and in the IBIS-1 chemoprevention trial, risk reduction and decline in density were significantly associated. Ultrasound tomography (UST) is an imaging modality that can create tomographic sound speed images of the breast. These sound speed images are useful because breast density is proportional to sound speed. The aim of this work is to examine the relationship between UST-measured breast density and the use of tamoxifen. So far, preliminary results for a small number of patients have been observed and are promising. Correlations between the UST-measured density and mammographic density are strong and positive, while relationships between UST density with some patient specific risk factors behave as expected. Initial results of UST examinations of tamoxifen treated patients show that approximately 45% of the patients have a decrease in density in the contralateral breast after only several months of treatment. The true effect of tamoxifen on UST-measured density cannot yet be fully determined until more data are collected. However, these promising results suggest that UST can be used to reliably assess quantitative changes in breast density over short intervals and therefore suggest that UST may enable rapid assessment of density changes associated with therapeutic and preventative interventions.

For women with dense breast tissue, who are at much higher risk for developing breast cancer, the performance of mammography is at its worst. Consequently, many early cancers go undetected when they are the most treatable. Improved cancer detection for women with dense breasts would decrease the proportion of breast cancers diagnosed at later stages, which would significantly lower the mortality rate. The emergence of whole breast ultrasound provides good performance for women with dense breast tissue, and may eliminate the current trade-off between the cost effectiveness of mammography and the imaging performance of more expensive systems such as magnetic resonance imaging. We report on the performance of SoftVue, a whole breast ultrasound imaging system, based on the principles of ultrasound tomography. SoftVue was developed by Delphinus Medical Technologies and builds on an early prototype developed at the Karmanos Cancer Institute. We present results from preliminary testing of the SoftVue system, performed both in the lab and in the clinic. These tests aimed to validate the expected improvements in image performance. Initial qualitative analyses showed major improvements in image quality, thereby validating the new imaging system design. Specifically, SoftVue's imaging performance was consistent across all breast density categories and had much better resolution and contrast. The implications of these results for clinical breast imaging are discussed and future work is described.

Purpose: To investigate the use of the whole-breast sound speed measurement as a marker of breast density (BD), a known risk factor for breast cancer., Methods: As part of an ongoing study of breast cancer detection, 249 patients were scanned with a clinical prototype that operates on the principles of ultrasound tomography. Typically, 40-100 sound speed tomograms were reconstructed from the scan data, corresponding to the entire volume of the breast of each patient. The data were used to estimate the volume averaged sound speed (VASS) of the breast for each patient. The corresponding mammograms were used to calculate mammographic percent density (MPD) using CUMULUS software. Film mammograms were available for 164 patients while 85 digital mammograms were available for the remaining patients. Standard statistical techniques were used to determine associations of breast sound speed with a variety of mammographic measures such as percent density, area of dense tissue, and area of nondense tissue. Furthermore, associations of breast sound speed with continuous variables such as age and weight and dichotomous variables such as parity and menopausal status were also assessed., Results: VASS was found to be significantly associated with MPD. The Spearman correlation coefficient (r(s)) between VASS and MPD was found to be 0.77 and 0.71 for film and digital mammography, respectively. VASS was positively correlated with dense areas by mammography, both digital (r(s) = 0.46) and film (r(s) = 0.56). VASS was negatively associated with nondense area by mammography, both digital (r(s) = -0.58) and film (r(s) = -0.63). BD by all methods was less in postmenopausal than in premenopausal women. The MPD was lower in the postmenopausal group (by 6.6%, p < 0.08, for the digital group and 7.73%, p < 0.007, for the film group). The VASS was also lower in the postmenopausal group (by 15 m∕s, p < 0.001 for the digital group and 8 m∕s, p < 0.08, for the film group). The association of MPD with age was characterized with r(s) = -0.06 (p < 0.6) for digital mammography and r(s) = -0.53 (p < 0.002) for film mammography. For weight, the MPD associations were characterized by r(s) = -0.53 (p < 0.0001) for digital mammography and -0.38 (p < 0.0001) for film mammography. The association of VASS with age was r(s) = -0.33 (p < 0.002) for the digital group and -0.17 (p < 0.03) for the film group. For weight, the relationship was characterized with r(s) = -0.45 (p < 0.001) for the digital group and -0.37 (p < 0.0001) for the film group., Conclusions: The association between VASS and MPD is strong for both film and digital mammography, suggesting that VASS is a viable measure of breast density. This result sets the stage for future work that will focus on directly testing the association of VASS with breast cancer risk.

Previous ultrasound tomography work conducted by our group showed a direct correlation between measured sound speed and physical density in vitro, and increased in vivo sound speed with increasing mammographic density, a known risk factor for breast cancer. Building on these empirical results, the purpose of this work was to explore a metric to quantify breast density using our ultrasound tomography sound speed images in a manner analogous to computer-assisted mammogram segmentation for breast density analysis. Therefore, volumetric ultrasound percent density (USPD) is determined by segmenting high sound speed areas from each tomogram using a k-means clustering routine, integrating these results over the entire volume of the breast, and dividing by whole-breast volume. First, a breast phantom comprised of fat inclusions embedded in fibroglandular tissue was scanned four times with both our ultrasound tomography clinical prototype (with 4 mm spatial resolution) and CT. The coronal transmission tomograms and CT images were analyzed using semiautomatic segmentation routines, and the integrated areas of the phantom's fat inclusions were compared between the four repeated scans. The average variability for inclusion segmentation was approximately 7% and approximately2%, respectively, and a close correlation was observed in the integrated areas between the two modalities. Next, a cohort of 93 patients was imaged, yielding volumetric coverage of the breast (45-75 sound speed tomograms/patient). The association of USPD with mammographic percent density (MPD) was evaluated using two measures: (1) qualitative, as determined by a radiologist's visual assessment using BI-RADS Criteria and (2) quantitative, via digitization and semiautomatic segmentation of craniocaudal and mediolateral oblique mammograms. A strong positive association between BI-RADS category and USPD was demonstrated [Spearman rho = 0.69 (p < 0.001)], with significant differences between all BI-RADS categories as assessed by one-way ANOVA and Scheffé posthoc analysis. Furthermore, comparing USPD to calculated mammographic density yielded moderate to strong positive associations for CC and MLO views (r2 = 0.75 and 0.59, respectively). These results support the hypothesis that utilizing USPD as an analogue to mammographic breast density is feasible, providing a nonionizing, whole-breast analysis.

Women with mammographic percent density >50% have a approximately three-fold increased risk of developing breast cancer, potentially making them screening candidates for breast MRI scanning. The purpose of this work is to introduce a new method to quantify mammographic percent density (MPD), and to compare the results with the current standard of care for breast density assessment. Craniocaudal (CC) and mediolateral oblique (MLO) mammograms for 104 patients were digitized and analyzed using an interactive computer-assisted segmentation routine implemented for two purposes: (1) to segment the breast area from background and radiographic markers, and (2) to segment dense from fatty portions of the breast. Our technique was evaluated by comparing the results to qualitative estimates determined by a certified breast radiologist using the BI-RADS Categorical Assessment (1 (fatty) to 4 (dense) scale). Statistically significant correlations (two-tailed, p < 0.01) were observed between calculated MPD and BI-RADS for both CC (Spearman rho = 0.67) and MLO views (Spearman rho = 0.71). For the CC view, statistically significant differences were revealed between the mean MPD for each BI-RADS category except between fatty (BI-RADS 1) and scattered (BI-RADS 2). Finally, for the MLO views, statistically significant differences in the mean MPD between all BI-RADS categories were observed. Comparing the CC and MLO views revealed a strong positive correlation (Pearson r = 0.8) in calculated MPD. In addition, an evaluation of the reproducibility of our segmentation demonstrated the average standard deviation of MPD for a subsample of eight patients, measured five times, was 1.9% (range: 0.03%-9.9%). Eliminating one misassignment reduced the average standard deviation to 0.75% (range: 0.03%-3.16%). Further analysis of approximately 10% of the patient sample revealed strong agreement (ICC = 0.80-0.85) in the reliability of MPD estimates for both mammographic views. Overall, these results demonstrate the feasibility of utilizing our approach for quantitative breast density segmentation, which may be useful for detecting small changes in MPD introduced through chemoprevention, diet, or other interventions.