Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy

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

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

A Novel Marker, Based on Ultrasound Tomography, for Monitoring Early Response to Neoadjuvant Chemotherapy.

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

Using Speed of Sound Imaging to Characterize Breast Density

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, rs = 0.722, p \u3c 0.001) and UST median sound speed (rs = 0.737, p \u3c 0.001). Both were stronger than the associations between MPD with two separate measures of UST percent density, a k-means (rs = 0.568, p \u3c 0.001) or a threshold (rs = 0.715, p \u3c 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 (rs = -0.239, p = 0.002), UST median sound speed (rs = -0.226, p = 0.004) and MPD (rs = -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 (rs = -0.429, p \u3c 0.001), UST median sound speed (rs = -0.447, p \u3c 0.001) and MPD (rs = -0.489, p \u3c 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

Rapid Reductions in Breast Density following Tamoxifen Therapy as Evaluated by Whole-Breast Ultrasound Tomography

Purpose: Women whose mammographic breast density declines within 12&ndash;18 months of initiating tamoxifen for chemoprevention or adjuvant treatment show improved therapeutic responses compared with those whose density is unchanged. We tested whether measuring changes in sound speed (a surrogate of breast density) using ultrasound tomography (UST) could enable rapid identification of favorable responses to tamoxifen. Methods: We evaluated serial density measures at baseline and at 1 to 3, 4 to 6, and 12+ months among 74 women (aged 30&ndash;70 years) following initiation of tamoxifen for clinical indications, including an elevated risk of breast cancer (20%) and diagnoses of in situ (39%) or invasive (40%) breast carcinoma, enrolled at Karmanos Cancer Institute and Henry Ford Health System (Detroit, MI, USA). For comparison, we evaluated an untreated group with screen negative mammography and frequency-matched on age, race, and menopausal status (n = 150), at baseline and 12 months. Paired t-tests were used to assess differences in UST sound speed over time and between tamoxifen-treated and untreated patients. Results: Sound speed declined steadily over the 12 month period among patients receiving tamoxifen (mean (SD): &minus;3.0 (8.2) m/s; p = 0.001), whereas density remained unchanged in the untreated group (mean (SD): 0.4 (7.1) m/s; p = 0.75 (relative change between groups: p = 0.0009)). In the tamoxifen group, we observed significant sound speed reductions as early as 4&ndash;6 months after tamoxifen initiation (mean (SD): &minus;2.1 (6.8) m/s; p = 0.008). Sound speed reductions were greatest among premenopausal patients (P-interaction = 0.0002) and those in the middle and upper tertiles of baseline sound speed (P-interaction = 0.002). Conclusions: UST can image rapid declines in sound speed following initiation of tamoxifen. Given that sound speed and mammographic density are correlated, we propose that UST breast imaging may capture early responses to tamoxifen, which in turn may have utility in predicting therapeutic efficacy

Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy

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. </p

Determinants of the reliability of ultrasound tomography sound speed estimates as a surrogate for volumetric breast density

PURPOSE: High breast density, as measured by mammography, is associated with increased breast cancer risk, but standard methods of assessment have limitations including 2D representation of breast tissue, distortion due to breast compression, and use of ionizing radiation. Ultrasound tomography (UST) is a novel imaging method that averts these limitations and uses sound speed measures rather than x-ray imaging to estimate breast density. The authors evaluated the reproducibility of measures of speed of sound and changes in this parameter using UST. METHODS: One experienced and five newly trained raters measured sound speed in serial UST scans for 22 women (two scans per person) to assess inter-rater reliability. Intrarater reliability was assessed for four raters. A random effects model was used to calculate the percent variation in sound speed and change in sound speed attributable to subject, scan, rater, and repeat reads. The authors estimated the intraclass correlation coefficients (ICCs) for these measures based on data from the authors\u27 experienced rater. RESULTS: Median (range) time between baseline and follow-up UST scans was five (1-13) months. Contributions of factors to sound speed variance were differences between subjects (86.0%), baseline versus follow-up scans (7.5%), inter-rater evaluations (1.1%), and intrarater reproducibility (∼0%). When evaluating change in sound speed between scans, 2.7% and ∼0% of variation were attributed to inter- and intrarater variation, respectively. For the experienced rater\u27s repeat reads, agreement for sound speed was excellent (ICC = 93.4%) and for change in sound speed substantial (ICC = 70.4%), indicating very good reproducibility of these measures. CONCLUSIONS: UST provided highly reproducible sound speed measurements, which reflect breast density, suggesting that UST has utility in sensitively assessing change in density