Sak, Mark

Purpose: Women whose mammographic breast density declines within 12–18 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 30–70 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): −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 4–6 months after tamoxifen initiation (mean (SD): −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.

Abstract Background: Tamoxifen therapy has been shown to have greater therapeutic benefit among women whose breast density declines subsequent to treatment than among women whose density does not decline. Although limited data suggests that endocrine symptoms after tamoxifen initiation may be associated with improved breast cancer outcomes, it is unknown whether these symptoms are associated with reductions in breast density. We therefore evaluated endocrine symptoms and change in breast density in a 12-month longitudinal study of women undergoing tamoxifen therapy for clinical indications. Methods: Cohort members (N=74) were aged 30-74 years in the Ultrasound Study of Tamoxifen at Karmanos Cancer Institute and Henry Ford Health Systems (Detroit, MI). Endocrine symptoms and breast density were both assessed prior to tamoxifen initiation (T0) and at 1-3 months (T1), 4-6 months (T2), and approximately 12 months (T3) post-tamoxifen initiation. Treatment-associated endocrine symptoms included treatment-emergent or increasing vasomotor and/or joint symptoms. Endocrine symptom severity was also assessed with a Likert scale for symptom frequency and categorized as no symptoms (score=0), low/moderate symptoms (score=1-5), and high symptoms (score=6+). Sound speed (m/s), a surrogate of volumetric breast density, was measured with whole breast ultrasound tomography. Change in breast density was calculated as density at T1-T3 minus density at T0. We used multivariable linear regression to estimate mean change in density by endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline sound speed. Generalized estimating equations were used to account for within-subject correlations over time. Results: Women with treatment-associated endocrine symptoms had an overall greater mean reduction in breast density compared with women without symptoms (mean change [95% CI]: -1.97 m/s [-3.80, -0.13]; -0.27 m/s [- 3.50, 2.95], respectively; p=0.22). Longitudinal trends in breast density significantly differed for women with versus without treatment-associated endocrine symptoms (p-interaction=0.02). Significant declines in breast density over time were observed among women with treatment-associated endocrine symptoms (p-trend=0.005), but not among women without symptoms (p-trend=0.16). Similar trends in breast density decline were observed among women with higher symptom severity (p-trends for no symptoms=0.53; low/moderate symptoms=0.04; high symptoms=0.008). Conclusions: These findings suggest that treatment-associated endocrine symptoms may be associated with a significant decline in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations can predict clinical outcome, and if confirmed, both treatment-associated endocrine symptoms and observed reductions in breast density may be useful for patients and providers to improve adherence. Citation Format: Cody Ramin, Ruth Pfeiffer, Shaoqi Fan, Maeve Mullooly, Roni T. Falk, Mark A. Sak, Michael S. Simon, David H. Gorski, Haythem Ali, Peter Littrup, Nebojsa Duric, Mark E. Sherman, Gretchen L. Gierach. Treatment-associated endocrine symptoms and change in ultrasound tomography measures of breast density after tamoxifen therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5805.

Abstract PURPOSE. Increased mammographic percent density (MPD) is a strong independent risk factor for developing breast cancer. Previous studies have shown that tissue sound speed, derived from ultrasound tomography, is a surrogate biomarker of MPD. We examined associations of sound speed and MPD with breast cancer risk in a case-control study. METHOD AND MATERIALS. We evaluated breast cancer risk associated with sound speed and MPD in a case-control study involving 59 participants with recent breast cancer diagnoses (cases, aged 30-70 years) and 150 participants with no history of breast cancer (controls), who were matched to cases on age, race, and menopausal status. The cases and controls were imaged with both ultrasound tomography (UST) and mammography. In cases, breast density was measured pre-treatment in the contralateral breast to avoid potential influences of tumor-related changes on MPD or sound speed. In controls, a randomly selected breast was imaged. The ultrasound tomography images were used to estimate the volume averaged sound speed of the breast, and the Cumulus software package was applied to mammograms to determine MPD. Odds Ratios (ORs) and 95% Confidence Intervals (CIs), adjusted for matching factors, were calculated for the relation of quartiles of MPD and sound speed with breast cancer risk. OR differences were tested using a bootstrap approach. RESULTS. MPD was associated with elevated breast cancer risk compared to controls, consistent with previous studies, although the trend did not reach statistical significance (OR per quartile=1.28, 95%CI: 0.95, 1.73; ptrend=0.10). In contrast, elevated sound speed was significantly associated with increased breast cancer risk in a dose-response fashion (OR per quartile=1.79, 95%CI: 1.30, 2.48; ptrend=0.0004). The OR-trend for sound speed was statistically significantly different from that observed for MPD (p=0.01). DISCUSSION. Our case-control study showed that increasing quartiles of whole breast sound speed were consistently and more strongly associated with increasing breast cancer risk than quartiles of MPD. These results show promise for UST’s role in breast cancer risk stratification. CONCLUSION. Elevated breast density strongly increases breast cancer risk. UST has the potential to provide a more accurate, non-ionizing method for assessing breast density and its associated breast cancer risk. Citation Format: Mark Sak, Neb Duric, Ruth Pfeiffer, Mark Sherman, Peter Littrup, Michael Simon, David Gorski, Teri Albrecht, Haythem Ali, Rachel Brem, Rachel Brem, Sharon Fan, Gretchen Gierach. Tissue sound speed is more strongly associated with breast cancer risk than mammographic percent density: A comparative case-control study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-28.

Abstract PURPOSE. Studies have shown that a decrease in mammographic density (MD) or lowering of background parenchymal enhancement (BPE) on MRI after initiation of tamoxifen therapy predicts a favorable response in the preventive or adjuvant settings. However, performing serial mammograms poses radiation concerns, while serial MRIs carry high cost as well as risk of multiple Gadolinium doses. Previous studies have shown that tissue sound speed, derived from whole breast ultrasound tomography measurements, is a surrogate biomarker of MD. Ultrasound is ideal for performing serial measurements because it is fast and poses almost no risks. The purpose of this study was to evaluate repeated measures of the sound speed biomarker at 3, 6 and 12-months following tamoxifen initiation. METHOD AND MATERIALS. We performed a case-control comparison involving 74 participants referred by a health professional to undergo tamoxifen therapy (cases) and 150 matched participants with no history of breast cancer (controls). The cases were scanned with ultrasound tomography at baseline (i.e. before start of tamoxifen therapy), and then at 3, 6 and 12 months after tamoxifen initiation. Controls were scanned at baseline and 12 months. In the case group, sound speed was measured pre-treatment in the contralateral breast to avoid potential influences of tumor-related changes on density. In the control group, a single randomized breast was scanned. A pairwise t-test was used to assess differences in sound speed over time and between cases and controls. RESULTS. There was a steady decline in sound speed over the 12-month period for women undergoing tamoxifen therapy (mean(SD): -3.0(8.2) m/s; P=0.001). Furthermore, significant sound speed reductions were observed as early as 4-6 months after tamoxifen initiation (mean(SD): -2.1(6.8) m/s; P=0.008). In contrast, the controls demonstrated no significant change in sound speed over a 12-month period, and the difference between case-control groups was statistically significant (P=0.0009). DISCUSSION. Breast sound speed decreases rapidly after tamoxifen initiation while it remains steady for the control group. These results suggest that sound speed may be a biomarker of response to tamoxifen. Further studies are needed to assess whether this observation can predict clinical response. CONCLUSION. Ultrasound tomography may have utility in monitoring breast sound speed change as a potential biomarker of clinical tamoxifen response. Citation Format: Neb Duric, Mark Sak, Mark Sherman, Ruth Pfeiffer, Sharon Fan, Michael Simon, David Gorski, Teri Albrecht, Haythem Ali, Peter Littrup, Rachel Brem, Gretchen Gierach. Tissue sound speed: A novel imaging biomarker for measuring tamoxifen response [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-11.

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; ptrend = 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; ptrend = 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.