Abstract
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.
Highlights
Tamoxifen is a selective estrogen receptor modulator which reduces risk of estrogen receptor (ER)-positive breast cancer risk by 50% in the prevention setting for women at high breast cancer risk [1] and lowers mortality by 30%in the adjuvant setting irrespective of grade [2]
In order to assess whether any observed changes in ultrasound tomography (UST) density over time were greater than the minimal declines in breast density that might be observed with aging in the absence of tamoxifen exposure, we identified an untreated group from patients undergoing screening mammography at
Using novel nonionizing whole-breast UST to repeatedly assess VASS, a reliable and accurate surrogate of volumetric breast density, we found that VASS decreased steadily and rapidly within the first year of tamoxifen therapy, while remaining stable in an untreated matched comparison group
Summary
Tamoxifen is a selective estrogen receptor modulator which reduces risk of estrogen receptor (ER)-positive breast cancer risk by 50% in the prevention setting for women at high breast cancer risk (e.g., based on the Gail model) [1] and lowers mortality by 30%in the adjuvant setting irrespective of grade [2]. Elevated mammographic breast density is one of the strongest risk factors for breast cancer in the general population [3], and studies suggest that declines in density with tamoxifen use may represent a marker of efficacy in both prevention and treatment [4–7]. To assess breast density repeatedly over time while avoiding ionizing radiation, we used a novel ultrasound tomography (UST) scanner to measure volumetric breast density without compression in women before and during their first year of tamoxifen use for clinical indications, including chemoprevention and treatment. UST whole-breast sound speed estimates have been previously shown to be highly reproducible surrogate measures of volumetric breast density [14–19], which are strongly and positively associated with breast cancer risk [17]. The broader objective was to assess the concept of breast density decline as a biosensor of tamoxifen response and UST as a useful tool for making this determination. We assessed a group of matched untreated women with screen negative mammography at a 12 month interval
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