Background Parenchymal Uptake on Molecular Breast Imaging and Breast Cancer Risk: A Cohort Study.

BACKGROUND. Background parenchymal uptake (BPU) on molecular breast imaging (MBI) was identified in a case-control study as a breast cancer risk factor beyond mammographic density. To our knowledge, this finding has not yet been confirmed in a cohort study. OBJECTIVE. The objectives of this study were to examine the association of BPU with breast cancer and to estimate the absolute risk and discriminatory accuracy of BPU in a cohort study. METHODS. A retrospective cohort was established that included women without a history of breast cancer who underwent MBI from 2004 to 2015. Radiologists who were blinded to future breast cancer diagnoses assessed BPU on baseline MBI examinations as low (photopenic or minimal) or elevated (mild, moderate, or marked). Associations of BPU with breast cancer were estimated using multivariable Cox proportional hazards models of the time to diagnosis. The 5-year absolute risk was calculated for study subgroups. The discriminatory accuracy of BPU was also assessed. RESULTS. Among 2992 women (mean age, 56.3 years; SD, 10.6 years) who underwent MBI, breast cancer events occurred in 144 women (median follow-up, 7.3 years). Median time to diagnosis after MBI was 4.2 years (range, 0.5-11.6 years). Elevated BPU was associated with a greater breast cancer risk (hazard ratio [HR], 2.39; 95% CI, 1.68-3.41; p ≤ .001). This association remained in postmenopausal women (HR, 3.50; 95% CI, 2.31-5.31; p < .001) but was not significant in premenopausal women (HR, 1.29; 95% CI, 0.72-2.32; p = .39). The 5-year absolute risk of breast cancer was 4.3% (95% CI, 2.9-5.7%) for women with elevated BPU versus 2.5% (95% CI, 1.8-3.1%) for those with low BPU. Postmenopausal women with dense breasts and elevated BPU had a 5-year absolute risk of 8.1% (95% CI, 4.3-11.8%) versus 2.8% (1.8-3.8%) for those with low BPU. Among postmenopausal women, discriminatory accuracy for invasive cancer was improved with the addition of BPU versus use of the Gail risk score alone (C statistic, 65.1 vs 59.1; p = .04) or use of the Breast Cancer Surveillance Consortium risk score alone (C statistic, 66.4 vs 60.4; p = .04). CONCLUSION. BPU on MBI is an independent risk factor for breast cancer, with the strongest association observed among postmenopausal women with dense breasts. In postmenopausal women, BPU provides incremental discrimination in predicting breast cancer when combined with either the Gail model or the Breast Cancer Surveillance Consortium model. CLINICAL IMPACT. Observation of elevated BPU on MBI may identify a subset of women with dense breasts who would benefit most from supplemental screening or preventive options.

Molecular Breast Imaging in Clinical Practice.

OBJECTIVE. The purpose of this article is to review clinical uses and image interpretation of molecular breast imaging (MBI) and clarify radiation risks. CONCLUSION. MBI detects additional cancers compared with conventional imaging in women with dense breasts and those with elevated risk of breast cancer. Its role as an imaging biomarker of cancer risk and in assessing neoadjuvant chemotherapy response is growing. Radiation risk is minimal; benefit-to-risk ratio is similar to that of mammography. MBI is low cost, well tolerated, and easily adapted into clinical practice.

Dose Reduction in Molecular Breast Imaging With a New Image-Processing Algorithm.

OBJECTIVE. The purpose of this study was to determine whether application of a proprietary image-processing algorithm would allow a reduction in the necessary administered activity for molecular breast imaging (MBI) examinations. MATERIALS AND METHODS. Images from standard-dose MBI examinations (300 MBq 99mTc-sestamibi) of 50 subjects were analyzed. The images were acquired in dynamic mode and showed at least one breast lesion. Half-dose MBI examinations were simulated by summing one-half of the dynamic frames and were processed with the algorithm under study in both a default and a preferred filter mode. Two breast radiologists independently completed a set of two-alternative forced-choice tasks to compare lesion conspicuity on standard-dose images, half-dose images, and the algorithm-processed half-dose images in both modes. RESULTS. Relative to the standard-dose images, the half-dose images were preferred in 4, the default-filtered half-dose images in 50, and preferred-filtered half-dose images in 76 of 100 readings. Compared with standard-dose images, in terms of lesion conspicuity, the half-dose images were rated better in 2, equivalent in 6, and poorer in 92 of 100 readings. The default-filtered half-dose images were rated better, equivalent, or poorer in 13, 73, and 14 of 100 readings. The preferred-filtered half-dose images were rated as better, equivalent, or poorer in 55, 34, and 11 of 100 readings. CONCLUSION. Compared with that on standard-dose images, lesion conspicuity on images obtained with the algorithm and acquired at one-half the standard dose was equivalent or better without compromise of image quality. The algorithm can also be used to decrease imaging time with a resulting increase in patient comfort and throughput.

Impact of short-term low-dose tamoxifen on molecular breast imaging background parenchymal uptake: a pilot study.

BACKGROUND: High background parenchymal uptake (BPU) on molecular breast imaging (MBI) has been identified as a breast cancer risk factor. We explored the feasibility of offering a short-term intervention of low-dose oral tamoxifen to women with high BPU and examined whether this intervention would reduce BPU. METHODS: Women with a history of high BPU and no breast cancer history were invited to the study. Participants had an MBI exam, followed by 30 days of low-dose oral tamoxifen at either 5 mg or 10 mg/day, and a post-tamoxifen MBI exam. BPU on pre- and post-tamoxifen MBI exams was quantitatively assessed as the ratio of average counts in breast fibroglandular tissue vs. average counts in subcutaneous fat. Pre-tamoxifen and post-tamoxifen BPU were compared with paired t tests. RESULTS: Of 47 women invited, 22 enrolled and 21 completed the study (10 taking 5 mg tamoxifen, 11 taking 10 mg tamoxifen). Mean age was 47.7 years (range 41-56 years). After 30 days low-dose tamoxifen, 8 of 21 women (38%) showed a decline in BPU, defined as a decrease from the pre-tamoxifen MBI of at least 15%; 11 of 21 (52%) had no change in BPU (within ± 15%); 2 of 21 (10%) had an increase in BPU of greater than 15%. Overall, the average post-tamoxifen BPU was not significantly different from pre-tamoxifen BPU (1.34 post vs. 1.43 pre, p = 0.11). However, among women taking 10 mg tamoxifen, 5 of 11 (45%) showed a decline in BPU; average BPU was 1.19 post-tamoxifen vs. 1.34 pre-tamoxifen (p = 0.005). In women taking 5 mg tamoxifen, 2 of 10 (20%) showed a decline in BPU; average BPU was 1.51 post-tamoxifen vs.1.53 pre-tamoxifen (p = 0.99). CONCLUSIONS: Short-term intervention with low-dose tamoxifen may reduce high BPU on MBI for some patients. Our preliminary findings suggest that 10 mg tamoxifen per day may be more effective than 5 mg for inducing declines in BPU within 30 days. Given the variability in BPU response to tamoxifen observed among study participants, future study is warranted to determine if BPU response could predict the effectiveness of tamoxifen for breast cancer risk reduction within an individual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979301 . Registered 01 December 2016.

Comparison of 99mTc-Sestamibi Molecular Breast Imaging and Breast MRI in Patients With Invasive Breast Cancer Receiving Neoadjuvant Chemotherapy.

OBJECTIVE. The purpose of this study is to prospectively compare the size of invasive breast cancer before and after neoadjuvant chemotherapy (NAC) at breast MRI and molecular breast imaging (MBI) and to assess the accuracy of post-NAC MBI and MRI relative to pathologic analysis. SUBJECTS AND METHODS. Women with invasive breast cancer greater than or equal to 1.5 cm were enrolled to compare the longest dimension before and after NAC at MRI and MBI. MBI was performed on a dual-detector cadmium zinc telluride system after administration of 6.5 mCi (240 MBq) 99mTc-sestamibi. The accuracy of MRI and MBI in assessing residual disease (invasive disease or ductal carcinoma in situ) was determined relative to pathologic examination. RESULTS. The longest dimension at MRI was within 1.0 cm of that at MBI in 72.3% of cases before NAC and 70.1% of cases after NAC. The difference between the longest dimension at imaging after NAC and pathologic tumor size was within 1 cm for 58.7% of breast MRI cases and 59.6% of MBI cases. Ninety patients underwent both MRI and MBI after NAC. In the 56 patients with invasive residual disease, 10 (17.9%) cases were negative at MRI and 23 (41.1%) cases were negative at MBI. In the 34 patients with breast pathologic complete response, there was enhancement in 10 cases (29.4%) at MRI and uptake in six cases (17.6%) at MBI. Sensitivity, specificity, positive predictive value, and negative predictive value after NAC were 82.8%, 69.4%, 81.4%, and 71.4%, respectively, for MRI and 58.9%, 82.4%, 84.6%, and 54.9%, respectively, for MBI. CONCLUSION. Breast MRI and MBI showed similar disease extent before NAC. MBI may be an alternative to breast MRI in patients with a contraindication to breast MRI. Neither modality showed sufficient accuracy after NAC in predicting breast pathologic complete response to obviate tissue diagnosis to assess for residual invasive disease. Defining the extent of residual disease compared with pathologic evaluation was also limited after NAC for both breast MRI and MBI.

Quantitative background parenchymal uptake on molecular breast imaging and breast cancer risk: a case-control study.

BACKGROUND: Background parenchymal uptake (BPU), which refers to the level of Tc-99m sestamibi uptake within normal fibroglandular tissue on molecular breast imaging (MBI), has been identified as a breast cancer risk factor, independent of mammographic density. Prior analyses have used subjective categories to describe BPU. We evaluate a new quantitative method for assessing BPU by testing its reproducibility, comparing quantitative results with previously established subjective BPU categories, and determining the association of quantitative BPU with breast cancer risk. METHODS: Two nonradiologist operators independently performed region-of-interest analysis on MBI images viewed in conjunction with corresponding digital mammograms. Quantitative BPU was defined as a unitless ratio of the average pixel intensity (counts/pixel) within the fibroglandular tissue versus the average pixel intensity in fat. Operator agreement and the correlation of quantitative BPU measures with subjective BPU categories assessed by expert radiologists were determined. Percent density on mammograms was estimated using Cumulus. The association of quantitative BPU with breast cancer (per one unit BPU) was examined within an established case-control study of 62 incident breast cancer cases and 177 matched controls. RESULTS: Quantitative BPU ranged from 0.4 to 3.2 across all subjects and was on average higher in cases compared to controls (1.4 versus 1.2, p < 0.007 for both operators). Quantitative BPU was strongly correlated with subjective BPU categories (Spearman's r = 0.59 to 0.69, p < 0.0001, for each paired combination of two operators and two radiologists). Interoperator and intraoperator agreement in the quantitative BPU measure, assessed by intraclass correlation, was 0.92 and 0.98, respectively. Quantitative BPU measures showed either no correlation or weak negative correlation with mammographic percent density. In a model adjusted for body mass index and percent density, higher quantitative BPU was associated with increased risk of breast cancer for both operators (OR = 4.0, 95% confidence interval (CI) 1.6-10.1, and 2.4, 95% CI 1.2-4.7). CONCLUSION: Quantitative measurement of BPU, defined as the ratio of average counts in fibroglandular tissue relative to that in fat, can be reliably performed by nonradiologist operators with a simple region-of-interest analysis tool. Similar to results obtained with subjective BPU categories, quantitative BPU is a functional imaging biomarker of breast cancer risk, independent of mammographic density and hormonal factors.

Background parenchymal uptake on molecular breast imaging as a breast cancer risk factor: a case-control study.

BACKGROUND: Molecular breast imaging (MBI) is a functional test used for supplemental screening of women with mammographically dense breasts. Additionally, MBI depicts variable levels of background parenchymal uptake (BPU) within nonmalignant, dense fibroglandular tissue. We investigated whether BPU is a risk factor for breast cancer. METHODS: We conducted a retrospective case-control study of 3027 eligible women who had undergone MBI between February 2004 and February 2014. Sixty-two incident breast cancer cases were identified. A total of 179 controls were matched on age, menopausal status, and MBI year. Two radiologists blinded to case status independently assessed BPU as one of four categories: photopenic, minimal to mild, moderate, or marked. Conditional logistic regression analysis was performed to estimate the associations (OR) of BPU categories (moderate or marked vs. minimal to mild or photopenic) and breast cancer risk, adjusted for other risk factors. RESULTS: The median age was 60.2 years (range 38-86 years) for cases vs. 60.2 years (range 38-88 years) for controls (p = 0.88). Women with moderate or marked BPU had a 3.4-fold (95 % CI 1.6-7.3) and 4.8-fold (95 % CI 2.1-10.8) increased risk of breast cancer, respectively, compared with women with photopenic or minimal to mild BPU, for two radiologists. The results were similar after adjustment for BI-RADS density (OR 3.3 [95 % CI 1.6-7.2] and OR 4.6 [95 % CI 2.1-10.5]) or postmenopausal hormone use (OR 3.6 [95 % CI 1.7-7.7] and OR 5.0 [95 % CI 2.2-11.4]). The association of BPU with breast cancer remained in analyses limited to postmenopausal women only (OR 3.8 [95 % CI 1.5-9.3] and OR 4.1 [95 % CI 1.6-10.2]) and invasive breast cancer cases only (OR 3.6 [95 % CI 1.5-8.8] and OR 4.4 [95 % CI 1.7-11.1]). Variable BPU was observed among women with similar mammographic density; the distribution of BPU categories differed across density categories (p < 0.0001). CONCLUSIONS: This study provides the first evidence for BPU as a risk factor for breast cancer. Among women with dense breasts, who comprise >40 % of the screening population, BPU may serve as a functional imaging biomarker to identify the subset at greatest risk.

Noninvasive 3-dimensional imaging of liver regeneration in a mouse model of hereditary tyrosinemia type 1 using the sodium iodide symporter gene.

Cell transplantation is a potential treatment for the many liver disorders that are currently only curable by organ transplantation. However, one of the major limitations of hepatocyte (HC) transplantation is an inability to monitor cells longitudinally after injection. We hypothesized that the thyroidal sodium iodide symporter (NIS) gene could be used to visualize transplanted HCs in a rodent model of inherited liver disease: hereditary tyrosinemia type 1. Wild-type C57Bl/6J mouse HCs were transduced ex vivo with a lentiviral vector containing the mouse Slc5a5 (NIS) gene controlled by the thyroxine-binding globulin promoter. NIS-transduced cells could robustly concentrate radiolabeled iodine in vitro, with lentiviral transduction efficiencies greater than 80% achieved in the presence of dexamethasone. Next, NIS-transduced HCs were transplanted into congenic fumarylacetoacetate hydrolase knockout mice, and this resulted in the prevention of liver failure. NIS-transduced HCs were readily imaged in vivo by single-photon emission computed tomography, and this demonstrated for the first time noninvasive 3-dimensional imaging of regenerating tissue in individual animals over time. We also tested the efficacy of primary HC spheroids engrafted in the liver. With the NIS reporter, robust spheroid engraftment and survival could be detected longitudinally after direct parenchymal injection, and this thereby demonstrated a novel strategy for HC transplantation. This work is the first to demonstrate the efficacy of NIS imaging in the field of HC transplantation. We anticipate that NIS labeling will allow noninvasive and longitudinal identification of HCs and stem cells in future studies related to liver regeneration in small and large preclinical animal models.

Diagnostic workup and costs of a single supplemental molecular breast imaging screen of mammographically dense breasts.

OBJECTIVE: The purpose of this study was to examine additional diagnostic workup and costs generated by addition of a single molecular breast imaging (MBI) examination to screening mammography for women with dense breasts. SUBJECTS AND METHODS: Women with mammographically dense breasts presenting for screening mammography underwent adjunct MBI performed with 300 MBq (99m)Tc-sestamibi and a direct-conversion cadmium-zinc-telluride dual-head gamma camera. All subsequent imaging tests and biopsies were tracked for a minimum of 1 year. The positive predictive value of biopsies performed (PPV3), benign biopsy rate, cost per patient screened, and cost per cancer detected were determined. RESULTS: A total of 1651 women enrolled in the study. Among the 1585 participants with complete reference standard, screening mammography alone prompted diagnostic workup of 175 (11.0%) patients and biopsy of 20 (1.3%) and yielded five malignancies (PPV3, 25%). Results of combined screening mammography plus MBI prompted diagnostic workup of 279 patients (17.6%) and biopsy of 67 (4.2%) and yielded 19 malignancies (PPV3, 28.4%). The benign biopsy rates were 0.9% (15 of 1585) for screening mammography alone and 3.0% (48 of 1585) for the combination (p < 0.001). The addition of MBI increased the cost per patient screened from $176 for mammography alone to $571 for the combination. However, cost per cancer detected was lower for the combination ($47,597) than for mammography alone ($55,851). CONCLUSION: The addition of MBI to screening mammography of women with dense breasts increased the overall costs and benign biopsy rate but also increased the cancer detection rate, which resulted in a lower cost per cancer detected than with screening mammography alone.

Journal club: molecular breast imaging at reduced radiation dose for supplemental screening in mammographically dense breasts.

OBJECTIVE. The purpose of this study was to assess the diagnostic performance of supplemental screening molecular breast imaging (MBI) in women with mammographically dense breasts after system modifications to permit radiation dose reduction. SUBJECTS AND METHODS. A total of 1651 asymptomatic women with mammographically dense breasts on prior mammography underwent screening mammography and adjunct MBI performed with 300-MBq (99m)Tc-sestamibi and a direct-conversion (cadmium zinc telluride) gamma camera, both interpreted independently. The cancer detection rate, sensitivity, specificity, and positive predictive value of biopsies performed (PPV3) were determined. RESULTS. In 1585 participants with a complete reference standard, 21 were diagnosed with cancer: two detected by mammography only, 14 by MBI only, three by both modalities, and two by neither. Of 14 participants with cancers detected only by MBI, 11 had invasive disease (median size, 0.9 cm; range, 0.5-4.1 cm). Nine of 11 (82%) were node negative, and two had bilateral cancers. With the addition of MBI to mammography, the overall cancer detection rate (per 1000 screened) increased from 3.2 to 12.0 (p < 0.001) (supplemental yield 8.8). The invasive cancer detection rate increased from 1.9 to 8.8 (p < 0.001) (supplemental yield 6.9), a relative increase of 363%, while the change in DCIS detection was not statistically significant (from 1.3 to 3.2, p =0.250). For mammography alone, sensitivity was 24%; specificity, 89%; and PPV3, 25%. For the combination, sensitivity was 91% (p < 0.001); specificity, 83% (p < 0.001); and PPV3, 28% (p = 0.70). The recall rate increased from 11.0% with mammography alone to 17.6% (p < 0.001) for the combination; the biopsy rate increased from 1.3% for mammography alone to 4.2% (p < 0.001). CONCLUSION. When added to screening mammography, MBI performed using a radiopharmaceutical activity acceptable for screening (effective dose 2.4 mSv) yielded a supplemental cancer detection rate of 8.8 per 1000 women with mammographically dense breasts.