The diagnosis and management of breast cancer are undergoing a paradigm shift from a one-size-fits-all approach to an era of personalized medicine. Sophisticated diagnostics, including molecular imaging and genomic expression profiles, enable improved tumor characterization. These diagnostics, combined with newer surgical techniques and radiation therapies, result in a collaborative multidisciplinary approach to minimizing recurrence and reducing treatment-associated morbidity. This article reviews the diagnosis and treatment of breast cancer, including screening, staging, and multidisciplinary management. In this article, we address current approaches to breast cancer diagnosis and management. These approaches include screening recommendations; diagnostic imaging and pathologic assessment to determine the extent of disease; surgery and radiation treatment; and an array of systemic options, such as chemotherapy, endocrine therapy, and targeted agents (Fig. 1). We also consider the potential contribution of functional imaging to a new era of personalized, tumor-specific treatment. BREAST CANCER DIAGNOSIS ScreeningBreast cancer is generally diagnosed through either screening or a symptom (e.g., pain or a palpable mass) that prompts a diagnostic exam. Screening of healthy women is associated with the detection of tumors that are smaller, have lower odds of metastasis, are more amenable to breast-conserving and limited axillary surgery, and are less likely to require chemotherapy (1). This scenario translates to reduced treatment-related morbidity and improved survival.The only screening modality proven to reduce breast cancerspecific mortality is mammography (2). Screening mammography leads to a 19% overall reduction in breast cancer mortality (3), with less benefit for women in their 40s (15%) and more benefit for women in their 60s (32%). As a result, screening mammography is recommended by the American Cancer Society beginning at age 45, or sooner depending on individual preference. The potential negative aspects of screening mammography are falsepositive examinations, radiation exposure, pain, anxiety, and other negative psychologic effects. Mammography has a 61% chance of a false-positive result over a 10-y period for women commencing screening between the ages of 40 y and 50 y. The risk of a falsepositive examination decreases with older age (3). The US Preventative Task Force cited a 15% breast cancer-related mortality reduction for women who were 39-49 y old and a mortality-related benefit from screening between ages 39 and 69. However, the task force released a controversial report recommending only biennial screening mammography for women who were 50-74 y old, excluding younger women to a large extent because of the high rate of false-positive results (4). Mammography for women in the 39-to 49-y-old age group was recommended if indicated after the use of a risk-based model of breast cancer screening, such as the models developed by the Population-Based Research Optimizing Screening Through Personalized Re...
Digital breast tomosynthesis screening outcomes are sustainable, with significant recall reduction, increasing cancer cases per recalled patients, and a decline in interval cancers.
Earlier detection of breast cancer reduces mortality from this disease. As a result, the development of better screening techniques is a topic of intense interest. Contrast-enhanced dual-energy mammography (DEM) is a novel technique that has improved sensitivity for cancer detection. However, the development of contrast agents for this technique is in its infancy. We herein report gold-silver alloy nanoparticles (GSAN) that have potent DEM contrast properties and improved biocompatibility. GSAN formulations containing a range of gold:silver ratios and capped with m-PEG were synthesized and characterized using various analytical methods. DEM and computed tomography (CT) phantom imaging showed that GSAN produced robust contrast that was comparable to silver alone. Cell viability, reactive oxygen species generation and DNA damage results revealed that the formulations with 30% or higher gold content are cytocompatible to Hep G2 and J774A.1 cells. In vivo imaging was performed in mice with and without breast tumors. The results showed that GSAN produce strong DEM and CT contrast and accumulated in tumors. Furthermore, both in vivo imaging and ex vivo analysis indicated the excretion of GSAN via both urine and feces. In summary, GSAN produce strong DEM and CT contrast, and has potential for both blood pool imaging and for breast cancer screening.
Despite the availability of PARP inhibitors for cancer therapy, a biomarker to clearly stratify patients for selection of this treatment remains lacking. Here we describe a radiotracer-based method that addresses this issue, using the novel compound [125I]KX1 as a PARP-1–selective radiotracer that can accurately measure PARP-1 expression in vitro and in vivo. The pharmacologic properties of the PARP radiotracer [125I]KX1 was characterized in multiple cell lines where single-agent sensitivity was correlated with [125I]KX1 binding to PARP-1. In vivo evaluation of [125I]KX1 verified in vitro results, validating PARP radiotracers to define PARP-1 enzyme expression as an in vivo biomarker. Notably, PARP-1 expression as quantified by [125I]KX1 correlated positively with the cytotoxic sensitivity of cell lines evaluated with PARP inhibitors. Overall, our results defined a novel technology with the potential to serve as a companion diagnostic to identify patients most likely to respond therapeutically to a PARP inhibitor.
Purpose:To evaluate the early implementation of synthesized two-dimensional (s2D) mammography in a population screened entirely with s2D and digital breast tomosynthesis (DBT) (referred to as s2D/DBT) and compare recall rates and cancer detection rates to historic outcomes of digital mammography combined with DBT (referred to as digital mammography/DBT) screening. Materials and Methods:This was an institutional review board-approved and HIPAA-compliant retrospective interpretation of prospectively acquired data with waiver of informed consent. Compared were recall rates, biopsy rates, cancer detection rates, and radiation dose for 15 571 women screened with digital mammography/DBT from October 1, 2011, to February 28, 2013, and 5366 women screened with s2D/ DBT from January 7, 2015, to June 30, 2015. Two-sample z tests of equal proportions were used to determine statistical significance. Results:Recall rate for s2D/DBT versus digital mammography/ DBT was 7.1% versus 8.8%, respectively (P , .001). Biopsy rate for s2D/DBT versus digital mammography/ DBT decreased (1.3% vs 2.0%, respectively; P = .001).There was no significant difference in cancer detection rate for s2D/DBT versus digital mammography/DBT (5.03 of 1000 vs 5.45 of 1000, respectively; P = .72). The average glandular dose was 39% lower in s2D/DBT versus digital mammography/DBT (4.88 mGy vs 7.97 mGy, respectively; P , .001). Conclusion:Screening with s2D/DBT in a large urban practice resulted in similar outcomes compared with digital mammography/DBT imaging. Screening with s2D/DBT allowed for the benefits of DBT with a decrease in radiation dose compared with digital mammography/DBT.q RSNA, 2016
Purpose: Conventional breast MRI is highly sensitive for cancer detection but prompts some false-positives. We performed a prospective, multicenter study to determine whether apparent diffusion coefficients (ADCs) from diffusion weighted imaging (DWI) can decrease MRI false-positives. Experimental Design: 107 women with MRI-detected BI-RADS 3, 4, or 5 lesions were enrolled from March 2014 to April 2015. ADCs were measured both centrally and at participating sites. Receiver operating characteristic (ROC) analysis was employed to assess diagnostic performance of centrally-measured ADCs and identify optimal ADC thresholds to reduce unnecessary biopsies. Lesion reference standard was based on either definitive biopsy result or at least 337 days of follow-up after the initial MRI procedure. Results: Of 107 women enrolled, 67 patients (median age 49, range 24–75 years) with 81 lesions with confirmed reference standard (28 malignant, 53 benign) and evaluable DWI were analyzed. 67/81 lesions were BI-RADS 4 (n=63) or 5 (n=4) and recommended for biopsy. Malignancies exhibited lower mean centrally-measured ADCs (mm2/s) than benign lesions (1.21×10−3 vs.1.47×10−3, p<0.0001, area under ROC curve=0.75, 95% confidence interval [CI] 0.65–0.84). In centralized analysis, application of an ADC threshold (1.53×10−3 mm2/s) lowered the biopsy rate by 20.9% (14/67; 95% CI 11.2–31.2%) without affecting sensitivity. Application of a more conservative threshold (1.68×10−3mm2/s) to site-derived ADCs reduced the biopsy rate by 26.2%(16/61) but missed three cancers. Conclusion: DWI can re-classify a substantial fraction of suspicious breast MRI findings as benign and thereby decrease unnecessary biopsies. ADC thresholds identified in this trial should be validated in future Phase III studies.
Digital breast tomosynthesis (DBT) is emerging as the standard of care for breast imaging based on improvements in both screening and diagnostic imaging outcomes. The additional information obtained from the tomosynthesis acquisition decreases the confounding effect of overlapping tissue, allowing for improved lesion detection, characterization, and localization. In addition, the quasi three-dimensional information obtained from the reconstructed DBT data set allows a more efficient imaging work-up than imaging with two-dimensional full-field digital mammography alone. Herein, the authors review the benefits of DBT imaging in screening and diagnostic breast imaging.
Conventional X-ray mammography has low diagnostic sensitivity for women with dense breasts. As a result, alternative contrast-enhanced screening tools such as dual energy mammography (DEM), computed tomography (CT), magnetic resonance imaging (MRI), and near-infrared fluorescence (NIRF) imaging are being used or investigated for these women. However, currently available contrast agents are non-ideal, have safety issues, and each imaging technique requires a different contrast agent. We therefore sought to develop a multimodal contrast agent that is functional for each breast imaging modality to simplify the diagnosis process and address the issues of existing contrast agents. Herein, we present a novel "all-in-one" nanoparticle (AION) multimodal imaging probe that has potent DEM, CT, MRI, and NIRF contrast properties and improved biocompatibility. AION were formed by co-encapsulation of a near-infrared fluorophore (DiR), silver sulfide nanoparticles (Ag2S-NP), and iron oxide nanoparticles (IO-NP) in PEGylated micelles. AION showed negligible cytotoxicity, which was in agreement with its minimal silver ion release profiles. AION generated strong contrast with all imaging modalities as demonstrated in phantom imaging. AION allowed in vivo tumor imaging as evidenced by the increase in contrast after injection. This study indicates the potential of AION as an effective multimodal contrast agent for breast cancer diagnosis with a range of imaging methods.
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