Purpose:To determine feasibility of performing bilateral dual-energy (DE) contrast agent-enhanced (CE) digital mammography and to evaluate its performance compared with conventional digital mammography and breast magnetic resonance (MR) imaging in women with known breast cancer. Materials and Methods:This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Patient accrual began in March 2010 and ended in August 2011. Mean patient age was 49.6 years (range, 25-74 years). Feasibility was evaluated in 10 women with newly diagnosed breast cancer who were injected with 1.5 mL per kilogram of body weight of iohexol and imaged between 2.5 and 10 minutes after injection. Once feasibility was confirmed, 52 women with newly diagnosed cancer who had undergone breast MR imaging gave consent to undergo DE CE digital mammography. Positive findings were confirmed with pathologic findings. Results:Feasibility was confirmed with no adverse events. Visualization of tumor enhancement was independent of timing after contrast agent injection for up to 10 minutes. MR imaging and DE CE digital mammography both depicted 50 (96%) of 52 index tumors; conventional mammography depicted 42 (81%). Lesions depicted by using DE CE digital mammography ranged from 4 to 67 mm in size (median, 17 mm). DE CE digital mammography depicted 14 (56%) of 25 additional ipsilateral cancers compared with 22 (88%) of 25 for MR imaging. There were two false-positive findings with DE CE digital mammography and 13 false-positive findings with MR imaging. There was one contralateral cancer, which was not evident with either modality. Conclusion:Bilateral DE CE digital mammography was feasible and easily accomplished. It was used to detect known primary tumors at a rate comparable to that of MR imaging and higher than that of conventional digital mammography. DE CE digital mammography had a lower sensitivity for detecting additional ipsilateral cancers than did MR imaging, but the specificity was higher.q RSNA, 2012

Importance: Improved screening methods for women with dense breasts are needed because of their increased risk of breast cancer and of failed early diagnosis by screening mammography. Objective: To compare the screening performance of abbreviated breast MRI (AB-MR), and digital breast tomosynthesis (DBT) in women with dense breasts. Design, Setting, and Participants: Cross-sectional study with longitudinal follow-up at 48 academic, community hospital, and private practice sites in the US and Germany, conducted between December 2016 and November 2017, that included average-risk women aged 40-75 years with heterogeneously dense or extremely dense breasts undergoing routine screening. Follow up ascertainment of cancer diagnoses was complete through September 12 th , 2019. Exposure: All women underwent screening by both DBT and AB-MR, performed in randomized order and read independently to avoid interpretation bias. Main outcome measures: The primary endpoint was the invasive cancer detection rate. Secondary outcomes included sensitivity, specificity, the additional-imaging-recommendation-rate, and positive predictive value (PPV) of biopsy, using invasive cancer and DCIS to define a positive reference standard. All outcomes are reported at the participant level. Pathology of core or surgical biopsy was the reference standard for cancer detection rate and PPV; interval cancers reported until the next annual screen were included in the reference standard for sensitivity and specificity. Results: Among 1516 enrolled women, 1444 (median age 54, range 40-75) completed both examinations and were included in the analysis. The reference standard was positive for invasive cancer with or without DCIS in 17 women, and for DCIS alone in another 6. No interval cancers were observed during follow-up. AB-MR detected all 17 women with invasive cancer, and 5/6 women with DCIS. DBT detected 7/17 women with invasive cancer, and 2/6 women with DCIS. The invasive-cancer-detection-rate was 11.8 per 1000 women [95% CI 7.4-18.8] for AB-MR versus 4.8 per 1000 women [95% CI 2.4-10.0] for DBT, a difference of 7 per 1000 women [95% CI for the difference 2.2-11.6] (exact McNemar p=0.002). For detection of invasive cancer and Comstock et al.

Purpose To assess the safety and tolerability of pre-operative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental design In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with pre-operative tumor cryoablation (n=7), single-dose ipilimumab at 10mg/kg (n=6), or both (n=6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results Pre-operative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1/19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and post-treatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions Pre-operative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intra-tumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic anti-tumor immunity with this strategy.

In early stage breast cancer, the degree of tumor-infiltrating lymphocytes (TILs) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryo-immunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared to monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring, and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T cell responses to therapy and for the study of cryo-immunotherapy in early-stage breast cancer.

Purpose:To compare the clinical, imaging, and histopathologic features of breast cancers detected at screening magnetic resonance (MR) imaging, screening mammography, and those detected between screening examinations (interval cancers) in women at high risk. Materials and Methods:This retrospective institutional review board-approved, HIPAA-compliant review of 7519 women at high risk for breast cancer who underwent screening with MR imaging and mammography between January 2005 and December 2010 was performed to determine the number of screeningdetected and interval cancers diagnosed. The need for informed consent was waived. Medical records were reviewed for age, risk factors (family or personal history of breast cancer, BRCA mutation status, history of high-risk lesion or mantle radiation), tumor histopathologic results, and time between diagnosis of interval cancer and most recent screening examination. The x 2 test and logistic regression methods were used to compare the features of screening MR imaging, screening mammography, and interval cancers. The Wilcoxon signed-rank test was used to calculate P values. Results:A total of 18 064 screening MR imaging examinations and 26 866 screening mammographic examinations were performed. Two hundred twenty-two cancers were diagnosed in 219 women, 167 (75%) at MR imaging, 43 (19%) at mammography, and 12 (5%) interval cancers. Median age at diagnosis was 52 years. No risk factors were associated with screening MR imaging, screening mammography, or interval cancer (P . .06). Cancers found at screening MR imaging were more likely to be invasive cancer (118 of 167 [71%]; P , .0001). Of the 43 cancers found at screening mammography, 38 (88%) manifested as calcifications and 28 (65%) were ductal carcinoma in situ. Interval cancers were associated with nodal involvement (P = .005) and the triple-negative subtype (P = .03). Conclusion:In women at high risk for breast cancer who underwent screening with mammography and MR imaging, invasive cancers were more likely to be detected at MR imaging, whereas most cancers detected at screening mammography were ductal carcinoma in situ. Interval cancers were found infrequently and were more likely to be node positive and of the triple-negative subtype.q RSNA, 2016