Giurescu, Marina E.

PURPOSE Contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) have shown similar diagnostic performance in detection of breast cancer. Limited CEM data are available for high-risk breast cancer screening. The purpose of the study was to prospectively investigate the efficacy of supplemental screening CEM in elevated risk patients. MATERIALS AND METHODS A prospective, single-institution, institutional review board–approved observational study was conducted in asymptomatic elevated risk women age 35 years or older who had a negative conventional two-dimensional digital breast tomosynthesis screening mammography (MG) and no additional supplemental screening within the prior 12 months. RESULTS Four hundred sixty women were enrolled from February 2019 to April 2021. The median age was 56.8 (range, 35.0-79.2) years; 408 of 460 (88.7%) were mammographically dense. Biopsy revealed benign changes in 22 women (22/37, 59%), high-risk lesions in four women (4/37, 11%), and breast cancer in 11 women (11/37, 30%). Fourteen cancers (10 invasive, tumor size range 4-15 mm, median 9 mm) were diagnosed in 11 women. The overall supplemental cancer detection rate was 23.9 per 1,000 patients, 95% CI (12.0 to 42.4). All cancers were grade 1 or 2, ER+ ERBB2–, and node negative. CEM imaging screening offered high specificity (0.875 [95% CI, 0.844 to 0.906]), high NPV (0.998 [95% CI, 0.993 to 1.000), moderate PPV1 (0.164 [95% CI, 0.076 to 0.253), moderate PPV3 (0.275 [95% CI, 0.137 to 0.413]), and high sensitivity (0.917 [95% CI, 0.760 to 1.000]). At least 1 year of imaging follow-up was available on all patients, and one interval cancer was detected on breast MRI 4 months after negative screening CEM. CONCLUSION A pilot trial demonstrates a supplemental cancer detection rate of 23.9 per 1,000 in women at an elevated risk for breast cancer. Larger, multi-institutional, multiyear CEM trials in patients at elevated risk are needed for validation.

Abstract Background: Contrast-enhanced mammography (CEM) is an emerging breast imaging technique utilizing iodinated contrast to highlight areas of neovascularity. The role of CEM in patients with breast implants has not yet been characterized. We report our clinical experience of CEM in patients with breast augmentation surgery to better understand the potential diagnostic utility and limitations of CEM in the setting of breast implants. Materials and Methods: A HIPPA compliant, IRB exempt single-institution review of prospective CEM cases who had “breast implants” in their report between 01/2015 and 03/2020. Medical records were reviewed to supplement database information. Results: Forty-six patients were included with a mean age of 52 years (range 33-72). Clinical indications included: high risk research screen 3 (6%), diagnostic evaluation for abnormal imaging 24 (52%), further evaluation of newly diagnosed breast cancer 12 (26%) or assessment of neoadjuvant treatment response 7 (15%). Thirty patients had malignant lesions. Histology was invasive ductal carcinoma (90%), invasive lobular carcinoma (7%), and ductal carcinoma in situ (3%). CEM identified the index cancer and extent of disease in 28/30 (93%) of malignant cases. In two patients (7%), the malignant lesion was not included in the field-of-view due to its location. One of these lesions was a far medial mass within the breast which was detected by ultrasound alone. The other false negative CEM was a palpable axillary mass negative on both mammogram (MG) and MRI but seen by ultrasound. Twenty-three (50%) underwent additional breast MRI of which 20 had an already diagnosed cancer. the findings on CEM were concordant with MR imaging for the index lesion in 19/20 (95%) cases (kappa=0.86; p <0.001). Six additional lesions were found by CEM and confirmed by MRI. Of these lesions, 33% were found to be malignant and changed the surgical procedure. Four were only seen on CEM (no MRI comparison was available) and 75% were found to be malignant. One was only seen on MRI and was benign. One additional lesion was only seen as an asymmetry on MG without CEM or MRI correlate. This was benign on both the biopsy and surgical pathology. Conclusions: CEM appears to be a valuable breast imaging modality for diagnostic evaluations and surgical staging, including patients with breast implants. Due to technical artifacts and positioning limitations for posterior lesions, we recommend performing CEM with implant displaced views. Breast centers that use CEM, should be aware of field of view as a potential limitation when evaluating extent of disease in patients with breast augmentation. Citation Format: Molly Carnahan, Barbara Pockaj, Victor Pizzitola, Marina Giurescu, Roxanne Lorans, William Eversman, Richard Sharpe, Patricia Cronin, Donald Northfelt, Karen Anderson, Brenda Ernst, Bhavika Patel. Experience of contrast-enhanced mammography in patients with breast augmentation surgery [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-23.

Abstract Objective and Rationale: To investigate the utility of screening Contrast Enhanced Mammography (CEM) imaging as a supplemental screening tool in women at elevated risk for breast cancer. Materials and Methods: This prospective, single institution, IRB approved observational study was conducted in asymptomatic women 35 years of age or older who were deemed at elevated risk of breast cancer, defined as IBIS v.8.0 lifetime risk of breast cancer score >15% or a prior personal history of breast cancer. Enrollment started in January 2019 and is on-going. An interim data analysis was performed. Women were invited to undergo supplemental CEM screening within 180 days of negative (BI-RADS 1 or 2) conventional 2D/3D screening mammography (MG). Patients with prior screening MBI, ultrasound or MR imaging within 12 months were excluded from study participation. Outcome measures were supplemental cancer detection rates, sensitivity, specificity, positive predictive value, and negative predictive value of CEM, along with their 95% confidence intervals, as well as the biologic profiles of MG-occult, CEM detected cancers. Results: A total of 351 women were enrolled in this prospective study over a 20-month period. To date, we have 1 year follow up on 106 cases with negative follow-up MG. Average age of the participants was 56 years ± 9.44 (standard deviation); 11 patients had screening 2D MG, 333 had combined 3-D and 2-D screening MG; 309 dense and 37 non-dense breasts based on ACR BI-RADS categories. CEM depicted 8 additional breast cancers (table 1), which were otherwise MG occult, for an overall supplemental cancer detection rate of 22.7 per 1000 patients, 95% CI (9.9, 44.3). 1 false negative cancer on CEM imaging which was further detected on MR imaging only. Biopsy revealed 16 benign changes (16/28=57%), 4 high-risk lesions (4/28=14%), and 8 breast cancers (8/28=29%) (table 2). CEM imaging screening offered high specificity (0.942, 95% CI (0.917, 0.967), high NPV 0.997, 95% CI (0.991, 1.000) and moderate PPV (0.286, 95% CI (0.118, 0.453) and sensitivity (0.889, 95% CI (0.684, 1.000)). Size of CEM detected cancers ranged from 7 to 57 mm. Conclusion: This pilot trial demonstrates a supplemental cancer detection rate of 22.7 per 1000 during prevalence round of CEM screening in women at an elevated risk for breast cancer. These initial results are comparable to results reported for high-risk surveillance MR imaging. Larger, multi-institutional high-risk CEM trials are needed for those patients who are not otherwise undergoing regular supplemental surveillance MR imaging. Citation Format: Bhavika K. Patel, Victor Pizzitola, Donald Northfelt, Karen Anderson, Marina Giurescu, Gina Mazza, Roxanne Lorans, William Eversman, Richard Sharpe, Juliana Kling, Denise Millstine, Ernst Brenda, Patricia Cronin, Heidi Apsey, Jennifer Palmieri, Barbara Pockaj, Michele Halyard. Supplemental contrast enhanced mammography screening of women with elevated risk of breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-41.

Excisional biopsy has been recommended for papillary lesions diagnosed on core needle biopsy (CNB) because a significant proportion of cases are upstaged to in situ/invasive cancer after surgical excision. The study goals were to identify patients at lowest risk of upstaging in whom excisional biopsy may potentially be avoided. We retrospectively evaluated 46 patients with a papillary lesion on CNB. Six patients were upstaged overall (13%), to intraductal papillary carcinoma (7%), invasive papillary carcinoma (4%), and mixed invasive ductal/lobular carcinoma (2%). The upstaging rate for patients with atypia on CNB was higher than for patients without atypia (33 vs 3%, P = 0.011). No patient younger than 65 years was upstaged to in situ or invasive carcinoma, and the mean lesion size was also higher among patients who were upstaged ( P > 0.05). Patients younger than 65 years with small papillary lesions lacking atypia on CNB may therefore represent a low-risk group that may be offered close clinical and radiologic follow-up.

Abstract Background: In an adaptive randomized trial, when new treatment combinations are being tested, it is important to be able to identify patients who are progressing on treatment so that they can be changed to a different therapeutic regimen. We know that even within the molecularly high risk patients in I-SPY 2, there is considerable variation in biology. In this study, we will present results of using MRI-calculated functional tumor volume (FTV) to identify tumor progression for each breast cancer subtype. Methods: Patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Four MRI exams were performed for each patient: pre-NAC (T0), after 3 weeks of NAC (T1), between regimens (T2), and post-NAC (T3). Functional tumor volume (FTV) was calculated at each exam by summing voxels meeting enhancement thresholds. Tumor progression at T1, T2 or T3 was identified by a positive FTV change relative to T0. Visual inspection was used to exclude false progression due to strong background parenchymal enhancement post-contrast, prominent vessels, motion, or insufficient image quality. pCR was defined as no invasive disease in the breast and lymph nodes. Negative predictive value for pCR was defined as:NPV=number of true non-pCRs / number of patients with MRI assessed tumor progressions, where “true non-pCRs” referred to patients who were non-pCRs at surgery and were assessed as progressors by MRI. The analysis was performed in the full cohort and in sub-cohorts defined by HR and HER2 statuses. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Total and non-pCR numbers for each subtype, number of patients with tumor progression assessed by MRI at T1, T2, and T3, and NPVs, are shown in Table 1. In the full cohort, the NPV increased consistently over treatment, from T1 (NPV=83%) to T2 (93%), and to T3 (100%). The HER2+ cancer subtypes showed fewer MRI-assessed tumor progressions than HER2- subtypes: e.g. 10/209 (5%) vs. 108/669 (16%) at T1. NPV was 100% for HER2+ subtypes at T1 and T2 except for a single misclassification of a HR- tumor at T1. Only 6 tumor progressors, all HER2- were identified at T3, and all were confirmed at surgery as non-pCRs (NPV=100%). For HR+/HER2-, the NPV increased slightly from 89% at T1 to 91% at T2, while triple negative subtype had a more substantial increase, from 78% to 92%. Conclusions: Our study showed strong association between tumor progressors assessed by MRI with true non-pCRs after NAC. For HER2+ tumors, although MRI progressors are rare, they strongly indicate non-pCR at all treatment time points, while HER2- subtypes show more accurate results later in treatment. We are evaluating MRI change at 6 weeks to determine if that time point is sufficient to predict progressors. Table 1 MRI assessed tumor progression at different treatment time pointN/non-pCRs/%non-pCRMRI assessed tumor progressionT1 (after 3 weeks)T2 (inter-regimen)T3 (post-NAC)NNPV (%)NNPV (%)NNPV (%)Full cohort878/572/65%11883.14192.76100%HR+/HER2-344/280/81%4588.91190.93100%HR+/HER2+134/85/63%610021000N/AHR-/HER2+75/23/31%47521000N/Atriple negative325/184/57%6377.82692.33100% Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Jessica Gibbs, Lisa J Wilmes, Ella F Jones, Bonnie N Joe, Laura S Sit, Christina Yau, A. Jo Chien, Elissa Price, Kathy S Albain, Theresa Kuritza, Kevin Morley, Judy C Boughey, Kathy Brandt, Sadia Choudhery, Amy S Clark, Mark Rosen, Elizabeth S McDonald, Anthony D Elias, Dulcy Wolverton, Kelly Fountain, David M Euhus, Heather S Han, Bethany Niell, Jennifer Drukteinis, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Smita M Asare, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Donald A Berry, Angela DeMichele, Hiroyuki Abe, Deepa Sheth, Kirsten K Edmiston, Erin D Ellis, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Michael Nelson, An Church, Claudine Isaacs, Qamar J Khan, Karen Y Oh, Neda Jafarian, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Pulin Sheth, Linda Hovanessian-Larsen, Mohammad Eghtedari, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Sally Goudreau, Thelma Brown, Laura J Esserman, Nola M Hylton. Breast cancer subtype specific association of pCR with MRI assessed tumor volume progression during NAC in the I-SPY 2 trial [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 PD9-04.

Abstract Background: Strong background parenchymal enhancement (BPE) may cause overestimation in tumor volume measured from dynamic contrast-enhanced (DCE) MRI, which may adversely affect the ability of MR tumor volume to predict treatment outcome for patients undergoing neoadjuvant chemotherapy (NAC). Specifically, an overestimation of tumor volume can result in misclassification of patients with complete pathologic response (pCR) as non-responders, leading to less confidence in MRI prediction. As well, overestimation of extent of disease might lead to more aggressive surgical therapy than necessary. This study investigated whether high BPE in the contralateral breast influences the predictive performance of MRI-measured functional tumor volume (FTV) for patients with locally advanced breast cancer undergoing NAC. Methods: patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Each patient had 4 MRI exams: pre-NAC (T0), after 3 weeks of NAC (T1), between NAC regimens (T2), and post-NAC (T3). FTV was calculated at each MRI exam by summing voxels meeting enhancement thresholds. Background parenchymal enhancement (BPE) in the contralateral breast was calculated automatically as mean percentage enhancement on the early (nominal 150sec post-contrast) image in the fibroglandular tissue segmented from 5 continuous axial slices centered in the inferior-to-superior stack. For each treatment time point, patients having both FTV and BPE measurements were included in the analysis. The area under the ROC curve (AUC) was estimated as the association between FTV and pCR at T1, T2, and T3. The analysis was conducted in the full patient cohort and in sub-cohorts defined by hormone receptor (HR) and HER2 status. In each patient cohort, a cut-off BPE value was selected to classify patients with high vs. low BPE by testing AUCs estimated with low-BPE patients reached maximum when the cut-off value varied from median to maximum in steps of 10%. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Table 1 shows the number of patients, pCR rate, and AUC of FTV for predicting pCR using all patients available vs. a subset patients with low BPE (< BPE cut-off). In the full cohort, AUC increased slightly across all time points after patients with high BPE were removed. In the HR+/HER2- subtype, AUC increased at T1 after removal of cases with high BPE (0.65 vs. 0.71). For HR-/HER2+, AUC increased substantially after removal of high BPE cases (0.65 to 0.86 at T1, 0.71 to 0.87 at T2, and 0.71 to 0.89 at T3), with greater improvement at the early time point (T1) compared to later time points (T2 and T3). Only a slight improvement in the AUC was observed in the HR+/HER2+ and HR-/HER2- subtypes across all time points. Conclusions: High background parenchymal enhancement adversely affected the predictive performance of functional tumor volume measured by DCE-MRI, at early treatment time point for HR+/HER2- and across all time points for HR-/HER2+ cancer subtype. The adverse effect might be offset using subtype-optimized enhancement threshold in calculating functional tumor volume. Table 1 Effect of BPE on the prediction of pCR using FTV at various treatment time pointsT1T2T3npCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offFullAll64734%0.662762334%0.701761134%0.6925Subset45334%0.6831133%0.7230534%0.72HR+/HER2-All26218%0.651924918%0.718225518%0.7519Subset13118%0.7124818%0.7120419%0.76HR+/HER2+All10636%0.642110538%0.62269634%0.7120Subset5332%0.668438%0.665740%0.73HR-/HER2+All5175%0.65204774%0.71204973%0.7116Subset3073%0.862871%0.872475%0.89HR-/HER2-All22842%0.682822243%0.751821143%0.6916Subset15940%0.7111137%0.7810540%0.75 Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Roy Harnish, Ella F Jones, Lisa J Wilmes, Jessica Gibbs, Elissa Price, Bonnie N Joe, A. Jo Chien, Donald A Berry, Judy C Boughey, Kathy S Albain, Amy S Clark, Kirsten K Edmiston, Anthony D Elias, Erin D Ellis, David M Euhus, Heather S Han, Claudine Isaacs, Qamar J Khan, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Christina Yau, Smita M Asare, Angela DeMichele, Sally Goudreau, Hiroyuki Abe, Deepa Sheth, Dulcy Wolverton, Kelly Fountain, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Theresa Kuritza, Kevin Morley, Michael Nelson, An Church, Bethany Niell, Jennifer Drukteinis, Karen Y Oh, Neda Jafarian, Kathy Brandt, Sadia Choudhery, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Mohammad Eghedari, Pulin Sheth, Linda Hovanessian-Larsen, Mark Rosen, Elizabeth S McDonald, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Laura J Esserman, Nola M Hylton. The effect of background parenchymal enhancement on the predictive performance of functional tumor volume measured in MRI [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 P6-02-01.

6 Background: Traditional screening mammography (MG) enables early detection of breast cancer and therefore results in decreased mortality. Mammography, however, is an imperfect tool and limited by an overall sensitivity of 75-85%. Specificity is limited as well resulting in many false-positive examinations and unnecessary follow-up examinations. The recent development of contrast-enhanced digital mammography (CEDM) has made the usage of IV contrast enhancement with mammography a possibility. CEDM is an angiographic technique that uses digital subtraction, which removes the normal mammary gland on images in order to detect breast tumors and visualize their vascularity. The literature is promising with regard to CEDM as studies have found that CEDM achieves increased sensitivity without reductions in specificity in comparison to MG, US and/or MRI. Methods: In this multi-reader study we compared the diagnostic accuracy of CEDM as an adjunct to MG/US in patients with suspicious findings (BI-RADS 4). The study population included 31 patients who were imaged with CEDM prior to their scheduled US or stereotactic-guided biopsy. We compared the relative performance of MG/US alone versus MG/US/CEDM in determining the probability of malignancy. Histology served as the gold standard. Results: See table below. Conclusions: The addition of CEDM to the workup of suspected lesions on MG and/or US preliminarily decreases the number of false-positive MG thereby with potential to reduce cost and unnecessary patient harm. [Table: see text]