Ductal Carcinoma In Situ Nuclear Grade Research Articles

Abstract PO4-17-05: Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK

Abstract Background The use of adjuvant radiotherapy (RT) and endocrine therapy (ET) in the management of pure ductal carcinoma in situ (DCIS) remains controversial. We investigate how the use of adjuvant RT after breast conserving surgery (BCS) and use of adjuvant ET (in BCS and mastectomy patients) has changed over time. Methods A prospective cohort SQL database of 11,284 patients (the Sloane Project) diagnosed 2003-2012 with screen-detected DCIS in the UK was interrogated for use of adjuvant RT and ET over time and association with factors reported to be predictive of recurrence (patient age, DCIS nuclear grade, size, comedo necrosis, resection margins), as well as institution of surgery, travel time to radiotherapy facility, Index of Multiple Deprivation and outcome (provided by the National Disease Registration Service, NDRS). RT data by site were confirmed with more recent data from the National Audit of Breast Cancer in Older Patients (NABCOP), which looked at patterns of care and outcomes for women aged 70 years and over, compared with those aged 50-64 in England and Wales. Results Among the 7,949 women (70.6%) treated by BCS, post-operative adjuvant RT was given to 4,939 (62.1%); RT use after BCS increased over time (R2 =0.92; p< 0.01). RT use was associated with year of diagnosis (p < 0.01), younger age at diagnosis (p < 0.01), larger DCIS size (p < 0.01), presence of comedo necrosis (p < 0.01), higher nuclear grade (p < 0.01) and presence of microinvasion (p < 0.01). Adjusted analyses showed the most significant factor for RT after BCS was the surgery institution. Travel time to RT facility, Index of Multiple Deprivation and final radial margin were not associated with RT use. When compared with the more recent data from the NABCOP, a marked variation in radiotherapy use across hospitals remains. Ipsilateral recurrence rate varied significantly by hospital, with some of the difference associated with RT utilisation. ET was prescribed in 1313 women (12%), more often following BCS than mastectomy (p < 0.001), with significant variation by institution and a decline in the use of ET over time. Conclusion Marked geographic variation in the use of RT and ET after surgery for DCIS persists in the UK and is likely due to physician choice rather than other factors such as travel times to RT facilities. This is contributing to geographic variation in ipsilateral recurrence rates, suggesting the need for adoption of more authoritative guidelines to support clinical decision-making. Consistent national practice could provide auditable performance standards for adjuvant therapy of screen detected DCIS and contribute to more uniform patient care. Citation Format: Karen Clements, David Dodwell, Elinor Sawyer, Ramsey Cutress, Nisha Sharma, Abeer Shaaban, Alastair Thompson. Patterns of care: radiotherapy after breast conserving surgery and the use of endocrine therapy for screen-detected ductal carcinoma in situ (DCIS) in the UK [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-05.

Clinicopathologic Features, Treatment Patterns, and Disease Outcomes in a Modern, Prospective Cohort of Young Women Diagnosed with Ductal Carcinoma In Situ.

Ductal carcinoma in situ (DCIS) is uncommon and understudied in young women. The objective of this study is to describe clinicopathologic features, treatment, and oncologic outcomes in a modern cohort of women aged ≤40 years with DCIS. Patients with DCIS were identified from the Young Women's Breast Cancer Study, a multisite prospective cohort of women diagnosed with stage 0-IV breast cancer at age ≤40 years, enrolled from 2006 to 2016. Clinical data were collected from patient surveys and medical records. Pathologic features were examined by central review. Data were summarized with descriptive statistics and groups were compared with χ2 and Fisher's exact tests. Among the 98 patients included, median age of diagnosis was 38 years; 36 (37%) patients were symptomatic on presentation. DCIS nuclear grade was high in 35%, intermediate in 50%, and low in 15% of lesions; 36% of lesions had comedonecrosis. The majority of patients underwent bilateral mastectomy (57%), 16 (16%) underwent unilateral mastectomy, and 26 (27%) underwent lumpectomy, most of whom received radiation. Few (13%) patients were receiving tamoxifen therapy 1 year postdiagnosis. Over a median follow-up of 8.4 years, six patients (6%) had disease recurrence, including five locoregional and one distant event. A high proportion of young women with DCIS underwent mastectomy with or without contralateral prophylactic mastectomy. Although DCIS was frequently symptomatic on presentation and exhibited unfavorable pathologic factors, clinicopathologic features were overall heterogeneous and few recurrences occurred. This underscores the need for careful consideration of treatment options in young women with DCIS.

US, Mammography, and Histopathologic Evaluation to Identify Low Nuclear Grade Ductal Carcinoma in Situ.

Background Low nuclear grade ductal carcinoma in situ (DCIS) identified at biopsy can be upgraded to intermediate to high nuclear grade DCIS at surgery. Methods that confirm low nuclear grade are needed to consider nonsurgical approaches for these patients. Purpose To develop a preoperative model to identify low nuclear grade DCIS and to evaluate factors associated with low nuclear grade DCIS at biopsy that was not upgraded to intermediate to high nuclear grade DCIS at surgery. Materials and Methods In this retrospective study, 470 women (median age, 50 years; interquartile range, 44-58 years) with 477 pure DCIS lesions at surgical histopathologic evaluation were included (January 2010 to December 2015). Patients were divided into the training set (n = 330) or validation set (n = 147) to develop a preoperative model to identify low nuclear grade DCIS. Features at US (mass, nonmass) and at mammography (morphologic characteristics, distribution of microcalcification) were reviewed. The upgrade rate of low nuclear grade DCIS was calculated, and multivariable regression was used to evaluate factors for associations with low nuclear grade DCIS that was not upgraded later. Results A preoperative model that included lesions manifesting as a mass at US without microcalcification and no comedonecrosis at biopsy was used to identify low nuclear grade DCIS, with a high area under the receiver operating characteristic curve of 0.97 (95% CI: 0.94, 1.00) in the validation set. The upgrade rate of low nuclear grade DCIS at biopsy was 38.8% (50 of 129). Ki-67 positivity (odds ratio, 0.04; 95% CI: 0.0003, 0.43; P = .005) was inversely associated with constant low nuclear grade DCIS. Conclusion The upgrade rate of low nuclear grade ductal carcinoma in situ (DCIS) at biopsy to intermediate to high nuclear grade DCIS at surgery occurred in more than a third of patients; low nuclear grade DCIS at final histopathologic evaluation could be identified if the mass was viewed at US without microcalcifications and had no comedonecrosis at histopathologic evaluation of biopsy. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Rahbar in this issue. An earlier incorrect version appeared online. This article was corrected on April 14, 2022.

Assessing the correlation between FDG PET findings of IDC breast carcinoma and histopathology of coexisting ductal carcinoma in-situ.

Ductal carcinoma in-situ (DCIS) often coexists with invasive ductal carcinoma (IDC) of the breast. DCIS is considered as a non-obligate precursor of IDC when both coexist. 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) imaging is commonly used in the staging and follow-up assessment of breast cancer. In this study, we aimed to assess if there is any correlation between primary tumor PET and histopathology findings and histopathological features of the coexisting DCIS. FDG PET/CT images and histopathology results of the patients with newly diagnosed breast cancer (IDC) with coexisting DCIS were analyzed in this retrospective study. The grade and size of the primary tumor and histopathological features of the coexisting DCIS (nuclear grade and architectural pattern) were obtained from the postoperative histopathology results. Maximum standardized uptake values (SUV: SUVmax and SULmax) of the primary tumor normalized by weight and lean body mass were measured. Statistical analysis was performed to assess the correlation between various parameters of IDC and DCIS. This study included sixty-two (62) patients with IDC-DCIS. Primary tumor grade was significantly correlated and associated with the nuclear grade of the coexisting DCIS (polychoric correlation r = 0.736, and Fisher exact test, PV < 0.001, respectively). Primary tumor SUV was not correlated with the nuclear grade and architectural pattern of the coexisting DCIS (polyserial correlation r = 0.172, PV = 0.155, and Point Bi-Serial correlation r = -0.009, PV = 0.955, respectively). Median primary tumor size was marginally significantly different among DCIS nuclear grades but it was not significantly different in comedo and non-comedo cases (Kruskal-Wallis test PV = 0.053, and Mann-Whitney U test PV = 0.890, respectively). Primary tumor grade is correlated with the nuclear grade of the coexisting DCIS. SUV of primary tumor does not seem to be correlated with the histopathological features of coexisting DCIS (nuclear grade and architectural pattern) but this may be further studied in a larger number of patients.

Evaluation of ductal carcinoma in situ grade via triple-modal molecular imaging of B7-H3 expression

Ductal carcinoma in situ (DCIS) will account for 62,930 cases of breast cancer in 2019. DCIS is a pre-invasive lesion which may not progress to invasive carcinoma, yet surgery remains the mainstay treatment. Molecular imaging of a specific marker for DCIS grade for detection and active surveillance are critically needed to reduce potential overtreatment. First, breast cancer marker B7-H3 (CD276) expression was evaluated by immunohistochemical staining in 123 human specimens including benign epithelium (H-score 10.0 ± 8.2) and low (20.8 ± 17.7), intermediate (87.1 ± 69.5), and high (159.1 ± 87.6) grade DCIS, showing a positive association with DCIS nuclear grade (P < 0.001, AUC 0.96). Next, a murine DCIS model was combined with ultrasound molecular imaging of B7-H3 targeted microbubbles to differentiate normal glands from those harboring DCIS (n = 100, FVB/N-Tg(MMTVPyMT)634Mul, AUC 0.89). Finally, photoacoustic and fluorescence molecular imaging with an anti-B7-H3 antibody-indocyanine green conjugate were utilized for DCIS detection (n = 53). Molecular imaging of B7-H3 expression may allow for active surveillance of DCIS.

Evaluating the role of sentinel lymph node biopsy in patients with DCIS treated with breast conserving surgery

IntroductionThe role of sentinel lymph node biopsy (SLNB) for patients with ductal carcinoma in-situ (DCIS) is limited given the rarity of nodal metastasis in non-invasive disease. Although SLNB is typically a safe procedure, there are potential complications and associated costs. The purpose of this study is to assess national surgical practice patterns and clinical outcomes with respect to the use of SLNB for DCIS in patients undergoing breast conserving surgery (BCS). MethodsCase-level data from the National Cancer Data Base (NCDB) was assessed to identify adult patients ≥ 18 with DCIS, who underwent BCS and SLNB. Patient demographics and hospital characteristics were grouped for analytic purposes. A multivariate analysis was performed for patient and hospital characteristics. ResultsWe identified 15,422 patients with DCIS undergoing BCS in 2015, of which 2,698 (18%) underwent SLNB. A multivariate analysis demonstrated a significant association between greater frequency of SLNB in patients age range of 60–69, receipt of care at a community facility, and higher nuclear grade DCIS. Positive sentinel nodes metastasis was identified in 0.9% patients undergoing BCS and SLNB for DCIS. ConclusionThe role of SLNB in patients with DCIS undergoing BCS is limited and does not routinely provide meaningful information or benefit to clinical management. Despite this, nearly one in five patients undergoing BCS for DCIS had lymph node sampling performed. Given the potential increased morbidity and financial implications, this finding represents an opportunity for further education and improvement in patient selection for SLNB.

Behaviour and characteristics of low‐grade ductal carcinoma in situ of the breast: literature review and single‐centre retrospective series

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease that has risen to prominence and more recently controversy, with the advent of screening mammography. Debate concerning the true biological potential of low nuclear grade DCIS continues to challenge therapeutic considerations. In this study, we carried out a comprehensive literature review of the behaviour, outcomes and current management trials of low-grade DCIS, as well as a retrospective study of a large single institutional series of low-grade DCIS diagnosed at our hospital. The study cohort comprised 195 cases of low-grade DCIS diagnosed at the Singapore General Hospital from 1994 to 2010. Clinicopathological parameters and follow-up data were retrieved and compared between screen-detected and symptomatic low-grade DCIS. Immunohistochemistry was performed for ER, PR and HER2. Among 195 cases, 123 (63.1%) were screen-detected, while 72 (36.9%) were symptomatic. Screen-detected cases had frequent calcifications (P < 0.001) and were smaller (P = 0.018) than symptomatic cases. All cases were ER-positive and rate of PR expression was high. No HER2 overexpression was observed. Mean and median follow-up periods were 107.8 and 109.6 months, respectively. Six patients recurred ipsilaterally, and one patient developed direct distant metastasis. One breast cancer-related death was recorded. Positive surgical margins (P = 0.023) were significantly associated with a higher risk of ipsilateral recurrences, as well as poorer disease-free survivals (P = 0.010). Our data indicate that low-grade DCIS may be followed by invasive recurrences and even metastatic disease, requiring more study before being regarded as innocuous and indolent.

Ductal carcinoma in situ (DCIS) breast cancer treated with 3-week accelerated hypofractionated whole-breast radiation therapy and concomitant boost

IntroductionIn patients with ductal carcinoma in situ (DCIS), the clinical outcomes with hypofractionated (HF) whole-breast radiation (WBRT), as well as the role of lumpectomy boost, continue to be evaluated. In this paper, we report our experience on DCIS patients treated with HF WBRT with concomitant boost (CB).MethodsEarly-stage (DCIS, stages I and II) breast cancer patients were treated on an IRB-approved prospective single-arm study with HF WBRT and CB. This study includes only the DCIS subset of patients prescribed a dose of 40.5 Gy × 2.7 Gy per fraction to WB with CB of 4.5 Gy × 0.3G y per fraction over 15 fractions. A total of 107 breasts in 104 patients met the study criteria.ResultsAll patients underwent lumpectomy with negative margins. Median age was 59 years. DCIS nuclear grade distribution was 9.3% grade 1, 50.5% grade 2, and 37.4% grade 3. Majority (86%) were ER positive. 41.1% received endocrine therapy. With median follow-up of 74 months (range, 12–158), 5-year actuarial overall survival was 97.2%. At the time of this report, no patient has experienced local relapse. The CTCAE grades 1 and 2 acute skin toxicity was 66.4% and 3.7%, respectively. No patients experienced grade 3 or higher skin toxicity, breast pain, and fatigue.ConclusionThe HF schedule with CB in DCIS patients is well tolerated and associated with excellent clinical outcomes. This schedule affords the benefit of delivering higher dose to the lumpectomy site without protracting overall treatment time.

Predictors of Invasive Breast Cancer in Patients With Ductal Carcinoma In Situ in Ultrasound-Guided Core Needle Biopsy.

To determine predictors of invasiveness of lesions with US-guided biopsy-confirmed ductal carcinoma in situ (DCIS), focusing on US features, including shear wave elastography (SWE). From January 2015 to September 2016, a total of 80 lesions with US-guided biopsy-confirmed DCIS were detected in patients who underwent preoperative mammography, B-mode US, and SWE. Data were retrospectively reviewed from clinical records, pathologic reports, and imaging assessments. Imaging data included mammographic findings, B-mode US findings based on the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS), and the mean and maximum elasticity values on SWE. The final BI-RADS assessment, including the degree of elasticity of the mass, was evaluated. Continuous variables were examined by an independent t test, and categorical variables were examined by the Fisher exact test. The independent factors for predicting a histologic upgrade were evaluated by a multivariate logistic regression analysis. Among the 80 lesions, 27 (33.8%) showed an invasive component after surgical excision. None of the BI-RADS US descriptors, which include shape, orientation, margin, and echogenicity, showed a significant correlation with the rate of a histologic upgrade to invasive cancer. However, the BI-RADS assessment category (P = .015) and nuclear grade (P = .005) were significantly correlated with invasiveness of the mass. The maximum stiffness value was lower in the pure DCIS group (119.04 vs 85.33 kPa; P = .041). The BI-RADS category based on US findings, maximum stiffness value on SWE, and nuclear grade of DCIS are predictive of invasive components in DCIS.

Abstract GS5-05: Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance)

Abstract Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS. Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05). Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p&amp;lt;0.001) and from baseline to 6 months by 1.82 cm3 (p&amp;lt;0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078). Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS. Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-05.

Multiparametric MRI analysis of morphologico-functional features of DCIS - correlation with grade of nuclear atypia.

The aim was to analyze morphologico-functional characteristics of ductal carcinoma in situ (DCIS) in breast MRI to assess signs correlating with the degree of nuclear atypia. From 636 malignant lesions, 114 were DCIS (17.92%): 44 cases of high-grade (38.60%), 37 intermediate (32.45%), 33 low-grade (28.95%). MRI characteristics - T2 signal intensity (SI), shape, margins, contrast enhancement, peripheral/ductal enhancement, kinetic curve, presence of restriction of diffusion were correlated with the nuclear grade of DCIS. Statistical analysis was performed, statistical significance and Odds ratio (OR) were calculated. Signs of high-grade lesions were low SI in T2w (p=0.042), nonhomogeneous contrast enhancement (p=0.012), wash-out phenomenon (p=0.04), high SI in diffusion weighted imaging (DWI) (p<0.0001), restriction of diffusion in apparent diffusion coefficient map (p<0.0001). DWI and wash-out phenomenon reached the highest OR (56.00, 9.76). Breast MRI using DWI and multiparametric analysis provides important information about the degree of nuclear atypia.

Abstract P1-10-19: Two-year follow-up results of a multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer

Abstract Objective To assess the safety and efficacy of single-fraction, intra-operative radiation therapy (IORT) delivered with the Xoft® Axxent® Electronic Brachytherapy System® (eBx®) immediately following surgical resection for treatment of early stage breast cancer. Methods This phase 4, open-label, single-arm, prospective, non-randomized trial is still enrolling participants and is currently being conducted at 26 hospitals in the USA (25) and Portugal (1). 878 participants with biopsy-proven ductal carcinoma in situ (DCIS) or invasive ductal carcinoma who met the inclusion criteria underwent lumpectomy followed by single-fraction IORT to the lumpectomy cavity. Briefly, a small, presterilized lead shield piece was placed on the chest wall to reduce the dose to the ribs, and then a balloon applicator, suitable to the surgical bed, was placed in the lumpectomy cavity and inflated with saline (30-75 cc); skin was temporarily closed over the balloon and ultrasound was used to confirm a balloon surface-to-skin distance ≥ 1.0 cm. The Xoft System was used to deliver the 20 Gy dose at the balloon applicator surface. The balloon was deflated, lead shield and balloon removed and the surgical site sutured. The prespecified primary outcome of this 10-year follow-up study is recurrence of ipsilateral breast tumor at 5 years. Prespecified secondary outcomes include 10-year recurrence and cosmesis (Harvard Scale). Trial Registry: ClinicalTrials.gov; Identifier: NCT01644669. Findings Of the 878 participants treated, 877 participants received the prescribed 20 Gy dose with a mean radiation treatment time of 594.5 seconds, whereas one participant received 14 Gy due to a source failure. 569 participants have reached 18-month (333), 2-year (199), and 3-year (37) follow-up. The mean age at enrollment was 65 years (range 41-90). 219 participants had DCIS and 658 had invasive ductal carcinoma. The DCIS nuclear grade was high (N=79), intermediate (N=100), or low (N=40). Invasive cancers were Grade 1 (N=282), 2 (N=282), or 3 (N=94). 664 participants had T1 lesions, 56 had T2 lesions, and 3 were unknown. The mean tumor size was 12.33 ± 10.5 mm. Cosmesis was excellent to good in 90% of participants who reached 2-year follow-up. To date, 155 reported adverse events were Grade 2 or higher. The most frequent side effects were breast pain, seroma, induration, and erythema. There were nine deaths, none of which were breast cancer related, four ipsilateral breast recurrences, and three new contralateral breast cancers. Conclusions Early results from this multi-center trial demonstrate that IORT using the Xoft Axxent eBx System at the time of breast conservation surgery continues to be a promising treatment option for early stage breast cancer. The short course of radiation therapy for select patients has excellent to good cosmetic results and a low rate of high-grade adverse events and recurrences. Funding Funded by Xoft, Inc., a subsidiary of iCAD, Inc. Acknowledgement Medical writing support from Dr. Theresa E. Singleton, Singleton Science, LLC. Citation Format: Syed AMN, Chang H, Schwartzberg BS, Bremmer AK, Boylan S, Lopez-Penalver C, Vito CA, Davis M, Dooley WC, Chakravarthy AB, Croomer C, Proulx GM, Golder SL, Ivanov O, Fernandez KL, Farha M, Gonzalez V, Wengler C, Bhatnagar A, Neuner G, Kopkash K, Rahman S, Corn C, Costa P, Ellenhorn J, Cox C. Two-year follow-up results of a multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-19.

Abstract P1-10-20: A multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer: Early results of unplanned boost participants

Abstract Objective To assess the safety and efficacy of single-fraction, intra-operative radiation therapy (IORT) delivered as a boost using the Xoft® Axxent® Electronic Brachytherapy System® (eBx®) immediately following surgical resection for treatment of early stage breast cancer. Methods This phase 4, open-label, single-arm, prospective, non-randomized trial is still enrolling participants and is currently being conducted at 26 hospitals in the USA (25) and Portugal (1). 878 participants with biopsy-proven ductal carcinoma in situ (DCIS) or invasive ductal carcinoma who met the inclusion criteria underwent lumpectomy followed by single-fraction IORT to the lumpectomy cavity. Briefly, a small, presterilized lead shield piece was placed on the chest wall to reduce the dose to the ribs, and then a balloon applicator, suitable to the surgical bed, was placed in the lumpectomy cavity and inflated with saline (30-75 cc); skin was temporarily closed over the balloon and ultrasound was used to confirm a balloon surface-to-skin distance ≥ 1.0 cm. The Xoft System was used to deliver the 20 Gy dose at the balloon applicator surface. The balloon was deflated, lead shield and balloon removed and the surgical site sutured. Upon the presence of additional risk factors, 37 participants subsequently received whole breast radiation therapy (WBRT); thus, these participants received an unplanned IORT boost and were removed from the primary analysis but will continue to be followed for the duration of the 10-year study. Cosmesis (Harvard Scale) was assessed in this subset of participants. The primary outcome for the main trial is recurrence of ipsilateral breast tumor at 5 years. Trial Registry: ClinicalTrials.gov; Identifier: NCT01644669. Early Findings 37 boost participants received WBRT (up to 50 Gy) after IORT (36 received the prescribed 20 Gy dose; one received 14 Gy). Mean follow-up time was 430 days (range 13-1119). Mean age at IORT was 62 years (range 45-78). Boost participants had either DCIS (N=5) or invasive ductal carcinoma (N=32). The DCIS nuclear grade was high (N=3), intermediate (N=1), or low (N=1). Invasive cancers were Grade 1 (N=15), 2 (N=10), 3 (N=6), or unknown (N=1). 29 participants had T1, 3 had T2, and 5 had Tis lesions. Mean tumor size was 13.04 ± 10.26 mm. For the two participants who have reached 3-year follow-up, cosmesis was excellent (N=1) and fair (N=1). For the six participants who have reached 2-year follow-up, cosmesis was excellent (N=4), good (N=1), and fair (N=1). There was one serious adverse event with a Grade 3 for skin necrosis. The most frequent side effects were seroma (10%), edema (9%), pain (9%), erythema (6%), and induration (5%). There have been no deaths, recurrences, or new primary tumors among the boost participants to date. Conclusions Early results from this multi-center trial suggest that IORT as a tumor-bed boost using the Xoft Axxent eBx System at the time of breast conservation surgery is safe and has low morbidity. To date, the majority of participants receiving an unplanned IORT boost have had excellent to good cosmetic results and the majority of adverse events have been low-grade. Funding Funded by Xoft, Inc., a subsidiary of iCAD, Inc. Citation Format: Syed AMN, Chang H, Schwartzberg B, Bremner A, Boylan S, Lopez-Penalver C, Vito C, Davis M, Dooley W, Chakravarthy AB, Coomer C, Proulx G, Golder S, Ivanov O, Fernandez K, Farha MJ, Gonzalez V, Wengler C, Bhatnagar A, Neuner GA, Kopkash K, Rahman S, Costa P. A multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer: Early results of unplanned boost participants [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-20.

Differential Gene Expression in Ductal Carcinoma In Situ of the Breast Based on ERBB2 Status.

The molecular signature of ductal carcinoma in situ (DCIS) in the breast is not well understood. Erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly known as HER2/neu]) positivity in DCIS is predictive of coexistent early invasive breast carcinoma. The aim of this study is to identify the gene-expression signature profiles of estrogen receptor (ER)/progesterone receptor (PR)-positive, ERBB2, and triple-negative subtypes of DCIS. Based on ER, PR, and ERBB2 status, a total of 18 high nuclear grade DCIS cases with no evidence of invasive breast carcinoma were selected along with 6 non-neoplastic controls. The 3 study groups were defined as ER/PR-positive, ERBB2, and triple-negative subtypes. A total of 49 genes were differentially expressed in the ERBB2 subtype compared with the ER/PR-positive and triple-negative groups. PROM1 was overexpressed in the ERBB2 subtype compared with ER/PR-positive and triple-negative subtypes. Other genes differentially expressed included TAOK1, AREG, AGR3, PEG10, and MMP9. Our study identified unique gene signatures in ERBB2-positive DCIS, which may be associated with the development of invasive breast carcinoma. The results may enhance our understanding of the progression of breast cancer and become the basis for developing new predictive biomarkers and therapeutic targets for DCIS.

Sensitivity of breast MRI for ductal carcinoma in situ appearing as microcalcifications only on mammography

PurposeThis study aims to investigate sensitivity of breast magnetic resonance imaging (MRI) for mammographic microcalcifications-only ductal carcinoma in situ (DCIS), based on its histopathology and mammographic extent of microcalcifications. MethodsMammograms were reviewed to measure the extent of microcalcifications. Sensitivity of MRI was calculated in the overall study population and in groups differing for DCIS nuclear grade, microinvasivity, and microcalcifications' extent. ResultsOverall sensitivity of MRI was 78.3% for dynamic contrast enhanced and 66.7% for diffusion-weighted imaging and did not vary with nuclear grade and microinvasivity, while it increased with larger extent of microcalcifications (ExpB=1.063–1.046, P=.037–.013). ConclusionsMammographic extent of microcalcifications positively affects sensitivity of breast MRI.

Screen-detected ductal carcinoma in situ found on stereotactic vacuum-assisted biopsy of suspicious microcalcifications without mass: radiological-histological correlation.

BackgroundCommonly identified on screening mammography breast microcalcifications are the predominant manifestation of ductal carcinoma in situ (DCIS). The aim of this study was to investigate the association between clinico-radiological features and histological findings in patients with screen-detected DCIS.Patients and methodsConsecutive 127 patients with pure DCIS found on stereotactic vacuum-assisted biopsy of screen-detected suspicious microcalcifications without mass entered the study. Patient age, type and distribution of microcalcifications, DCIS nuclear grade (NG) and the presence of comedonecrosis were investigated. Association between parameters was statistically analysed with P < 0.05 as a significance level. Results. Powdery microcalcifications were most often clustered while regional were most common of casting-type (P < 0.001). High, intermediate and low NG of DCIS was significantly related to casting-type, crushed stone-like and powdery microcalcifications, respectively (P < 0.01). Low and intermediate NG DCIS were the most common in clustered and grouped microcalcifications while high NG DCIS was the most often when regional distribution was observed (P < 0.05). Comedonecrosis was significantly more common in high NG DCIS (P < 0.01). The association between comedonecrosis and type of microcalcifications was not significant, but with their distribution was close to the significance level (P = 0.07). Patient age was not significantly related to imaging or histological findings.ConclusionsThe association between pattern of mammographic microcalcifications and histological findings related to more aggressive disease can be helpful in optimal surgery planning in patients with screen-detected DCIS, regarding the extent of breast intervention and consideration of synchronous sentinel node biopsy.

Abstract P2-04-06: Demonstration of immune cell and pathway heterogeneity in Singapore DCIS samples using novel hyperplexing method (MultiOmyx®)

Abstract Breast cancer is the most common malignancy in Singapore women with rising incidence across all ethnic groups (Chinese, Malays and Indians). Ductal carcinoma in situ (DCIS) is the earliest non-invasive stage of disease and has been shown to account for approximately 26% of diagnoses in all women participating in the Breast-Screen Singapore program. Despite availability of breast screening, there are still Singapore women presenting with locally advanced breast cancer. The goal of the current study was to investigate pathway and immune cell heterogeneity in low, intermediate and high nuclear grade DCIS using a newly developed method for in situ hyperplexed analysis of multiple proteins in a single FFPE tissue (MultiOmyx). FFPE samples from patients (n= 15) diagnosed with DCIS were provided by Singapore General Hospital. Patients were of Chinese origin, ranged from 50-59 years, were all post-menopausal, and included low (n=5), intermediate (n=5) and high grade (n=5) samples. All histological diagnoses were reviewed by a single pathologist. Following a single antigen retrieval step, DAPI and cytokeratin staining was conducted and imaged at 10X. Based on DAPI, cytokeratin and autofluorescence, an H&amp;E-like image was generated for each sample. Using this image, approximately 30 regions of interest (ROI) were selected per slide/patient, including normal and DCIS regions with and without immune cells. In total, 15 biomarkers were imaged following an iterative process of IF staining and dye inactivation. These included CD4 (T-cells), CD8 (T-cells), CD20 (B-cells), CD68 (macrophages), CD10 (myoepithelial cells), CD44v6 (cancer stem cell), Her2, Her4, EGFR (ErbB family proteins), pmTOR (cell growth), SLC7A5 (Mammostrat) and epithelium and cell segmentation markers (pan-cadherin, pan-cytokeratin, S6 and Na+K+ATPase). Images were evaluated for quality and processed to generate single cell quantification data for each marker in the epithelium and stroma. Single cell data was compared with clinical and histological features (grade, DCIS/ low immune cells, DCIS/ high immune cells). Cell-based k-means clustering was then performed for biomarkers in both the epithelial cells (Her4, Her2, panCK, SLC7A5, EGFR, NaKATPase, pmTOR, and CD10) and stromal cells (CD4, CD8, CD20, CD68). Using consensus clustering, the optimum number of clusters was found to be six in both the epithelium and stroma. No distinct clusters were associated with histological grade. Normal ROIs tended to be associated with higher CD10 and EGFR, moderate CD20 and low or negative for other markers. DCIS with low immune cells tended to have higher Her4, pmTOR and moderate CD68 while DCIS with high immune cells tended to have high Her2 and moderate to high CD4, CD20 and CD68. A larger study is needed to associate the findings with outcome. This technology provides a way to elucidate mechanisms of early disease and illustrates the complex inter-play between grade, pathway activation and immune response. Citation Format: Nicole E LaPlante, Yunxia Sui, Michael J Gerdes, Sean Dinn, Rong Zhang, Sireesha Kaanumalle, Elizabeth McDonough, Christina Lowes, Craig Allred, Fiona Ginty, Thomas Foo, Puay-Hoon Tan. Demonstration of immune cell and pathway heterogeneity in Singapore DCIS samples using novel hyperplexing method (MultiOmyx®) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-04-06.

Molecular profiling of breast ductal carcinoma in-situ

Ductal carcinoma in-situ (DCIS) is a precursor of invasive breast carcinoma (IBC) and highly heterogeneous with variable presentation, morphology, and behavior. Although significant advance has been made in understanding the molecular changes in IBC in the past decade, the exact molecular behavior of DCIS, especially how it progresses to IBC is not well understood. Biomarkers that predict development of IBC are needed to improve personalized therapy. We have shown HER2 positivity in DCIS is significantly predictive of co-existent early IBC, raising a hypothesis that there are significant, differentially expressed genes in HER2 positive DCIS that are associated with high risk of developing IBC, as compared to more indolent DCIS. Gene expression profiles were performed in high nuclear grade DCIS, with different receptor status, using Affymetrix Human Gene 1.0 ST array and analyzed with the MATLAB software. Approximately thirty genes were identified to be expressed differently in the HER2 subtype as compared to the two other groups (ER/PR+ and triple negative). Uncovering gene expression signatures of HER2 positive DCIS can enhance our understanding of the mechanisms of breast cancer progression and become the basis for developing new predictive biomarkers and/or therapeutic targets, enhancing the management of patients with DCIS.

Abstract P5-16-04: Predictive biomarkers for invasion on final pathology in patients with preoperative diagnosis of ductal carcinoma in situ of the breast by needle biopsy

Abstract Background Predictors of synchronous invasive breast cancer in patients diagnosed with only ductal carcinoma in situ (DCIS) in pre-operative needle biopsies have not been well-defined. Establishing such predictors of invasion has potential to significantly alter management by identifying those patients for whom surgery may be avoidable en lieu of conservative management. This study aims to identify clinicopathologic factors from pre-operative needle biopsies that are predictive of invasive cancer on subsequent surgical excision. Methods The study population consisted of 69 breasts from 67 patients initially diagnosed with only DCIS on needle biopsy (core needle or mammotome) at St. Luke's International Hospital, Japan from 2006 until 2008. Parameters analyzed included presenting clinical features, DCIS nuclear grade and morphologic pattern, and immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor-2 (HER2), Ki-67 antigen, p16, p53 and cyclooxygenase-2 (COX2) in biopsy specimens. These immunohistochemical markers were previously identified to foretell invasive carcinoma subsequent to DCIS (Kerlikowske, JNCI 2010). Associations between clinical, pathological, and immunohistochemical findings in initial biopsy specimens and the presence of invasive cancer on subsequent excision were analyzed for significance using univariate and multivariate analysis. Results Of 69 breasts with only DCIS on initial needle biopsy, subsequent surgical excision revealed pure DCIS in 46 (66.7%), microinvasive carcinoma in 4 (5.8%), and invasive carcinoma in 19 (27.5%) cases. Sentinel node biopsy was performed in 57 (82.6%) of 69 cases, and 53 (93.0%) of these showed no evidence of lymph node metastases. All 4 cases with lymph node metastases revealed invasive carcinoma in surgical excisions. By univariate analysis, pre-operative factors significantly associated with invasion on surgical excision included detection of a lump by palpation (p&amp;lt;0.05), sampling by core needle biopsy rather than mammotome (p&amp;lt;0.01), p53 positivity (p&amp;lt;0.01), and lack of ER expression (p&amp;lt;0.05) in needle biopsy samples. Combined absence of p16 and COX2 with low Ki-67 expression in needle biopsies was associated with pure DCIS (and absence of invasive cancer) in surgical excisions (p&amp;lt;0.05). Multivariate analysis using all five significant univariate variables revealed two independent pre-operative predictors of invasive cancer on final pathology, namely sampling by core needle biopsy (odds ratio 7.0; 95% CI 1.2-41.7; p&amp;lt;0.05) and p53 positivity (odds ratio 7.1; 95% CI 1.1-44.9; p&amp;lt;0.05). Conclusion If confirmed in a larger sample, predictive clinical and biomarker parameters can help identify those patients diagnosed with only DCIS in needle biopsy who are at high risk of harboring unsampled invasive cancer on final pathology. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-04.

Abstract P2-11-19: Expression of folate receptor alpha in ductal carcinoma in situ of the breast and comparison with that of invasive ductal carcinoma

Abstract Background: We have previously shown that the expression of Folate receptor alpha (FRA) is associated with high grade ER-/PR- or triple negative (TN) invasive ductal carcinoma of the breast. The aim of the current study is to investigate the expression pattern of FRA in a cohort of ductal carcinoma in situ (DCIS), analyze its relationship with different clinicopathological features and expression of several key biomarkers, and compare these findings to our previous data on invasive ductal carcinoma (IDC). Methods: Ninety-eight cases of DCIS of the breast diagnosed between 1997 and 2008 in our institution were identified, reviewed and 6 blocks of tissue microassays (TMA) were constructed. The association between the expression of FRA (≥10% designed as positive expression) and the clinicopathologic features, the expression of ER, PR, HER2 and Ki-67, and the clinical outcome were evaluated, and these results were compared to those from IDC (399/430 cases with informative data). Results: Among the 98 cases of DCIS in TMA, 88 cases were informative. The expression rate of FRA was 21% for DCIS, less than the 29% seen in IDC. Expression of FRA was associated with high nuclear grades (42%), though less frequently than with IDC (52%). FRA expression was also associated with ER negativity (46%), PR negativity (33%) and high Ki-67 expression (50%) in DCIS, although significantly less than in IDC (75%, 63%, and 56%, respectively for negative ER and PR, and high Ki-67). Also, only 50% of ER/PR negative, TN and basal-like DCIS expressed FRA, significantly lower than that of IDC (74%, 80% and 80%, respectively). Due to the limited cases of DCIS, we did not demonstrate a significant difference in disease-free survival between FRA positive and negative tumors (p-value = 0.1792), although we did observe that IDC with FRA expression was significantly associated with a worse disease-free survival (p-value = 0.04). Comparison between FRA expression between DCIS and IDC FRA≥10% in DCISFRA≥10% in IDCp-value 88 cases399 cases Nuclear 342%52%0.0185ER negative46%75%0.0442PR negative33%63%0.0214HER2 3+31%37%0.7003ER-/PR-50%74%0.0973Triple Negative50%80%0.1622Basal-Like50%80%0.1739 Conclusion: Our data demonstrates that FRA expression is associated with high nuclear grade, ER/PR negative and TN DCIS, though at a significantly lower rate than was observed in IDC, suggesting a possible role for this receptor in early breast carcinogenesis. There are differences in the rates of FRA expression between DCIS and IDC, suggesting that FRA may be one of the key molecules involved in progression of DCIS to IDC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-19.