Low-grade Ductal Carcinoma In Situ Research Articles

Inter-observer variability between general pathologists and a specialist in breast pathology in the diagnosis of lobular neoplasia, columnar cell lesions, atypical ductal hyperplasia and ductal carcinoma in situ of the breast

BackgroundThis study aimed to assess inter-observer variability between the original diagnostic reports and later review by a specialist in breast pathology considering lobular neoplasias (LN), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) of the breast.MethodsA retrospective, observational, cross-sectional study was conducted. A total of 610 breast specimens that had been formally sent for consultation and/or second opinions to the Breast Pathology Laboratory of Federal University of Minas Gerais were analysed between January 2005 and December 2010. The inter-observer variability between the original report and later review was compared regarding the diagnoses of LN, CCL, ADH, and DCIS. Statistical analyses were conducted using the Kappa index.ResultsWeak correlations were observed for the diagnoses of columnar cell change (CCC; Kappa = 0.38), columnar cell hyperplasia (CCH; Kappa = 0.32), while a moderate agreement (Kappa = 0.47) was observed for the diagnoses of flat epithelial atypia (FEA). Good agreement was observed in the diagnoses of atypical lobular hyperplasia (ALH; Kappa = 0.62) and lobular carcinoma in situ (LCIS; Kappa = 0.66). However, poor agreement was observed for the diagnoses of pleomorphic LCIS (Kappa = 0.22). Moderate agreement was observed for the diagnoses of ADH (Kappa = 0.44), low-grade DCIS (Kappa = 0.47), intermediate-grade DCIS (Kappa = 0.45), and DCIS with microinvasion (Kappa = 0.56). Good agreement was observed between the diagnoses of high-grade DCIS (Kappa = 0.68).ConclusionsAccording to our data, the best diagnostic agreements were observed for high-grade DCIS, ALH, and LCIS. CCL without atypia and pleomorphic LCIS had the worst agreement indices.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1640072350119725.

The radiological excision of high risk and malignant lesions using the INTACT breast lesion excision system. A case series with an imaging follow up of at least 5 years

PurposeTo evaluate the efficacy of a BLES procedure as a primary excisional biopsy rather than a surgical wide local excision for treatment of a high risk or a malignant lesion. Methods41 patients underwent a BLES procedure in order to attempt to remove a small breast lesion using a 15 mm or 20 mm wand from August 2007 to January 2009. The lesions were either proven on prior core biopsy to show high risk or malignant pathology or were considered to be indeterminate or suspicious on ultrasound or mammography. The pathology was reviewed to include the final status of lesion excision. If margin involvement was demonstrated then a formal surgical excision was subsequently recommended. Follow up mammography or ultrasound was performed annually in patients following the final pathological diagnosis. Results9 patients had a primary diagnosis of atypia (columnar cell change with atypia or atypical ductal hyperplasia (ADH)), 23 patients had ductal carcinoma in situ (DCIS) and 9 had an invasive carcinoma (IC) at the original BLES pathology. Clear BLES margins of >1 mm were obtained in 3/9 atypia lesions, 15/23 DCIS and 0/9 IC. 12/13 low grade DCIS were completely excised. Subsequent surgical margin excisions were undertaken in 20 patients. After at least 5 years of follow up (mean 66 months), 1 lesion had recurred on imaging. ConclusionA BLES excision has potential as an alternative technique to traditional surgical wide local excision in the management of certain small breast lesions with high risk and low grade malignant potential.

Renaming Ductal Carcinoma in Situ: Would Removing “Carcinoma” Reduce Overtreatment?

In both the medical literature and lay press, a flurry of controversy has arisen surrounding the treatment and, more specifically, the potential overtreatment of ductal carcinoma in situ (DCIS). Since the advent of population-based screening mammography in the mid-1980s, the incidence of DCIS has increased more than 8-fold, with DCIS now accounting for nearly 22% of new breast cancer diagnoses.1,2 Since 1990, death rates from breast cancer in the United States have decreased by approximately 34%,1,3 a favorable outcome that has been attributed to the combination of increased screening mammography and improved adjuvant therapy.4 However, despite the steady increase in DCIS detection and treatment in the 1990s, the subsequent incidence of invasive breast cancers did not proportionately decrease.5 Invasive breast cancer incidence among women older than 50 years declined sharply between 2002 and 2003 but has since stabilized, a finding that could reflect a reduced pool of prevalent breast cancer cases as a result of widespread screening, but also could relate to the decreased use of hormone replacement therapy or trends in mammography screening rates that peaked in 2000.1 Approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS, of which up to 30% will be treated with mastectomy.6,7 Several recent publications suggest the possibility that, although implementation of routine screening mammography has led to an overall increase in breast cancer detection and has been associated with a decrease in overall breast cancer mortality, it has not produced the magnitude of reduction in advanced-stage cancers one would expect based on detection of breast cancer at its nascent stage, namely DCIS.8 DCIS can be defined, to patients and providers alike, as noninvasive, preinvasive, a precursor to, stage 0, or, quite simply, what most patients hear at the end of such a preface: breast cancer. This dilemma in terminology has led to heated discourse at national breast specialty meetings and to front-page cover stories in The New York Times, and is an important issue to the growing constituency of breast cancer survivors who drive breast cancer awareness in this country.9 DCIS is a non–life-threatening, atypical intraductal proliferation that, if left untreated, can progress to invasive breast cancer. However, DCIS progression is not obligatory and not inevitable. Sanders et al10 showed that a significant fraction of DCIS cases will not progress to clinically apparent invasive disease. They examined the incidence of invasive breast cancer among a large cohort of patients originally diagnosed in the 1950s and 1960s as having benign breast pathology but who, on retrospective review were found to have low-grade DCIS. Of those with DCIS, only 40% subsequently developed an invasive breast cancer in the same quadrant of the same breast, most of which occurred within 10 years. Other studies, including population-based modeling experiments, have examined the natural history of low-grade DCIS and suggest that as few as 20% of cases might progress to invasive cancer over a protracted period spanning from 5 to 40 years.5 In the absence of progression to invasive cancer, overall survival after a diagnosis of DCIS is upwards of 98%. The goal of treatment is solely to prevent either local recurrence or progression to invasive breast cancer. Based on data from 4 randomized clinical trials, local treatment options for patients with DCIS currently include either breast-conserving surgery followed by radiation therapy, or mastectomy.11–14 Tamoxifen is also considered as possible adjuvant therapy for patients with estrogen receptor–positive DCIS, both for reduction of local recurrence risk after breastSara H. Javid, MD

Breast screening saves lives: now is the time to address overtreatment

Breast screening saves lives: now is the time to address overtreatment

Digital Mammography Screening: Association between Detection Rate and Nuclear Grade of Ductal Carcinoma in Situ

To determine the relationship between overall detection rates of ductal carcinoma in situ (DCIS) and the specific detection rates of low-, intermediate-, and high-grade DCIS at the start of a digital mammography screening program. The study was approved by the local ethics board and did not require informed consent. Data were included of the first round of digital mammography examinations, performed in 17 screening units in women aged 50-69 years from 2005 to 2008. Grading was provided by the cancer registry for 1018 DCIS cases. The association between the overall cancer detection rate (cases per 100 women screened) and the separate cancer detection rate for invasive cancers and for DCIS was assessed. Likewise, the total DCIS cancer detection rate was separated into rates for low, intermediate, and high grades. Spearman rank correlations were used for analysis. The overall cancer detection rate correlated with both the cancer detection rate of invasive cancers and the cancer detection rate of DCIS (r = 0.96 and r = 0.88, respectively; P < .001 for both). The cancer detection rate of total DCIS with grading varied among screening units (range, 0.05-0.25), it was borderline not significantly correlated with the cancer detection rate of low-grade DCIS (range, 0.004-0.05; r = 0.49; P = .052), and it showed significant correlations with higher cancer detection rate of intermediate-grade DCIS (range, 0.02-0.12; r = 0.89; P < .001) and of high-grade DCIS (range, 0.03-0.11; r = 0.88; P < .001). This study demonstrates that high overall cancer detection rates in digital mammography screening are related to high detection rates of invasive cancers, as well as DCIS. Increases in the detection rates of DCIS were not driven by disproportionate increments of the slowly progressive low-grade subtype but rather by increased rates of intermediate- and high-grade subtypes that carry a higher risk of transition to invasive cancers.

Concordance between vacuum assisted biopsy and postoperative histology: Implications for the proposed Low Risk DCIS Trial (LORIS)

The recent Breast Cancer Screening Review has estimated that for one life saved three patients are overtreated. The dramatic increase in the diagnosis of Ductal carcinoma in-situ (DCIS) has not lead to the expected decrease in the incidence of invasive cancer. It is not clear if all DCIS progress to invasive cancer if untreated. The Low Risk DCIS Trial (LORIS) intends to compare the current treatment of low risk DCIS i.e. surgery, with active monitoring. For effective implementation, concordance between diagnostic biopsy using large volume vacuum assisted biopsy (VAB) and excision histology is vital. A two-centre UK audit was done to assess concordance in patients diagnosed with low grade DCIS diagnosed using VAB. Data of DCIS diagnosed with VAB from year 2001-2010 in University Hospital Birmingham and Leeds Teaching Hospitals was retrospectively collected and concordance between diagnostic and excision histology was assessed. Low Grade DCIS diagnoses were further evaluated retrospectively with regard to their eligibility for LORIS. Of 225 DCIS diagnoses 128 (57%) were high grade, 66 (29%) intermediate grade and 31 (14%) low grade. Overall 18% were upgraded to invasive cancer. The upgrade rate to invasive cancer for high grade was 23% and for low grade DCIS was 10%. In the low grade group eligible for LORIS, there were no upgrades to invasive cancer. The upgrade rates to invasive cancer are comparable to series published in literature. The concordance for the low risk DCIS with zero upgrade to invasive cancer supports the stringent LORIS eligibility criteria for trial selection.

Role of sentinel lymph node biopsy (SLNB) and preoperative MRI in the management of patients with pure high-grade ductal carcinoma in situ (DCIS).

87 Background: The overall incidence of SLN metastases in pure DCIS is &lt; 1% and the results of SLNB do not usually impact treatment or survival but adds significant surgical morbidity. In addition, there is no evidence regarding the role of preoperative MRI in the management of DCIS. The purpose of our study was to identify the efficacy of SLNB and the benefit of preoperative MRI in high-grade DCIS. Methods: We performed retrospective review of 364 patients with DCIS, identified through our cancer registry database, that were seen from 2003 to 2012 at our institution. Of these, 62 patients were diagnosed with high-grade DCIS (Grade 3 or 2 with comedonecrosis) by core needle biopsy, and underwent SLNB. The remaining 302 patients had either low-grade DCIS or did not have a SLNB. Results: Median age was 56 years (range 33-80). Sixty two patients had high-grade DCIS on definitive excision and 2/62 patients were noted to have small invasive focus of disease. 15/62 (24.19%) patients underwent mastectomy and 47/62(78.1%) underwent lumpectomy. No patient had a positive SLN (0/62). 15/62 (24.2%) patients had breast MRI preoperatively and among them, in 5 (33.3%) patients, MRI findings changed the surgical decision to mastectomy. Among these 5 mastectomy patients, four of them (80%) had pathologically confirmed findings consistent with preoperative MRI suspicions. In lumpectomy patients, close margin of less than 1mm was seen in 4/9 (44.4%) patients with staging MRI and in 24/38 (63.15%) patients without MRI (p = 0.45. Fisher’s exact test). However the positive margin leading to re-excision was seen in 2/9 (22.2%) patients who underwent lumpectomy with staging MRI, and 9/38 (23.6%) patients who underwent lumpectomy without staging MRI. Conclusions: In our study, no patient with high grade DCIS had a positive sentinel node suggesting that routine sentinel node biopsy is not necessary in DCIS patients. The use of MRI changed the surgical planning in 33.3% of patients, but did not improve the surgeon's ability to achieve clear margins.

Analysis of expression of membrane-bound tumor markers in ductal carcinoma in situ of the breast: paving the way for molecular imaging

Achieving radicality during breast conserving surgery for pure ductal carcinoma in situ (DCIS) of the breast and invasive cancer surrounded by DCIS is challenging. Molecular imaging holds promise here, when applied as a tool for image-guided surgery of DCIS. Tissue microarrays containing 24 pure DCIS and 63 DCIS with adjacent invasive breast cancer cases were stained by immunohistochemistry for a panel of membrane-bound targets. GLUT1 expression was present in 60.9%, IGF1-R in 55.2% HER2 in 28.7%, MET in 18.4%, EGFR in 16.1%, CD44v6 in 69%, carbonic anhydrase XII (CAXII) in 24.1% and Mammaglobin in 14.9% of DCIS cases. No expression differences between pure DCIS and DCIS with adjacent cancer were observed. Further, HER2 and EGFR expression were correlated with high grade DCIS (p=0.001) and CAXII with low grade DCIS (p=0.027). A putative panel containing HER2, EGFR, GLUT1 and IGF1-R had a detection rate of 90.2% for DCIS and 78.3% for adjacent breast cancer. We found that membrane-bound targets are more frequently expressed in DCIS than in invasive breast cancer, but that single membrane proteins are too infrequently expressed to serve as single imaging targets for the detection of DCIS. However, a panel of markers consisting of IGF1-R, CD44v6, GLUT1, EGFR, and HER2 was found to be positive in 96.3% of DICS based on marker expression in the adjacent invasive breast cancer as described earlier. This implies that detection of DCIS based on marker expression in the adjacent invasive breast cancer during breast conserving surgery should be possible with a panel of molecular imaging tracers targeting CD44v6, GLUT1, HER2, IGF1-R, and EGFR.

Recognizing breast ductal carcinoma in situ on fine‐needle aspiration: A diagnostic dilemma

In this study, we evaluated cytomorphologic features of different subgroups of ductal carcinoma in situ (DCIS); we compared seven cytologic features between DCIS and invasive ductal carcinoma (IDC) aspirates to determine whether diagnosis of stromal invasion can be made based on fine-needle aspiration (FNA) findings. There were 142 cases of DCIS and 1,978 cases of IDC enrolled in our study. FNA analysis revealed 80.3% sensitivity for DCIS and 94.7% sensitivity for IDC. High and intermediate grade DCIS exhibited marked nuclear abnormality (92.1% vs. 35.7%, 30.0%; P1 < 0.001, P2 < 0.001) and necrosis (69.7% vs. 0%, 10.0%; P1 < 0.001, P2 = 0.001) in a higher percentage of cases compared to low grade DCIS and intraductal/intracystic papillary carcinoma. The rates of background macrophages (71.3% for DCIS and 21.9% for IDC, P < 0.001) and extensive necrosis (54.0% for DCIS and 16.7% for IDC, P < 0.001) were significantly higher in DCIS compared to IDC. Lymphocytes were observed in conjunction with tumor cells more frequently in IDC (81.3%) compared to DCIS (36.8%, P < 0.001). Stromal fragments associated with tumor cells were only observed in invasive lesions (11.9% micro-invasive DCIS and 52.1% IDC). Tubular structures were found exclusively in IDC (11.5%). Cytologic criteria for diagnosis of high and low grade DCIS are different. The suspicion of DCIS is raised when background macrophages and extensive necrosis are observed. Stromal invasion is suggested by FNA if lymphocytes are entwined around tumor cells or if stromal fragments associated with tumor cells or tubular structures are observed.

Ductal carcinoma in situ : a ticking time bomb

85 ISSN 1758-1923 10.2217/BMT.12.69 © 2013 Future Medicine Ltd Breast Cancer Manage. (2013) 2(2), 85–88 The goal of screening is to detect cancer early and improve survival. Most screen-detected cancers should be treated effectively with fewer and less morbid therapies. Over the last decade, the quality of mammography and other imaging modalities for breast cancer screening has improved, resulting in a dramatic increase in the number of women diagnosed with noninvasive ductal carcinoma in situ (DCIS). In 2005, almost 60,000 cases of DCIS were recorded in the USA, representing nearly a quarter of all screen-detected cancers [1]. Evidence that earlier detection of DCIS improves diseasespecific survival is controversial, however, and many groups question the value of current breast-screening programs. Despite technological improvements in imaging, treatment for DCIS has not changed. Women with small foci of lowgrade DCIS are often treated with a onesize-fits-all barrage of surgery, radiotherapy and hormonal therapy. Analyses of trends over time show that, since 1998, both the mastectomy rate and the contralateral prophylactic mastectomy rate for DCIS have increased dramatically. DCIS is an independent risk factor for bilateral mastectomy in many studies, despite the results of the NSABP B-17 and B-24 trials, which demonstrate the safety of breastconserving surgery (BCS) for DCIS [2]. For those selecting BCS, there also appears to be a very high rate of intervention in the first decade after treatment [3], leading many to wonder if, from both a psychological and an economic standpoint, BCS is really worth it. Here, we present some current therapies and opportunities for future research regarding the treatment of DCIS.

Abstract P2-10-35: The grade of accompanying DCIS in IDC as important prognostic factor

Abstract Backgrounds: The issue of whether concomitant ductal carcinoma in situ (DCIS) affects the prognosis of with invasive breast cancer is important but studies of this have reported inconsistent results. So we aimed to assess the character and prognostic difference in infiltrating ductal carcinoma (IDC) according to accompanying DCIS status. Methods: We reviewed the medical records of the patients who underwent surgery for IDC. Male patients, patients who had received neoadjuvant chemotherapy, patients with synchronous bilateral breast cancer, follow-up periods &amp;lt;6months or those with other malignancies were excluded from the study. In cases in which a DCIS component was present in IDC, the degree of differentiation and the presence of necrosis were assessed to subdivide DCIS into two groups; low and high grade. Results: A total of 1751 patients were included, and 1384 patients (79.0%) had concomitant DCIS; 337 had low-grade DCIS, and 1047 patients had high-grade DCIS. The low-grade DCIS group had a significantly lower TNM stage than the high-grade DCIS group. The majority of cases with low-grade DCIS, were ER-positive (85.2%), PR-positive (81.3%) and had low Her-2 (98.7%). When we analyzed the survival rates according to the presence of DCIS, no statistical significance was founded. However, a subgroup analysis showed that the patients with low-grade DCIS survived significantly longer than other patients, whereas those with high-grade DCIS had poorer survival (5 year event-free survival rate; low-grade DCIS vs. without DCIS vs. high-grade DCIS, 97% vs. 93% vs. 86%, p = 0.001). Specially, in patients with lymph node involvement, accompanying high-grade DCIS was independent predictor distant metastasis (HR 5.0, p = 0.026, 95% CI 1.21–20.92). Conclusion: The important factor that affect prognosis of IDC with DCIS is not the presence itself of DCIS component but the grade of DCIS. The patients with low-grade DCIS had a good prognosis and those with high-grade DCIS had a poor prognosis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-35.

Abstract P3-14-06: The Utility of Margin Index to Predict Residual DCIS Following Breast Conserving Surgery

Abstract Background: Although breast conserving surgery (BCS) is commonly performed for ductal carcinoma in situ (DCIS), patients may require re-excision for close or positive margins to rule out residual disease. The concept of margin index (defined as margin distance/tumor size) has been found to predict residual disease in patients with invasive breast cancer, but this concept has yet to be evaluated for patients with DCIS. We sought to determine if DCIS margin index (defined as the closest margin of DCIS/extent of DCIS) was predictive of residual disease. Methods: We performed a chart review of all in situ breast cancers treated with BCS at an academic breast center in 2009. DCIS margin index was calculated as closest margin distance of DCIS (mm)/extent of DCIS (mm). Non-parametric statistical analyses were performed to evaluate the relationship between margin index and residual DCIS. Results: 177 patients with DCIS were treated with BCS in 2009. Of these, 87 (49.1%) underwent resection of additional tissue for close margins or as routine practice, and had recorded quantitative margin distances and tumor sizes such that margin index could be calculated. Of these, 18 (20.7%) had residual DCIS in the additional tissue excised. Median patient age was 60.4 years (range; 31.9–91.4). Of the 50 patients with available immunohistochemistry analysis, 42 (84%) were ER-positive and 36 (72%) were PR-positive respectively. 12 (13.8%) had low grade DCIS, 53 (60.9%) intermediate grade DCIS, and 22 (25.3%) high grade DCIS. Median tumor size was 16mm (range; 1–80 mm); and median margin distance was 2 mm (range; 0–18 mm). Median margin index was 0.125 (range; 0 to 18). Factors correlating with residual DCIS on univariate analysis were high tumor grade (33.3% vs. 23.2%, p = 0.044), PR-negativity (66.7% vs. 22.7%, p = 0.044), increasing tumor size (median 27.5 mm vs. 15.0 mm, p = 0.003), decreasing margin distance (median 1.0 mm vs. 2.1 mm, p = 0.004), and lower margin index (median 0.032 vs. 0.200, p &amp;lt; 0.001). Patient age and ER status were not correlated with residual DCIS. In a multivariate model controlling for grade and PR-status, margin index was no longer a significant predictor of residual disease, although a trend was noted (p = 0.076). To determine the relative strength of margin index (vs. extent of DCIS and margin distance) in predicting residual DCIS, a second multivariate model including PR-status, grade, extent of DCIS and margin distance was created. In this second model, extent of DCIS (p = 0.634) and margin distance (p = 0.152) were less predictive of residual disease than margin index was in the first model. PR-negativity remained the only predictor of residual disease in both. Conclusions: Margin index is a stronger predictor of residual DCIS than either margin distance or extent of DCIS, but loses significance when taking PR status into account. That PR-negativity is strongly associated with residual DCIS (independent of tumor size, grade and margin status) is intriguing and warrants further research. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-14-06.

Basal Cytokeratin in Ductal Carcinoma in Situ: Potential Marker of Low Risk of Invasive Disease

INTRODUCTION: The prevalence of DCIS has been rising in the last decades, probably due to better screening programs. This increase in the diagnosed cases of DCIS shows the heterogeneity of the group, particularly the risk of associated invasive disease and the risk of recurrences, most of these as invasive cancer. We investigated the role of basal cytokeratin 5/6 (CK5/6) in the risk of invasion of ductal carcinoma in situ (DCIS). MATERIAL AND METHODS: Tissue microarrays from 236 DCIS samples, consisting of 90 without invasive ductal carcinoma (IDC) (group 1) and 146 with IDC (group 2), with both groups having similar patient age and nuclear grade, were compared in terms of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), CK5/6, epidermal growth factor receptor, and the immunohistochemically defined molecular subtype. RESULTS: ER- and PR-negative status was associated with a invasion component (OR 4.67, CI 1.87- 11.70), whereas HER2-positive and CK5/6-positive status was negatively associated with invasion. Among high-grade tumors, the hybrid luminal/HER2 profile and CK5/6 were negatively associated with invasion. In low-grade DCIS, only CK5/6 showed a negative impact on the probability of invasion (OR 0.22, CI 0.09-0.57). DISCUSSION AND CONCLUSIONS: Our results suggest that the low-grade DCIS patients that would benefit more with conservative approaches would be those with CK5/6 expression, regardless of the molecular profile. On the other hand, high-grade DCIS with the triple-positive phenotype (ER/PR/ HER2) and CK5/6 expression might correspond to less aggressive lesions.

Comparison of Digital Screening Mammography and Screen-Film Mammography in the Early Detection of Clinically Relevant Cancers: A Multicenter Study

To compare screen-film mammography with digital mammography in a breast cancer screening program, with a focus on the clinical relevance of detected cancers. The study was approved by the regional medical ethics review board. Informed consent was not required. Before the nationwide transition to digital mammography in the Dutch biennial screening program, the performance of digital mammography was studied in three screening regions. For initial screening examinations, mediolateral oblique and craniocaudal views were obtained of each breast. In subsequent examinations, the mediolateral oblique view was standard. A craniocaudal view was added if indicated. Screening outcomes obtained with screen-film mammography and digital mammography, including radiologic and pathologic characteristics, were compared for initial and subsequent examinations. A total of 1,198,493 screening examinations were performed between 2003 and 2007. Recall was indicated in 18 896 cases (screen-film mammography: 2.6% at initial examinations, 1.3% at subsequent examinations; digital mammography: 4.4% at initial examinations, 2.1% at subsequent examinations; P < .001 for both). Breast cancer was diagnosed in 6410 women (detection rate per 1000 women with screen-film mammography: 5.6 at initial examinations, 5.2 at subsequent examinations; detection rate per 1000 women with digital mammography: 6.8 at initial examinations, 6.1 at subsequent examinations; P = .02 and P < .001, respectively). Digital mammography depicted significantly more ductal carcinoma in situ (DCIS) lesions, irrespective of screening round. Invasive carcinoma was detected significantly more often in subsequent examinations, particularly when associated with microcalcifications (P = .047). The distribution of the histopathologic differentiation grades for DCIS and invasive carcinoma were similar with both modalities. However, with digital mammography more high-grade DCIS lesions were detected at subsequent examinations (P = .013). In a population-based breast screening program, the performance of digital mammography in the detection of DCIS and invasive carcinoma was substantially better than that of screen-film mammography. There is no sign of an increase in detection of low-grade DCIS lesions-indicative of possible overdiagnosis-with digital breast cancer screening. Rather, digital mammography appears to add to the detection of high-grade DCIS.

Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast

BackgroundLysine-specific demethylase1 (LSD1) is a nuclear protein which belongs to the aminooxidase-enzymes playing an important role in controlling gene expression. It has also been found highly expressed in several human malignancies including breast carcinoma. Our aim was to detect LSD1 expression also in pre-invasive neoplasias of the breast. In the current study we therefore analysed LSD1 protein expression in ductal carcinoma in situ (DCIS) in comparison to invasive ductal breast cancer (IDC).MethodsUsing immunohistochemistry we systematically analysed LSD1 expression in low grade DCIS (n = 27), intermediate grade DCIS (n = 30), high grade DCIS (n = 31) and in invasive ductal breast cancer (n = 32). SPSS version 18.0 was used for statistical analysis.ResultsLSD1 was differentially expressed in DCIS and invasive ductal breast cancer. Interestingly, LSD1 was significantly overexpressed in high grade DCIS versus low grade DCIS. Differences in LSD1 expression levels were also statistically significant between low/intermediate DCIS and invasive ductal breast carcinoma.ConclusionsLSD1 is also expressed in pre-invasive neoplasias of the breast. Additionally, there is a gradual increase of LSD1 expression within tumour progression from pre-invasive DCIS to invasive ductal breast carcinoma. Therefore upregulation of LSD1 may be an early tumour promoting event.

Pure flat epithelial atypia is uncommon in subsequent breast excisions for atypical epithelial proliferation

The management of atypical intraductal lesions of the breast remains controversial. In the present study, the subsequent surgical excision results and follow-up data on 86 (3.65%) atypical intraductal lesions and 78 (3.31%) low-grade ductal carcinoma in situ (DCIS) from a cohort of 2358 needle biopsies were examined. There were 17 cases (0.72%) of pure flat epithelial atypia (FEA), 44 (1.87%) pure atypical ductal hyperplasia (ADH), three (0.13%) pure atypical lobular hyperplasia (ALH), 18 (0.76%) combined ADH + FEA, three (0.13%) combined ALH + FEA and one (0.04%) combined ALH + FEA + ADH. Subsequent surgical excisions were done in 53 cases and revealed the following incidences of malignancy: pure FEA (1/8); pure ADH (17/31); FEA + ADH (7/10); FEA + ALH (2/3); and FEA + ALH + ADH (0/1), with pure FEA showing significantly lower incidence of malignancy. In this cohort, there were 703 carcinomas including 155 DCIS with 78 cases (50.3%) being low-grade. FEA with ADH (and/or ALH) was present in 22 (28.2%) of these 78 cases of low-grade DCISs at surgical excisions. Pure FEA was not detected in any of the subsequently excised surgical materials of the atypical intraductal lesions nor the low-grade DCISs. Thus, pure FEA was very unusual in surgical specimens. When pure FEA is detected at needle biopsy, a wait and see approach can be adopted. However, when the FEA is associated with other concomitant atypical intraductal lesions, especially ADH, further excision should be contemplated.

Serum Autoantibody Signature of Ductal Carcinoma In Situ Progression to Invasive Breast Cancer

The identification of markers associated with progression to invasive breast cancer (IBC) is a major factor that can guide physicians in the initial therapeutic decision and the management of ductal carcinoma in situ (DCIS). We examined autoantibody targets in 20 DCIS and 20 IBC patients using protein microarrays and identified humoral responses that can be used to distinguish the two groups. The five most differentially targeted antigens were selected to generate an autoantibody signature for the in situ to invasive breast cancer transition. This signature was next tested on 120 independent samples (61 DCIS and 59 IBC) using specific ELISA assays. The prognosis value of the autoantibody signature was finally evaluated in a cohort of DCIS patients followed for 5 years. A set of five autoantibody targets (RBP-Jκ, HMGN1, PSRC1, CIRBP, and ECHDC1) with the highest differential signal intensity found in the protein microarrays experiment was used to establish an autoantibody signature of the DCIS to IBC transition. Using ELISA, this signature significantly discriminated DCIS from IBC [area under the ROC curve (AUC) = 0.794, 95% confidence interval (CI): 0.674-0.877]. Interestingly, our panel could highly distinguish low-grade DCIS from high-grade DCIS exhibiting an AUC of 0.749 (95% CI: 0.581-0.866). Finally, using a Kaplan-Meier analysis, the autoantibody signature could significantly divide the DCIS patients into a poor prognosis group and a good prognosis group (P = 0.01). These results indicate the potential of autoantibody detection as a new prognostic test with possible clinical implications for the management of DCIS.

P5-12-02: Vacuum Assisted Biopsies of Ductal Carcinoma In Situ and Concordance with Post-Operative Histology: Implications for the Low Risk DCIS Trial.

Abstract Aim The enormous increase in the diagnosis of ductal carcinoma in situ (DCIS) by the NHS Breast screening has not lead to an expected decrease in the incidence of invasive breast cancer. It is not clear if all grades of DCIS progress inexorably to invasive cancer if left untreated. There is recognition that DCIS is overtreated, ie if left alone may not cause harm during the woman's lifetime. In the absence of new clinical trial data, surgery still remains the universal treatment. It is known that a higher proportion of patients with screen detected DCIS receive mastectomy than those with screen detected invasive cancer. Recently a randomized trial called the Low risk DCIS Trial has been proposed which intends to specifically compare the current treatment of low grade DCIS ie surgery with active monitoring using annual mammography. In order to effectively implement this, concordance between diagnostic biopsy and excision histology is vital and therefore vacuum assisted mammotome biopsy (VAB) and a central pathology review of diagnostic biopsy specimens prior to randomization will be mandatory. Therefore, in this study, we assessed the concordance between diagnostic biopsies performed by VAB technique and the post operative histology for DCIS in our institution. Methods Retrospective data of all diagnostic breast biopsies specifically using the VAB technique with the primary diagnosis of DCIS from year 2001 to 2010 in our institution was collected. Both screening and symptomatic patients were included. Concordance between diagnostic histology and post operative excision histology was assessed for high, intermediate and low grade DCIS. Demographic details and potential factors influencing concordance including number of cores taken and lesion size were also collected for analysis. Results A total of 161 cases were identified out of which 102 (63%) were of high grade, 35 (22%) of intermediate grade and 24 (15%) were of low grade histology. In the High grade group, the concordance with final histology was 70% (72/102). In this group, the diagnosis was upgraded to invasive carcinoma in 21% (21/102). 9% (9/102) were downgraded to intermediate or low grade. In the intermediate grade group, the concordance with final histology was 66% (23/35). In this group, the diagnosis was upgraded to invasive carcinoma in 11% (4/35) and to high grade in 17% (6/35). 6% (2/35) were downgraded to low grade. In the low grade group, the concordance with final histology was 71% (17/24). In this group, the diagnosis was upgraded to intermediate grade in 17% (4/24) and invasive carcinoma in 12% (3/24). All factors associated with lack of concordance were noted. Conclusion Concordance between VAB diagnostic biopsies of high, intermediate and low grade DCIS and post operative histology is good in this series and is to our knowledge the first to be reported using only large volume biopsies by VAB techniques. This audit has identified possible factors influencing the lack of concordance and these results with concordance data from other UK centres will be used by trial pathologists to refine protocols for the Low risk DCIS trial. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-12-02.

S4-6: A Quantitative Multigene RT-PCR Assay for Predicting Recurrence Risk after Surgical Excision Alone without Irradiation for Ductal Carcinoma In Situ (DCIS): A Prospective Validation Study of the DCIS Score from ECOG E5194.

Abstract Background: We have previously reported the results of surgical excision without irradiation for selected patients with DCIS in ECOG E5194, where the 5-year rates of local recurrence varied with age, grade, and lesion size (Hughes et al. J Clin Oncol 27:5319, 2009). New methods are needed to provide more accurate and reproducible assessment of recurrence risk. Methods: ECOG E5194 included 670 eligible patients with DCIS treated with surgical excision (≥ 3 mm negative margins) without irradiation, 228 of whom received tamoxifen. Patients had low or intermediate grade DCIS ≤ 2.5 cm, or high grade DCIS ≤ 1 cm. The Oncotype DX® assay was performed by quantitative RT-PCR using formalin fixed paraffin embedded tumor specimens from 327 patients (49% of the parent study). Recurrence Score® (RS) was calculated using the published algorithm. A new, prespecified DCIS Score™ was designed to predict recurrence using an optimized gene expression algorithm. The primary objective was to determine whether there was a significant association between the risk of an ipsilateral breast event (IBE) and the continuous DCIS Score in Cox models. 46 patients had an IBE (defined as ipsilateral local recurrence of DCIS [n=20] or invasive cancer [n=26]). Median follow-up was 8.8 years. Results: The 10-year IBE rates were 15.4% for low/intermediate grade DCIS and 15.1% for high-grade DCIS (as determined by central pathology review), and for invasive IBE, 5.6% and 9.8%, respectively. Comparison between local and expert grading showed substantial disagreement. Continuous DCIS Score was significantly associated with IBE (HR 2.34 per 50 units; 95% CI 1.15, 4.59; p=0.02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (HR 3.73; CI 1.34, 9.82; p=0.01). DCIS Score was significantly associated with outcome when evaluated by the prespecified risk groups (see Table). Similar results were observed with and without adjustment for tamoxifen use or for negative margin width. Features associated with IBE in multivariate models included menopausal status (HR 0.49; 95% CI 0.27, 0.90; p=0.02), tumor size (HR 1.52 per 5 mm; 95% CI 1.11, 2.01; p=0.01), and continuous DCIS Score (HR 2.41; 95% CI 1.15, 4.89; p=0.02). The standard RS, which is calculated using thresholding of many genes unlike the DCIS Score, was not associated with IBE or invasive IBE (p &amp;gt; 0.6). Conclusions: We have prospectively validated a multigene assay that quantifies recurrence risk and complements traditional clinical and pathologic factors in selected patients with DCIS treated with surgical excision without irradiation. The DCIS Score provides a new clinical tool for individualized selection of treatment for patients with DCIS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-6.

P5-15-01: Words Matter: Influence of DCIS Diagnosis Terminology on Patient Treatment Decisions.

Abstract Background: Treatment of ductal carcinoma in-situ (DCIS) poses significant challenges. Although retrospective studies suggest that most cases of low grade DCIS will never progress to invasive disease, it remains difficult to accurately identify those patients at greatest risk. In this situation where many diagnosed tumors could follow an indolent course for the patient's lifetime, both systemic therapy and watchful waiting could be reasonable options, similar to those currently offered to patients with early prostate cancer. One strategy that has been suggested to reduce overtreatment is to use terms other than “ductal carcinoma in situ” when explaining a diagnosis of DCIS to a patient. In the current study, we have investigated the effect of terminology on women's stated treatment preference for DCIS. Methods: Women 40–65 years of age were recruited from a database of volunteers at an academic hospital. Subjects with a personal history of breast cancer were excluded. Endpoints were gathered from a web-based survey. Each subject was presented with three different scenarios, each of which used a different terminology for DCIS: non-invasive breast cancer, breast lesion, and abnormal cells. The scenarios included a detailed explanation of the risks and benefits of three treatment options: surgery, systemic treatment only and active surveillance. After reading each scenario, the subject was asked to choose among the treatment options and to explain her choice. Results: 187 subjects completed the survey. More women chose active surveillance when DCIS was described using the terms “abnormal cells” or “breast lesion” than using the term “non-invasive cancer” (Table 1). The majority of women (97/187, 52%) changed their treatment preference when a different term was used to describe DCIS. Of the 97 women who changed their treatment preference, 47 (48%) chose surgery when the term “non-invasive cancer” was used to describe DCIS, but chose a less invasive treatment when “cancer” was not used in the diagnosis. Of 90 people who did not change their treatment preference, 39 (43%) chose active surveillance. Among the three treatments, the percent of women who chose surgery was the highest (84/187; 46%) when the term “non-invasive cancer” was used. 47/84 (56%) of the women who chose surgery when using the term “non-invasive breast cancer” changed their treatment preference when a different term was used. 36/84 (43%) switched to active surveillance while 11/84 (13%) switched to medication. Conclusion: These results support that the specific terminology used to explain a diagnosis of DCIS influences patients’ treatment preference. Moreover, we found that women may entertain treatment preferences other than surgery for DCIS when the tradeoffs of each choice are clearly explained. Avoiding the word “cancer” in the diagnosis may offer a strategy that reduces fear-based treatment decisions and may reduce the burden of overtreatment for DCIS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-01.