Ductal carcinoma in situ and ductal carcinoma in situ with microinvasion: correlation of FDG uptake with histological and biological prognostic factors

Background

Several studies investigated the correlation between the intensity of fluorodeoxyglucose (FDG) uptake and some histological and biological characteristics in breast cancer. Ductal carcinoma in situ (DCIS) is generally thought to be a precursor lesion of invasive breast cancer. The aim of this study was to assess the correlation between FDG uptake values on positron emission tomography/computed tomography (PET/CT) with histological and biological prognostic factors in DCIS and ductal carcinoma in situ with microinvasion (DCIS-Mi).

Materials and methods

PET/CT images for initial staging of confirmed DCIS and DCIS-Mi patients, taken between July 2004 and December 2009, were reviewed retrospectively. Maximum standardized uptake values (SUVmax) and tumor background count density ratio on PET/CT were compared with tumor characteristics. Histological and biological prognostic factors included tumor size, nuclear grade, Van Nuys Prognostic Index, estrogen receptor, progesterone receptor, HER2, and Ki-67 index.

Results

In total, 87 lesions from 83 patients (all females; mean age 51 ± 9 years) were studied. The Van Nuys Prognostic Index group was 1 in 25 lesions, 2 in 36, and 3 in 26. On statistical analysis, significant differences in SUVmax and tumor background count density ratio were seen between the Van Nuys Prognostic Index groups and according to tumor size and HER2. The correlation between SUVmax and Ki-67 was significant. However, the correlation between tumor background count density ratio and Ki-67 was not statistically significant.

Conclusion

In DCIS and DCIS-Mi cases, significant correlations were found between increased FDG uptake and several histological and biological factors for poor prognosis (tumor size, Van Nuys Prognostic Index, and HER2).

     

Expression analysis of carbohydrate antigens in ductal carcinoma <Emphasis Type="Italic">in situ</Emphasis>of the breast by lectin histochemistry

Background  

The number of breast cancer patients diagnosed with ductal carcinoma in situ (DCIS) continues to grow. Laboratory and clinical data indicate that DCIS can progress to invasive disease. Carbohydrate-mediated cell-cell adhesion and tumor-stroma interaction play crucial roles in tumorigenesis and tumor aggressive behavior. Breast carcinogenesis may reflect quantitative as well as qualitative changes in oligosaccharide expression, which may provide a useful tool for early detection of breast cancer. Because tumor-associated carbohydrate antigens (TACA) are implicated in tumor invasion and metastasis, the purpose of this study was to assess the expression of selected TACA by lectin histochemistry on DCIS specimens from the archival breast cancer tissue array bank of the University of Arkansas for Medical Sciences.     

Ductal carcinoma <Emphasis Type="Italic">in situ</Emphasis> of the breast (DCIS) with heterogeneity of nuclear grade: prognostic effects of quantitative nuclear assessment

Background  

Previously, 50% of patients with breast ductal carcinoma in situ ( DCIS) had more than one nuclear grade, and neither worst nor predominant nuclear grade was significantly associated with development of invasive carcinoma. Here, we used image analysis in addition to histologic evaluation to determine if quantification of nuclear features could provide additional prognostic information and hence impact prognostic assessments.     

Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study

Background  

Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort.     

Pathologic characteristics of second breast cancers after breast conservation for ductal carcinoma in situ

BACKGROUND:

The number of women diagnosed with ductal carcinoma in situ (DCIS) is increasing. Although many eventually develop a second breast cancer (SBC), little is known about the characteristics of SBCs. The authors described the characteristics of SBC and examined associations between the pathologic features of SBC and index DCIS cases.

METHODS:

Women were identified in the National Comprehensive Cancer Network Outcomes Database who were diagnosed with DCIS from 1997 to 2008 and underwent lumpectomy and who subsequently developed SBC (including DCIS or invasive disease that occurred in the ipsilateral or contralateral breast). The Fisher exact test and the Spearman test were used to examine associations between the pathologic characteristics of SBC and index DCIS cases.

RESULTS:

Among 2636 women who underwent lumpectomy for DCIS, 150 (5.7%) experienced an SBC after a median of 55.5 months of follow‐up. Of these 150 women, 105 (70%) received adjuvant radiotherapy, and 50 (33.3%) received tamoxifen for their index DCIS. SBCs were ipsilateral in 54.7% of women and invasive in 50.7% of women. Among the index DCIS cases, 60.6% were estrogen receptor (ER)‐positive, and 54% were high grade, whereas 77.5% of SBCs were ER‐positive, and 48.2% were high grade. Tumor grade (P = .003) and ER status (P = .02) were associated significantly between index DCIS and SBC, whereas tumor size was not (P = .87).

CONCLUSIONS:

After breast conservation for DCIS, SBC in either breast exhibited pathologic characteristics similar to the index DCIS, suggesting that women with DCIS may be at risk for developing subsequent breast cancers of a similar phenotype. Cancer 2012. © 2012 American Cancer Society.     

Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma <Emphasis Type="Italic">in situ</Emphasis>: implications for clinicopathology and patient outcome

Introduction  

Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.     

Concurrent lobular neoplasia increases the risk of ipsilateral breast cancer recurrence in patients with ductal carcinoma in situ treated with breast‐conserving therapy

BACKGROUND:

Multiple clinicopathologic factors have been analyzed for their association with an increased risk of ipsilateral breast tumor recurrence (IBTR) after women receive breast‐conserving treatment (BCT) for ductal carcinoma in situ (DCIS). The reported incidence of proliferative lesions, such as atypical ductal hyperplasia (ADH), columnar cell changes (CCC), and lobular neoplasia associated with breast cancer, has been as high as 23%; however, the relevance of these lesions on the natural history of DCIS and the risk of IBTR remains unknown.

METHODS:

Two hundred ninety‐four patients with DCIS who received BCT between 1991 and 1995 were identified from the authors' institutional database. Slides were reviewed by a dedicated breast pathologist with particular attention to the presence of lobular neoplasia, ADH, and CCC. The actuarial 5‐, 10‐, and 15‐year IBTR rates were calculated using the Kaplan‐Meier method and were compared using the log‐rank test.

RESULTS:

Concurrent lobular neoplasia was present in 41 of 294 patients (14%), ADH was present in 37 of 294 patients (13%), and CCC was present in 71 of 294 patients (24%). The median follow‐up was 11 years. IBTR occurred in 40 of 227 patients without lobular neoplasia (18%) versus 15 of 41 patients with lobular neoplasia (37%; P=.005; hazard ratio [HR], 2.49). The 5‐, 10‐, and 15‐year cumulative incidence rates of IBTR were twice as high in women who had DCIS and lobular neoplasia compared with women who had DCIS alone (P=.002). Concomitant ADH (HR, 1.53) and CCC (HR, 1.24) were not associated significantly with IBTR (P=.20 and P=.44, respectively).

CONCLUSIONS:

Concurrent lobular neoplasia is associated with a significantly higher risk of IBTR in women with DCIS who received BCT. Women with coexisting DCIS and lobular neoplasia who receive BCT should consider using additional risk‐reducing strategies. Cancer 2009. © 2009 American Cancer Society.     

Classification of ductal carcinoma in situ by gene expression profiling

Introduction  

Ductal carcinoma in situ (DCIS) is characterised by the intraductal proliferation of malignant epithelial cells. Several histological classification systems have been developed, but assessing the histological type/grade of DCIS lesions is still challenging, making treatment decisions based on these features difficult. To obtain insight in the molecular basis of the development of different types of DCIS and its progression to invasive breast cancer, we have studied differences in gene expression between different types of DCIS and between DCIS and invasive breast carcinomas.     

Identification of early molecular markers for breast cancer

Background  

The ductal carcinoma in situ (DCIS) of the mammary gland represents an early, pre-invasive stage in the development of invasive breast carcinoma. Since DCIS is a curable disease, it would be highly desirable to identify molecular markers that allow early detection. Mice transgenic for the WAP-SV40 early genome region were used as a model for DCIS development. Gene expression profiling was carried out on DCIS-bearing mice and control animals. Additionally, a set of human DCIS and invasive mammary tumors were analyzed in a similar fashion. Enhanced expression of these marker genes in human and murine samples was validated by quantitative RT-PCR. Besides, marker gene expression was also validated by immunohistochemistry of human samples. Furthermore in silico analyses using an online microarray database were performed.     

Comparative analysis of loss of heterozygosity and expression profi le in normal tissue,DCIS and invasive breast cancer

Introduction  

Ductal carcinoma in situ (DCIS) is considered to be related to the development of invasive breast cancer. The aim of molecular biological research of preinvasive breast lesion characteristics and comparison with normal tissues and tissue of invasive tumours is to identify patients at high risk of developing invasive tumour on the basis of already established preinvasive lesions, and thus influence clinical decision-making. The aim of our study was to analyse several key molecules involved in different cellular pathways important for cancer development and progression in different types of breast tissue and to describe similarities and differences between premalignant and malignant lesions.     

Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel

Background  

ARHI is a Ras-related imprinted gene that inhibits cancer cell growth and motility. ARHI is downregulated in the majority of breast cancers, and loss of its expression is associated with its progression from ductal carcinoma in situ (DCIS) to invasive disease. In ovarian cancer, re-expression of ARHI induces autophagy and leads to autophagic death in cell culture; however, ARHI re-expression enables ovarian cancer cells to remain dormant when they are grown in mice as xenografts. The purpose of this study is to examine whether ARHI induces autophagy in breast cancer cells and to evaluate the effects of ARHI gene re-expression in combination with paclitaxel.     

Reproductive and menstrual factors and risk of ductal carcinoma in situ of the breast in a cohort of postmenopausal women

Purpose  

The contribution of menstrual and reproductive factors to risk of ductal carcinoma (DCIS) of the breast is poorly understood.     

Evidence that molecular changes in cells occur before morphological alterations during the progression of breast ductal carcinoma

Introduction  

Ductal carcinoma in situ (DCIS) of the breast includes a heterogeneous group of preinvasive tumors with uncertain evolution. Definition of the molecular factors necessary for progression to invasive disease is crucial to determining which lesions are likely to become invasive. To obtain insight into the molecular basis of DCIS, we compared the gene expression pattern of cells from the following samples: non-neoplastic, pure DCIS, in situ component of lesions with co-existing invasive ductal carcinoma, and invasive ductal carcinoma.     

Radiographic features for triple negative ductal carcinoma in situ of the breast

Background  

Triple negative (TN) breast cancer is characterized as having a high malignancy potential and a poor prognosis. An understanding of the radiological features of TN DCIS will enable the early detection of intractable TN invasive breast cancer.     

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

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.     

Impact of race and ethnicity on features and outcome of ductal carcinoma in situ of the breast

BACKGROUND:

The impact of race and ethnicity on the biologic features and outcome variables of women who are diagnosed with preinvasive breast cancer—ductal carcinoma in situ (DCIS)—has not been addressed widely in the published literature.

METHODS:

Patient demographic, clinical, and pathologic features and outcome variables were analyzed with respect to the patient's initial self‐reported race/ethnicity among women who received treatment for a diagnosis of pure DCIS from 1996 to 2009.

RESULTS:

Of 1902 patients, 1411 were white (74.2%), 214 were African American (11.3%), 175 were Hispanic (9.1%), and 102 were Asian/Pacific Islander (5.4%). The majority of patients were between ages 41 and 70 years (83%). Patients of Hispanic and Asian/Pacific Islander descent were significantly younger than white and African American patients (P < .001). DCIS size and grade, the presence of necrosis, and the frequency of breast‐conserving surgery did not differ significantly between groups. African American patients aged >70 years and Hispanic patients aged <50 years were significantly more likely to have estrogen receptor‐positive DCIS than patients of other races in the same age categories (P < .001). Adjuvant radiotherapy and tamoxifen were received significantly less often by white women (P < .001). At a median follow‐up of 4.8 years (range, 1‐14 years), recurrence rates and the development of contralateral breast cancer did not differ significantly among racial/ethnic groups when stratified by treatments received.

CONCLUSIONS:

There was variation in age at presentation, biologic features, and treatment of DCIS among the different ethnic groups. Additional studies with larger numbers of ethnic minority patients are needed to confirm whether the consistent application of evidence‐based treatment practices presents an opportunity for reducing disparities in patients with DCIS. Cancer 2013. © 2012 American Cancer Society.     

The association of mammographic density with ductal carcinoma in situ of the breast: the Multiethnic Cohort

Introduction  

It is well established that women with high mammographic density are at greater risk for breast cancer than are women with low breast density. However, little research has been done on mammographic density and ductal carcinoma in situ (DCIS) of the breast, which is thought to be a precursor lesion to some invasive breast cancers.     

Prognostic markers and long-term outcomes in ductal carcinoma in situ of the breast treated with excision alone

BACKGROUND:

Increased use of breast cancer screening has led to an increase in the number of diagnosed cases of ductal carcinoma in situ (DCIS). However, there is no definite way to predict progression or recurrence of DCIS. We analyzed the significance of biological markers and tumor characteristics in predicting recurrence in a large series of DCIS patients with long‐term follow‐up treated with breast conservation surgery (BCS) alone.

METHODS:

Clinical and pathological data were analyzed for 141 patients who underwent BCS for DCIS. All had negative surgical margins. Using local disease recurrence as an endpoint, we sought to determine the prognostic significance of several histopathological characteristics (tumor size, presence of necrosis, and subtype) and biological markers (estrogen receptor, progesterone receptor, and Her‐2/neu.)

RESULTS:

At a median follow‐up of 122 months (maximum follow‐up, 294 months), 60 recurrences occurred, with a median time to recurrence of 191 months. On multivariate analysis, Her‐2 positivity (3+) was found to be significantly associated with reduced time to tumor recurrence (P = .028). Tumor size and higher grade were marginally statistically significant (P = .099, P = .070). Neither necrosis nor tumor pathological characteristics were found to be significantly related to time to disease recurrence.

CONCLUSIONS:

Our results suggested that status of Her‐2/neu, larger tumor size, and higher nuclear grade were significantly correlated with time to tumor recurrence in patients treated with BCS alone. Using logistical analyses, no significant correlation was found between tumor pathological characteristics and disease recurrence. Cancer 2011. © 2011 American Cancer Society.     

Tamoxifen added to radiotherapy and surgery for the treatment of ductal carcinoma in situ of the breast: A meta-analysis of 2 randomized trials

Background

Surgical excision with adequate margins is the treatment of choice for ductal, in situ carcinoma of the breast (DCIS). The addition of radiotherapy (RT) halved local in situ and invasive recurrence. The purpose of our meta-analysis is to evaluate the reduction in recurrence (in situ or invasive) with the addition of tamoxifen (T), in particular in patients with DCIS treated with surgery + RT.

Patients and methods

The eligible studies (NSABP-B24 and UK ANZ DCIS trials) included prospective, randomized, controlled trials in which the addition of T had been compared with surgery + RT without T in women with DCIS of the breast. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for both in situ and invasive recurrence (local and controlateral).

Results

Tamoxifen does not reduce breast cancer-specific or overall mortality when added to loco-regional therapy for DCIS of the breast (surgery plus or minus RT). Tamoxifen reduces overall breast cancer recurrence by 29% in all patients and by 33% in those treated with both surgery and RT. Only ipsilateral invasive (RR 0.61 [95% CI 0.41, 0.92]; p = 0.02) and controlateral in situ relapses (RR 0.40 [95% CI 0.16, 0.96]; p = 0.04) are significantly lowered when T is added to RT. Tamoxifen seems to exert a local synergistic effect with RT. Both young and older women (< and >50 years) achieve some benefit from the addition of T (RR 0.6 and 0.74, respectively).

Conclusion

The addition of T to surgery and RT for DCIS of the breast reduces the risk of local invasive and controlateral in situ relapses, but not the survival. The benefit is independent of age. In conclusion, surgery associated with RT and T is the treatment of choice for patients with (estrogen-receptor positive) DCIS of the breast.     

Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice

Introduction

Human models of noninvasive breast tumors are limited, and the existing in vivo models do not mimic inter- and intratumoral heterogeneity. Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The aim of this study was to develop an in vivo model whereby the natural progression of human DCIS might be reproduced and studied. To accomplish this goal, the intraductal human-in-mouse (HIM) transplantation model was developed. The resulting models, which mimicked some of the diversity of human noninvasive breast cancers in vivo, were used to show whether subtypes of human DCIS might contain distinct subpopulations of tumor-initiating cells.

Methods

The intraductal models were established by injection of human DCIS cell lines (MCF10DCIS.COM and SUM-225), as well as cells derived from a primary human DCIS (FSK-H7), directly into the primary mouse mammary ducts via cleaved nipple. Six to eight weeks after injections, whole-mount, hematoxylin and eosin, and immunofluorescence staining were performed to evaluate the type and extent of growth of the DCIS-like lesions. To identify tumor-initiating cells, putative human breast stem/progenitor subpopulations were sorted from MCF10DCIS.COM and SUM-225 with flow cytometry, and their in vivo growth fractions were compared with the Fisher's Exact test.

Results

Human DCIS cells initially grew within the mammary ducts, followed by progression to invasion in some cases into the stroma. The lesions were histologically almost identical to those of clinical human DCIS. This method was successful for growing DCIS cell lines (MCF10DCIS.COM and SUM-225) as well as a primary human DCIS (FSK-H7). MCF10DCIS.COM represented a basal-like DCIS model, whereas SUM-225 and FSK-H7 cells were models for HER-2⁺ DCIS. With this approach, we showed that various subtypes of human DCIS appeared to contain distinct subpopulations of tumor-initiating cells.

Conclusions

The intraductal HIM transplantation model provides an invaluable tool that mimics human breast heterogeneity at the noninvasive stages and allows the study of the distinct molecular and cellular mechanisms of breast cancer progression.